BCIS R&D Group Literature Update

October 2021

Prepared by Michael Mahmoudi, Paul Morris & Natalia Briceno
Edited by Michael Mahmoudi

Stable CAD & ACS

 

TOMAHAWK rejects early angiography in OOHCA patients without ST-elevation

Angiography after out-of-hospital cardiac arrest without ST-segment elevation

NEJM 2021 Online

The value of immediate coronary angiography and revascularization in survivors of out-of-hospital cardiac arrest (OOHCA) without ST-segment elevation remains uncertain. The TOMAHAWK investigators tested the hypothesis that routine immediate coronary angiography (and/or revascularization if appropriate) is superior to a deferred approach in 554 patients with successfully resuscitated OOHCA of possible coronary origin without ST-segment elevation. Patients with both shockable and non-shockable rhythms were included. The primary endpoint was death from any cause at 30 days. Secondary endpoints included a composite of death from any cause or severe neurologic deficit at 30 days. Patients in the immediate-angiography group were transferred to the lab as soon as possible after admission. Those in the delayed group were first transferred to the ICU for further evaluation of the cause of cardiac arrest and for treatment. If the likelihood of an acute coronary trigger for the cardiac arrest was deemed to be high the patient could proceed to angiography after a minimum delay of 24 hours after cardiac arrest. The median age in the overall population was 70 years, 37.6% of the patients had known CAD, 55.5% of patients had a shockable arrest rhythm, and median Glasgow Coma Scale was 3. The median time from cardiac arrest to return of spontaneous circulation was 15 minutes. At 30 days, death from any cause occurred in 54% of the immediate-angiography group and 46% of the delayed group (HR: 1.28; 95% CI: 1-1.63; p=0.06). The composite of death or severe neurologic deficit occurred more frequently in the immediate-angiography group (64.3% vs. 55.6%; RR:1.16; 95% CI:1-1.34). Values for peak troponin release and for the incidence of moderate or severe bleeding, stroke, and renal-replacement therapy were similar in both groups. TOMAHAWK supports the results of the COACT trial which enrolled only patients with a shockable arrest rhythm. Proposed reasons for a lack of benefit for immediate angiography in such patients include a relatively low percentage for the presence of a culprit lesion (40% in the overall TOMAHAWK trial), and neurological injury having the most impactful effect on overall prognosis and thereby attenuating a possible beneficial effect of coronary revascularization.

 

MASTER DAPT favours shorter duration of DAPT

Dual antiplatelet therapy after PCI in patients at high bleeding risk

NEJM 2021 Online

The ultimate duration of dual antiplatelet therapy (DAPT) in patients at high bleeding risk who receive a drug-eluting stent remains uncertain. The MASTER DAPT investigators evaluated 1 month of DAPT compared to a longer course of DAPT with respect to clinical outcomes in 4,434 such patients who had undergone implantation of a biodegradable-polymer sirolimus-eluting stent (Ultimaster, Terumo). The trial was designed to test hierarchically whether the abbreviated dual antiplatelet regimen, as compared with the standard dual antiplatelet regimen, would be noninferior with regard to net adverse clinical events, noninferior with regard to major adverse cardiac or cerebral events, and superior with regard to major or clinically relevant bleeding. The trial protocol prespecified three ranked primary outcomes: net adverse clinical events (a composite of death from any cause, MI, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, MI, or stroke), and major or clinically relevant nonmajor bleeding, occurring between randomization and 335 days. Major bleeding was defined as a bleeding event of BARC type 3 or 5, and major or clinically relevant nonmajor bleeding was defined as a bleeding event of BARC type 2, 3, or 5. Secondary outcomes included the individual components of the three primary outcomes; a composite of death from cardiovascular causes, MI, or stroke; death from any cardiovascular or non-cardiovascular causes; definite or probable stent thrombosis; and all bleeding events. Patients were considered candidates for the trial if they had an acute or chronic coronary syndrome, had successful PCI, and no further revascularization was planned. Criteria for high bleeding were age ≥75 years, systemic conditions associated with increased bleeding or any known coagulation disorder, indication for treatment with an oral anticoagulant for at least 12 months, recent (<12 months) nonaccess site bleeding that required medical attention, previous bleeding episode that required hospitalization if the underlying cause had not been definitively treated, anaemia defined as haemoglobin <11 g/dL or transfusion during the 4 weeks before inclusion, need for chronic treatment with steroids or nonsteroidal anti-inflammatory drugs, diagnosed malignancy considered at high bleeding risk, stroke or transient ischaemic attack in the previous 6 months, and PRECISE-DAPT score ≥25. One month after they had undergone PCI, patients were randomized to either an abbreviated therapy group (n=2,295) or standard therapy group (n=2,284). In patients without an indication for oral anticoagulation participants in the abbreviated group immediately stopped DAPT and continued single antiplatelet therapy. In the standard therapy group, participants continued DAPT for 5 months, then remained on single antiplatelet therapy. In patients with an indication for oral anticoagulation, participants in the abbreviated group immediately stopped DAPT and continued single antiplatelet therapy. In the standard therapy group, participants continued DAPT for 2 months and then remained on single antiplatelet therapy. At follow-up net adverse clinical events were 7.5% in the abbreviated group and 7.7% in the standard group (Difference -0.23 percentage points; 95% CI: -1.80-1.33; p<0.001 for noninferiority). Major adverse cardiac or cerebral events were 6.1% in the abbreviated group and 5.9% in the standard group (Difference 0.11 percentage points; 95% CI: -1.29-1.51; p=0.001 for noninferiority). Major or clinically relevant non-major bleeding were 6.5% in the abbreviated group and 9.4% in the standard group (Difference -2.82 percentage points; 95% CI: -4.40- -1.24; p<0.001 for superiority). Salient features of the trial population included 40% of patients had stable angina, 11% had silent ischemia, 26% had NSTEMI, 12% has STEMI, median duration of DAPT in the abbreviated group was 34 days and 193 days in the standard group.

 

SCAPIS describes prevalence of coronary atherosclerosis

Prevalence of subclinical coronary artery atherosclerosis in the general population

Circulation 2021; 44:916-29

Despite advances in detection and treatment myocardial infarction remains a common cause of morbidity and mortality in many developed and developing countries. Detailed knowledge of the prevalence and characteristics of atherosclerotic coronary artery disease (CAD) in the general population will be essential in the design and implementation of any future screening strategies. The Swedish Cardiopulmonary Bioimage study (SCAPIS) is a general population-based prospective study conducted between 2013 to 2018 in 25,182 men and women aged 50-64 years without a history of previous cardiac disease with the aim of determining the prevalence and burden of CCTA detected CAD and its association with coronary artery calcium score (CACS). CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1-49% stenosis, or ≥50% stenosis. Noncontrast images were scored for CACS. Mean age was 57.44.3 years, 12.5% were smokers, total cholesterol 5.51.0, glucose 5.71.0 (mmol/L), previous stroke 1.4%, PAD 0.4%, systolic BP 12617 and diastolic BP 7810mmHg. Any CCTA-detected atherosclerosis was present in 42.1% (95% CI: 41.3-42.7%) and stenosis ≥50% in 5.2% (95% CI: 4.9-5.5%). Severe CAD were less common with stenosis ≥50% in the left main, proximal LAD, or 3-vessel disease present in 1.9% (95% CI: 1.7-2%) of the population. The prevalence of CAD was 1.9x greater in men than women and increased with age in both sexes being1.8x greater in the 60–64-year-olds versus 50-54 year olds. Modelling showed that the delay in disease onset in women compared with men was approximately 10 years for both 1-49% stenosis and ≥50% stenosis. The prevalence of atherosclerosis was 2.1 and 2.9x more common in participants at high versus low risk according to SCORE and PCE. Among participants with CACS>400, all had atherosclerosis and 45.7% had significant stenosis. In those with CACS=0, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with CACS=0 and intermediate 10-year risk, 9.2% had CCTA confirmed atherosclerosis. In the total participants, 57.9% had no atherosclerosis, 42.1% had atherosclerosis, stenosis ≥50% was present in 5.2%, one vessel disease in 4.3%, two vessel disease in 0.8%, three vessel disease in 0.2%, left main disease in 0.1%, and proximal LAD disease in 1.9%. Coronary calcification was present 40.2% of the participants with 11.5% having CACS 1-10, 17.1% having CACS 11-100, 8.1% having CACS 101-400, and 3.5% having CACS >400. SCAPIS concluded in a large, random sample of the Swedish population without established CAD, coronary atherosclerosis is common, CACS conveys a significant risk of significant CAD and CACS of (0) does not exclude the presence of coronary atherosclerosis.

