R&D Literature Review: October 2023

R&D Literature Review: October 2023

BCIS R&D Group Literature Review

October 2023

Prepared by Michael Mahmoudi and Natalia Briceno

Edited by Michael Mahmoudi

 

Coronary Artery Disease

Imaging should be encouraged in complex bifurcation PCI

OCT or angiography guidance for PCI in complex bifurcation lesions.

NEJM 2023 Online

Coronary bifurcation lesions may require complex stenting techniques and may be associated with higher risks of MI, repeat revascularization, and death. The OCTOBER trial investigated whether OCT-guided PCI was superior to angiography-guided PCI in revascularization of bifurcation lesions in 1201 patients. Eligible patients were at least 18 years old and had stable angina (54%), unstable angina (9%), NSTEMI (13%), or staged procedure after an acute MI (24%). Eligible bifurcation lesions had a main branch diameter of at least 2.75mm and stenosis of at least 50% by visual estimation. The side branch had to have a diameter of at least 2.5mm and stenosis of at least 50% within 5mm from the ostium of the side branch by visual estimation. The functional significance of the main branch stenosis had to be demonstrated either non-invasively or by pressure wire interrogation. A stenosis of >80% was considered functionally significant. Main exclusion criteria included STEMI within 72 hours before randomization, cardiogenic shock, previous CABG to a target vessel, GFR < 50, expected survival < 2 years, LVEF < 30%, NYHA class II symptoms or greater, severe tortuosity at the target lesion, or large thrombus at the left main stem. The primary endpoint was a composite of MACE defined as death from cardiac causes, target-lesion MI, ischaemia-driven TLR at a median follow-up of 2 years. The mean age of the patients was 66.3±10.2 years, 21.1% were women, 41.7% had had prior PCI,18.9% had left main bifurcation lesions, 19.2% had multivessel disease, and 65% were treated with a 2-stent strategy. Although the use of imaging in the angiography-guided PCI group was discouraged, 15% of this group has IVUS guidance. The median volume of contrast used was 300ml in the OCT-guided PCI group and 200ml in the angiography-guided PCI group. The median procedure time was 113 minutes in the OCT-guided PCI group and 80 minutes in the angiography-guided PCI group. The primary endpoint at 2 years was lower in the OCT-guided PCI group (10.1% vs. 14.1%; HR 0.70; 95% CI: 0.50-0.98; p=0.035). The values for the individual components of the primary endpoint also favoured the OCT-guided PCI: cardiac death (1.4% vs. 2.6%; HR 0.53; 95% CI: 0.22-1.25), ischaemia-driven TLR (2.8% vs. 4.6%; HR 0.60; 95% CI: 0.32-1.13), and target lesion MI (7.8% vs. 8.5%; HR 0.90; 95% CI: 0.60-1.34). In summary, this study supports the use of OCT in patients undergoing complex bifurcation PCI.

 

Routine use of OCT should be discouraged

Optical coherence tomography-guided versus angiography guided PCI.

NEJM 2023 Online

Several randomized trials have indicated that by achieving larger luminal area, IVUS guided PCI reduces adverse cardiovascular events including cardiac death and stent thrombosis. Given the advantages of OCT over IVUS, the ILUMIEN IV: OPTIMAL PCI trial was designed to examine the safety and effectiveness of OCT-guided PCI in high-risk patients and lesions in a cohort of 2487 patients. A high-risk patient was defined as a patient with diabetes treated with medical therapy. A high-risk coronary lesion was defined as a lesion that was responsible for a recent MI, long or multiple lesions requiring treatment with > 28mm of stents, a bifurcation lesion requiring a two-stent strategy, a severely calcified lesion, a CTO, diffuse or multifocal in-stent restenosis. Key exclusion criteria were STEMI, creatinine clearance ≤ 30ml/min/1.73m2, cardiogenic shock, NYHA class ≥ 3 symptoms, LVEF ≤ 30%, and unstable ventricular arrhythmias. In patients undergoing OCT-guided PCI, the operator was given specific protocol to direct the use of imaging. For patients undergoing angiography-guided PCI, a final OCT run was undertaken but the result was concealed from the operator. The trial had two primary efficacy endpoints: a primary imaging endpoint defined as the final minimum stent area upon completion of PCI assessed by OCT and a primary clinical endpoint of target vessel failure at 2 years defined as a composite of cardiac death, target vessel MI, or ischemia driven TVR. The mean age of the patients was 66 years, 40.1% had medically treated diabetes mellitus, 67.6% had lesions requiring stent length of at least 28mm, 29.6% had a culprit lesion responsible for a recent MI< 11.5% had severe coronary calcification, 10.8% had diffuse or multifocal in-stent restenosis, 7% had CTO, and 3.3% had a bifurcation lesion requiring a 2-stent strategy. The minimum stent area in the OCT-guided PCI group (n=1233) was greater than the angiography-guided PCI group (n=1234) (5.72±2.04 mm2 vs. 5.36±1.87 mm2; mean difference 0.36mm2; 95% CI: 0.21-0.51; p<0.001). The clinical endpoint was similar in the OCT and angiography-guided group (7.4% vs. 8.2%; HR 0.90; 95% CI: 0.67-1.19; p=0.45). Regarding the individual components of the primary clinical endpoint, cardiac death occurred in 0.8% in the OCT group and 1.3% in the angiography group (HR 0.57; 95% CI: 0.25-1.29), target vessel MI occurred in 2.5% of the OCT group and 3.3% of the angiography group (HR 0.77; 95% CI: 0.48-1.22), and ischaemia driven TVR occurred in 5.6% of the OCT group and 5.6% of the angiography group (HR 0.99; 95% CI: 0.71-1.40). In contrast to previous intravascular imaging studies, the current study failed to demonstrate a clinical benefit with OCT-guided PCI which was driven by the low-incidence of ischemia-driven TVR. In conclusion, the routine use of OCT in patients undergoing PCI is not supported by this study.

 

The expanding indications for complete revascularization in STEMI

Complete or culprit-only PCI in older patients with myocardial infarction.

NEJM 2023; 389:889-898

The clinical safety and efficacy of complete revascularization in elderly patients has not been adequately addressed. The FIRE trial was an investigator-initiated, multicentre, prospective, superiority, randomized trial designed to evaluate a strategy of physiology-guided complete revascularization in 1445 patients aged ≥75 years who had presented with either STEMI or NSTEMI. Patients were eligible if they were at least 75 years old, had been admitted with a STEMI or NSTEMI, had undergone successful PCI of the culprit lesion, and had multivessel disease defined as at least one lesion in the NIRA that had a minimum vessel diameter of 2.5mm and visually estimated stenosis of 50%-99%. Key exclusion criteria included inability to identify a culprit lesion, left main lesion as the NIRA, previous CABG, life expectancy < 1 year, and planned surgical revascularization. Patients who had been randomized to complete revascularization (n=720) underwent PCI either at the time of the index PCI or in a staged procedure within the index admission. Physiologic assessment was either wire (FFR, iFR) or angiography based (QFR). The primary endpoint was a composite of death, MI, stroke, or ischemia-driven revascularization within 1 year after randomization. The median age of the patients was 80 years, 36.5% were women, 35.2% were admitted with STEMI, and the median length of hospital stay was 5 days.  In patients undergoing physiologic assessment, 49.6% had a wire-based hyperaemic index, 15.2% a wire-based non-hyperaemic index, and 35.2% had QFR. In the complete revascularization group, physiological assessment of at least one NIRA was undertaken in 97.2% of patients identifying at least one significant NIRA in 49.6% of patients. The primary endpoint was significantly lower in the complete revascularization group (15.7% vs. 21.0%; HR 0.73; 95% CI: 0.57-0.93; p=0.01). The number needed to treat to prevent one primary outcome was 19 patients. Apart from stroke, the incidence of the individual components of the primary endpoint was lower in the complete revascularization group, including death from any cause (HR 0.70; 95% CI: 0.51-0.96). The number needed to treat to prevent one death was 27 patients. There was no difference between the two groups in the composite safety outcome consisting of contrast related acute kidney injury, stroke, or BARC type 3, 4, or 5 bleeding (25% vs. 20.4%; HR 1.11; 95% CI: 0.89-1.37; p=0.37). The FIRE trial thus supports the concept of complete revascularization in selected, elderly patients.

 

No benefit in the use of ECLS in cardiogenic shock

Extracorporeal life support in infarct-related cardiogenic shock.

NEJM 2023 Online

The prognosis of patients presenting with cardiogenic shock secondary to an acute MI  is poor with mortality rates of up to 50%. Although a variety of mechanical circulatory devices are available as an adjunct to coronary revascularization and pharmacological therapy, the evidence base is limited. The ECLS-SHOCK investigators examined if routine use of extracorporeal life support (ECLS) improved survival in patients with cardiogenic shock secondary to MI in whom early coronary revascularization was planned (PCI or CABG). Cardiogenic shock was defined as systolic BP < 90mmHg for more than 30 minutes or initiation of catecholamines to maintain systolic BP > 90mmHg, arterial lactate concentration > 3mmol/L, and signs of poor oxygen perfusion with at least one of the following: altered mental status, cold or clammy peripheries, or urine output < 30ml/hour. Eligible patients underwent coronary angiography and were randomized to either ECLS plus OMT (n=209), or OMT alone (n=209). PCI was the revascularization method of choice unless non feasible in which case CABG could be undertaken. ECLS was commenced before PCI and the use of an antegrade arterial femoral sheath was recommended to minimise the risk of leg ischemia. The primary endpoint was death from any cause at 30 days. Key secondary endpoints were time until hemodynamic stabilization, duration of ITU stay, renal impairment requiring renal-replacement therapy, recurrent MI, and hospitalization for congestive cardiac failure. The median age was 63 years, 81.3% were men, 67% presented with STEMI, the LAD was the infarct-related vessel in 47.6%, 67% had multivessel CAD, 77.7% underwent cardiopulmonary resuscitation before randomization, median lactate before randomization was 6.9mmol/L, and 96.6% were revascularized by PCI. In the ECLS group, ECLS could not be initiated in 17 patients including 4 patients who died before initiation. In the control group, 26 patients had ECLS, and 28 patients had an alternative circulatory device. Death from any cause was similar in the ECLS and control group (47.8% vs. 49%; RR 0.98; 95% CI: 0.80-1.19; p=0.81). The rates of renal-replacement therapy (8.1% vs. 13.9%; RR 0.98), repeat revascularization (8.6% vs. 10.6%; RR0.81), MI (1.0% vs. 1.0%; RR 1.0), and rehospitalization for cardiac failure (1.4% vs. 1.0%; RR 1.49) were also similar in the two group. Moderate or severe bleeding (23.4% vs. 9.5%; p<0.05) as well as vascular complication requiring surgery or intervention (11.0% vs. 3.8%; p<0.05) were greater in the ECLS group. In summary, this trial does not support the use of ECLS therapy in cardiogenic shock secondary to MI.

 

Cardiogenic shock remains a challenging endeavour

Reperfusion delays and outcomes among patients with ST-segment-elevation myocardial infarction with and without cardiogenic shock.

Circ Cardiovasc Intv 2023; 16:e012810

STEMI complicated by cardiogenic shock (CS) is associated with high mortality, despite early reperfusion through established PPCI networks and technological advances such as mechanical circulatory support devices. This study sought to investigate the impact of first medical contact (FMC) to device times on in hospital outcomes in patients with STEMI presenting with and without cardiogenic shock. Prospective data was collected between 2010 and 2020 from the Vancouver Coastal Health Authority STEMI registry, which included patients from 10 hospitals, 2 of which are PCI capable centres. After exclusion of patients with no CS status, 2929 patients were included in the analysis and stratified according to CS status. A separate sensitivity analysis was performed excluding those patients presenting with cardiac arrest. Mixed effects logistic regression with hospital site specific random intercept and restricted cubic lines was used to express the relationships between FMC to device time and primary (mortality) and secondary (composite of death, cardiac arrest, heart failure, cerebral event or reinfarction, MACE) outcomes. A total of 275 patients (9.4%) presented with CS. Patients presenting with CS were older, more likely to have had a previous MI, heart failure, anterior infarction, dialysis dependence and prior cocaine use. 76.6% of patients with CS did not meet the guideline recommendations for FMC to device times versus 54.1% of patients without CS (p<0.001). As to be expected, patients presenting with STEMI complicated by CS had higher rates of in hospital mortality (41% vs. 1.9%) and in hospital MACE (81.1% vs 19.4%). In the FMC to device time period between 60 to 90 minutes, every ten-minute delay increased absolute mortality by 4-7% in the CS group. This effect was not seen in the patients without CS and was seen despite shorter symptom onset to FMC times in patients with CS. The rates of MACE in both the CS and non-CS groups increased with increasing FMC to device times. Following a sensitivity analysis removing those patients presenting with cardiac arrest, patients with CS remained to have higher incidences of mortality and MACE. Whilst the impact of reperfusion delays in the non-CS group were not as significant, this may be in part due to the overall low morality in this cohort. What was not looked at which is important to note is the impact of delayed reperfusion on medium to long term morbidity such as development of heart failure alongside neurological outcomes particularly in those post cardiac arrest, which was not assessed in this study. It would have also been of interest to see data on the use of inotropes and mechanical circulatory support in these patients.

 

Delayed revascularization in LMD increases MACE rates

Deferred versus performed revascularization for left main coronary disease with haemodynamic significance.

Circ Cardiovasc Intv 2023; 16:e012700

The natural history of patients with stable coronary artery disease and haemodynamic significant left main disease (LMD) is uncertain. The current study examined the long-term clinical outcomes of such patients according to treatment strategies of revascularization versus ongoing medical therapy using data from the DEFINE-LM registry. The DEFINE-LM registry is an international, multicentre registry including consecutive patients with LMD between October 2012 and October 2018. Inclusion criteria were patients with stable angina, LMD of 405-79% stenosis on visual angiographic assessment, and iFR interrogation for LMD. Key exclusion criteria were previous CABG or previous PCI for LMD, severe valvular heart disease, and any form of non-ischaemic cardiomyopathy. The primary endpoint was the rate of MACE (defined as a composite of all-cause death, non-fatal MI, and ischemia driven TLR of the left main). A total of 225 patients included in the analysis. Mean age was 68.5±10.3 years, 78.2% were male, mean SYNTAX score 22.1±9.0, mean percent diameter stenosis was 47±14.1%, and median iFR was 0.83. Revascularization was performed for 151 patients (PCI=85, CABG=66). Revascularization was deferred in 74 patients despite physiological confirmation of ischaemia. Following propensity score matching, 148 patients were selected for analysis. There were comparable frequencies of LM bifurcation, multivessel disease, downstream disease of LAD, and CTO. Angiographic (42.6±14.2% vs 48.5±14.8%, p=0.014) and physiological (iFR=0.86 vs iFR=0.82; p<0.001) severity were greater in the revascularization group. In patients undergoing PCI (n=44), DES with IVUS/OCT guidance were utilised in all cases. Over a median follow-up of 34 month, the MACE rate was greater in the deferred group (28.4% vs. 14.9%). KM event-free survival estimates at 4 years showed lower MACE rate in the revascularized group (HR, 0.42; 95% CI: 0.20-0.89; p=0.023). For the secondary endpoints, cardiac death or spontaneous LM-MI was greater in the deferred group (8.1% vs. 0%; p=0.004). The rate of ischaemia-driven LM-TLR was also greater in the deferred group (17.6% vs. 5.4%; HR, 0.20; 95% CI;0.056-0.70; p=0.012). In univariate analysis, deferral was significantly associated with MACE (p=0.019). In multivariate analysis, revascularization was the sole predictor of reducing MACE. In summary, in patients with stable CAD and haemodynamically significant LMD, revascularization reduces the rate of cardiovascular events including cardiac death, LMD-related spontaneous MI, and TLR.

 

Exercise moderation

Lifelong endurance exercise and its relation with coronary atherosclerosis.