 

To cool or not to cool in OOHCA patients

Hypothermia versus normothermia after out-of-hospital cardiac arrest

NEJM 2021; 384:2283-94

The overall evidence supporting targeted temperature management to prevent hypoxic-ischaemic brin injury in the setting of out-of-hospital cardiac arrest (OOHCA) is of low certainty. The Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial assessed the beneficial and harmful effects of hypothermia as compared with normothermia and early treatment of fever in 1,900 adults with coma who had had an OOHCA of presumed cardiac or unknown cause irrespective of the initial rhythm. All the patients were unconscious and not able to obey verbal commands and did not have a verbal response to pain. Eligible patients had more than 20 minutes of spontaneous circulation after resuscitation. The intervention period of 40 hours began at the time of randomization. Patients in the hypothermia arm were immediately cooled to a target temperature of 33C for 28 hours followed by rewarming to 37C in hourly increments of one third of a degree. In the normothermia group, the aim was to maintain a temperature of 37.5C or less. If body temperature reached ≥37.8C despite conservative or pharmacological measures, cooling with a surface or intravascular device was initiated to maintain a temperature of 37.5C. Sedation was mandated in both groups until the end of the intervention period. After the intervention period, a normothermic target of 36.5C to 37.7C was maintained until 72 hours after randomization in patients who remained sedated or comatose. The primary outcome was death from any cause at 6 months. Secondary endpoints included functional outcome at 6 months (modified Rankin scale). Prespecified adverse events included pneumonia, sepsis, bleeding, arrhythmia resulting in haemodynamic compromise, and skin complications related to the temperature management device. The groups were similar with respect to the length of sedation (40 hours), degree of sedation, and sedative agents used. There were minor differences in the medications used with the hypothermia group more likely to have received a neuromuscular blocker (66% vs 45%), and the normothermia group more likely to have received paracetamol (6000mg vs. 4875mg). At 6 months the primary outcome was similar in the hypothermia and normothermia group (50% vs. 48%; RR with hypothermia 1.04; 95% CI: 0.94-1.14; p=0.37). Functional outcome was also similar in the two groups (55% vs. 55%; RR with hypothermia 1; 95% CI: 0.92-1.09). Arrhythmia resulting in haemodynamic compromise was more common in the hypothermia group (24% vs. 17%; p<0.001). The incidence of other adverse events was similar in both groups.

 

BRS making a comeback

Thinner strut sirolimus-eluting BRS versus EES in patients with coronary artery disease: FUTURE-II trial.

JACC Cardiovasc Interv 2021; 14:1450-62

The Absorb BVS first generation bioresorbable scaffold (BRS) has been associated with increased risk of device thrombosis and adverse clinical events. Potential explanation for these findings included increased strut thickness (>150 µm), delayed reendothelialization, and unfavourable dismantling during the resorption process. The Firesorb BRS (MicroPort, Shanghai, China) is a thinner strut (100/125 µm) poly-L-lactic based sirolimus-eluting BRS designed to decrease luminal protrusion and enhance local haemodynamic profile. The FUTURE-II trial investigators examined the angiographic efficacy, neointimal response and vessel healing, as well as clinical outcomes of the Firesorb BRS versus the cobalt-chromium everolimus-eluting stent (EES) in 433 patients. The primary endpoint was 1-year angiographic in-segment late loss (LL) powered for noninferiority. Key secondary endpoint was 1-year proportion of covered struts assessed by OCT, powered for noninferiority and subsequent superiority testing. Key features of the device include abluminal coating with sirolimus (4µg/mm), strut thickness of 100µm for scaffolds 2.5 and 2.75mm in diameter and 125µm for scaffolds 3.0-4.0mm in diameter, and resorption within 3 years. Patient level 1-year in-segment LL was 0.170.27mm in the BRS group and 0.180.37mm in the EES group (difference -0.01mm; 95% CI: -0.07-0.06; p for noninferiority<0.0001) in the intention to treat population and 0.170.27mm in the BRS group and 0.190.37mm in the EES group (difference -0.005mm; 95% CI: -0.07-0.06; p for noninferiority<0.0001) in the per-protocol population. The proportion of covered struts was 99.3% in the BRS group and 98.8% in the EES group (difference 0.8%; 95% CI: -0.5-2.1; p for noninferiority<0.0001 and p for superiority=0.21). Target lesion failure, ischaemia driven target lesion revascularization, and periprocedural MI were similar in both groups. There were no definite or probable device thrombosis with 1-year follow-up. Salient features of the trial include lack of power for clinical endpoints, lack of complex anatomy, and a relatively short follow-up.

 

How should we manage type 2 MI?

Performance of the GRACE 2.0 score in patients with type 1 and type 2 myocardial infarction.

EHJ 2021; 42:2552-61

As use of high-sensitivity troponin assays increases, we diagnose more and more type 1 and type 2 MI. The natural history, prognosis and management of type 2 MI is less well established than for type 1. Patients with type 2 MI tend to be older with more comorbidities. There are no validated tools to predict mortality or cardiovascular events in this group. The current study evaluated the GRACE 2.0 score in patients with both type 1 and type 2 MI. Patients with suspected ACS who had a high-sensitivity troponin assay were studied in Scottish and Swedish hospitals. Diagnosis of type 1 and 2 MI was consistent with the fourth Universal definition of MI and the primary outcome was all-cause death at one year. The secondary outcome was all-cause death or MI at one year. Over 70,000 consecutive patients were studied. 21% of the Scottish patients had elevated troponins, of which 55% (n=4,981) were deemed to be type1 and 12% (n= 1,121) type 2. The rest had either chronic troponin elevation or type 4 MI. 17% of the Swedish cohort had elevated troponin, of which 28% (n=1,080) were diagnosed with type 1 MI and 6% (n=247) with type 2 MI. As expected, the patients with type 2 MI were older (74 vs. 68 years), more likely to be female (50% vs. 44%) and were around 20 times less likely to undergo revascularisation. The Scottish and Swedish cohorts were analysed separately throughout the manuscript. When predicting death at one year, the GRACE 2.0 score performed reasonably well in the type 2 MI (AUC 0.73 and 0.73) but not as good in the type 1 MI group (AUC 0.83 and 0.85). When predicting death or MI at one year, again the performance of GRACE 2 was slightly better in the type 1 MI group compared with the type 2 MI group (AUC 0.70 and 0.72 vs 0.76 and 0.81). Thus, the GRACE 2.0 score has slightly better accuracy when predicting death than death or MI at 12 months and performed better in type 1 than type 2 MI. The authors deemed the discriminative power of the GRACE 2.0 score to be ‘good’ in type 1 MI and ‘moderate’ in type 2 MI. Important unanswered questions include (a) what should we do with these data? (b) how can we optimise the management of type 2 MI? (c) should we manage higher risk type 2 MI patients differently to lower risk patients, and if so, how?

 

ACHD patients at increased risk of MI & MACE

Long-term outcomes after myocardial infarction in middle-aged and older patients with congenital heart disease-a nationwide study.

EHJ 2021; 42:2577-86

With improvements in the medical and surgical treatment of patients with congenital heart disease, we see more patients reaching adulthood and into middle and older age. It is, therefore, not uncommon to see patients in the catheter laboratory with adult congenital heart disease (ACHD) for investigation and treatment of coronary disease. This study sought to determine whether middle-aged and older patients with ACHD were at increased risk of MI and of MACE (defined as recurrent MI, new-onset heart failure, or CVD mortality) following MI. 17,189 Swedish ACHD patients with 18,0131 age and gender-matched controls were followed up from the age of 40 for a mean of 23 (±11) years. Patients with ACHD had a 1.6-fold higher rate of MI than controls. The increased risk was observed across the full spectrum of congenital problems but was highest in those with the higher complexity lesions like cono-truncal abnormalities. The elevated risk was independent of other risk factors like hypertension, dyslipidaemia and diabetes. 1,272 ACHD patients and 8,572 control patients survived an index MI. Patients with ACHD had a 1.4-fold higher risk of MACE compared with controls which was driven mainly by an increased risk of new-onset heart failure. The increased risk was independent of other risk factors and was stronger in those with cono-truncal and abnormalities and coarctation. Patients with ACHD appear to be at increased risk of MI, and of MACE post-MI, but with only a slightly increased long-term mortality. The strength of this association appears to be related to lesion complexity, but the association is maintained across all types of congenital pathologies. It is interesting that the relative risk was highest in the younger patients and that survival of the initial MI was similar between ACHD and control groups. It is rare to see such a large study of ACHD patients with such long follow up. In fact, the follow up period was so long that many cases pre-dated troponin assays and, in many cases, even PCI. The elevated risk appears to be independent of traditional risk factors. The authors propose some reasons for this including surgical manipulation of the arteries and other coronary anomalies. These data appear to support enhanced screening and more aggressive management of modifiable risk factors in patients with ACHD.

 

Antiplatelet Therapy

 

Time to change from aspirin to clopidogrel monotherapy?

Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial.

Lancet 2021; 397:2487-96

Following a period of dual antiplatelet therapy (DAPT) after PCI, anti-platelet monotherapy is continued lifelong for prevention of secondary cardiovascular events. Aspirin is the most widely used antiplatelet agent, and its use as maintenance therapy is based on outdated trial data that demonstrated a benefit of aspirin in secondary prevention. HOST-EXAM trial compared the efficacy and safety of aspirin and clopidogrel monotherapy following PCI. This was a prospective randomised open label multi-centre trial undertaken in South Korea. Eligibility criteria included patients 20 years or older who had undergone PCI with a drug eluting stent and who had completed a period of DAPT between 6 months and 18 months without any clinical events. Patients on a more potent P2Y12 inhibitor during DAPT could also be enrolled. Following enrolment, patients were randomised to receive either aspirin 100mg or clopidogrel 75mg. Follow up occurred at 12 and 24 months. The primary endpoint was a composite of all cause death, non-fatal MI, stroke, readmission due to an acute coronary syndrome, or major bleeding (defined as a BARC score>3). 5,438 patients were randomised, with 2,728 receiving aspirin and 2,710 receiving clopidogrel monotherapy. The two groups were well balanced with respect to demographics, clinical and procedural characteristics. At 24 months, the primary endpoint occurred less frequently in the group receiving clopidogrel as compared with aspirin (HR 0.73; 95% CI: 0.59-0.90; p=0.0035), with an absolute risk reduction of 2%. There were numerically more deaths in the clopidogrel group but this did not reach significance (with more cancer related deaths documented in the clopidogrel group). Minor gastrointestinal complications were more frequent in the aspirin treated group. The effect on the primary endpoint was consistent across all pre-specified sub-groups.  This large contemporary trial demonstrates that clopidogrel monotherapy is superior to aspirin during the maintenance phase following PCI in reducing ischaemic and bleeding events.

 

Catheter Based Valvular Intervention

 

Not enough evidence for EPD use in TAVI

Cerebral embolic protection and outcomes of transcatheter aortic valve replacement: results from the transcatheter valve therapy registry.

Circ 2021; 143:2229-40

Stroke remains a devastating complication of TAVI. The landmark SENTINEL trial showed that embolic protection devices (EPD) captured debris in 99% of cases but there was no significant reduction in MRI measured lesion volume, number of new lesions, or clinical strokes. An observational study from the Society for Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry examined the in-hospital stroke rate in 123,186 patients across 599 US sites between January 2018 to December 2019. The use of EPD during TAVI increased over time reaching 13% of TAVI procedures by December 2019. There were variations in EPD use across hospitals with 8% utilising EPD in >50% of TAVI procedures and 72% performing no procedures with an EPD in the last quarter of 2019. In the primary analysis using an instrumental variable model, no association was found between EPD use and in-hospital stroke (Adjusted RR 0.90; 95% CI: 0.68-1.13; Absolute risk difference -0.15; 95% CI: -0.49-020). In the secondary analysis using propensity score-based model, EPD was associated with 18% lower odds of in-hospital stroke (Adjusted OR 0.82; 95% CI: 0.69-0.97; absolute risk difference -0.28%; 95% CI: -0.52- -0.03). The study concluded that EPD use in patients undergoing TAVI does not reduce the risk of in-hospital stroke and found only a modestly lower risk in the secondary propensity-weighted analysis. It is anticipated that future randomized studies such as the BHF PROTECT study may shed further light on the safety and efficacy of EPD in TAVI patients.

 

Edoxaban noninferior to warfarin in ENVISAGE-TAVI AF

Edoxaban versus vitamin K antagonist for atrial fibrillation after TAVR

NEJM 2021 Online

The oral anticoagulant of choice in patients with atrial fibrillation (AF) undergoing TAVR remains uncertain. The ENVISAGE-TAVI AF trial compared the safety and efficacy of edoxaban with those of vitamin K antagonists (VKA) in 1,426 patients with prevalent or incident AF after TAVR. The edoxaban group (n=713) received 60mg once daily. The dose of edoxaban was reduced to 30mg once daily in the presence of a creatinine clearance of 15-50ml/min, body weight of 60Kg or less, and the use of certain P-glycoprotein inhibitors. The target INR for the VKA group was 2.0-3.0. Specified antiplatelet therapy in either group was allowed at the discretion of the treating physician’s discretion, including DAPT for up to 3 months after TAVR or single antiplatelet therapy indefinitely. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, MI, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding. Major secondary outcomes included all-cause mortality, ischaemic stroke, valve thrombosis, and intracranial haemorrhage.  The mean age of the patients was 82.1 years, 99% had AF before TAVR, 47.5% were women, mean STS risk score was 4.9%, mean CHA₂DS₂-VASc score was 4.5, 17% had had a prior stroke, 48% received a balloon-expandable valve, 46% received a supra-annular self-expanding valve, and the median time within the therapeutic range in the VKA arm was 68.2%. The rates of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the VKA group (HR: 1.05; 95% CI: 0.85-1.31; p=0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years respectively (HR: 1.40; 95% CI: 1.03-1.91; p=0.93 for noninferiority). The difference between groups was mainly driven due to more GI bleeding with edoxaban. Rates of death from any cause or stroke were 10 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the VKA group (HR: 0.85; 95% CI: 0.66-1.11). The rate of intracranial haemorrhage was 1.5 per 100 person-years in the edoxaban group and 2.1 per 100 person-years in the VKA group (HR: 0,72; 95% CI: 0.38-1.39).  There were no cases of valve thrombosis.

 

PASCAL provides sustained reduction in MR & LV remodelling

2-year outcomes for transcatheter repair in patients with mitral regurgitation from the CLASP study.

JACC Cardiovasc Interv 2021; 14:1538-48

The Edwards PASCAL Transcatheter Mitral Valve Repair System (CLASP) study examined the safety and efficacy of the PASCAL system in 124 patients (67% FMR, 33% DMR). At 30 days, there was 1 cardiovascular death, MR≤1+ was achieved in 80% of patients (77% FMR, 86% DMR) and MR≤2+ in 96% (96% FMR, 97% DMR). At 1 year, KM survival was 92% with 88% freedom from heart failure hospitalization, MR was ≤1+ in 82% and ≤2+ in 100% of patients, 88% of patients were in NYHA class I or II, and Kansas City Cardiomyopathy Questionnaire score had improved by 14 points. The current study reports 2 years outcome of the study with KM estimates showing 80% survival (72% FMR, 94% DMR) and 84% freedom from heart failure hospitalization (78% FMR, 97% DMR), with 85% reduction in annualized heart failure hospitalization rate (81% FMR, 98% DMR). MR≤1+ was achieved in 78% of patients (84% FMR, 71% DMR) and MR≤2+ being achieved in 97% (95% FMR, 100% DMR). There was significant reverse left ventricular remodelling with a decrease in left ventricular end-diastolic volume by 33Ml (p<0.001) and 93% of patients were in NYHA class I or II (p<0.0001). Although the sample size in the CLASP is study is relatively small, the PASCAL system appears to provide sustained reduction in MR and left ventricular remodelling.

 

Degree of MR at 30 days determines long-term outcome in COAPT

Relationship between residual mitral regurgitation and clinical and quality-of-life outcomes after transcatheter and medical treatment in heart failure. COAPT Trial.

Circ 2021; 144:426-37

In the COAPT trial the Mitraclip was shown to reduce rates of hospitalization for heart failure and all-cause mortality within 24 months of follow-up in patients with heart failure and moderate-to-severe or severe mitral regurgitation (MR) who remained symptomatic despite optimal medical therapy (OMT). The current manuscript described the outcomes between 30 days and 2 years on the basis of the severity of residual MR at 30 days. Patients in the Mitraclip arm had less severe residual MR at 30 days compared to patients in the OMT arm (0/1+, 2+, 3+/4+: 72.9%, 19.9%, and 7.2% vs. 8.2%, 26.1%, 65.8%; p<0.0001). The composite of death or heart failure hospitalization between 30 days and 2 years were lower in patients with 30-day residual MR of 0/1+ and 2+ compared with patients with 30-day residual MR of 3+/4+ (37.7% vs. 49.5% vs. 72.2% respectively p<0.0001). This relationship was consistent in the Mitraclip and OMT arms (p_interaction=0.92). The improvement in Kansas City Cardiomyopathy Questionnaire score from baseline to 30 days was maintained between 30 days and 2 years in patients with 30-day MR≤2+ but deteriorated in those with 30-day MR 3+/4+ (-0.3±1.7 vs. -9.4±4.6; p=0.0008). The study thus suggests that the degree of MR at 30 days post edge-to-edge repair with the Mitraclip will be an important determinant of long-term freedom from death, heart failure hospitalization, and quality of life.

 

Mitral valve repair is rare post TEER

Mitral surgery after transcatheter edge-to-edge repair: Society of Thoracic Surgeons Database analysis.

JACC 2021; 78:1-9

Mitral transcatheter edge-to-edge-repair (TEER) has been recommended for prohibitive and high-risk patients with severe symptomatic primary MR and a select subset of patients with severe symptomatic secondary MR. TEER with clipping of the anterior and posterior leaflets improve symptoms, reduce the degree of MR, and promote reverse LV remodelling. TEER, however, may not sufficiently reduce the degree of MR or lead to residual gradients ≥5mmHg thus leading to a requirement for mitral valve surgery in a high-risk patient. The current manuscript reports the in-hospital mortality or 30-day mortality among 463 such patients from the Society of Thoracic Surgeons Database over a 6-year period (July 2014 to June 2020). The annual number of surgical interventions for failed TEER increased from 32 in 2015 to 126 in 2019 and 74 cases between January to June 2020. The median age was 76 years, median LVEF was 57%, 86.1 had heart failure symptoms, 24.7% had severe tricuspid regurgitation, 66.5% had a history of AF, and 4.5% had active or treated endocarditis. The median STS predicted mortality was 7.7%, 4.8% had mitral repair, 91.8% had bioprostheses, and 3.4% had mechanical prostheses, and 51.2% had concomitant surgery in addition to mitral valve surgery. In patients undergoing isolated mitral surgery, the observed mortality was 10.2% and the ratio of observed to expected mortality was 1.2 (95% CI: 0.8-1.9). Predictors of mortality included urgent surgery (OR 2.4; 95% CI: 1.3-4.6), non-degenerative/unknown aetiology (OR 2.2; 95% CI: 1.1-4.5), creatinine > 2.0 mg/dl (OR 3.8; 95% CI:1.9-7.9) and age > 80 years (OR 2.1; 95% CI: 1.1-4.4). When operative mortality in the overall group was analysed according to hospital case volume, the operative mortality was 2.6^ in the quantile of highest-volume centres that performed >10 cases versus 12.4% in centres that performed fewer (p=0.01). Salient features include lower mortality in experienced centres, repair being seldom feasible in these patients, and the lower operative mortality than expected raising questions about the validity of the risk scores to guide management of patients.