EHJ 2023; 44:2388-2399

Regular exercise is associated with improvements in blood pressure control, lipid and glycaemic control and enhanced life expectancy. The impact of long-term endurance training on coronary atherosclerosis and acute cardiac events is less well defined. The Master@Heart study was a multicentre prospective cohort study designed to study the prevalence of coronary plaques (calcified, mixed, and non-calcified) on CTCA at baseline in 176 control subjects, 191 late-onset endurance athletes, and 191 lifelong endurance athletes. Inclusion criteria included male sex and age between 45-70 years. Athletes were defined as questionnaire reported engagement in cycling ≥ 8 hours or running ≥ 6 hours per week, or triathelon (combination of swimming, cycling, and running) ≥ 8 hours per week for at least 6 months prior to baseline. Lifelong and late-onset athletes were defined as those starting regular endurance training at < 30 years and > 30 years of age respectively. Non-athletes engaged in ≤ 3 hours per week of physical activity. Exclusion criteria included a history of CVD, history of conventional risk factors for CAD, current or history of smoking, BMI > 27.2 Kg/m2, and allergy to iodine-based contrast. Mean age of the participants was 56±6 years, controls had a higher BMI (24 vs. 23.2 vs. 23.5 Kg/m2) and higher body fat percentage (19.4% vs 13.9% vs 15%) than lifelong and late-onset athletes. Blood pressure, total cholesterol, LDL-cholesterol, HBA1c, and family history of CAD were similar in the three groups. Lifelong and late-onset athletes were predominantly cyclists whilst 77% of controls performed ≤ 3 hours per week of exercise mostly running and non-endurance sports. Lifelong and late-onset athletes had similar VO2peak which was significantly higher than controls (48 vs 46 vs 37 ml/min/Kg). The median number of plaques per individual (lifelong 2 (0-5) vs late-onset 1 (0-3) vs control 0 (0-4)) and the average calcium score (8.5 (0-90.9) vs 1.3 (0-54) vs 0(0-41.6) was similar between groups but lifelong athletes had a higher calcium score percentile than controls. The coronary plaque burden was higher in lifelong athletes than controls (between-group difference 0.86; 95% CI: 0.22-1.51). The distribution of calcified (62.3% vs 68.4% vs 67%), non-calcified (11.8% vs 9.8% vs 13.7%), and mixed plaques (25.9% vs 21.8% vs 19.3%) were similar. As compared to controls, lifelong endurance training was associated with having ≥ 1 coronary plaque (OR 1.86, 95% CI: 1.17-2.94), ≥ proximal plaques (OR 1.96, 95% CI: 1.24-3.11), ≥ 1 calcified plaque (OR 1.58, 95% CI: 1.01-2.49), ≥1 calcified proximal plaque (OR 2.07, 95% CI: 1.28-3.35), ≥ 1 non-calcified plaque (OR 1.95, 95% CI: 1.12-3.40), ≥ non-calcified proximal plaque (OR 2.80, 95% CI: 1.39-5.65) and ≥ mixed plaque (OR 1.78, 95% CI: 1.06-2.99). As compared to late-onset athletes, a ≥ 50% stenosis in any coronary segment (OR 2.79, 95% CI: 1.20-6.5) and ≥50% stenosis in a proximal segment (OR 5.92, 95% CI: 1.22-28.8) was more common in lifelong athletes. Salient features of the study include lack of female athletes, lack of non-white athletes, and a cross-sectional design and thus a definitive causal relationship between endurance exercise and CAD cannot be made.

 

Caution in the use of DEB in ISR

Sirolimus-coated balloon in an all-comer population of coronary artery disease patients: The EASTBOURNE prospective registry.

JACC Intv 2023; 16:1794-1803

Drug-coated balloons (DCB) have merged as a novel therapeutic strategy for the treatment of in-stent restenosis (ISR) an de novo CAD. The EASTBOURNE prospective registry was designed to examine the safety and efficacy of the MagicTouch sirolimus-coated DCB for the treatment of both native CAD and ISR in 2,123 patients (2,440 lesions). Inclusion criteria included all clinical indications for PCI. Exclusion criteria were patients with hypersensitivity to antiplatelet/antithrombotic therapy, hypersensitivity to sirolimus, unsuccessful predilatation of the target lesion with persisting residual stenosis 50%, severe target vessel calcification, tortuous vessels, and visible thrombus at the lesion site not removed by thrombectomy. The primary endpoint was clinically indicated TLR at 12 months. Secondary endpoints were procedural success, a compound of angiographic success without in-hospital complications. The average age was 66.6±11.3 years, 41.5% were diabetic, 59.3% had multivessel CAD, 42.9% had a previous MI, 66.3% had undergone PCI previously, ACS was the presentation in 46.6%, de novo lesions treated in 56%, and 44% had ISR.  The reference vessel diameter was 2.62±0.58mm, and lesion length was 18.76±9.14. Multivessel PCI was undertaken in 42% of patients during the index PCI. Device malfunction occurred in 0.2% and procedural complications occurred in 40 lesions including periprocedural MI (n=29), and vessel perforation (n=3). Flow limiting dissection or acute vessel recoil, requiring stenting, occurred in 181 lesions. Procedural success occurred in 97.6% of the lesions. At 1 year, TLR occurred in 5.9% of patients and was more common in patients with ISR (10.5% vs. 2.0%; RR: 1.90; 95% CI: 1.13-3.19; p<0.001). Patients with ISR had higher rates of MACE (14.9% vs. 4.9%; p<0.001), MI (4.3% vs 1.0%; p<0.001), and death (3.9% vs. 1.5%; p<0.001). After multivariate Cox regression model, the main determinant of the primary endpoint was ISR (OR: 5.5; 95% CI: 3.82-8.88). Salient features of the study include its open label design, use of DCB was left to the discretion of the operator, lack of a core angiography lab, and lack of balloon predilatation in 11.2% of de novo lesions.

 

Hs-cTNI is an adverse marker in stable CAD

High-sensitivity cardiac troponin for risk assessment in patients with chronic coronary artery disease.

JACC 2023; 82:473-485

High-sensitivity cardiac troponin (hs-cTn) is emerging as an attractive biomarker beyond patients with an ACS. The MICA (Myocardial Injury in patients referred for Coronary Angiography) study examined the role of hs-cTnI testing for risk stratification in patients with chronic CAD in a cohort of 4,240 patients with symptoms suggestive of angina who had been referred for invasive coronary angiography. Patients were included if they were permanent residents in Scotland, were not enrolled into a previous study, and had blood samples taken on the same day as their angiography. Patients were excluded if angiographic data was incomplete. Hs-cTnI was measured using the ARCHITECTSTAT High Sensitivity Troponin-I assay (Abbott). The assay has a sex-specific 99th percentile upper reference limit of 34 ng/L in men and 16 ng/L in women. The responsible cardiologist was blinded to the result and the assay result did not impact routine clinical care. The primary outcome was a composite of MI or cardiovascular death. Secondary outcomes were MI, death, and coronary revascularization within 30 days. The median age was 66 years, 33% were women, 91.7% had CAD of whom 32,2% had non-obstructive CAD and 67.8% had obstructive disease, 72% of patients with CAD had troponin concentrations above the limit of detection. Troponin concentration was higher in patients with CAD compared to those without (3.4 vs 1.9 ng/L; p<0.001). Over the follow-up period, 6% of patients had a primary outcome event, 4.3% of whom had a MI and 2.1% died of cardiovascular disease. The primary outcome was more common in patients with CAD (6.4%) than in patients without CAD. Troponin concentration was 2x greater in patients with CAD and a primary outcome event compared to those with CAD who did not have an event (6.7 vs. 3.3 ng/L; p<0.001). In patients with CAD, the incidence rate of the primary outcome was highest in those with troponin concentration above the sex-specific 99th percentile (6.13 events per 100 patient-years) compared with those with intermediate (4.64 events per 100 patient-years) or low (1.58 events per 100 patient-years) concentrations. Patients with troponin concentration below the limit of detection were 5x less likely to have a primary outcome event than those above the 99th percentile (2.8% vs 13.4%). After adjustments for age and gender, troponin concentration was an independent predictor or the primary outcome (aHR: 3.3; 95% CI: 2.6-4.4). As compared to patients with troponin concentration < 5 ng/L, the HR for MI or cardiovascular death reached 1.5 at troponin concentrations > 10 ng/L.

 

 

 

 

 

Valvular Heart Disease

Implications of stroke in mTEER

Cerebrovascular events after transcatheter edge-to-edge repair and guideline-directed medical therapy in the COAPT Trial.

JACC Intv 2023; 16:1448-1459

The COAPT trial has established mitral transcatheter edge-to-edge repair (mTEER) as a therapeutic strategy in patients with severe secondary mitral regurgitation who remain symptomatic despite guideline-directed medical therapy (GDM). Cerebrovascular events (CVE) such as stroke and transient ischemic attack are potential vascular complications of mTEER and may occur in as many as 4.7% of cases. The current study examined the temporal risks, predictors, and implications of CVE in participants of the COAPT trial. The trial randomized 614 patients in the US and Canada with 302 patients randomized to mTEER plus GDM and 312 to GDM alone. The two groups had similar rates of previous CVE (18.5% vs. 15.7%; p=0.35) and CHA2DS2VASCc scores (4.84±1.6 vs. 4.92±1.3; p=0.48). Anticoagulant therapy at baseline (47% vs. 39.7%; p=0.07) and anticoagulation at 30 days (49% vs. 41.2%; p=0.08) was numerically greater in the mTEER group. At 4-year follow-up, CVE had occurred in 7.8% of the entire study cohort (40 strokes and 10 TIAs, including 2 patients who had both). Most stokes were ischemic and 5 were haemorrhagic. The rates of stroke were similar in both the mTEER and GDM group (KM estimated rate: 12.3% vs. 10.2%; p=0.91). Stoke occurred in 10.5% of the mTEER group and 8.7% of the GDM group (p=0.87). Within 30 days of randomization, CVE occurred in 0.7% of patients randomized to mTEER and 0% of patients randomized to GDM (p=0.15). CVE occurred in a linear fashion over the 4-year follow-up period in both groups. Following multivariable analysis, independent predictors of CVE were worse baseline renal function and diabetes mellitus. CVE, in particular stroke, was associated with an increased 4-year risk of death that was particularly marked within the first 30 days after the neurological insult regardless of the treatment assignment.

 

Increasing sophistication of the MitraClip

Real-world outcomes of fourth-generation mitral transcatheter repair: 30-day results from EXPAND G4.

JACC Intv 2023; 16:1463-1473

The EXPAND G4 trial is an ongoing prospective, multicentre, single-arm, post-market observational study within a real-world setting to examine the safety and efficacy of the fourth generation MitraClip (Abbot Vascular) in patients with primary or secondary severe symptomatic mitral regurgitation. The current manuscript reports the 30-day outcomes of the entire study cohort of 1,164 patients. The average age was 77.5±9.1 years, 44.1% were women, STSPROM for repair and replacement were 5.9%±6.2% and 7.6%±6.2 respectively, 43.6% had heart failure hospitalization within the year prior to enrolment, the aetiology was primary or mixed in 41.6%, and 8.1% had baseline moderate to severe (3+) or severe (4+) MR. 65% received 1 clip, 31% received two clips, and the 4% received ≥ 3 clips. Fourteen different clip combinations were utilised, of which 11 included a wide clip. 87.8% received wide clips, either NTW only, XTW only, both NTW and XTW, or NTW or XTW and any combination of the other 2 clips. In the entire cohort, 98% achieved ≤ 2+ MR severity and 91% achieved ≤ 1+ MR severity. Trace MR was present in 35% of patients. The adverse event rates were all-cause death 1.3%, MI 0.2%, stroke 0.5%, non-elective cardiovascular surgery for device-related complications 0.9% and leaflet adverse events 1.1%. Functional capacity and quality of life were significantly improved with 83% of patients achieving NYHA functional class I or II. An 18-point improvement was observed in the KCCQ summary scores compared with baseline. In summary, the EXPAND G4 summary is the largest report of 30-day clinical and echocardiographic outcomes of the fourth generation MitraClip system and supports the early safety and efficacy of the device in the treatment of patients with severe symptomatic MR.

 

Increasing evidence for tTEER

Short-term outcomes of tricuspid edge-to-edge repair in clinical practice.

JACC 2023; 82:281-291

Severe tricuspid (TR) regurgitation is associated with significant morbidity and mortality. Patients presenting with primary or secondary TR are often elderly with a multitude of comorbidities rendering surgery high risk. In the TRILUMINATE Pivotal trial, Tricuspid transcatheter edge-to-edge repair (tTEER) using the TriClip system was shown to be safe, effective and associated with improvements in the quality of life. The BRIGHT post-approval study is a prospective, single-arm, open-label, multicentre, post-market registry designed to evaluate the safety and efficacy of the TriClip system in 511 patients with severe symptomatic TR. The primary outcome was acute procedural success (APS) defined as successful implantation of the device with resulting TR reduction of at least 1 grade. Baseline characteristics included mean age 78.9 years, 44% men, 90% had functional TR, 61.3% had massive TR, 26.7% had torrential TR, mean LVEF55.8%, 40.3% had had prior HF hospitalization, 88% were in NYHA functional class III/IV, 27% had prior mitral valve intervention, 23% had a permanent pacemaker/implantable cardioverter, and baseline KCCQ score was 44.5. Successful device implantation occurred in 99% of patients and TR was reduced to ≤ moderate at 30 days in 77%. At 30 days, there were significant improvements in NYHA class (I/II, 20% to 79%; p<0.001) and KCCQ score (19±23 points improvement; p<0.0001). Major adverse events occurred in 2.5% and included cardiovascular mortality (0.8%), stroke (0.4%), new onset renal failure (1.4%), and non-selective CV surgery for device-related adverse events (0.2%). Salient features include lack of data regarding the characteristics of patients declined for t-TEER and approximately a quarter of the patients had < 5 points improvement in KCCQ indicating lack of an early benefit.

 

Selection remains key for tTEER success

Characterization of screening failures among patients evaluated for transcatheter tricuspid valve repair (Triselect-Study).

JACC Intv 2023; 16:1579-1589

Transcatheter tricuspid valve repair (TTVr) is increasingly recognised as a safe and effective treatment modality for patients with severe symptomatic secondary tricuspid regurgitation. Such patients, however, often present with a multitude of comorbidities and tricuspid anatomical features that prohibits TTVr. The TriSelect study is a retrospective, multicentre study of 547 patients from 3 centres in the US and Germany designed to identify clinical characteristics and cardiac anatomical features that would preclude patients from undergoing t-TEER. The baseline characteristics of the 547 patients in the study included median age 80 years, 60% female, 87% had atrial fibrillation, and EuroSCORE II 4.8%. Among the 229 (41.9%) patients that were deemed unsuitable for TTVr, the most common reasons were anatomical features (57%), clinical futility (17.9%), technical limitations (12.7%) and low symptom burden (12.7%). Larger RV basal diameter, larger RA area, larger IVC diameter, larger TV ring diameter, severe TV leaflet tethering, and larger leaflet coaptation defect were independently associated with screen failure. Poor clinical status/frailty, pulmonary hypertension, other comorbid disorders, and recurrent heart failure requiring ventricular assist devices or heart transplant were the main clinical reasons for exclusion. Poor imaging quality and pacemaker lead with leaflet impingement/attachment were the main other reasons for exclusion.

 

Encouraging additional data for the durability of tTEER

Two-year outcomes for tricuspid repair with a transcatheter edge-to-edge valve repair from the Transatlantic TRILUMINATE trial.