 

TAVI for all??

Eight-year outcomes for patients with aortic valve stensosi at low surgical risk randomized to transcatheter vs. surgical aortic valve replacement.

EHJ 2021; 42:2912-19

Multiple RCTs have shown TAVI to be effective and even superior to SAVR in the short and medium term, in patients that span all surgical risk levels. However, questions remain over outcomes and valve durability over the longer term. The current manuscript reports the 8-year outcomes of 280 patients with severe symptomatic AS who were randomised 1:1 to transcatheter or surgical (bioprosethic) valve intervention. All patients were >70 years (mean 79 y). Mean STS-PROM score was 3.0% (±1.7). The groups were well matched at baseline. After eight years, the composite primary endpoint of all-cause mortality, stroke, or MI was almost identical in both groups (54.5% TAVI vs. 54.8% SAVR; p= 0.94). There were no significant differences when these outcomes were compared individually. New onset AF was more common in the surgical group (54% vs. 74%) and pacemaker implantation was higher in the TAVI group (43% vs. 11%). The effective orifice area was higher and mean gradient lower in the TAVI group throughout the entire length of the study and that structural valve deterioration (new or worsening gradient) was more common in surgical valves than TAVI (13.9% vs. 28.3%). Valve failure was low in both groups with no significant differences overall (8.7% vs. 10.5%; p= 0.61). These are strong data; no difference in hard clinical outcomes or valve failure up to eight years in low-risk individuals. Moreover, TAVI was superior in terms of valve dysfunction. This is impressive given that all TAVI valves were first generation and improvements and refinements have been made since with sealing skirts, smaller delivery catheters, re-positioning capability and improved, CT-guided sizing. As the body of evidence for TAVI continues to grow in lower risk individuals with increasing follow up periods, the big question appears to be: what length of trial follow-up is required before TAVI becomes the default procedure in patients planned for a bioprosthetic valve.

 

Miscellaneous

 

RADIANCE favours renal denervation for BP control

Ultrasound renal denervation for hypertension resistant to a triple medication pill (RADIANCE-HTN TRIO): a randomised, multicentre, single-blind, sham-controlled trial.

Lancet 2021; 397:2476-86

Renal denervation has been shown to reduce blood pressure in patients with mild to moderate hypertension but its effects on blood pressure in patients with resistant hypertension has not been fully evaluated. RADIANCE-HTN TRIO examined the safety and efficacy of ultrasound renal denervation in resistant hypertension. Eligibility criteria included patients that had a blood pressure of at least 140/90mmHg on at least three agents including a diuretic. Eligible patients were swapped to a once daily fixed dose pill which included amlodipine 5 or 10mg, olmisartan or valsartan, and hydrochlorthiazide 25mg. After 4 weeks of standard treatment if the blood pressure remained at least 135/85 patients were randomised 1:1 to ultrasound renal denervation or a sham procedure (renal angiography alone). The primary endpoint was a change in daytime ambulatory BP at two months analysed in the intention to treat population. Adverse events were recorded including all-cause mortality, renal failure, an embolic event, renal artery or vascular complications requiring intervention, HTN crisis or new onset renal artery stenosis greater than 70%. Missing data and addition of medications following the intervention had their baseline blood pressure imputed at two months. A total of 989 patients were enrolled, with 136 meeting eligibility criteria for randomisation (69 were randomised to renal denervation and 67 to the sham procedure). Recruitment was slowed due to the COVID pandemic, so enrolment stopped after 134 patients (with trial sample size planned for 146 patients). Baseline characteristics were matched, including variations in type of angiotensin receptor blocker and dose of calcium channel blocker. At two months, there was no difference in adherence to medications. There was a greater reduction in daytime ambulatory systolic blood pressure with renal denervation (–8·0 mm Hg [IQR –16·4 to 0·0] vs. –3·0 mm Hg [–10·3 to 1·8]; median between-group difference –4·5 mm Hg [95% CI –8·5 to –0·3]; adjusted p=0·022). This effect was seen across all the systolic blood pressure parameters. There was no difference observed in the diastolic blood pressure parameters. A higher percentage of patients in the sham group required additional anti-hypertensives on follow up. The effect of renal denervation on the primary efficacy endpoint was consistent across gender, ethnicity, age, abdominal circumference, and baseline blood pressures. Three adverse events were reported after renal denervation, with only one was attributed to the procedure (access site pseudoaneurysm successful treated). This alongside previous studies suggests that catheter based renal denervation therapy in addition to guideline directed anti-hypertensives lowers blood pressure across a range of hypertension severity, with an adequate safety profile.

 

QUARTET provides further support for the polypill concept

Initial treatment with a single pill containing quadruple combination of quarter doses of blood pressure medicines versus standard dose monotherapy in patients with hypertension (QUARTET): a phase 3, randomised, double-blind, active-controlled trial.

Lancet 2021; 398:1043-52

Treatment inertia, intolerance to medication, and lack of compliance are recognised barriers to optimal blood pressure control. In order to address some of these barriers the QUARTET investigators sought to evaluate whether a hypertension management strategy which included initial commencement of a single pill containing four anti-hypertensives at a quarter strength dose was more effective at lowering blood pressure than the standard dose monotherapy treatment.  Adults aged ³18 years with hypertension that were untreated or receiving monotherapy were eligible, with specific blood pressure eligibility criteria depending on whether patients were untreated or treated, with lower thresholds for enrolment for the patients already receiving monotherapy. The quadruple pill included irbesartan 37.5 mg, amlodipine 1.25mg, indapamide 0.625mg and bisoprolol 2.5mg. Monotherapy consisted of irbesartan 150mg alongside placebo tablets to make up an identical capsule to the intervention group. Patients who were already on monotherapy were asked to stop their treatment at randomisation. Patients were followed up at 6 and 12 weeks, and for those invited for extended follow up at 6 months and 12 months. Assessments during follow-up included office blood pressures, bloods tests, 12 lead ECGs and 24-hour ambulatory blood pressure tests. If the target blood pressure (<140/90mmHg) was not achieved by 6 weeks as dictated by the trial protocol amlodipine 5mg was added to the treatment. The primary outcome was a change in mean blood pressure at 12 weeks. The study enrolled 591 patients (390 in the intervention arm and 291 in the control arm) which was lower than the pre-specified sample size of 650, because of slow recruitment during the COVID pandemic. The groups were balanced with regards to baseline characteristics, with 60% of overall participants male, average age 59 years and 82% were Caucasian. At 12 weeks, 15% of the intervention arm had additional amlodipine prescribed as compared with 40% in the control arm. There was an overall greater reduction in blood pressure in the intervention group as compared with the control group (lower by 6.9mmHg, 95% CI 4.9-8.9; p<0.0001) with a greater blood pressure control rate in the intervention group (76% versus 58% in control, relative risk (RR) 1.30, 95% CI 1.15-1.47, p<0.0001). These differences persisted in the participants that were followed up to 12 months. At 12 months 7.3% of patients in the intervention group versus 3.8% in the control group had treatment discontinuation due to adverse effects (p=0.12). There were reported higher rates of documented systolic blood pressure less than 100mmHg in the intervention arm, and dizziness was reported more frequently (p=0.07) although there were no differences in adverse effects due to syncope, falls or acute kidney injury. Whilst this trial did not assess the effects of treatment on cardiovascular outcomes, the data does suggest that a single combined pill with four anti-hypertensives at quarter doses is superior in terms of blood pressure lowering at 12 weeks and overall blood pressure control as compared with a single monotherapy strategy with similar tolerability.

 

Carotid artery stenting and endarterectomy are equally safe & effective

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy.

Lancet 2021; 398:1065-73

Carotid endarterectomy (CEA) and carotid artery stenting (CAS) have been shown to halve long term stroke rates in asymptomatic patients but carry procedural risks including a a 1% procedural risk of disabling stroke or death.  A number of randomised trials have examined the protective effects and hazards of CEA and CAS but they have been hampered by small number of asymptomatic patients. ASCT-2 was an international multi-centre randomised trial comparing CEA and CAS in asymptomatic patients with severe carotid artery stenosis thought to require intervention, where both clinician and patient were uncertain which procedure to select.  Eligibility criteria included a unilateral or bilateral severe stenosis (defined as greater than 60% on ultrasound) that had not resulted in any neurological symptoms in the preceding six months. Following randomization, patients were followed up at 1 month and then annually for a mean of 5 years. Procedural events were those within 30 days of the intervention. Due to an overall smaller sample size than initially dictated by the original trial design, the results from this study were interpreted in conjunction with other trials. 3,625 patients were randomly allocated to CEA (1814) or CAS (1811), with no significant difference in baseline characteristics observed. There was a degree of cross over; 6% allocated to CAS crossed over to CEA, and 3% allocated to CEA crossed over to CAS. In the per protocol analysis there was a greater number of non-disabling strokes following CAS. The overall risk of death and disabling stroke was similar between groups (around 1%). There was an overall 2% risk of non-disabling procedural stroke. KM estimates for 5-year non-procedural stroke were 2.5% in each group for fatal or disabling stroke, and 5.3% versus 4.5% for CAS versus CEA for any stroke (rate ratio 1.16, 95% CI 0.86-1.57, p=0.33).  When combining this data with all other CAS versus CEA trials, the rate ratio was similar between symptomatic and asymptomatic patients. There was no difference in overall mortality between CAS or CEA. Salient features include the study not being powered to draw concrete conclusions about outcomes, and its sample were drawn from a selected group that were referred for carotid intervention. Despite the limitations, and with the data analysed with previous trial data published, complications have been shown to be largely comparable between CAS and CEA, and the long-term effects on stroke are also similar between the two group.