Circ Cardiovasc Intv 2023; 16:e012888

Tricuspid regurgitation is a relatively common valvular lesion which is associated with progressive morbidity and mortality. There are limited treatment options, with surgical repair or replacement often reserved for the younger less co-morbid patients due to a high operative risk, with early mortality varying between 4-10%. Following the success of the transcatheter MitraClip, the TriClip was developed for percutaneous repair of TR in patients at high surgical risk. The TRILUMINATE trial was a small international multi-centre prospective single arm study to assess the safety and efficacy of the TriClip device for tricuspid valve edge to edge repair in patients with moderate or greater TR.  The investigators had previously published favourable 6 month and 1-year outcomes following TriClip tTEER and in this publication present the 2-year outcome data. The study investigators recruited symptomatic patients at high surgical risk with moderate or greater TR and procedural success was defined as a reduction in TR to moderate or less at 30 days. The original cohort consisted of 85 patients, however following 14 deaths, 6 withdrawals, 3 missed visits and 14 patients with lack of readable echo images the final cohort analysed at 2 years consisted of 48 patients. A reduction of TR to moderate or less was achieved in 60% of patients, and there was no significant change in TR grade between 30 days and 2 years. Overall, 75% of patients maintained a reduction in TR at 2 years, whilst in 25% there was an observed increase in TR, although 50% of these remained at moderate or less. Improvements in right heart remodelling metrics including RV end diastolic diameter and fractional area change were maintained at 2 years. TAPSE was seen to increase as compared with baseline at 2 years (p=0.001). Improvements in quality-of-life metrics including NYHA class, KCCQ score, and 6-minute walk test were maintained. Cardiovascular mortality occurred in 11 patients (13%) and all cause hospitalization rate decreased from 1.3 events per patient-year 1 year before device implant to 0.66 events per patient-year 2 years after the TriClip implant. This was driven by a reduction in heart failure hospitalization rates. Despite its limitations including an observational design and small sample size, it does demonstrate a signal that tTEER results in a relatively durable reduction in TR, translating to improvements in right heart remodelling alongside improvements in symptoms and reductions in heart failure hospitalizations.

 

ACURATE Neo remains a work in progress

Final 3-year outcomes of a randomized trial comparing a self-expanding to a balloon-expandable transcatheter aortic valve.

Circ Cardiovasc Intv 2023; 16:e012873

There are two main types of transcatheter aortic valve replacement (TAVR) platforms that are being commercially used, the self-expanding and balloon expandable valves. With the indications for TAVR expanding into the lower risk and younger populations, minimising complications and longer-term durability is of upmost importance. The SCOPE I investigators present the 3-year outcome data from their trial comparing the first generation ACURATE Neo self-expanding valve with the Edwards SAPIEN 3 balloon expandable valve in patients with severe aortic stenosis, having enrolled 739 patients across 20 European countries. The initial 30-day data published previously reported higher rates of prosthetic valve regurgitation and acute kidney injury in patients receiving the ACURATE Neo valve. In a separate trial, the ACURATE Neo valve did not meet non-inferiority as compared with the EVOLUT self-expanding valve at one year. At 3 years, 24.3% had died in the ACURATE Neo group and 25% had died in the Edwards SAPIEN group (HR 0.98; 95% CI: 0.73-1.33).  There were no significant differences in rates of cardiovascular death or stroke, and there was a trend for reduction in hospitalization for valve related dysfunction or heart failure with the ACURATE Neo valve (subhazard ratio 0.74; 95% CI: 0.51-1.07). Effective orifice areas were higher and mean gradients were lower in the ACURATE Neo cohort. There were numerically higher numbers of bioprosthetic valve dysfunction and bioprosthetic valve failure in the Edwards SAPIEN cohort, however the numbers were small overall.  There are a few points to highlight from this trial. Firstly, the early increased rates of paravalvular regurgitation and AKI seen at 30 days did not translate into worse clinical outcomes at 3 years. The rate of cross over was higher from the ACURATE Neo group to the SAPIEN group, and there were numerically higher rates of multiple valve implantations in the ACURATE Neo group (11 vs. 2), with all of these patients having a SAPIEN 3 valve implanted as the second valve. This may have mitigated any longer-term effect on outcomes. Furthermore, this was a relatively high-risk group of enrolled patients, with around a quarter in each group having died at 3 years, and therefore challenging to truly ascertain the impact of the early increased rates of paravalvular regurgitation on outcomes. Whilst the initial rates of paravalvular regurgitation at 30 days are higher in the ACURATE Neo group, the haemodynamic performance of the valve does appear superior. There are now two further iterations of this valve with improved designs including a change to the scaffold with a view to increase radial force, which may have a beneficial effect in reducing paravalvular regurgitation.

 

 

Miscellaneous

Mild hypercapnia does not improve outcomes in OOHCA

Hypercapnia or normocapnia after out-of-hospital cardiac arrest.

NEJM 2023; 389:45-57

Hypoxic brain injury remains a major cause of morbidity and mortality in patients who survive an out-of-hospital cardiac arrest (OOHCA). The PaCO2 is a major regulator of cerebrovascular tone with several small studies suggesting that relative hypercapnia may be associated with improved neurological outcomes. The Targeted Therapeutic Mild Hypercapnia after Resuscitated Cardiac Arrest (TAME) trial is an international, open-label, randomized trial designed to determine whether mild hypercapnia would improve neurological outcomes at 6 months as compared with targeted normocapnia in 1700 patients with coma who had been resuscitated after an OOHCA of a presumed cardiac or unknown cause and who had a sustained return of spontaneous circulation. The main exclusion criteria were an interval of 180 minutes from the return of spontaneous circulation to screening, unwitnessed cardiac arrest with an initial detected rhythm of asystole. Patients were assigned to targeted mild hypercapnia (PaCO2: 50-55 mmHg; n=847) or targeted normocapnia (PaCO2: 35-45 mmHg; n=853) for 24 hours beginning at randomization. The protocol recommended deep sedation, assessment of arterial blood gases with no adjustment for blood pH for hypothermia-mediated effects on blood gases every 4 hours, and use of end-tidal CO2 levels by clinicians to guide ventilation management. Mean age of the study cohort was 61 years, 88% had bystander-witnessed cardiac arrest, 80% had bystander-performed CPR, 71% had a shockable rhythm, and ventricular fibrillation was the presenting rhythm in 67%.  The primary outcome of a favourable neurological outcome, defined as a score of 5 or higher on the Glasgow Coma Scale occurred in 43.5% in the mild hypercapnia group and 44.6% in the normocapnia group (RR, 0.98; p=0.76). By 6 months, 48.2% in the mild hypercapnia group and 45.9% in the normocapnia group had died (RR with mild hypercapnia, 1.05; 95% CI: 0.94-1.16). In the mild hypercapnia group, 53.4% had a poor functional outcome, defined as a Modified Rankin Scale score of 4 to 6, compared with 51.3% in the normocapnia group. Health-related quality of life, as assessed by the EQ Visual Analogue Scale component of the EuroQol-5D-5L, was similar in the two groups. The most common adverse events were pneumonia, arrhythmia leading to haemodynamic instability, bleeding, and sepsis, and did not differ in the two groups. The study concluded that in survivors of OOHCA, mild hypercapnia did not improve neurological outcomes at 6 months as compared to normocapnia.

 

 

 

R&D Literature Review: May 2023

R&D Literature Review: May 2023

BCIS R&D Group Literature Review

May 2023

Prepared by Michael Mahmoudi and Natalia Briceno

Edited by Michael Mahmoudi

 

 

Coronary Artery Disease

Is intracoronary imaging mandatory in complex PCI?

Intravascular imaging-guided or angiography-guided complex PCI.

NEJM 2023 Online

Data regarding the potential benefits of intracoronary imaging in complex PCI is limited. The RENOVATE-COMPLEX-PCI trial investigated whether IVUS or OCT guided PCI improved clinical outcomes as compared with angiography-guided PCI in patients with complex coronary anatomy. Patients were randomized to either IVUS/OCT guided PCI (n=1092) or angiography guided PCI (n=547). The patient population included 49% with stable ischemic heart disease, and 51% with acute coronary syndrome. In the intravascular imaging cohort 75% had IVUS and 25% had OCT at the time of their PCI.  Complex coronary anatomy was defined as bifurcation lesion, chronic total occlusion, unprotected left main disease, implanted stent length ≥ 38mm, multivessel (≥2) or multi-stents (≥3) PCI, in-stent-restenosis, severely calcified lesion, and ostial lesions. Exclusion criteria included PCI not being feasible, cardiogenic shock, intolerance to aspirin, P2Y12 inhibitor, heparin, or everolimus, anaphylaxis to contrast dye, pregnancy, and limited life expectancy. The primary endpoint was a composite of death from cardiac causes, target-vessel-related MI, or clinically driven target-vessel revascularization. Mean age was 65.6±10.2 years, 79.3% were male, 37.6% were diabetic, 21.9% bifurcation lesions, 19.5% had a CTO, 11.7% had unprotected left main disease, 37.9% had multivessel PCI, 14.4% had in-stent restenosis, 14.1% had severe calcific disease, and 15.3% had ostial lesions. At a median follow-up of 2.1 years, the primary endpoint was lower in the IVUS/OCT group (7.7% vs. 12.3%; HR 0.64, 95% CI: 0.45-0.89; p=0.008). The cumulative incidence of target-vessel related MI or death from cardiac causes was 5.3% in the IVUS/OCT group and 8.5% in the angiography group (HR 0.63, 95% CI: 0.42-0.93). The cumulative incidence of definite stent thrombosis was 0.3% in the overall trial population and was 0.1% in the IVUS/OCT group and 0.7% in the angiography group (HR 0.25, 95% CI: 0.02-2.75).

 

Plaque morphology determines behaviour of non-culprit lesions

Identification of high-risk coronary lesions by 3-vessel optical coherence tomography.

JACC 2023; 81:1217-1230

Several plaque anatomical features have been identified as “high-risk” features and predictive of adverse clinical outcomes. The current study investigated the prognostic value of OCT for identifying patients and lesions that are at risk of cardiac events in 883 patients with acute MI undergoing primary PCI (PPCI). Patients 18 years or older undergoing PPCI of the culprit lesion for STEMI or non-STEMI were eligible for inclusion if they were considered suitable for OCT of all the three main epicardial coronary arteries. The main exclusion criteria were cardiogenic shock, end-stage renal disease, serious liver dysfunction, allergy to contrast media, and anatomical features precluding OCT examination (CTO, extremely tortuous or heavily calcified vessels, and left main disease).  The primary endpoint was the composite of cardiac death, non-culprit lesion related nonfatal MI, and unplanned coronary revascularization. Mean age was 56.9±11.4 years, 75% were men, and 70.1% were admitted with STEMI. Upon angiography, 1,872 non-culprit lesions with a stenosis of at least 30% were identified in the coronary tree and the mean stenosis by QCA was 42.5%±10.2%. The mean analysable OCT pullback length per patient was 170.1±36.0 mm. On OCT, 3,757 non-culprit lesions were detected, and the mean MLA was 4.5±2.5 mm2. Specifically, 515 TCFAs (13.7%) were identified in 324 (36.7%) of patients and 1,535 lesions (40.9%) with MLA <3.5 mm2 were identified in 638 (72.3%) of patients. Patients with TCFA had a higher baseline risk profile (older age, DM, hypertension, higher level of serum lipids) and more diseased arteries than those without TCFA. Patients were followed for up to 4 years (median 3.3 years). There were 71 patients who experienced adverse cardiac events and 3 event types were tracked: 22 patients had culprit lesion related events, 34 patients had non-culprit lesion related events, and 17 patients had cardiac death. The 4-year cumulative rate of the primary endpoint was 7.2%. The angiographic diameter stenosis of non-culprit lesions subsequently responsible for events was 43.8%±13.4% at baseline and progressed to 63.7%±20.4% at the time of the event (p<0.001). Patients with TCFA (adjusted HR 3.05; 95% CI 1.67-5.57; p<0.001), or MLA <3.5 mm2 (adjusted HR 3.71; 95% CI: 1.22-11.34; p=0.021) had an increased risk for the primary endpoint. These high-risk characteristics were also predictive of events arising from each specific lesion. In a multivariable model in which 2 high-risk characteristics were entered simultaneously, TCFA and MLA <3.5 mm2 were still independent predictors of lesion-level events. TCFAs with an MLA <3.5 mm2 were detected in 21.9% of patients and 6.9% of lesions. Patients harbouring 1 or more TCFA lesions with an MLA <3.5 mm2 had a 4-year primary endpoint rate of 17.4%. The cumulative event rate arising from such lesions was 9.5% which was much higher than lesions with only 1 or none of these 2 high-risk features. The patient-level (adjusted HR 5.75; 95% CI: 3.12-10.61; p<0.001) and lesion specific (adjusted HR 15.5; 95% CI: 6.89-34.89; p<0.001) risks were more pronounced when these 2 high-risk characteristics were combined.

 

MACE in Diabetic patients is not explained by plaque morphology alone

Coronary artery lesion lipid content and plaque burden in diabetic and nondiabetic patients: PROSPECT II.

Circulation 2023; 147:469-481

Diabetes mellitus is both a risk factor for CAD as well as an adverse prognostic marker in patients with established CAD. The PROSPECT II investigators had postulated that diabetes associated differences in plaque morphology and lipid content may account for the increased MACE rates. PROSPECT II had enrolled 898 patients with acute MI with or without ST-segment elevation who underwent 3-vessel quantitative coronary angiography and co-registered NIRS and IVUS following successful PCI. This substudy stratified patients based upon diabetic status and assessed baseline culprit and non-culprit prevalence of high-risk plaque characteristics (maximum plaque burden ≥70% and maximum lipid core burden index ≥324.7. Over a median follow-up of 3.7 years, MACE was significantly in the diabetic group (20.1% vs. 13.5%; OR, 1.94; 95% CI: 1.14-3.30), driven primarily by increased risk of MI related to culprit lesion restenosis (4.3% vs. 1.1%; OR, 3.78; 95% CI: 1.12-12.77) and non-culprit lesion related spontaneous MI (9.3% vs. 3.8%; OR, 2.74; 95% CI: 1.25-6.04). High-risk plaque characteristics were similar in diabetic and non-diabetic patients in culprit lesions (max plaque burden ≥70%: 90% vs. 93%; p=0.34; maximum lipid core burden index 324.7: 66% vs. 70%; p=0.94) as well as non-culprit lesions (max plaque burden ≥70%: 23% vs. 22%; p=0.37; maximum lipid core burden index 324.7: 26% vs. 24%; p=0.47). In multivariate analysis, diabetes was associated with MACEs in non-culprit lesions (OR, 2.47; 95% CI: 1.21-5.04) but not with prevalence of high-risk plaque characteristics (OR, 1.21; 95% CI: 1.21-0.86-1.69).

 

What is the optimal timing for complete revascularization in ACS patients?

Immediate versus staged complete revascularization in patients presenting with acute coronary syndrome and multivessel coronary disease (BIOVASC): a prospective, open-label, non-inferiority, randomized trial.

Lancet 2023; 401:1172-1182

The optimal timing of complete revascularization in ACS patients with multivessel CAD remains uncertain. Investigated whether PCI for non-culprit lesions should be attempted during the index procedure or staged. Patients aged 18-85 years presenting with STEMI (40%) or non-NSTEMI (53%) were randomized to immediate (n=764) or staged complete revascularization (n=761). Patients in the staged arm had PCI of the culprit vessel during the index admission and delayed PCI of the non-culprit lesions within 6 weeks. The primary endpoint was the composite of all-cause mortality, MI, any unplanned ischaemic-driven revascularization, or cerebrovascular events at 1 year after the index procedure. Secondary outcomes included all-cause mortality, MI, and unplanned ischaemia driven revascularization at 1 year after the index procedure. Key exclusion criteria included previous CABG, cardiogenic shock, and CTO. Mean age of the study patients was 66 years, 22% were female, and 21% had diabetes. Approximately 60% of patients had complex lesions including 22.6% with type B2 and 37.7% with type C lesions. Immediate complete revascularization was performed off-hours in 27.1% of cases. Most lesions were treated based on visual assessment with angiography. Use of FFR or iFR was low at 15.4% and 23.3% in the immediate and staged groups respectively. The primary outcome occurred in 7.6% of the immediate group and 9.4% of the delayed group (p for noninferiority=0.0011 and p for superiority=0.17). There was no difference in all-cause death between the immediate and staged groups (1.9% vs. 1.2%; HR 1.56; 95% CI: 0.68-3.61; p=0.30). MI (1.9% vs. 4.5; HR 0.41; 95% CI=0.22-0.76; p=0.0045) and ischaemia-driven revascularizations (6.7%; HR 0.61; 95% CI=0.39-0.95; p=0.030) were more common in the staged group.

 

Predictors of angina post-PCI

Angina after percutaneous coronary intervention: patient and procedural predictors.

Circulation Interv 2023; 16:e012511

In patients with stable angina, PCI plus optimal medical therapy may provide greater improvement in angina-related health status than medical therapy alone. However, as many as 20-40% of patients may experience either persistence or recurrent angina during short and medium-term follow-up. The current study examined patients and procedural factors associated with post-PCI angina at 3-month post PCI in the TARGET-FFR study. The TARGET-FFR study, which has been published previously, randomized 260 patients undergoing PCI for either chronic or medically stabilized acute coronary syndrome to either physiology-guided or angiographically guided PCI. All patients completed questionnaires on angina symptoms (SAQ-7) and health status (EQ-5D-5L) at baseline and after 3 months post PCI. Patients underwent blinded intracoronary physiology before and after stenting. A post hoc analysis was undertaken comparing clinical and procedural characteristics amongst patients and without post-PCI angina defined by follow-up SAQ-angina frequency score <100. 38.3% of patients had post-PCI angina at 3-month follow-up. Such patients had higher incidence of smoking, atrial fibrillation, and previous history of MI. Patients with post-PCI angina had significantly high CCS scores at baseline and were prescribed more antianginal drugs with greater utilization of oral nitrate tablets. There were no differences between groups in the angiographic severity of stenoses or procedural characteristics such as lesion preparation, stent length, postdilatation, and use of intracoronary imaging. Patients who were angina-free at follow-up had physiologically more severe lesions prior to PCI (0.56±0.15 vs. 0.62±0.13; p=0.003) and achieved significantly larger improvements in FFR (43.1±33.5% vs. 67.0±50.7%; p<0.001). There were no differences in either post-PCI physiology metrics or in the proportion of patients who received additional intervention through the study’s post-PCI physiology-guided optimization protocol. Patients with post-PCI angina had lower baseline SAQ summary scores (64±22 vs. 95.2±8.7; p<0.001) and EQ-5D-5L health index scores (069±0.26 vs. 0.91±0.17; p<0.001). In multivariate analysis, smaller changes in FFR predicted the presence of post-PCI angina. The rate of target vessel failure at a median follow-up of 3 years was 1.7% with no significant difference between groups (no angina, 0.7% vs. post-PCI angina, 3.4%; p=0.16) but the study was not powered to detect differences in clinical outcomes.

 

Revalidation of UK-BCIS CHIP across the pond

Validation of UK-BCIS CHIP score to predict 1-year outcomes in a contemporary United States population.

JACC Interv 2023; 16:1011-1020

Several risk assessment tools have been proposed to aid shared decision making in patients undergoing high-risk PCI. One such risk score, the British Cardiovascular Intervention Society (BCIS) Complex High-Risk Indicated PCI (CHIP) score, has been shown to be associated with in-hospital morbidity and mortality. The main limitation of this risk-score included lack of an external validation cohort, and outcomes beyond hospitalization were not examined. The current study sought to evaluate the performance of the BCIS-CHIP score in predicting the risk of MACCE at 1 year amongst 20,799 patients undergoing PCI at the Mount Sinai Hospital in New York from January 2011 to December 2020 and thus circumvent some of the limitations of the original risk-score.  The BCIS-CHIP score consists of 7 patient factors (age≥80, female sex, PVD, prior stroke, prior MI, CKD, LVEF<30%) and 6 procedural factors (PCI involving 3 vessels, left main PCI, total stent length >60mm, dual arterial access, use of LV mechanical support, & rotational atherectomy). Patients were stratified into 4 risk groups according to their score: group 1=score 0, group 2=score 1 or 2, group3=score 3 or 4, and group 4=score ≥5 points. The primary endpoint was MACCE at 1 year defined as a composite of death, MI, and stroke. Secondary endpoints included the individual endpoints of the primary endpoint, TVR, major bleeding at 1-year follow-up, in-hospital MACCE, and in-hospital bleeding. Mean age was 66.3±11.4 years, and 29.4% were female. Patients were distributed across a wide range of BCIS-CHIP score values and patients with lower score values were more represented than patients with higher scores. Female sex (29.4%), CKD (27.3%), and prior MI (23%) were the most frequently met BCIS-CHIP factors. The BCIS-CHIP score groups consisted of group 0 (23.7%), 1 or 2 (38.5%), 3 or 4 (22.9%), and ≥5 (14.9%). The study population was ethnically diverse and consisted of 44% Caucasians, 10% African Americans, 14.4% Asians, 18.2% Hispanics, and 13.4% other ethnicities. A higher BCIS-CHIP score was more common in Caucasians, African Americans, and Hispanic patients and associated with an increased burden of comorbidities such atrial fibrillation, anaemia, chronic lung disease and cancer, as well as complexity of CAD including bifurcation lesions, chronic total occlusions, and higher SYNTAX scores. MACCE at 1 year occurred in 1.7% of patients with score 0, 3% with score 1 or 2 (HR: 1.72; 95% CI: 1.32-2.24), 6.1% with score 3 or 4 ((HR:3.6; 95% CI: 2.78-4.66) and 12% with score ≥5 (HR: 7.4; 95% CI: 5.75-9.51). Each point increase of the BCIS-CHIP score conferred a 28% increase of MACCE risk. The rate of all-cause death rose progressively across the BCIS-CHIP score. The 1-year risk of all-cause death was significantly higher in patients with a BCIS-CHIP score of 3 or 4 (HR: 4.76; 95% CI: 3.22-7.03; p<0.001) or BCIS-CHIP score ≥5 (HR: 12; 95% CI: 8.26-17.5; p<0.001) as compared to patients with BCIS-CHIP score 0. The BCIS-CHIP score showed a moderate ability to predict in-hospital MACCE (area under the receiver-operating characteristic=0.65). This study has thus validated the BCIS-CHIP score in a more contemporary population and has shown it to have moderate discrimination capacity for the prediction of 1-year MACCE.

 

CFR as the predictor of clinical outcome

Prognostic impact of coronary microvascular dysfunction according to different patterns by invasive physiologic indexes in symptomatic patients with intermediate coronary stenosis.

Circulation Cardiovasc Interv 2023; 16:e012621

Coronary microvascular dysfunction (CMD) is a significant cause of myocardial ischaemia across differing cardiovascular pathologies including angina with unobstructed coronary arteries and heart failure, and its presence is associated with a poorer prognosis. It has been defined as having a coronary flow reserve (CFR) of less than 2.0, or an index of microcirculatory resistance (IMR) of ³25 by the COVARDIS group. This published work sought to compare the prognostic impact of CMD according to different patterns of invasively acquired CFR and IMR in patients presenting for invasive angiography with suspected ischaemic heart disease. The study population was obtained from the Prognostic Impact of Cardiac Diastolic Function and Coronary Microvascular Function Registry, which recruited consecutive patients with presumed ischaemic heart disease undergoing clinically indicated invasive coronary angiography. Patients with functionally significant stenoses, haemodynamic instability, severe valve disease, severe left ventricular systolic dysfunction and culprit vessel of an ACS were excluded, leaving a final population of 375 patients. Invasive data was obtained in most patients from the LAD with a pressure wire X and CFR and IMR were obtained using the thermodilution method. In this study CMD was defined as having a CFR of <2.5 and an IMR of  ³25, and patients were grouped according to the differing patterns of these indices (group 1 normal CFR and IMR-49.6%, Group 2 normal CFR and high IMR-12.5%, Group 3 low CFR and low IMR-19.5%, Group 4 Low CFR and high IMR-18.4%). The primary outcome was cardiovascular death or admission for heart failure and secondary outcomes were individual components of the primary outcome. 40.5% of patients were prescribed anti-platelet therapy and 58.9% statins, which is surprising given that these patients had a degree of coronary atheroma. The mean FFR was 0.89. Patients in group 4 had more diastolic dysfunction with higher levels of BNP and were also older. Median follow up was 3.5 years. There was differing flow patterns seen across the four groups. Group 2 had higher resting and hyperaemic flow, with an increased IMR and maintained CFR. Group 3 had increased resting flow and Group 4 had reduced hyperaemic flow.  The cumulative primary outcome was significantly different between groups. When group 1 was set as the reference group, there was no difference in primary outcome between Group 2 and Group 1, but was significantly different between Groups 1, and groups 3 and 4. IMR did not alter prognosis when groups were classified by CFR, but the reverse was true. When plotted as continuous variables, IMR adjusted CFR was significantly associated with the primary outcome (HRadj, 0.644; 95% CI: 0.537–0.772; p<0.001) but CFR adjusted IMR was not (HRadj, 1.004 ; 95% CI: 0.992–1.016; p=0.515). The key findings of this study are that when patients are classified according to their CFR and IMR status, they unsurprisingly demonstrate different flow patterns. Overall, it is CFR status that predicts outcome, not IMR. What was unclear due to small numbers was whether an increased IMR impacted outcome within patients with a reduced CFR. IMR has been shown previously to be a prognostic index in STEMI and other CV conditions, however this often goes alongside a reduced CFR also. Salient features of the study include its observational design and overall small numbers in groups 2-4, with multiple post hoc analyses making the study prone to Type 1 error, a high proportion of patients presenting with shortness of breath and higher prevalence of diastolic dysfunction.

 

Where next for shocked patients?

Extracorporeal membrane oxygenation in the therapy of cardiogenic shock: results of the ECMO-CS randomized clinical trial.

Circulation 2023; 147:454-464

Despite advances in acute cardiovascular care with respect to both pharmacotherapy and interventional technologies and techniques, cardiogenic shock (CS) remains to have both a high morbidity and mortality. Whilst it often begins with haemodynamic derangement due to reduced cardiac output, it can quickly lead to significant metabolic derangement with a subsequent systemic inflammatory response. At present no mechanical circulatory support (MCS) device has been shown to improve prognosis in CS. The ECMO CS trial was a multicentre randomised control trial conducted in four centres in the Czech Republic, with patients recruited between 2014 and 2022. Patients were recruited if they were either in severe shock or rapidly deteriorating shock (SCAI stages of cardiogenic shock D-E). Patients were randomised in a 1:1 fashion to receive either immediate VA ECMO or conservative treatment. In the conservative arm, downstream ECMO was allowed in the presence of ongoing clinical decline. There was a composite primary endpoint which included death from any cause, resuscitated cardiac arrest and implantation of another MCS at 30 days. In total 117 patients were included in the final analysis, 59 in the immediate VA ECMO group and 58 in the conservative group. The baseline characteristics were well balanced. Most patients were male (73.5%) and over 70% of patients were mechanically ventilated reflecting the severity of their illness. 62.4% of patients overall had cardiogenic shock because of an acute coronary syndrome. The use of revascularisation via PCI or CABG did not differ between groups. There was no significant difference between the composite endpoint between the immediate VA ECMO group and the conservative group (63.8% versus 71.2%). All-cause mortality (secondary endpoint) at 30 days was similar between groups (50% vs 47.5%, HR, 1.110; 95% CI: 0.660-1.866]. Over a third of patients in the conservative arm required downstream ECMO. Neurological status at 30 days was comparable between groups. This lack of impact on the primary endpoint was also seen when patients were stratified according to the aetiology of their cardiogenic shock. There was no difference in safety endpoints between groups. Whilst there was a higher than predicted composite endpoint, no difference in outcomes were seen. The patients recruited were the most severely unwell in terms of the shock spectrum, and at SCAI level D-E you are likely to have entered the metabolic downward spiral, and any improvement in haemodynamic with mechanical support would at this stage not have an appreciable clinical impact. There was also significant cross over in this trial which will have had an impact on the outcome. Although this was a larger RCT, the results mirror those of the IMPRESS RCT, where MCS with Impella was compared with IABP in rapidly deteriorating shock. There was likely a degree of selection, as on average 3.5 patients were recruited per year per centre and follow up was short in this trial.

 

FFR guided PCI of non-culprit lesions: will the pendulum swing again?

Fractional flow reserve versus angiography-guided strategy in acute myocardial infarction with multivessel disease: a randomized trial.

EHJ 2023; 44:473-484

Revascularisation of non-culprit lesions in acute myocardial infarction (AMI) deemed significant either angiographically or through FFR has been shown in multiple studies to be superior to culprit artery only PCI. However, the best strategy in which to select which lesions to treat remains unclear. The FLOWER AMI, comparing FFR guided PCI to angiography guided PCI in non-culprit arteries presenting with STEMI, showed no difference in the primary outcome. However, there was a lower than predicted incidence of events, a low proportion of patients having undergone PCI to the non-culprit arteries at the index procedure, and there was also lack of a core laboratory. The results of this trial re-ignited the debate between anatomy and physiology in terms of predicting outcomes. FRAME-AMI was an investigator initiated, randomised open label multicentre trial in 14 sites in South Korea enrolling consecutive patients presenting with either STEMI or NSTEMI having undergone successful primary or urgent PCI to the infarct related artery (IRA). Successful PCI was deemed to have at least TIMI II flow and less than 30% residual diameter stenosis. These patients also had to have at least one non-culprit lesion with a diameter stenosis of at least 50%, which did not include a CTO or left main stenosis. Only lesions angiographically greater than 50% diameter stenosis were treated in the angiography group and only those lesions with FFR less than 0.80 were treated in the FFR group. Complete revascularisation was recommended in the index procedure. The primary endpoint was time to death, MI or repeat revascularisation with median follow up of 3.5 years. The study required enrolment of 1292 patients to achieve adequate power, however due to poor recruitment because of the COVID pandemic the trial was terminated early. A total of 562 patients were enrolled (284 in FFR arm and 278 in angiography arm). Baseline characteristics were well matched. Most participants were male (84.3%) with an average age of 63.3 ±11.4 years. Overall, 47.2% of patients enrolled presented with a STEMI, and 52.8% presented with an NSTEMI. There were similar rates of intravascular imaging used in both groups (around 30%). There was a numerically higher proportion of 3 vessel disease in the FFR group. Overall, 64% of patients in the FFR group underwent non-IRA PCI, and 97% in the angiography group. In the FFR group, 16.8% of non-IRA lesions PCI was performed without FFR as diameter stenosis was greater than 90%. As to be expected, the angiography guided arm used more contrast and put in more stents.  At the median follow up of 3.5 years, the primary endpoint occurred in 18 patients in the FFR group and 40 patients in the angiography group (Kaplan-Meier event rates at 4 years, 7.4% vs 19.7%; HR 0.43; 95% CI: 0.25-0.75; p=0.003), and this benefit was consistent across the pre specified subgroups. The significantly lower incidence of MI in the FFR group was driven mainly by lower procedural related MI.  Interestingly, the differences in the primary outcome appeared to be driven more by the NSTEMI population within this trial.

 

Gender disparities in the DES era

Sex differences in 10-year outcomes after percutaneous coronary intervention with drug-eluting stents: insights from the DECADE cooperation.

Circulation 2023; 147:575-585

Women are underrepresented in interventional trials, and previous data comparing outcomes in men and women following PCI has been conflicting and limited by differences in baseline characteristics. This study sought to assess whether there are sex related differences in outcomes at ten years following DES implantation. The authors present data from the DECADE cooperation (adverse events and coronary artery disease progression), which is a pooled analysis of individual patient data from five trials with ten year follow up (ISAR-TEST 4, ISAR-TEST 5, SORT OUT III, SIRTAX and EXAMINATION). The main outcomes were cardiovascular death, MI, target lesion revascularisation, target vessel revascularisation, non-target vessel revascularisation, and definite stent thrombosis. The patients were divided into two groups by sex and the analysis of the individual participant data was performed using a one stage approach by entering a clustering effect by parent study in all univariable and multivariable models focusing on sex. Multivariable analyses were performed with adjustment for age, DES generation, diabetes, hypertension, smoking, hypercholesterolaemia, MI history, acute coronary syndrome and vessel treated. A landmark analysis was performed with a landmark at one year for death, TLR, and at 30 days for MI. Further analyses were performed to assess for a statistical interaction between age and sex, clinical presentation, and DES generation. A total of 9700 (2296 female, 7404 male) patients were included in this analysis. In general, females were older (p<0.001), and they were more frequently hypertensive and diabetic. There was a higher proportion of smokers and a history of prior MI in men. In general, men had a lower LV ejection fraction and more extensive coronary artery disease. 47% of the patients underwent PCI for an ACS. In general, females had smaller reference vessel diameters before PCI and a smaller minimal lumen area after PCI compared to men. In the unadjusted analysis, cardiovascular death occurred more frequently in females than males, but following adjustment this difference did not persist (adjusted HR, 0.94; 95% CI: 0.80-1.11; p=0.47]. All-cause mortality was lower in men in both the unadjusted and adjusted analyses. Females had lower repeat revascularisation than males, even after adjustment, with both reduced TLR (adjusted HR, 0.80; 95% CI: 0.74-0.87; p<0.001) and TVR. There was no difference in definite stent thrombosis. In the landmark analysis, females were more likely to have an MI at 30 days. Further sensitivity analyses performed with age excluded from the multivariable analysis, with female sex associated with a higher CV mortality at ten years, demonstrating that age is the main confounder. Salient features of the study include its observational nature, use of multiple analyses to correct for confounders, and lack of data on secondary prevention including anti-platelet therapy which may have impacted the results.