 

 

Interventional cardiology services have undergone an enormous transformation in the last 20 years. The numbers of PCI procedures per year has increased substantially and the typical case mix has changed from a mostly elective service to the current day situation where most procedures are performed on patients presenting with acute coronary syndromes. Patients are now typically older and sicker with PPCI, cardiogenic shock, out of hospital cardiac arrest, surgical turn downs, left mainstem and CTO procedures being common clinical situations. This increased risk profile has coincided with an era of greater scrutiny of doctors.

We are all expected to provide data on our individual clinical service for appraisal purposes. In addition, we may be required to discuss difficult cases with patients and their relatives, local serious incident enquiries, the Care Quality Commission, Coroners courts, the General Medical Council and even the police. When dealing with these challenging situations it may be very helpful for clinicians to have up to date information describing an overview of their practice as a whole in order to put an individual case in context.

The NICOR database of PCI procedures is one of the best of its kind and provides an excellent overview of procedures in the UK. Patients who do not have procedures performed do not appear on this database but local departments are still accountable for these cases. The purpose of this current document is to describe a local governance framework which can used by PCI centres on a voluntary basis. This is based on the system currently in use at the Essex Cardiothoracic Centre which works well and is popular with clinicians.

View the full document using the download link. 

BCIS R&D Group

Literature Review September 2020

Prepared by: Michael Mahmoudi, Julian Gunn, Paul Morris & Aung Myat

Edited by Michael Mahmoudi

 

STABLE CAD & ACS

 

Colchicine as a potent anti-inflammatory agent

Colchicine in patients with chronic coronary disease.

NEJM 2020 Online

A number of studies have indicated that colchicine may have clinical benefits in patient with coronary artery disease (CAD). The low-dose colchicine (LoDoCo2) trial randomized 5522 patients with stable chronic coronary artery disease (CAD) to either colchicine 0.5mg daily (N=2762) or placebo (N=2760). Patients 35 to 82 years of age were eligible if they had any evidence of coronary disease on invasive coronary angiography or computed tomography angiography or a coronary artery calcium score of at least 400 Agatston units. Patients were required to have been in a clinically stable condition for at least 6 months before enrolment. Patients were excluded if they had moderate to severe renal impairment, severe heart failure, severe valvular heart disease, or known side effects from colchicine. At a median follow-up of 28.6 months, the primary endpoint (a composite of cardiovascular death, spontaneous MI, ischemic stroke, or ischemia-driven coronary revascularization) was lower in the colchicine group (6.8% vs. 9.6%; incidence: 2.5 vs. 3.6 events per 100 person-years; HR, 0.69; 95% CI: 0.57-0.83; p<0.001). The secondary endpoint (a composite of cardiovascular death, spontaneous MI, or ischemic stroke) was also lower in the colchicine group (4.2% vs. 5.7%; incidence: 1.5 vs. 2.1 events per 100 person-years; HR: 0.72; 95% CI: 0.57-0.92; p=0.007). The incidence rates of spontaneous MI or ischemia-driven coronary revascularization (composite endpoint), cardiovascular death or spontaneous MI (composite endpoint), ischemia driven coronary revascularization, and spontaneous MI were also significantly lower in the colchicine group. The incidence of death from non-cardiovascular causes was higher in the colchicine group (incidence: 0.7 vs. 0.5 events per 100 person-years; HR: 1.51; 95% CI: 0.99-2.31). The individual causes of death have not permitted a clear interpretation of this finding. The effects of colchicine were consistent in the prespecified subgroups defined according to sex, age (>65 years vs. ≤65 years), smoking status, hypertension, diabetes, prior acute coronary syndrome, prior coronary revascularization, atrial fibrillation, statin dose, and ezetimibe use.

 

Time to reconsider a strategy of 12 Months DAPT

Effect of ticagrelor monotherapy vs. ticagrelor with aspirin on major bleeding and cardiovascular events in patients with acute coronary syndrome. The TICO randomized clinical trial.

JAMA 2020; 323:2407-16

Bleeding complications following PCI are associated with increased risk of morbidity and mortality. The current study tested the hypothesis whether a strategy of switching to ticagrelor monotherapy following a 3-months course of dual antiplatelet therapy (DAPT) reduced the 1-year net adverse clinical events defined as a composite of major bleeding and adverse cardiac and cerebrovascular events (death, MI, stent thrombosis, stroke, or target vessel revascularization). Prespecified secondary outcomes included major bleeding and major adverse cardiac and cerebrovascular events. The study randomized 3056 ACS patients (36% with STEMI) to receive either ticagrelor monotherapy after 3-months of DAPT (N=1527) or ticagrelor-based 12-month DAPT (N=1529). The average was 61 years, 79% were men, 27% had diabetes, and all patients were treated with the Orsiro drug-eluting stent. The primary outcome was lower in the ticagrelor monotherapy after a 3-month course of DAPT (absolute difference, -1.98 (95% CI:-3.5% – -0.45%) HR: 0.66 (95% CI: 0.48-0.92); p=0.01). This difference was driven by a reduced risk of major bleeding in the ticagrelor monotherapy after a 3-month course of DAPT (1.7% vs. 3%; HR: 0.56; 95% CI: 0.34-0.91; p=0.02). The incidence of major adverse cardiac and cerebrovascular events was similar in both groups (2.3% vs. 3.4%; HR: 0.69; 95% CI: 0.45-1.06; p=0.09). A prespecified subgroup analysis showed that ticagrelor monotherapy had a consistent effect on the primary outcome across subgroups except in patients with multivessel disease who did better with 12-month DAPT. The results of TICO have been confirmed in three additional meta-analysis. For example, McClure and colleagues (JAHA 2020; 9:e017109) undertook a meta-analysis of 5 muticenter trials including GLOBAL LEADERS, STOPDABT2, SMART-CHOICE, TWILIGHT and TICIO which in total included 32361 patients of whom16898 had a history of ACS demonstrated that compared to a 12 months course of DAPT, a strategy of P2Y₁₂ inhibitor monotherapy from 1 to 3 months after DAPT substantially reduces the risk of major and fatal bleeding. This strategy was also associated with a potentially protective effect for MACE and all-cause mortality.

 

De-escalation of DAPT-Time to change duration of DAPT

Prasugrel-based de-escalation of dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (HOST-REDUCE-POLYTECH-ACS): an open-label, multicentre, non-inferiority randomised trial.

Lancet 2020 Online

The concept of de-escalation is based on the hypothesis that there is a temporal change of ischaemic and bleeding risks after PCI. Immediately after PCI, especially in patients with ACS, the risk of thrombosis is greatest because the patient has a thrombotic milieu and the culprit coronary artery needs to recover from balloon-induced injury and dissection with exposure of the subendothelial tissue to blood. Upon endothelialisation of the implanted stent, the constant bleeding risk from using potent P2Y₁₂ inhibitors comes sharper into focus and is maintained thereafter for the total duration of DAPT. This South Korean study was conducted at 35 hospitals to investigate the feasibility of a prasugrel-based dose de-escalation strategy in ACS patients proceeding to PCI. All ACS patients with at least 1 culprit coronary lesion in a native coronary artery requiring stent deployment were eligible for recruitment. From September 2014 to December 2018, 2338 patients were randomised to the de-escalation arm (N=1170) or to standard therapy (N=1168). All patients received loading doses of aspirin and prasugrel. After PCI all patients received 100 mg aspirin and 10 mg prasugrel once a day up to 30 days. Thereafter the de-escalation group took 5 mg of prasugrel once daily as maintenance and the conventional arm continued on prasugrel 10 mg once daily. Both arms continued aspirin. DAPT was recommended for a minimum of a year although this duration could be adjusted in the case of clinical events. The primary endpoint was net adverse clinical events, defined as a composite of all-cause death, non-fatal myocardial infarction, stent thrombosis, clinically driven revascularisation, stroke, and bleeding events of grade 2 or higher according to Bleeding Academic Research Consortium (BARC) criteria, at 1 year. Mean age was 58.8 years. At 1 year, the primary endpoint occurred in 82 patients (7.2%) in the de-escalation group and 116 patients (10.1%) in the conventional group (absolute risk reduction -2.9%, P_{non-inferiority}<0.0001; HR: 0.70; 95% CI: 0.52-0.92, P_equivalence=0.12). There was no increase in ischaemic risk (0.76 [0.40-1.45]; p=0.40), and the risk of bleeding events was significantly lower (0.48 [0.32-0.73]; p=0.0007) in favour of the de-escalation group. In post-hoc subgroup analyses, the clinical effect of de-escalation was consistent regardless of subgroup (age, sex, diabetes, chronic kidney disease, smoking status, type of ACS, ejection fraction, polyvascular disease, or stent length), with no significant interaction noted. The investigators were quick to emphasise the trial results were only applicable to east Asian ACS patients, so may not necessarily be generalisable to other ethnic cohorts.