 

Is the evidence robust for angiography in OOHCA?

Coronary angiography after cardiac arrest without ST-elevation myocardial infarction: a network meta-analysis.

EHJ 2023; 44:1040-1054

Whilst the clinical pathway for patients presenting following an out of hospital cardiac arrest (OHCA) in the context of an ST elevation myocardial infarction is clear, it is less so in patients presenting following OHCA without ST elevation.  Both the COACT and TOMAHAWK trials published in 2019 and 2021 respectively did not demonstrate a prognostic benefit in performing early coronary angiography (CAG) as opposed to selective CAG in OHCA patients without ST elevation. This was in contrast to previously published nonrandomised studies demonstrating superiority of early CAG in this cohort of patients. The aim of this network meta-analysis was to assess the effect of early CAG compared with selective CAG for patients with OHCA without ST elevation.  A literature search was performed using MEDLINE, EMBASE and Web of Science databases. Randomised controlled trials comparing unselected early CAG to a selective late CAG strategy and non-randomised studies comparing early CAG to late and/or no CAG after non-STE OHCA that provided quantitative data on survival and/or neurological outcome were included. Risk of bias was assessed for all included studies, as was publication bias. A meta-analysis was performed to compare early CAG with selective late CAG at earliest follow up. The study investigators went on to perform a network meta-analysis to compare early, late and no CAG. The definition of early CAG was anywhere between 2 to 24 hours. 16 studies were included in the final analysis (six RCTs and 10 non-randomised studies), resulting in a total of 5819 predominantly male patients across all studies. The meta-analysis showed improved survival after early CAG (OR: 1.40, 95% CI: 0.12-1.76; p<0.01, substantial heterogeneity). This was also seen in the subgroup analysis of non-randomised studies but was not seen in the subgroup analysis of RCTs (OR: 0.89, 95% CI: 0.73- 1.10; p=0.29, no relevant heterogeneity). The results looking at neurological outcomes mirror these. The random effects model network meta-analysis showed that survival was significantly more likely after late CAG compared with early or no CAG. Early CAG improved survival compared with no CAG. It is clear that the non-randomised studies are significantly affected by bias and this has as a result influenced the overall outcome of this meta-analysis. In the non-randomised studies the patients selected for early CAG are likely to have been those that the treating clinicians thought would be most likely to survive. In current clinical practice the most recent RCTs do not support routine early coronary angiography in these patients. However, what is still unknown and what future studies should focus on is whether there is a cohort of patients that may still benefit from early CAG.

 

Valvular Heart Disease

The tricuspid journey is truly on

Transcatheter repair for patients with tricuspid regurgitation.

NEJM 2023 Online

Tricuspid transcatheter edge-to-edge repair (TTEER) is emerging as an effective treatment strategy in patients with symptomatic severe tricuspid regurgitation (TR) who are anatomically suitable for this type of therapy. The TRILUMINATE Pivotal investigators examined the safety and efficacy of TEER utilising the TriClip Transcatheter Tricuspid Valve Repair system (Abbott Vascular) in symptomatic patients with severe TR. Patients were eligible for participation if they had symptomatic severe TR, NYHA class II, III, Iva symptoms, were on guideline-directed optimal medical therapy for heart failure for ≥30 days, and were considered as intermediate or greater risk for mortality/morbidity for tricuspid valve surgery. Major exclusion criteria included indication for other valve intervention, severe pulmonary hypertension (>70mmHg), LV ejection fraction ≤20%, and anatomically unsuitable for TTEER. The primary endpoint was a hierarchical composite that included death from any cause or tricuspid valve surgery, hospitalization for heart failure, and an improvement in quality of life as measured with the KCCQ, with an improvement defined as an increase of at least 15 points assessed at the 1-year follow up. The secondary endpoints examined at 1 year were freedom from MACE (defined as death from CV causes, new-onset renal failure, endocarditis treated with surgery, and non-elective CV surgery from a TriClip device-related adverse event  within 30 days, change from baseline KCCQ score at 1 year follow-up, reduction in severity of TR to moderate or less by the 30-day follow-up and the change from baseline in the 6-minute walk distance at 1 year follow-up. Between August 21, 2019, and September 29, 2021, 350 patients were randomized to either TTEER (n=175) or control group (n=175). Mean age was 78±7 years, 54.9% were women, 90% had atrial fibrillation, 80.9% had hypertension, 36.9% had had previous mitral or aortic valve intervention, 25.1% had been hospitalized for heart failure within 1 year before enrolment, 93.9% had functional TR, and 70.7% had grade 4 or 5 TR. In the TTEER group, the device was successfully implanted in 98.8%, a mean of 2.2±0.7 clips were used per patient, mean device time was 90±66 minutes, and the median length of hospital stay was 1 day. The primary outcome was 11,348 wins in the TTEER group and 7,643 wins in the control group (win ratio=1.48, p=0.02). TR of moderate or less severity at 30 days was greater in the TTEER group (87% vs. 4.8%, p<0.001), as was the change in the KCCQ score from baseline to 12 months (12.3 vs. 0.6; p<0.001). Death from any cause or tricuspid valve surgery were similar in the two groups (9.4% for TTEER vs. 10.6% for control). The annualized rate of hospitalization for heart failure were also similar (0.21 events per patient-year for TTEER vs. 0.17 events per patient-year for control). TTEER is thus safe and associated with improvements in the KCCQ score in patients with symptomatic severe TR.

 

Safety & efficacy of tTEER

1-year outcomes of transcatheter tricuspid valve repair.

JACC 2023; 81:1766-1776

Severe tricuspid regurgitation (TR) is associated with significant morbidity and mortality. Given the high surgical risk associated with the treatment of isolated severe TR, transcatheter approaches are being explored for their safety and clinical efficacy. The single-arm, multicentre, prospective CLASP TR (Edwards PASCAL Transcatheter Valve Repair System in Tricuspid Regurgitation (CALSP TR) Early Feasibility Study) evaluated 1-year outcomes of the PASCAL system to treat 65 patients with severe to torrential TR. The study evaluated primary safety and performance outcomes, with echocardiographic, clinical, and functional endpoints. Enrolled patients had symptomatic, severe functional or degenerative TR as assessed by TTE or TEE. Eligible patients experienced symptoms despite medical therapy and were deemed suitable for the procedure by their local heart team. Major exclusion criteria included unsuitable tricuspid valve anatomy, previous tricuspid valve repair or replacement, severe CKD, hemodynamic instability or intravenous inotropic therapy and significant frailty (Katz index of Independence in Activities of Daily Living ≤2). Mean age was 77.4 years and 55.4% were female. The mean STS mortality score was 7.7% and the mean EuroSCORE II was 5.0%. 70.8% of patients were in NYHA class III or IV at baseline and 36.9% had a previous history of heart valve surgery. Common comorbidities included atrial fibrillation/flutter (89.2%), hypertension (92.3%), and renal impairment (43.1%). Implant success was 90.8% with a median of 1.0 devices implanted per patient. The median implantation time was 118 minutes. All 6 unsuccessful implants were the result of complex anatomy. At 30 days, CV mortality was 3.1%, stroke rate was 1.5%, and no device-related reinterventions were reported. Between 30 days and 1 year, there were 3 additional CV death (4.8%), 2 strokes (3.2%), and 1 unplanned or emergency reintervention (1.6%). 1-year post procedure, TR severity significantly reduced (p<0.001) with 86% of patients achieving moderate or less TR. 100% of patients at least 1 TR grade reduction. Freedom from all-cause mortality and heart failure hospitalization were 87.9% and 78.5% respectively. NYHA functional class significantly improved (p<0.001) with 92% in class I or II, 6-minute walk distance increased by 94 m (p=0.014), and overall KCCQ scores improved by 18 minutes (p<0.001). CLASP TR thus demonstrated that transcatheter treatment of severe or torrential TR is associated with low complication rate and high survival rates, and sustained improvements in TR severity, functional class, and quality of life at 1 year.

 

The enduring benefits of COAPT

Five-year follow-up after transcatheter repair of secondary mitral regurgitation. NEJM 2023 Online

The COAPT trail has demonstrated that in patients with severe symptomatic secondary mitral regurgitation (MR) who are on guideline-directed optimal medical therapy (GDOMT), transcatheter edge-to-edge repair with the MitraClip was safe and improved 2-year clinical outcomes. The current manuscript describes the final 5-year outcomes of the COAPT trial. Eligible patients had ischemic or non-ischemic cardiomyopathy with a LV ejection fraction of 20-50%, moderate-to-severe (3+) or severe (4+) secondary MR who remained symptomatic (NYHA class II, III, or IV) despite GDOMT. Major exclusion criteria were LV end-systolic dimension >7cm, severe pulmonary hypertension, and moderate or severe symptomatic RV failure. The primary effectiveness was all hospitalization for heart failure through 2 years after randomization. The primary safety endpoint was freedom from device-related complications at 12 months. Five-year follow-up was completed in 270 patients (89.4%) of the device group and 264 patients (84.6%) in the control group. The annualized rate of hospitalization for heart failure was lower in the device group (33.1% per year vs. 57.2%; HR, 0.53; 95% CI: 0.41-0.68). Death from any cause through 5 years was also lower in the device group (57.3% vs. 67.2%; HR, 0.72; 95% CI: 0.58-0.89) as was death or hospitalization for heart failure through 5 years (73.6% vs. 91.5%; HR, 0.53; 95% CI: 0.44-0.64). The 5-year rates of MI, revascularization, AF, stroke, CRT, PPM implantation, and LVAD or heart transplantation were similar in the two groups. The procedure was extremely safe (with only 4 device-specific events all occurring in the first 30 days after randomization) and durable with over 90% of patients still being in MR ≤2 plus at five years. In patients who crossed over from GDOMT to MitraClip after two years, outcomes in the first three years after treatment were like those in patients who received mTEER at the start of the study.

 

Expanding indications for mTEER

Transcatheter edge-to-edge repair in patients with anatomically complex degenerative mitral regurgitation.

JACC 2023; 81:431-442

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as a safe and effective therapy in patients with severe symptomatic degenerative MR who are at prohibitive risk of surgery. The PASCAL IID registry, within the construct of the CLASP IID trial, was designed to assess the safety and efficacy of the PASCAL system in prohibitive risk patients with complex mitral valve anatomy. Patients presented with at least 1 of the following complex mitral valve anatomic features: moderate to severe calcification in the grasping area, severe bileaflet/multi scallop involvement, significant cleft or perforation in the grasping area, leaflet mobility length <8mm, ≥2 independent jets, 1 significant jet in the commissural area, or mitral valve orifice area 4 cm2. Key exclusion criteria were contraindications to TEE, severe RV dysfunction, intracardiac mass, refractory heart failure, clinically significant and untreated CAD requiring revascularization, unstable angina, recent ACS or MI, recent stroke, need for urgent surgery for any reason, or any planned cardiac surgery within 12 months. The current study reports on outcomes to 6 months for 98 patients enrolled between April 2019 and December 2021 of whom 37.2% had ≥2 independent significant jets, 15% had bileaflet/multiscallop prolapse, 13.3% had mitral valve orifice area <4cm2, and 10.6% had large flail gap and/or large flail width. The median follow-up duration was 1.3 years. Mean age was 81.1 years, 61.2% were men, and 69.4% had NYHA class III/IV symptoms. The mean mitral valve area was 5.6cm2, mean LVEF was 59%, mean PAP was 42.8mmHg, STS score for mitral valve repair was 4.6% and mitral valve replacement 6.6%. Successful implantation of the PASCAL device was achieved in 92.9%. In total, 6 patients did not receive a study device because of inability to grasp leaflets (n=3), increased mitral valve gradient (n=2), or insufficient MR reduction (n=1). The 30-day composite MACE (CV mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve reintervention) was 11.2%. At 6 months, 92.4% of patients achieved MR≤2+, and 56.1% achieved MR≤1+. The KM estimates for survival, freedom from MACE, and heart failure hospitalization at 6 months were 93.7%, 85.6%, and 92.6% respectively. The NYHA functional class improved significantly from baseline (p<0.001) and 84.2% of patients were in NYHA functional class I/II. The mean overall KCCQ score significantly improved by 14.8 points (p<0.001). Salient features of the study include lack of blinding, lack of power to assess outcomes against prespecified performance goals, and relatively small sample size.

 

mTEER as an alternative to mitral surgery

Impact of transcatheter mitral valve repair availability on volume and outcomes of surgical repair. JACC 2023; 81:521-532

Mitral transcatheter edge-to-edge repair (mTEER) has had a transformative effect in the treatment of patients with severe symptomatic degenerative mitral regurgitation (DMR). The impact of mTEER availability upon mitral valve repair (MVr) volume and outcomes is unknown. Using the STS ACSD in the DMR population, the investigators examined the overall annualized MVr volumes and volumes by risk-strata and compared 30-day and 5-year outcomes within centres before and after the introduction of mTEER. Overall, 33,847 patients underwent MVr at 1,035 institutions during the study period (July 2021 to December 2018). Of these 22,095 patients at 972 institutions were linked to Medicare claims. There were 278 sites meeting criteria as mTEER capable with median annualized mTEER volume of 17 procedures. Among the final study population of 13,959 patients undergoing MVr or attempted repair, 6,806 surgeries were before and 7,153 after the first mTEER at the institution. At an institutional level, there was no significant change in median annualized MVr volume of 32 before the first mTEER vs. 29 after the first mTEER (p=0.06). Once patients were stratified into intermediate and high-risk groups, there was a significant decrease in the proportion operations at mTEER-capable centres (p<0.001). Patients undergoing MVr after the introduction of mTEER were slightly younger (median age 72 years), and less commonly presented with comorbidities such as chronic lung disease and NYHA functional class III or IV heart failure. The introduction of mTEER was associated with reduced risk-adjusted odds of mortality after MVr at 30 days (OR: 0.73; 95% CI: 0.54-0.99) and over 5 years (HR: 0.75; 95% CI: 0.66-0.86).

 

Further support for long-term outcome of TAVI in low-risk patients

3-year outcome after transcatheter or surgical aortic valve replacement in low-risk patients with aortic stenosis.

JACC 2023; 81:1663-1674

TAVI has emerged as the dominant therapy for severe symptomatic aortic stenosis and has surpassed SAVR in the United States. Longer term data regarding clinical and haemodynamic data, particularly in low-risk patients, are emerging to lend further support in favour of TAVI and aid shared decision making. The current study provides 3-year clinical outcomes from the landmark Evolut Low Risk trial. The trial was an international, prospective, randomized trial of 1414 patients demonstrating the noninferiority of TAVI to SAVR with respect to the composite endpoint of death or disabling stroke at 23 months. The prespecified endpoints reported in this analysis include 3-year incidences of all-cause mortality or disabling stroke as well as valve performance as determined using Doppler echocardiographic assessment, quality of life as assessed using KCCQ, NYHA functional class, and 3-year safety events including new PPM implantation, prosthetic valve endocarditis, prosthetic valve thrombosis, and aortic valve hospitalization. At the time of treatment, mean age was 74 years, 35.3% were women, and the mean STS predicted risk of mortality score was 2% in the TAVI group and 1.9% in the surgery group. At 3 years, the primary endpoint occurred in 7.4% of TAVI patients and 10.4% of surgery patients (HR: 0.70; 95% CI: 0.49-1.0; p=0.051). The difference between treatment arms for all-cause mortality or disabling stroke remained consistent over time: -1.8% at year 1, -2.0% at year 2, and -2.9% at year 3. The incidence of mild paravalvular regurgitation (20.3% TAVI vs. 2.5% SAVR) and PPM implantation (23.2% TAVI vs. 9.1% SAVR; p<0.001) were lower in the SAVR group. Rates of moderate or greater paravalvular regurgitation for both groups were <1% and not significantly different. Patients who underwent TAVI had significantly lower valve mean gradient (9.1 mmHg vs. 12.1 mmHg; p<0.001) and larger effective orifice area (2.2 cm2 vs. 2.0 cm2; p<0.001) at 3 years. KCCQ overall summary score demonstrated a more rapid improvement in quality of life at 30 days and that both groups had maintained improvements between 1 and 3 years. Improvements in NYHA score by at least 1 functional class from baseline to 3 years occurred in 72.7% of TAVI and 68.1% of surgery patients.