 

Mortality benefit with PCI in patient with stable angina

Survival of Patients With Angina Pectoris Undergoing Percutaneous Coronary Intervention With Intracoronary Pressure Wire Guidance.

JACC 2020; 75:2785-99

The impact of coronary revascularization on hard clinical endpoint in patients with stable angina is controversial. The objective of the current study was to compare the association of FFR-guided versus angiography-guided PCI with long-term mortality, restenosis, and stent thrombosis and periprocedural complications (defined as in-hospital occurrence of procedure related death, neurological complications, cardiac tamponade, vessel perforation, vessel occlusion and major bleeding) in patients with stable angina registered in the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Between 2005-2016, a total of 23860 patients underwent PCI; FFR was used in 3367 patients and 20493 patients underwent PCI without intracoronary pressure measurements. Patients in the FFR group were younger, more likely to be men, and more likely to have hypertension, hyperlipidaemia, and previous PCI. After a median follow-up of 4.7 years, the adjusted risk estimates for all-cause mortality (HR: 0.81; 95% CI: 0.73-0.89; p<0.001) and stent thrombosis and restenosis (HR: 0.74; 95% CI: 0.57-0.96; p=0.022) was lower in the FFR group. The periprocedural complications were similar between the two groups (OR: 0.96; 95% CI: 0.77-1.19; p=697). Limitations of the study included lack of data regarding the rates of MI and the investigators were unable to distinguish between cardiac and non-cardiac death. There were important baseline differences between the two groups that may have influenced the results including patients in the FFR group were more likely to receive current generation DES, more likely to undergo PCI via the radial route, and more likely to receive ticagrelor as opposed to clopidogrel.

 

Trimetazidine safe but not particularly effective post PCI

Efficacy and safety of trimetazidine after percutaneous coronary intervention (ATPCI): a randomised, double-blind, placebo-controlled trial.

Lancet 2020;396:830-838

Trimetazidine is an antianginal agent widely used outside of Europe and the US. It works by enhancing the metabolic efficiency of the myocardium under threat of ischaemia but does not mediate any haemodynamic effects. The ATPCI trial was a large international multicentre randomised, double-blind, placebo-controlled study conducted in patients who had had successful PCI for either stable angina or NSTE-ACS within 30 days of study enrolment and subsequent randomisation. The primary efficacy endpoint was the composite of cardiac death; hospital admission for a cardiac event; recurrent or persistent angina leading to adding, switching, or increasing the dose of one of the evidence-based antianginal therapies; or recurrent or persistent angina leading to coronary angiography. From September 2014 to June 2016, 6007 patients were randomised to trimetazidine at 35 mg twice daily (N=2998) or matching placebo (N=3009) on top of standard antianginal therapy. The primary efficacy endpoint event rate was lower than expected so follow-up was extended for a further 12 months. Overall median follow-up was 47.5 months. The frequencies of primary composite endpoint events were similar between trimetazidine (700 [23·3%] patients) and placebo (714 [23·7%]; HR: 0∙98; 95% CI: 0∙88–1∙09; p=0∙73), as were the frequencies of the components analysed individually. Neither all-cause mortality nor the composite of hospital admission for myocardial infarction (fatal or non-fatal) or cardiac death, or any of the other secondary endpoints were modified by assigned treatment. The investigators concluded that trimetazidine did not reduce the risk of cardiac events compared with placebo. In the ATPCI population, where atherosclerotic burden was generally low (approximately half had only single-vessel disease) and most recruits had preserved left ventricular function, combining successful PCI with optimal preventive and antianginal therapy was probably sufficient for symptom control in most cases. Importantly the study drug was not associated with any safety issues.

 

Age not a barrier to revascularization in NSTEMI patients

Invasive versus non-invasive management of older patients with non-ST elevation myocardial infarction (SENIOR-NSTEMI): a cohort study based on routine clinical data.

Lancet 2020;396:623-34

The very elderly (≥80 years old) are typically under-represented in randomised trials of NSTE-ACS management. Furthermore, the evidence base used to support contemporary practice guidelines in the elderly comprise mainly observational data and meta-analyses. Randomised controlled trial data are scant, heterogeneous in relation to what age stratum is designated elderly and beset by small sample populations. There have been just two randomised trials of optimal NSTE-ACS management strategy conducted specifically in the very elderly (≥80 years). The Italian Elderly ACS Study and the Norwegian After Eighty trial. The UK multicentre RINCAL trial has completed but had to end prematurely due to slow recruitment. The results are awaiting formal publication. The much larger BHF-funded SENIOR RITA (NCT03052036) trial is also looking at optimal management strategy in the elderly, but here the cut-off for enrolment is ≥75 years. This trial is aiming to recruit 1668 participants with an estimated study completion date of 2029. Here SENIOR-NSTEMI is yet another retrospective observational cohort study designed to estimate the effect of invasive versus non-invasive management of NSTE-ACS in patients aged ≥80 years on survival using routinely collected clinical data from 5 academic medical centres hosting NIHR BRCs in the UK via the NIHR Health Informatics Collaborative. Notably, the investigators have employed statistical methods to minimise the effects of immortal time bias in particular whereby previous registry studies had assigned, rightly or wrongly, those patients who died early in the course of their presentation to the non-invasive arm of their analysis before an invasive strategy could even be considered. Overall the records of 1976 patients from a study period starting in January 2008 to April 2017 were included in the analysis. Propensity scores were derived for those with high probabilities for a conservative or invasive strategy, leaving 1500 patients that could have been amenable to either strategy. The median age was 86 (IQR 82-89). Overall the adjusted cumulative 5-year mortality was 36% in the invasive arm and 55% in the conservative arm (HR 0.68, 95% CI 0.55-0.84). An invasive strategy was associated with a lower incidence of hospital admission for heart failure (HR 0.67, 95% CI 0.48-0.93). This is an important study, albeit based on retrospective observational data, that helps to strengthen the advocacy for early intervention in those patients ≥80 years old presenting with NSTE-ACS.

 

Focus on the culprit lesion in cardiogenic shock

Multivessel Versus Culprit-Vessel Percutaneous Coronary Intervention in Cardiogenic Shock.

JACC Cardiovasc Interv. 2020; 13:1171-78

There are conflicting studies on the optimal revascularization strategy in patients with multivessel CAD (MVCAD) who present with STEMI and cardiogenic shock. The landmark CULPRIT-SHOCK trial showed improved survival at 30 days when using a strategy of culprit vessel only PCI (CV-PCI) as opposed to multivessel PCI (MV-PCI). To date, studies comparing revascularization strategies with the aid of mechanical circulatory support (MCS) have been limited. The National Cardiogenic Shock Initiative (NCSI) trial, encompassing 57 hospitals in the US, sought to assess clinical outcomes associated with the use of a shock protocol emphasizing early MCS and PCI in patients presenting with acute MI and cardiogenic shock (AMICS). The algorithm is based upon (1) early identification and cath lab activation for patients presenting with AMICS, (2) early use of MCS, and (3) routine use of invasive haemodynamic monitoring with PA catheter to guide management of MCS and use of inotropes. Of 198 patients with MVCAD , 126 (64%) underwent MV-PCI and 72 (36%) underwent CV-PCI. The MV-PCI group had a trend toward more severe impairment of cardiac output and worse lactate clearance on presentation, and cardiac performance was significantly worse at 12 hours. 24 hours from PCI, the haemometabolic derangements were similar. Survival rates (69.8% vs. 65.3%; p=0.51) and acute kidney injury (29.9% vs. 34.2%; p=0.64) were similar between the MV-PCI and CV-PCI groups. The major strength of this study is that patients were treated using a robust protocol as defined by the NCSI and differs from other studies in that patients were treated with early and aggressive use of MCS. However, major limitations include lack of randomization, modest sample size, and the decision to perform nonculprit PCI was left at the discretion of the operator. It is feasible to assume that more straightforward nonculprit lesions were selected for PCI whilst more complex lesions were deferred for potential surgical revascularization at a later date.

 

STENTS AND BALLOONS

 

BioFreedom not as good as Orsiro in SORT OUT IX

Randomized Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent With the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated With Percutaneous Coronary Intervention. The SORT OUT IX Trial.

Circ 2020; 141:2052-63

Although the biolimus A9-coated BioFreedom stent, a stainless-steel drug-coated stent free from polymer has shown superiority to BMS, its performance against modern DES has not been tested. The Scandinavian Organization for Randomized Trials with Clinical Outcome IX (SORT OUT IX) was designed to compare the safety and efficacy of BioFreedom drug-coated stent with the biodegradable polymer sirolimus-eluting stent (Orsiro) in reducing clinical outcomes in 3151 patients undergoing PCI. Mean age was 66.3 ± 10.9 years, 19.3% had diabetes, and 53% presented with ACS). The primary endpoint, MACE, was defined as the composite of cardiac death, MI not related to any segment other than the target lesion, or target lesion revascularization. The trial was powered to assess noninferiority for MACE events of the BioFreedom (N=1572) with the Orsiro stent (N=1579) with a predetermined noninferiority margin of 0.021.  At 1 year, the primary endpoints 5% in the BioFreedom stent group and 3.7% in the Orsiro stent group (HR:1.34;95% CI: 0.96-1.89; p for noninferiority=0.14, p for superiority=0.09). The BioFreedom stent therefore did not meet the criteria for noninferiority driven by a higher risk of target lesion revascularization (3.5% vs. 1.3%; p<0.0001). This may be due to the thicker stent struts in the BioFreedom stent (120 micometers) than the Orsiro stent (60-80 micrometers). The rates of cardiac mortality (1% vs. 1.8%; p=0.06) and MI not related to other lesion (1.7% vs. 1.6%; p=0.99) were similar in both groups. In the LEADERS FREE and LEADERS FREE II trials, the BioFreedom stent were superior to BMS suggesting that its efficacy may lie somewhere between BMS and contemporary DES.

 

Biologically coated stents may represent a new paradigm in PCI

Titanium-Nitride-Oxide–Coated Versus Everolimus-Eluting Stents in Acute Coronary Syndrome. The Randomized TIDES-ACS Trial.

JACC Cardiovasc Interv. 2020; 13:1697-1705

Three randomized trials with 5 years of follow-up have indicated that a stainless steel, titanium-nitride-oxide-coated stent resulted in superior clinical outcomes compared with zotarolimus-eluting stents and everolimus-eluting stents. Stent coating with a vapor deposition of titanium in a mixed nitrogen-oxygen atmosphere aims to achieve inhibition of platelet aggregation while limiting neointimal hyperplasia without an antiproliferative drug. The Comparison  Titanium-Nitride-Oxide Coated Bioactive-Stent (Optimax) to the Drug (Everolimus) Eluting Stent (Synergy) in Acute Coronary Syndrome (TIDES-ACS) trial of 1491 ACS patients sought to compare the safety and efficacy of the cobalt-chromium-based titanium-nitride oxide coated stent (TiNO) (N=989) with the Synergy stent (N=502). The trial met both its hypotheses of noninferiority concerning a composite of major adverse ischemic events at 12 months (6.3% vs. 7.0%; HR: 0.93; 95% CI: 0.71-1.22; p<0.001 for noninferiority) and superiority concerning a composite of ischemic and bleeding events at 18 months (3.7% vs. 7.8%; HR: 0.64; 95% CI: 0.51-0.80; p=0.001). Salient features in interpreting the data include few patients with diabetes (12%), two-thirds had single vessel disease, and only one-third had complex angiographic features.

 

To DEB or to DES-that is the question

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

JACC 2020; 75:2664-78

The optimal treatment strategy for in-stent restenosis (ISR) is uncertain. The Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis (DAEDALUS) study is a pooled analysis of individual patient data (N=1976) from 10 randomized clinical trials that sought to compare long-term outcomes between drug-coated balloon (DCB) angioplasty and repeat stenting with drug-eluting stent (DES) according to bare metal stent (BMS) and DES-ISR and individually assess the relative safety and efficacy of treatments between ISR types. A total of 710 patients with BMS-ISR (724 lesions) and 1248 patients with DES-ISR (1338 lesions) underwent treatment by DCB angioplasty or repeat stenting with DES. The primary safety endpoint was a composite of all-cause death, MI, or target lesion thrombosis. The primary efficacy endpoint was target lesion revascularization (TLR) defined as any revascularization, percutaneous or surgical, due to recurrent stenosis of the target lesion segment. At 3-year follow-up, in patients with BMS-ISR, the primary safety (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65-1.96) and efficacy (9.2% vs. 10.2%; HR: 0.83; 95% CI: 0.51-1.37) endpoints were similar with both treatments. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16-2.13) whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47-1.00). Regardless of the treatment used, the risk of TLR was lower in BMS-versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42-0.74), whereas safety was not significantly different between ISR types. Several limitations of the analysis are noteworthy. Firstly, post-procedure minimum lumen diameter was less and percent residual stenosis greater in the DCB arm despite randomization. Second, although 1-year TLR was increased after DCB, binary angiographic restenosis rates were similar across all the trials. Third, a signal for hazard with restenting was observed with non-significant trends for all-cause death, cardiac death, and for death, MI, and target lesion thrombosis. Finally, the DCB in the DAEDALUS study were paclitaxel whilst the newer sirolimus DCB may be more effective in suppressing neointimal hyperplasia and restenosis.

 

More data in favour of Biodegradable polymer coated stents

Final 3-year outcomes of MiStent biodegradable polymer crystalline sirolimus-eluting stent versus Xience permanent polymer everolimus-eluting stent. Insights from the DESSOLVE III all-comers randomized trial.

Circ Cardiovasc Interv. 2020; 13:e008737

A number of studies have confirmed the superiority of ultrathin-strut biodegradable polymer second-generation DES to first generation DES and noninferiority to the thin-strut second-generation permanent polymer DES. Data on the longer-term performance of ultrathin DES is lacking. The Multicentre Randomized Study of the MiStent Sirolimus Eluting Absorbable Polymer Stent System for Revascularization of Coronary Arteries (DESSOLVE III) trial randomized 1398 all-comers patients with any ischemic coronary syndrome and any type of lesion (left main, SVG, CTO, bifurcation, ISR) to either the MiStent sirolimus eluting stent (N=703) or a Xience stent (N=695). The primary endpoint was device-oriented composite endpoint, defined as the composite of cardiac death, target vessel MI, or clinically indicated target lesion revascularization. The secondary endpoint was patient-oriented composite endpoint, defined as the composite of all-cause mortality, MI, or any revascularization. At 3 years, the primary endpoint was similar in both groups (10.5% vs. 11.5%; p=0.55). Rates of cardiac death (3.9% vs. 3.8%; p=0.88), target vessel MI (3.2% vs. 2.5%; p=0.43), and clinically indicated target lesion revascularization (5.2% vs. 6.5%;p=0.30) were similar in both groups. The risk of patient oriented composite endpoint was also similar in both groups (22.7% vs. 22.9%; p=0.34).

 

CATHETER BASED VALVULAR INTERVENTION

 

Antiplatelet therapy post TAVI

Aspirin with or without clopidogrel after transcatheter aortic valve implantation.

NEJM 2020 Online

Dual antiplatelet therapy with aspirin and clopidogrel for a period of 3 to 6 months is recommended after TAVI in patients who do not have an indication for anticoagulation. Although small studies have indicated that such combination is associated with a lower incidence of ischemic events than aspirin alone, although dual antiplatelet therapy was associated with an increased risk of bleeding in the ARTE trial. Cohort A of the POPular TAVI trial (Antiplatelet Therapy for Patients Undergoing Transcatheter Aortic-Valve Implantation) compared aspirin alone (N=343) with aspirin plus clopidogrel for 3 months (N=347) in patients undergoing TAVI who did not have an established indication for long-term oral anticoagulation. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding), and non-procedure-related bleeding over a period of 12 months. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or MI and a composite of death from cardiovascular causes, ischemic stroke, or MI at 1 year for both outcomes sequentially for noninferiority and superiority. At 12 months, the rate of bleeding of any type was lower in the aspirin alone group (15.1% vs. 26.6%; RR, 0.57; 95% CI: 0.42-0.77; p=0.001). Non-procedure-related bleeding was also lower in the aspirin alone group (15.1% vs. 24.9%; RR, 0.61; 95% CI: 0.44-0.83; p=0.005).   The first secondary endpoint (composite of bleeding, death, stroke or MI) was also lower in the aspirin alone group (23% vs. 31.3%; difference -8.2 percentage points; 95% CI for noninferiority: -14.9-1-.5; p<0.001; RR, 0.74; 95% CI for superiority: 0.57-0.95; p=0.04). The second secondary endpoint (composite of thromboembolic events including death from CV causes, ischemic stroke, or MI) were 9.7% in the aspirin group and 9.9% in the aspirin plus clopidogrel group indicating that aspirin alone was noninferior to combined therapy (difference -0.2 percentage points; 95% CI for noninferiority: -4.7-4.3; p=0.004) but it was not superior (RR, 0.98; 95% CI for superiority: 0.62-1.55; p=0.93).

 

Leaflet thrombosis an issue in both surgical & TAVI devices

Subclinical Leaflet Thrombosis in Transcatheter and Surgical Bioprosthetic Valves. PARTNER 3 Cardiac Computed Tomography Sub-study.

JACC 2020; 75:3003-15

Subclinical leaflet thrombosis characterized by hypoattenuated leaflet thickening (HALT) and reduced leaflet motion (RLM) seen on high resolution 4D CT is found with significant frequency both in transcatheter and surgical bioprosthetic valves. Given the expansion of TAVI across the full spectrum of surgical risks, the US FDA has FDA mandated CT ancillary studies to be incorporated into TAVI trials of patients at low surgical risk to understand the natural history of subclinical leaflet thrombosis of transcatheter and surgical bioprosthetic valves and its association with valve haemodynamic and clinical outcomes. The PARTNER 3 CT substudy was a randomized trial embedded in the PARTNER 3 randomized trial of TAVI with current generation balloon-expandable valve compared with standard surgical AVR in patients at low surgical risk with symptomatic severe aortic stenosis. Patients were eligible for inclusion if they had no pre-existing indication for anticoagulation and no contraindication to undergo a CT scan. Patients underwent cardiac 4D-CT at 30 days and 1 year after TAVI or SAVR . Treating investigators were blinded to the results of the CT scans. Primary imaging endpoints of interest were the percent HALT and RLM at 30 days and 1 year. HALT was significantly higher in the TAVI group at 30 days (13% vs. 5%; p=0.03) but not at 1 year (28% vs. 20%; p=0.19). The presence of HALT fluctuated over time, such that amongst patients with HALT at 30 days spontaneous resolution was observed at 1 year in 56% of cases. Conversely, amongst patients without HALT at 30 days, new HALT was observed in 21% of patients at 1 year. HALT at any time point was associated with higher rates of valve thrombosis, stroke, TIA, and thromboembolic complications. The presence of HALT did not significantly alter the mean aortic valve gradient at 30 days or 1 year. When placed in the context of the ancillary GALLILEO 4D-study where a rivaroxaban-based strategy did not translate into significant improvements in valve haemodynamic as evaluated with TTE or reduction in thromboembolic events, a strategy of routine anticoagulation after TAVI appears to have an unfavourable risk-benefit balance.