 

Miscellaneous

Another alternative for statin intolerance

Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. NEJM 2023 Online

Statin therapy is one critical component of a multifaceted approach in the primary and secondary prevention of atherosclerotic CVD. The use of statin therapy may be hindered in 7-29% of patients due to musculoskeletal adverse effects. Bempedoic acid, an ATP citrate lyase inhibitor, has been shown to reduce LDL cholesterol by reducing hepatic cholesterol synthesis and upregulating LDL receptor expression but whether this translates into favourable clinical outcomes is uncertain. The CLEAR Outcomes trial was designed to examine the effects of bempedoic acid on adverse cardiovascular events in patients intolerant to statin therapy in the context of primary or secondary prevention. Key inclusion criteria included age between 18 and 85 years, history of, or high risk for CVD including CAD, symptomatic PAD, cerebrovascular atherosclerotic disease, or high risk for cardiovascular events, patient-reported history of statin intolerance, fasting blood LDL cholesterol ≥ 2.6 mmol/L at screening. Key exclusion criteria included fasting blood triglycerides ≥ 5.6 mmol/L at screening, recent history of major cardiovascular events, TIA, unstable or symptomatic cardiac arrhythmia, history of severe heart failure, uncontrolled hypertension, or uncontrolled diabetes. The primary endpoint was a four-component composite of MACE defined as death from cardiovascular causes, non-fatal MI, non-fatal stroke, or coronary revascularisation. Key secondary endpoints included a three-component composite of death from cardiovascular causes, non-fatal stroke, or non-fatal MI; fatal or non-fatal MI; coronary revascularisation; fatal or non-fatal stroke; death from cardiovascular causes; and death from any cause. Between December 2016 and August 2019, 13,970 patients were randomized to either bempedoic acid 180mg daily (n=6992) or placebo (n=6978). The mean age was 65.5±9 years, 48.2% were female, 45.6% had diabetes, 69.9% had had a previous cardiovascular event, 22.7% were taking a statin, 11.5% were receiving ezetimibe, mean LDL cholesterol was 3.59 mmol/L, mean HDL cholesterol was 1.28 mmol/L, median TG level was 1.8 mmol/L, and media hs-CRP was 2.3 mg/L. Patients were followed for a median of 40.6 months. Premature discontinuation of the trial medication occurred in 29.1% of the bempedoic acid group and 31.7% of the placebo group. The incidence of the primary endpoint was lower in the bempedoic acid group (11.7% vs. 13.3%; HR, 0.87; 95% CI:0.79-0.96; p=0.006); fatal or non-fatal MI (3.7% vs. 4.8%; HR, 0.77; 95% CI: 0.66-0.91; p=0.002); and coronary revascularization (6.2% vs. 7.6%; HR, 0.81; 95% CI: 0.72-0.92; p=0.001). Bempedoic acid had no significant effects on fatal or non-fatal stroke, death from cardiovascular causes, and death from any cause. The incidences of gout and cholelithiasis were higher in the bempedoic acid group (3.1% vs. 2.1% and 2.2% vs. 1.2% respectively) as were the incidences of small increases in serum creatinine, uric acid, and hepatic-enzyme levels.

R&D Literature Review: January 2023

R&D Literature Review: January 2023

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.

 

R&D Literature Review September 2022

R&D Literature Review September 2022

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.

 

R&D Literature Review JUNE 2022

R&D Literature Review JUNE 2022

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.

 

Launch of Acute Aortic Dissection Pathway Toolkit

Launch of Acute Aortic Dissection Pathway Toolkit

Dear stakeholder

Launch of Acute Aortic Dissection Pathway Toolkit

We are pleased to let you know that we have launched NHS England and NHS Improvement’s new Acute Aortic Dissection (AAD) Pathway Toolkit. This consists of three separate documents which you will find attached. These are:
– Acute Aortic Dissection Toolkit Final Version 20220314
– 45.2a AAD Toolkit Interaction pdf
– 45.2b AAD Self-Assessment Questionnaire

The toolkit aims to improve patient outcomes through optimising the pathway from the point of diagnosis to definitive care and is underpinned by 7 key principles.

The toolkit has been developed as part of the work programme of the Vascular and Cardiac Clinical Reference Groups and is one of the products of the Cardiac Pathway Improvement Programme (CPIP). It is primarily a resource for those delivering cardiac services and is not intended to be a patient-facing resource, however we are very grateful for the range of patient groups and people with experience of acute aortic dissection who have supported its development, alongside clinical experts. The toolkit will be housed on the FutureNHS platform – an online workspace for NHS staff.

A webinar is taking place on 4th May 2022 from 9:30am-11am where attendees will have the opportunity to ask questions about the toolkit. This is an open invitation to anyone who is interested in the toolkit and further details will be shared in due course.

Should there be any queries in the interim, please contact tarana.akther@nhs.net.

Kind regards,

Tarana Akther (she / her)
Project Manager 
Specialised Commissioning, Service Transformation Programme
NHS England and NHS Improvement

R&D Literature Review January 2022

R&D Literature Review January 2022

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.

 

R&D Literature Review October 2021

R&D Literature Review October 2021

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.

 

R&D Literature Review June 2021

R&D Literature Review June 2021

BCIS R&D Group Literature Review

January 2023

Prepared by Michael Mahmoudi, Paul Morris, Julian Gunn and Natalia Briceno

Edited by Michael Mahmoudi

Coronary Artery Disease

Can routine CV screening be justified?

Five-year outcomes of the Danish cardiovascular screening (DANCAVAS) trial. NEJM 2022; 387:1385-1394

Cardiovascular disorders and their sequels such as myocardial infarction and stroke remain the leading causes of morbidity and mortality worldwide. It is uncertain whether a strategy of general population cardiovascular screening can have a meaningful clinical impact. The DANCAVAS trial was a multicentre, parallel-group, randomised-controlled trial of 46,611 men aged between 65-74 years participants living in 15 selected Danish municipalities that were randomised in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. The screening program included non-contrast electrocardiography-gated CT to detect a calcium score that was higher than the sex and age-specific median score, atrial fibrillation, aortic and iliac aneurysms, ankle-brachial blood pressure measurements, and blood samples for diabetes mellitus and hypercholesterolemia. The primary endpoint was death from any cause. Prespecified subgroup analyses were performed according to age (<70 or ≥70 years), history of cardiovascular disease, stroke, MI, heart failure, peripheral artery disease, aortic aneurysm, hypertension, diabetes mellitus, and use of lipid-lowering agents. Secondary outcomes included stroke, MI, amputation due to vascular disease, aortic dissection, and aortic rupture. Apart from more men with previous stroke and use of lipid lowering agents in the control group, there were no significant differences in the baseline characteristics. Positive findings in the participants undergoing screening included a calcium score above the age and sex-specific median score, ascending aortic, aortic arch, descending aortic, infrarenal abdominal aortic and iliac aneurysms, atrial fibrillation, peripheral artery disease, hypertension, diabetes, and hypercholesterolemia. After a median follow-up of 5.6 years, the rates of death in the invited and control group were similar (12.6% vs. 13.1%; HR: 0.95; 95% CI: 0.90-1; p=0.06). The cumulative incidence of death at 5 years was 10.6% in those undergoing screening and 10.9% in those who did not. Subgroup analyses suggested a difference according to age with a lower incidence of death from any cause among men in the invited group aged under 70 years (HR: 0.89). The hazard ratio for stroke in the invited group as compared with the control group was 0.93 (95% CI: 0.86-0.99), for MI 0.9 (95% CI: 0.81-1.03), for aortic dissection 0.95 (95% CI: 0.61-1.49), and for aortic rupture 0.81 (95% CI: 0.49-1.35). Salient features include restriction of the trial population to men only as well as age restricted to 65 to 74 years.

 

Natural history of SCAD

Canadian spontaneous coronary artery dissection cohort study: 3-year outcomes. JACC 2022; 80:1585-1597

Spontaneous coronary artery dissection (SCAD) may account for 24%-35% of all myocardial infarctions in women aged less than 60 years and may be associated with significant morbidity and mortality. SCAD results from spontaneous, nontraumatic separation of the coronary arterial wall by intramural haematoma caused by intimal tear or spontaneous haemorrhage, is unrelated to atherosclerosis, is often precipitated by an underlying arteriopathy, and may be triggered by emotional/physical stress. The Canadian SCAD Cohort Study is a prospective cohort study that enrolled patients presenting with acute SCAD in 22 North American centres and who were followed-up long-term. The study enrolled 750 patients from 2014 to 2018; 726 completed 3-year follow-up, 5 died during follow-up, 9 had follow-up at least 2 years 7 were lost to follow-up, and 3 patients withdrew from the study. Mean age was 51.7±10.5 years, 88.5% were women of whom 55% were postmenopausal, 87.3% were Caucasians, 33.9% had no cardiovascular risk factors, 19.5% had depression and 19.7% had anxiety. Screening for fibromuscular dysplasia (FMD) was complete in 58.4%, incomplete in 18.4%, and not done in 23.2%. Extra-coronary FMD was present in 42.9%. Other predisposing factors were less frequent including 4.5% who were peripartum, 2.9% with connective tissue disease, 1.6% with genetic disorders, and 3.9% with systemic inflammatory disease. Precipitating stressors were present in 66.4%: emotional stress in 50.3%, physical stressors in 28.9%, and heavy isometric activities in 9.8%.   Presentation was as STEMI in 31.3%, NSTEMI in 68.3%, and unstable angina in 0.4%. There were 13.1% with multivessel SCAD, 30.6% with total occlusion, and 7.6% with proximal vessel dissection. Vessels dissected were LM in 1.5%, LAD or branches of in 52.1%, circumflex or branches of in 37.7%, and the RCA in 23.2%. Most patients (86.4%) were treated conservatively of whom 2% subsequently required PCI. In the overall population, 14.7% underwent revascularisation (14.1% PCI and 0.7% CABG). The median hospital stay was 4 days. At 3-year median follow-up, mortality was 0.8%, recurrent MI 9.9%, and MACE (composite of all-cause mortality, stroke, or TIA) was 14%. The presence of genetic disorders, peripartum SCAD, and extra-coronary FMD were independent predictors of 3-year MACE. Patients who underwent PCI at their index hospitalisation had similar post-discharge MACE compared with no PCI. At 3 years, 80% of patients remained on aspirin and 73.5% on a beta-blocker.

 

Should we stock bivalirudin in our cath labs?

Bivalirudin plus a high-dose infusion versus heparin monotherapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a randomised trial. Lancet 2022; 400:1847-1857

The efficacy of bivalirudin in patients undergoing primary PCI (PPCI) in patients presenting with an ST-elevation myocardial infarction (STEMI) has generated conflicting results in randomised clinical trials. The BRIGHT-4 trial evaluated the safety and efficacy of a high-dose infusion of bivalirudin in 6016 STEMI patients undergoing PPCI with radial access within 48 hours of symptom onset who had not received fibrinolytic therapy, anticoagulants, or glycoprotein IIb/IIIa inhibitors (GPI) at 87 centres in China. Patients were randomised in a 1:1 fashion to receive either unfractionated heparin monotherapy (n=3007) or bivalirudin (n=3009). Bivalirudin was given as a bolus of 0.75mg/kg followed by an infusion of 1.75mg/Kg/hour during the PCI procedure and for 2-4 hours thereafter. The infusion dose was reduced to 1.0mg/Kg/hour in patients with an estimated GFR < 30ml/min and to 0.25mg/Kg in patients on dialysis. The primary endpoint was a composite of all-cause mortality or BARC types 3-5 bleeding at 30 days. Mean age was 60.5 years, 22% were women, mean BMI was 25mg/Kg2, radial access was used in 93%, ticagrelor was the second antiplatelet agent in 66%, average duration of bivalirudin infusion post PCI was 3 hours, and GPI use for bivalirudin versus heparin was 11.5% versus 13.7% (p=0.01). The primary outcome was lower in the bivalirudin group (3.1% vs. 4.4%; HR 0.69; 95% CI: 053-0.91; p=0.007). Secondary outcomes were lower for the bivalirudin group: all-cause mortality 3% vs. 3.6% (p=0.04), BARC 3-5 bleeding 0.2% vs. 0.8% (p=0.0014), and stent thrombosis 0.4% vs. 1.1% (p=0.0015). Let’s consider the results in comparison with HEAT. What were the methodological differences? BRIGHT was in China, HEAT in the UK.  BRIGHT included 6016 patients, and HEAT 1829.  Both used heparin 70 U/kg vs bivalirudin. In BRIGHT the bivalirudin bolus was followed by a 2-4h infusion (the only pharmacological difference), and in HEAT it was only for the duration of the PCI. The rates of IIb/IIIa inhibitor bailout (11-14%) and radial access (80-90%) were similar in both.  In BRIGHT the symptom to ‘wire’ time was 4.5h, and in HEAT just over 2.8h. So, what are the results? The timing of these was similar; 30 days for BRIGHT, and 28 for HEAT. But the primary endpoints were slightly different; in BRIGHT they were all cause death and major bleeding, and in HEAT they were death, CVA, re-infarction and unplanned repeat revascularisation. The rates (for bivalirudin vs heparin) in BRIGHT were 3.1 vs 4.4%, and in HEAT 8.7 vs 5.7%, respectively. The mortality rate in BRIGHT was 3.0% vs 3.9%, and in HEAT 5.1% vs 4.3%, respectively. The rate of major bleeding in BRIGHT was 0.2 vs 0.8%, and in HEAT 3.5 vs 3.1%, respectively. Similarly, small advantages were noted in BRIGHT for the secondary endpoints of MACCE, stent thrombosis and minor bleeding.  What is to be made of this new study? A very large number of patients was required to demonstrate a very small benefit, and in terms of mortality this benefit was almost undetectable. The rate of major bleeding was extremely low in BRIGHT in both groups, and much lower than in both arms of HEAT, with a small absolute benefit in the bivalirudin group.

 

Poor clinical outcomes in CKD patients presenting with NSTEMI

Early invasive strategy and outcomes of non-ST-segment elevation myocardial infarction patients with chronic kidney disease. JACC Intv 2022; 15:1977-1988

Chronic kidney disease (CKD) is associated with significant cardiovascular risk and subsequent poor outcomes. With an ageing population with increasing co-morbidities, the numbers of patients with CKD presenting with acute coronary syndromes are increasing. The investigators sought to evaluate the association between an early invasive strategy and long-term survival in patients with CKD and NSTEMI. This study was a single centre retrospective analysis performed in Israel of consecutive patients presenting with NSTEMI between 2008 and 2021 from the SHEBAHEART Big data registry. Out of 7107 patients presenting with NSTEMI, 50% were treated invasively. This was defined as a referral for coronary angiography regardless of subsequent coronary intervention. Invasively managed patients were split into early (within 24 hours) and delayed groups, and further divided into CKD severity. Inverse probability treatment weighting (IPTW) was performed to address confounding. The mean age of patients was 66 ±11 years and 77% patients were male, with a median follow up of 4 years (IQR: 2-6years). Over half of patients underwent coronary angiography within 24 hours. Prior to IPTW analysis, patients in the early invasive group were younger, with less comorbidities, less renal dysfunction, with higher troponin values and lower rates of left main and three vessel disease. After IPTW, there were no significant differences in baseline characteristics. In the unadjusted original cohort, 14% of patients invasively treated had moderate to severe CKD (eGFR <45ml/min/1.73m2). Patients with CKD were less likely to undergo early coronary angiography, were older, with more co-morbidities and complex coronary artery disease. During follow up lower renal function was associated with poor survival. After adjustment, patients with moderate to severe CKD were 63% more likely to die during follow up as compared with normal or mild CKD. The early mortality benefit seen with an early invasive strategy was affected by eGFR and declined with lower renal function (Pinteraction<0.001). The main finding of this study was that CKD impacted the mortality benefit seen with an early invasive strategy in a gradient fashion, with no difference in mortality seen in those with moderate to severe CKD. The mortality benefit seen in those with an eGFR greater than 45ml/min/1.73m2 was apparent on longer term follow up, as seen the by the late separation of the survival curves. The main limitation of this retrospective observational study is selection bias, which the authors attempted to mitigate with an IPTW analysis. It is unclear both the rates of revascularisation and the completeness of revascularisation between the early and the delayed invasive groups, which may have had an impact on longer term mortality. Finally, the presence of significant CKD is a poor prognostic marker independently, and therefore revascularisation will unlikely have a meaningful impact on mortality.  Selection and timing of angiography in patients with moderate to severe CKD will continue to be on a per patient basis until further studies are performed.

 

Ticagrelor or prasugrel? The debate continues

Ticagrelor or prasugrel in patients with acute coronary syndrome and high bleeding risk. Circ Cardiovasc Intv 2022; 15:e012204

Selection of antithrombotic strategy is patients with a high bleeding risk presenting with acute coronary syndrome (ACS) is challenging and requires careful consideration, as the more potent P2Y12 inhibitors recommended offer greater ischemic protection at the expense of a greater bleeding risk. The ISAR-REACT 5 trial was a large randomised controlled trial that compared head-to-head ticagrelor with prasugrel in patients presenting with ACS (STEMI and NSTEMI) undergoing invasive management, demonstrating superiority of prasugrel over ticagrelor at reducing MACE without increasing bleeding. The investigators sought to evaluate the impact of these more potent P2Y12 inhibitors in patients with a high bleeding risk, defined by having at least one major or two minor criteria from the Academic Research Consortium High bleeding risk (ARC-HBR). These included baseline eGFR, haemoglobin, platelet count, age, and use of long-term steroids or NSAIDs. The primary end point was a composite of death, myocardial infarction, and stroke. The secondary endpoint was BARC type 3-5 bleeding. The outcomes were assessed at 12 months, and analyses were performed according to intention to treat. The results presented were from a post hoc analysis of the original trial population. Patients were classified by their HBR status, with comparisons between groups performed using the Cox proportional hazards model. The treatment allocation by HBR status interaction was assessed. The presented analysis included 3239 out of 3377 patients undergoing PCI accounting for 80.6% of total trial population. 486 patients were classified as having HBR, and 2753 non-HBR. The HBR patients were older, had more co-morbidities including higher cardiovascular risk factors, and a higher proportion were female. They were more likely to have more complex coronary artery disease and lower ejection fraction. There was a higher rate of MACE in the HBR group (20.6% versus 6.3%, HR=3.57 [2.79-4.57]. The individual components were all higher in HBR group except for stroke. There was an almost three-fold increase in BARC type 3-5 bleeding [12.7% versus 4.6%, HR 2.94 [2.17-3.99]. This was consistent across the different clinical presentations. Outcomes were assessed according to treatment allocation with ticagrelor or prasugrel. In the HBR group, the primary and secondary endpoints were similar between patients receiving prasugrel or ticagrelor. The superiority of prasugrel in reducing the primary endpoint was seen in the non-HBR group. There was no significant treatment allocation by HBR status interaction with respect to the endpoints. Whilst these results are of interest, they are only hypothesis generating as this was not a prespecified analysis in the original trial design. The sample size is small, so it does not have sufficient statistical power. Also, in the primary trial patients were excluded if they had significant anaemia (Hb <10g.dL) which impacts these results as it excluded those most likely at highest risk. Patients with high bleeding risk have higher MACE rates and bleeding rates regardless of type of potent P2Y12 inhibition, reflecting a co-morbid population with more complex coronary anatomy. Dedicated randomised trials need to be conducted in patients with high bleeding risk to evaluate this further.

 

Valvular Heart Disease

Risk score for mTEER

Prediction of death or HF hospitalisation in patients with severe FMR: the COAPT risk score. JACC Intv 2022; 15:1893-1905

The COAPT trial has demonstrated that in patients with functional severe mitral regurgitation and heart failure, transcatheter edge-to-edge repair with the MitraClip (Abbott Vascular) plus guideline directed medical therapy (GDMT) reduced the primary endpoint of heart failure hospitalisation and the secondary endpoint of all-cause mortality at 24 months as compared to GDMT alone. Despite such advances such patients remain at high risk of adverse clinical events including mortality. To address this challenge, the authors have sought to develop and validate a predictive risk score using the COAPT trial. A risk score for the 2-year rate of death or heart failure hospitalisation was generated from Cox proportional hazard models. The predictive value of the model was assessed using the area under the curve of receiver-operating characteristic plot. During the derivation process, 26 variables representing clinical and echocardiographic parameters were tested for association with the primary endpoint. Eight parameters were independently associated with mortality  and because the hazard ratios were different point values were assigned as follows: CKD stage III =1 point, CKD stage IV or greater, NYHA class III or Iva +1 point, COPD +1 point, history of atrial fibrillation or flutter +1 point, RVSP >45mmHg +3 points, LVEF 25% to 35% +1 point, LVEF<25% +2 points, LVESD >5.5cm +2 points, and TR grade ≥2 +2 points. Finally, -3 points were assigned for patients who were treated with the MitraClip. The COAPT risk score thus ranges from -3 to +15 points. The score’s discriminative ability was modest in the derivation cohort (C statistics=0.74) while model calibration was excellent (Hosmer-Lemeshow chi-square statistic=2.26; p=0.97). The relative benefit of the MitraClip in reducing the 2-year hazard of death or heart failure hospitalisation was consistent across the range of baseline risk. Salient features include lack of validation analysis and restriction of the current model to patients with heart failure and functional mitral regurgitation.

 

mTEER provides differing benefits depending on MR aetiology

Outcomes after transcatheter edge-to-edge mitral valve repair according to mitral regurgitation aetiology and cardiac remodelling. JACC Cardiovasc Interv 2022; 15:1711-1722

Mitral trans catheter edge-to-edge mitral valve repair (TEER) has emerged as a therapeutic option for many patients with mitral regurgitation that are prohibitive for conventional mitral valve surgery, and several randomised trials in selective populations have demonstrated its clinical efficacy. However, with respect to functional MR, these trials have largely evaluated those with poor LV function and resultant annular dilatation (v-FMR). There is an emerging subset of FMR known as atrial FMR (a-FMR), which is characterised as FMR with no or mild LV remodelling and moderate to severe left atrial dilatation. Little is known about outcomes of TEER in this population. The investigators therefore sought to evaluate the outcomes of TEER in patients with differing types of MR.  This was a retrospective single study performed in the United States between March 2007 and April 2020. All patients underwent comprehensive baseline transthoracic and transoesophageal echocardiographic assessment according to US and European echo guidelines and all cases were reviewed by the heart team. Patients were grouped according to the type of MR, with three groups described in this study (DMR, a-FMR and v-FMR). Patients with mixed aetiology were excluded. The primary outcome was a composite endpoint of all-cause mortality and heart failure hospitalisation at 2 years.  1044 patients were included in this retrospective study, which included 423 patients with DMR and 621 with FMR (116 characterised as a-FMR and 505 as v-FMR).  Mean age was 76.3 years and 41% were female. Patients with a-FMR were more likely to be women, more likely to have severe TR and more often had chronic atrial fibrillation compared with v-FMR and DMR. Both a-FMR and v-FMR had higher incidence of coronary artery disease. Echocardiographic data obtained reflected the described group characteristics, with v-FMR having higher LV volumes and lower ejections fractions as compared with a-FMR and DMR. a-FMR had significantly lower LV dimensions and volumes and larger LA volume index. Despite differences in LV dimensions and function, PA pressures across the three groups did not differ. Procedural outcomes were similar across all three groups, with no difference in the incidence of residual MR of more than moderate immediately post op or on subsequent follow up.  During a median follow up of 540 days, 31% of patients died and 38% reached the primary composite endpoint. Compared with DMR both a-FMR and v-FMR had significantly higher 2 -year event rates and all-cause mortality. Amongst all subgroups, presence of severe TR was associated with significantly higher rates of primary outcome and all-cause mortality, which remained after multivariable adjustment. Salient features include single centre study, retrospective nature of the study, and lack of a core laboratory.

 

Broadening indications for mTEER

Transcatheter edge-to-edge repair for atrial secondary mitral regurgitation. JACC Cardiovasc Interv 2022; 15:1731-1740

This single centre retrospective study from Germany aimed to evaluate the efficacy of TEER in patients with atrial secondary mitral regurgitation (ASMR). These patients have an associated excess mortality despite normal LV ejection fractions and LV dimensions, and at present there is no robust data supporting therapeutics in this group. The study investigators defined ASMR as normal structure of the mitral leaflets in the absence of an organic disorder, a normal LVEF of >50% and absence of LV enlargement and segmental abnormality. The effect of TEER was evaluated in this group, with the primary outcome measure of MR reduction less than or equal to 1+. This was performed via a retrospective analysis of the data from the Bonn registry, which is a prospective consecutive collection of patient data from the Heart Center Bonn. Consecutive patients undergoing TEER from September 2010 to September 2021 were identified and those with previous surgical or transcatheter MR interventions were excluded. Primary versus secondary MR was characterised retrospectively, as was ASMR and ventricular SMR (VSMR). Procedures were performed using standard practices under general anaesthetic and with 3D TOE guidance. Four generations of MitraClip were used across the study period. Echo assessments were performed, and MR severity was determined based on qualitative and quantitative criteria adapted from the Mitral Valve Academic Research Consortium guidelines. A leaflet to annulus index (LAI) was measured (ratio of the sum of anterior and posterior leaflet lengths in relation to the anteroposterior length on the mitral annulus), which has been shown to be an indicator of inadequate leaflet adaption to mitral annulus dilatation. The primary endpoint of the study was a reduction in MR to less than or equal to 1+ on echo pe discharge. Secondary endpoints included in hospital mortality, technical success, and device success. In 415 patients with SMR who underwent TEER, 28.4% met the criteria for ASMR. Patients with ASMR had a larger mitral annulus diameter, shorter mobile posterior leaflet length, smaller coaptation depth, and more severe TR compared with those with VSMR. LAI and PA pressures were similar between groups. Patients with ASMR were more likely to have severe TR. They were older, and more likely to be female. Overall, there was a 94.1% technical success rate. Three patients died of non-cardiovascular causes during hospital admission. Severity of MR in these patients significantly improved compared with baseline and was sustained on follow up. The reduction of MR to ≤ 1+ was achieved in 79.7% of patients with ASMR, which was comparable to those with VSMR. The echocardiographic predictors of optimal MR reduction in a multivariate model were LA volume index and LAI, with a smaller LA volume index and a higher LAI associated with a higher incidence of MR reduction to 1+ or less. Patients with a large LA volume index and low LAI had the least improvement in MR, with only 41% of patients in this group achieving ≤ 1+ MR. In terms of procedural data, the number of implanted clips were less with the use of the newer generation devices, with no implantation failures. Those treated with the newer systems were more likely to achieve greater reductions in MR. This study has provided a signal that TEER can be used safely and effectively in patients with ASMR. Whether or not this translates to improved outcomes is at present unknown in patients with this pathology. This study also provided data suggesting that LA volume index and LAI can be used to select patients that are most likely to benefit in terms of MR reduction with TEER.

 

PASCAL & MitraClip are equally safe and effective for TEER

Randomised comparison of transcatheter edge-to-edge repair for degenerative mitral regurgitation in prohibitive surgical risk patients. JACC Interv 2022; 15:2523-2536

Mitral transcatheter edge-to-edge repair (mTEER) has emerged as an effective treatment modality in patients with severe mitral regurgitation (MR) secondary to degenerative MR (DMR) who are considered at prohibitive surgical risk. The CLASP IID randomised trial compared the safety and efficacy of the PASCAL system and the MitraClip system in 180 patients (PASCAL=117, MitraClip=63) with 3+ or 4+ DMR and hypothesised that the PASCAL system was not inferior to the MitraClip system with respect to safety on the basis of the proportion of patient with major adverse events (MAE) comprising cardiovascular mortality, stroke, MI, new need for renal replacement therapy, severe bleeding, and nonelective mitral valve intervention at 30 days and effectiveness on the basis of the proportion of patients with MR ≤ 2+ at 6 months. The study had aimed to recruit 300 patients but the planned interim analysis of 180 patients demonstrated noninferiority of the PASCAL system for the primary safety and efficacy endpoints. Mean age was 81 years, 67% were male, and frailty was the most common reason for prohibitive risk (84.6% for PASCAL and 90.5% for MitraClip). All patients received devices except for 1 aborted case in the PASCAL group due to inability to grasp the posterior leaflet. The mean number of devices implanted per patient was 1.5 predominantly in the A2-P2 region. The median procedure time was 88 minutes for the PASCAL group and 79 minutes for the MitraClip group (p=0.023). The primary safety endpoint was met, with noninferiority of the PASCAL system compared to the MitraClip system. The absolute difference in the 30-day composite MAE rate was -1.3%. The 1-sided 95% upper confidence bound was 5.1%, which was within the prespecified noninferiority margin of 15%. The MAE rate was 3.4% for the PASCAL group comprising 1 CV death, 3 patients with severe bleeding, 1 nonelective mitral valve intervention. In the MitraClip group, the MAE rate was 4.8% comprising 1 CV death, and 2 patients with severe bleeding. The proportion of patients with MR ≤ 2+ at 6 months was 96.5% for the PASCAL group and 96.8% for the MitraClip group, with an absolute difference of -0.3%.

 

mTEER a useful tool in cardiogenic shock

Transcatheter edge-to-edge mitral valve repair in patients with severe mitral regurgitation and cardiogenic shock. JACC 2022 80, 2071-2084

Mitral transcatheter edge-to-edge repair (mTEER) is an effective treatment modality in high-risk patients with severe symptomatic MR across various MR aetiologies and across a wide range of high-risk patients including those with CKD, severe left ventricular systolic dysfunction, and pulmonary hypertension. Data regarding the outcome of patients with cardiogenic shock (CS) and concomitant severe MR is limited and restricted to small series. To address this knowledge gap data from the STS/ACC TVT Registry has been used to investigate the characteristics and outcomes of patients with severe MR and CS who have undergone mTEER is the US. A total of 3,797 patients undergoing mTEER met at least one of the prespecified inclusion criteria of CS based on the presence of coding for: CS, inotrope use, or mechanical circulatory support before the procedure. Mean age was 73±11.9 years, 59.5% were male, 82.7% were of white race, mean STS score for MV repair was 14.9%±15.3%, MR aetiology was degenerative in 53.4% and functional in 27.5%. Device success was achieved in 85.6% given successful achievement of final MR grade ≤2+ (88.2%) and MR reduction ≥1 (91.4%). Assessing those who died in hospital versus those who were discharged alive indicated that those who died had higher STS scores, dialysis rates, LVEF and lower LV dimensions. At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs. 55.5%; adjusted HR: 0.49; 95% CI: 0.41-0.59; p<0.001) and a composite of mortality or heart failure admission (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42-0.62; p<0.001).

 

The enduring benefits of TAVI in intermediate risk patients

Self-expanding transcatheter vs. surgical aortic valve replacement in intermediate-risk patients. 5-year outcomes of the SURTAVI randomised clinical trial. JAMA Cardiol 2022; 7:1000-1008

Transcatheter aortic valve replacement (TAVI) indications are expanding into lower risk and younger patients; however, less is known about long term outcomes, alongside the durability of the valves in these patients as compared with conventional surgical aortic valve replacement (SAVR). Five-year data on balloon expandable TAVI demonstrate similar rates of mortality and disabling stroke, but higher readmissions with heart failure and valve related hospitalisations, and redo valve interventions in the TAVI group. The SURTAVI trial was an international multi-centre study that enrolled patients with severe symptomatic aortic stenosis who had an intermediate operative risk, as defined by a Society of Thoracic Surgery Predicted Risk of Mortality (STS-PROM) of between 3 to 15% at 30 days and randomised them on a 1:1 basis to receive either a self-expanding TAVI or surgical aortic valve replacement. Staged or concomitant PCI or CABG was performed where indicated by the Heart team. The 2-year outcome data of this trial reported clinical noninferiority of the self-expanding TAVI. This study reported on the five-year outcome data from a primary analysis of the modified intention to treat cohort. The primary outcome was a composite of death or disabling stroke. A total of 1660 patients underwent either TAVI (n=864) or surgical AVR (n=796). Most patients in the TAVI group received the first generation bioprosthesis (CoreValve, 84%), had an iliofemoral approach (93.6%) and had their TAVI implanted under general anaesthetic (75%). There was incomplete data in approximately 19% including incomplete echo data at 5 years. At five years, there was no difference in the primary endpoint between TAVI and SAVR groups (31.3% versus 30.8%; HR 1.02; 95% CI 0.85-1.22). The TAVI group had higher rates of pacemaker implantation and a greater proportion of more than mild paravalvular leaks (p=0.05). At five years, more patients in the TAVI group required a valve reintervention which was driven by more re-interventions in the first 2 years. TAVI provided better haemodynamic parameters as compared with SAVR, with larger effective orifice area and lower mean gradients post implant. There were no differences in quality of life as assessed by KCCQ and NYHA functional class. The higher early re intervention rate was likely driven by the higher rates of residual PVL seen with the first-generation device. The latest generation Evolut Pro has an external pericardial wrap which helps in reducing paravalvular leak, whilst its low delivery profile and ability to recapture and reposition aid optimal implantation. Overall, this study adds to the large data available in support of TAVI in intermediate risk groups. The durability of the valves appears like SAVR between 2 and 5 years (excluding the initial re do interventions in the first 2 years). However, there is a cost with respect to higher rates of pacemaker implant following TAVI. All these need to be considered during Heart team discussions and when counselling your patients who are at intermediate risk. Alongside the high rate of missing data, there was a higher proportion of patients lost to follow up or withdrew from the study in the surgical arm, which may have impacted results.

 

Miscellaneous

Restrict oxygen use in cardiac arrest patients

Oxygen targets in comatose survivors of cardiac arrest. NEJM 2022; 387:1467-1476

Amongst survivors of out-of-hospital cardiac arrest (OOHCA), hypoxic-ischaemic brain injury remains the most common cause of death as well as resulting in significant morbidity. The optimal oxygenation target in such patients receiving mechanical ventilation has not been adequately addressed. The BOX trial was an open-label, randomised trial with a 2-by-2 factorial design in which comatose patients with an OOHCA were randomised to a restrictive or a liberal oxygen target and one two target blood pressures. The oxygenation strategy of the trial is summarised here. A total of 789 patients who had been admitted to two tertiary cardiac centres in Denmark were randomised to receive either a restrictive oxygen target of a partial pressure of arterial oxygen of 9-10 KPa or a liberal oxygen target of 13-14 KPa. All patients underwent temperature control at 36°C with sedation and mechanical ventilation for at least 24 hours. The primary endpoint was a composite of death from any cause or discharge from the hospital with severe disability or coma, whichever occurred first within 90 days after randomisation. Severe disability or coma was defined as a Cerebral Performance Category (CPC) 3 or 4. Mean age was 62 years, 80% were male, 22% had a history of MI, and 85% had a shockable rhythm at presentation. At 90 days, the primary endpoint had occurred in 32% of the restrictive-target group and 33.9% of the liberal-target group (HR: 0.95; 95% CI: 0.75-1.21; p=0.69). The results were consistent across prespecified subgroups and there was no interaction with the blood pressure intervention. Within 90 days, death had occurred in 28.7% of the restrictive-target group and 31.1% of the liberal-target group. Prespecified adverse events such as infection, bleeding, and arrhythmia were similar in both groups.

 

Expanding pharmacology for lipid lowering therapy

Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. NEJM 2022; 387:1855-1865

Although lipoprotein(a) has been identified as a causal factor for atherosclerosis and calcific aortic stenosis, there is currently very little treatment for patients with an elevated concentration of this lipoprotein. Olpasiran is a small interfering RNA (siRNA) molecule which disrupts the expression of LPA, the gene controlling the expression of lipoprotein (a). The phase 2 OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Dose Finding Study) evaluated the safety and efficacy of olpasiran at different doses in 281 patients who had a serum lipoprotein(a) concentration >150 nmol/L and a history of atherosclerotic cardiovascular disease including established coronary artery disease, peripheral artery disease, or cerebrovascular disease. Key exclusion criteria chronic kidney disease (GFR<30 ml/min/1.73m2) a history or clinical evidence of active liver disease. Eligible patients were randomly assigned in a 1:1:1: 1:1 ratio to one of four doses of olpasiran (10mg every 12 weeks, 75mg every 12 weeks, 225mg every 12 weeks, or 225mg every 24 weeks) or placebo administered subcutaneously. The treatment period was for 48 weeks after which patients were followed for an extended safety follow-up without further treatment with olpasiran or placebo for a minimum of 24 weeks. The primary endpoint was the percent change in lipoprotein(a) concentration from baseline to week 36. Mean age was 61.9±9.5 years, 32% were women, 88% were taking a statin, 52% were on ezetimibe, 23% were on PCSK inhibitor, median baseline lipoprotein(a) concentration was 260.3 nmol/L, and median LDL cholesterol concentration was 67.5mg/dL. At 36 weeks, the lipoprotein(a) concentration increased by a mean of 3.6% in the placebo group whilst olpasiran significantly reduced lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent change of -70.5% with the 10mg dose, -97.4% with the 75mg dose, -101.1% with the 225mg dose given every 12 weeks, and -100.5% with the 225mg dose given every 24 weeks (p<0.001 for all comparisons). The incidence of adverse events leading to olpasiran discontinuation was 2% in each group. The most common olpasiran-related side effect was injection site pain. Injection site reactions led to olpasiran discontinuation in three patients. Salient features include relative short duration of treatment and follow-up of patients and the need to determine whether this drug will achieve hard clinical endpoints in future randomised trials.

 

Novel defibrillation strategy for refractory VF

Defibrillation strategies for refractory ventricular fibrillation. NEJM 2022; 387:1947-1956

Despite advances in advanced life support protocols, the treatment of patients presenting with refractory ventricular fibrillation (VF) remains challenging. Modified strategies for performing defibrillation in such patients have included double sequential external defibrillation (DSED), in which rapid sequential shocks are given with two defibrillators and vector change (VC) defibrillation, in which pad placement is moved from anterior-lateral to anterior-posterior positions. The DOSE VF study evaluated DSED and VC defibrillation as compared with standard defibrillation in a cohort of 405 patients including 152 from an internal pilot trial in the prehospital setting in adult patients with refractory VF of presumed cardiac cause. Patients who remained in VF after three defibrillation attempts were assigned to one of three groups: standard defibrillation (n=136), VC defibrillation (n=144), and DSED (n=125). The primary outcome was survival to hospital discharge. Secondary outcomes included termination of VF, return of spontaneous circulation, and a good neurological outcome at hospital discharge (defined as a modified Rankin scale ≤2. The mean age was 63.6 years, 84.4% were men, 67.9% of out-of-hospital cardiac arrests were witnessed by bystanders and 58% of the patients received bystander CPR. A total of 30.4% in the DSED group survived to hospital discharge as compared with 13.3% in the standard group (RR, 2.21; 95% CI: 1.33-3.67) and 21.7% in the VC group (RR vs. standard, 1.71; 95% CI: 1.01-2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (RR, 2.21; 95% CI: 1.26-3.88 and 1.48; 95% CI: 0.81-2.71 respectively). Salient features include lack of data regarding post resuscitation care include targeted temperature management and PCI, sample size whereby a priori analysis estimated a sample size of 930 patients and overlap of the confidence intervals for the relative risk estimates for DSED and VC defibrillation.

 

Surgical myectomy confers a survival advantage in HCM patients

Survival after septal reduction in patients >65 years old with obstructive hypertrophic cardiomyopathy. JACC 2023; 81:105-115

In patients with symptomatic obstructive HCM, invasive septal reduction therapy, such as alcohol septal ablation (ASA) and surgical myectomy (SM), may provide improvements in survival, symptoms, and quality of life. An analysis from a U.S inpatient sample has indicated surgical mortality rates ranging from 3.8% in high-volume centres to 15.6% in lower volume centres and ASA related mortality ranging from 0.6% to 2.3%. The current study examined long-term outcomes of SRT in 5,679 patients (SM=3,680 and ASA=1,999) Medicare beneficiaries aged > 65 years from 2013 through 2019. The primary outcome was all-cause mortality. Secondary outcomes included in-hospital and 30-day mortality, length of hospital stay, in-hospital stroke and acute kidney injury requiring dialysis, new second or third degree heart block, and need for redo SRT at follow-up. Patients who underwent SM were younger (72.9±5.7 vs. 74.8±7.1; p<0.001), less likely to be female (67.2% vs. 71.1%; p=0.002), and had a lower burden of comorbidities including hypertension, diabetes, anaemia, heart failure, pulmonary hypertension, lung, kidney, liver, and neurological disease and lower frailty score (median 1.9 vs. 2.6; p<0.001). SM was associated with longer length of hospital stay, and higher in-hospital mortality (4.5% vs. 1.5%; p<0.001), stroke (3.0% vs. <0.6%; p<0.001), acute kidney injury with new dialysis (2.2% vs. <0.6%; p<0.001), and 30-day mortality (5.1% vs. 2.0%; p<0.001). After a median follow-up of 4 years, there was no difference in long-term mortality between SM and ASA (HR: 0.87; 95% CI: 0.74-1.03; p=0.1). On landmark analysis at 2 years, there was no difference in mortality between SM and ASA in the first 2 years (HR: 1.11; 95% CI: 0.88-1.40; p=0.4), but SM was associated with lower mortality after 2 years of follow-up (HR: 0.72; 95% CI: 0.60-0.87; p<0.001). If landmark analysis was undertaken at 3 months, SM was associated with higher risk of mortality in the first 3 months, then lower risk of mortality in follow-up beyond 3 months. SM resulted in 35% heart failure readmissions rate reduction (RR: 0.65; 95% CI: 0.57-0.73; p<0.001) and ASA in 45% rate reduction (RR: 0.55; 95% CI: 0.49-0.62; p<0.001) with no difference between the two groups (p for interaction=0.40). High volume centres (>3 SM/year) were associated with better short and long-term survival compared to low-volume centres.

 

PPM implantation does not alter long-term outcome post-ASA

Outcomes of patients with hypertrophic obstructive cardiomyopathy and pacemaker implanted after alcohol septal ablation. JACC Intv 2022; 15:1910-1917

High degree AV block with subsequent permanent pacemaker (PPM) implantation is a well-recognised complication of alcohol septal ablation (ASA), which is a therapeutic strategy for reducing outflow track gradient in patients with hypertrophic obstructive cardiomyopathy (HOCM). Whilst complication rates and predictors of PPM implant have been previously described, less is known about the longer-term outcomes of these patients. This was a retrospective analysis of patients who were enrolled prospectively into a European multicentre registry of patients with HOCM undergoing ASA. The indication for ASA was intractable clinical symptoms despite pharmacotherapy. All patients underwent temporary pacing, and patients were admitted to CCU for 48 hours post procedure. A PPM was implanted if high grade AV block persisted for greater than 24 hours or occurred late after procedure. The investigators identified those patients having undergone a PPM implant and used a propensity score to match each patient with a comparable patient that did not have a PPM implanted. Both short- and long-term outcomes were compared, and logistic regression used to identify predictors of PPM implant. A total of 1,977 patients underwent ASA between 1996 and 2001. 8.2% of patients were excluded from the final cohort, including patients with previous myectomy, patients already with an implanted PPM or ICD at time of ASA, or patients having undergone ICD implant for primary prevention in first 30 days following ASA, leaving a cohort of 1,814. 9.4% of patients underwent a PPM implant post ASA, with the majority undergoing implant within the first week following ASA. In the unmatched cohort, patients in the PPM group were older, had higher rates of bundle branch block pre procedure, had a high NYHA functional class, received a higher alcohol dose, had a higher LVOT gradient pre procedure and a lower gradient at last follow up. They also had a lower basal septum thickness at last clinical review and lower LVEF. In multivariable analysis, the predictors of PPM implant included older age at baseline, lower NYHA class, lower LVEF, lower basal septum thickness, high alcohol dose, and a bundle branch block before ASA. Patients £60 years of age were less likely to undergo PPM following ASA (p<0.01). In the matched cohort, there were 139 matched pairs. Patients requiring PPM more often had bundle branch block pre procedure, were treated with higher alcohol dose, had a more pronounced reduction in outflow tract gradient and a lower LVEF. In both the unmatched and matched cohort survival was similar. A total of 24 patients underwent reintervention, and those in the PPM group were less likely to undergo intervention. This multicentre observational study has shown that overall, 9% of patients that undergo ASA require PPM post procedure, but despite this complication there was no observed significant impact on outcomes.  Interestingly, those with PPM were more likely to have a greater reduction in LVOT gradient post procedure. Whether this is related to a larger alcohol dose leading to great septal infarction or related to the pacing itself is unknown. Unfortunately, there was no functional pacing data reported, and therefore it is unknown how many were dependant on pacing. Finally, follow up was up to an average of 5 years, therefore we are unable to factor in the potential late complications of PPM implant.

 

Simple in performance but complex in interpretation

Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022; 400:1405-1416

The SYMPLICITY HTN-3 study was a seminal RCT of (single-electrode radiofrequency) renal artery denervation (RAD) in patients with hypertension. At six months, the trial reported safety, but did not meet its primary efficacy endpoint. In this paper, the authors report the results after 36 months of follow up. The original study was a sham-controlled, single-blind, RCT performed across 88 US centres. Included patients had to be on the maximal tolerated dose of ≥3 anti-hypertensive drugs (including a diuretic) with an office systolic BP ≥160 mmHg and 24 hr ABPM systolic ≥135 mmHg. Patients were randomised 2:1 to denervation or a sham control. Between 2011 and 2013, 535 patients were assigned to RAD (n=364) or sham control (n=171). Importantly, the study was unblinded at the six months point. At this point, 101 of the original sham control group crossed over to have RAD. At 36 months, data were only available for 219 patients in the original RAD group, 63 patients who crossed over from the control group to have RAD, and 33 patients in the original sham group that did not cross over. The 36-month analysis, however, includes higher numbers of sham control cases, because the authors included the last measurement ‘carried forward imputed for patients in the crossover group from when they were masked to intervention’. The 36-month data revealed that the average office systolic BP had fallen by -26 mmHg (SD 25·9) in the RAD group, compared with a drop of -5·7 mmHg (24·4) in the sham control group. For ABPM systolic measurements, there was a -15·6 mmHg (SD 20·8) drop with RAD and -0·3 mmHg (15·1) in the control group. Moreover, the RAD group spent twice as long in estimated therapeutic BP range than the controls (18% vs 9%). Although the relative change is impressive, presumably this still means that they were not in range 81% of the time. Medication burden and rates of adverse events were similar between groups. No late safety issues arose. It was anticipated that this trial would provide definitive evidence in support of RAD for treating hypertension. In this paper, the headline results and BP reductions do appear impressive, more so than more contemporary studies. However, at 36 months this study had experienced a high attrition in case numbers and many of the strengths of the original blinded, sham-controlled study design had been either eroded or lost. Patients were unblinded at six months, 101 patients crossed over and then imputed carried forward data from crossed over cases were included in the stats. If the latter were not included, the statistically significant reductions in BP were not present (data that can be found in the supplementary material). Although the number of prescribed medications was similar between the groups, adherence was not assessed and understanding this is very important in the context of resistant hypertension, especially once unblinded. Thus, whilst these data are interesting and do add to the evidence base, it will require additional, rigorous, sham-controlled, RCTs before RAD becomes a routine, guideline-indicated treatment for resistant hypertension.