 

Incidence & predictors of IE in TAVI

Infective Endocarditis After Transcatheter Aortic Valve Replacement.

JACC 2020; 75:3020-30

The incidence of infective endocarditis following TAVI, the responsible microorganisms, and the outcome of such patients has not been adequately elucidated. Using the Swiss Transcatheter Aortic Valve Implantation Registry, the current study examined the incidence of TAVI prosthetic valve endocarditis, risk factors for developing the disease, and the downstream incidence of stroke and mortality. Between 2011-2018, 7203 patients underwent TAVI at 15 Swiss centres. During follow-up of 14832 patient-years, endocarditis occurred in 149 patients. The incidence of peri-procedural, delayed-early, and late endocarditis was 2.59, 0.71, and 0.40 events per 100 person-years respectively. Enterococcus species were the most common microorganism in early endocarditis (30.1%). Younger age, male sex, lack of predilatation, and treatment in the cath lab as opposed to a hybrid operating room were independently associated with endocarditis. In a case-control matched analysis, patients with endocarditis were at increased risk of mortality (HR: 6.55; 95% VI: 4.44-9.67) and stroke (HR: 4.03; 95% CI: 1.54-10.52). Of note, the modified Duke criteria had a very low sensitivity with only 63% of patients meeting a definite diagnosis. Furthermore, echocardiographic appearances were normal or inconclusive in 47.7%.

 

Neurocognitive impairment post TAVI

Evolution, Predictors, and Neurocognitive Effects of Silent Cerebral Embolism During Transcatheter Aortic Valve Replacement.

JACC Cardiovasc Interv. 2020; 13:1291-1300

Histopathological examination of embolic debris captured during TAVI has confirmed its dual origin from both the aortic valve and the aortic wall. In addition to symptomatic stroke or TIA, systematic performance of brain imaging after TAVI has shown a high incidence of silent cerebral ischaemic lesions (SCILs) raising concerns for increased risk of cognitive impairment post TAVI. The current study examined the incidence, time course, and predictors of SCILs and their impact on neurocognition in 96 patients who underwent cerebral MRI within 7 days prior to and again post TAVI. The MRI was repeated after 3 months if results were abnormal. Patients with neurological or neurocognitive impairment were excluded. SCILs were observed in 76% of patients, distributed in all vascular territories, with a median number of 2 lesions, a median diameter of 4.5mm, and a median total volume of 140 mm³. Independent predictors of SCIL occurrence were higher baseline age-related white matter change score, and the use of self-expanding or mechanically expanded bioprostheses. SCIL occurrence was associated with a more pronounced transient neurocognitive decline early after TAVI and lower recovery at follow-up. Important limitations of the study included the low number of patients enrolled, slow recruitment (6 patients per year per centre), limited follow-up with the last evaluation at 3 months post TAVI, and the modest magnitude of change in the Mini Mental State Examination and Montreal Cognitive Assessment scores raising the question of whether these changes are clinically meaningful.

 

Encouraging long-term data for TAVI

Long-term clinical outcome and performance of transcatheter aortic valve replacement with a self-expandable bioprosthesis.

EHJ 2020; 41:1876-86

TAVI has transformed the management of severe aortic stenosis, first in high-risk, frail, elderly patients, then in patients at moderate surgical risk and increasingly, in those in lower risk groups. Initially, evidence demonstrated superiority to standard care in inoperable patients and non-inferiority to surgery in high and medium risk groups. However, questions regarding long term outcomes had to remain uncomfortably unanswered until sufficient time had elapsed to allow appropriate analysis. TAVI has been available for little over a decade now and studies with ≥ 5 years follow-up data are emerging. In this study, outcomes following implantation of the first-generation self-expandable CoreValve bioprosthesis were studied in 999 patients, across eight Italian centres. These were predominantly elderly patients (mean age 82 y), at high surgical risk (mean Log-EuroSCORE 23) with reasonable LV function and severe valve disease (mean gradient 53 mmHg). Femoral access was used in 84% and 74% were under local anaesthetic. Follow up was for a median of 4.4 years with the longest at 11 years. Cumulative incidence functions (which control for increasing mortality rates over time) were used to analyse 8-year data. Overall mortality was 78% with median survival of 4.2 years. 36% of deaths were deemed to be cardiovascular in nature. In surviving patients NYHA remained at ≤ 2 in 79% and trans valvular gradient did not change from discharge (9±6 mmHg). Although paravalvular leak was common (CT sizing was not used routinely), there was no significant change in PVL over time. Moderate and severe structural valve deterioration at 8 years were 3.0% and 1.6% respectively. Late BVF was 2.5%. The study is one of the biggest studies of long term TAVI outcomes and is multicentre. Similar to other recent registry reports, the mortality in this elderly, frail, high risk group was high. However, it is reassuring that, in surviving patients, measures of valve function (gradient and PVL) and metrics of device failure did not reveal any overt red flags in terms of safety. Although unavoidable, perhaps the greatest problem when interpreting this uncontrolled study is common to many long-term observational studies; by the time they are reported, there has been considerable evolution in device design, implant technique, supporting medical therapy and, as is the case with TAVI, the age and frailty of the patients.

 

MISCELLANEOUS

 

More is better in LM PCI

Are higher operator volumes for unprotected left main stem percutaneous coronary intervention associated with improved patient outcomes? A survival analysis of 6724 procedures from the British Cardiovascular Intervention Society National Database.

Circ Cardiovasc Interv. 2020; 13:e008782

A historical debate regarding operator volume and patient outcome in all field of medicine has continued to the present day. This study has examined the relationship between operator volume and patient survival after unprotected left main PCI ((ULMS-PCI) utilising data from the British Cardiovascular Intervention Society National Database (BCIS). A total of 6724 ULMS-PCI procedures were analysed between 2012-2014 and 4 quartiles of annualized volumes (Q1-Q4) were generated.  Operator volume ranged from 1 to 54 cases/year. In Q1, 347 operators performed a median of 2 procedures/year; in Q2, 134 operators performed a median of 5 procedures/year; in Q3, 59 operators performed a mean of 10 procedures/year, and in Q4, 29 operators performed a mean of 21 procedures/year. Higher volume operators tackled patients with greater morbidity and greater complexity of disease burden. Adjusted in-hospital survival (OR: 0.39; 95% CI: 0.24-0.67; p<0.001), in-hospital major adverse cardiac and cerebral events (OR: 0.41; 95% CI: 0.27-0.62; p<0.001), and 12-month survival (OR: 0.54; 95% CI: 0.39-0.73; p<0.001) were lower in Q4 operators than Q1 operators. The authors have identified a lower volume threshold of ≥ 16 ULMS-PCI cases/year to be associated with improved patient survival.

 

 

 

What is the optimal bifurcation technique?

Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial.

EHJ 2020; 41:2523-36

The optimal bifurcation strategy is yet to be determined despite a number of landmark studies favouring a provisional single stent strategy. The current study was designed to assess the benefits of two-stent techniques in patients with DEFINITION criteria-defined complex coronary bifurcation lesions. Consecutive patients (N=653) were enrolled if they presented with silent ischaemia, stable or unstable angina (50%), or MI > 24 hours prior to treatment (22%). All bifurcation lesions were Medina 1,1,1 or 0, 1, 1 with reference vessel diameter (RVD) in the SB ≥ 2.5mm by visual estimation and had to meet the DEFINITION criteria. The DEFINITIONS criteria, developed from a previous registry, consists of any one major criterion (SB lesion length >10mm with diameter stenosis of SB >70% for distal LM bifurcation lesions or >90% for non-LM bifurcation lesions) plus any two minor criteria (moderate-to-severe calcification, multiple lesions, bifurcation angle < 45° or > 70°, main vessel RVD < 2.5mm, thrombus-containing lesions, or main vessel lesion length >25mm). Patients were randomised to either a provisional (N=325) or two-stent strategy (N=328; 77.8% DK-crush and 17.9% culotte); 62.5% of lesions in the trial were LAD/diagonal and 28.7% at the LMS. At the 1-year follow-up, the primary endpoint of target lesion failure (TLF) (defined as the composite of cardiac death, target vessel MI, or clinically driven target lesion revascularization) was greater in the provisional group (11.4% vs. 6.1%; HR: 0.52; 95% CI: 0.30-0.90; p=0.019). The difference was driven by lower 1-year rates of target vessel MI (HR: 0.43; 95% CI: 0.20-0.90; p=0.025) and clinically driven target lesion revascularization (HR: 0.43; 95% CI: 0.19-1.0; p=0.049). There were no differences in the rates of cardiac death, all-cause death, or stent thrombosis. Of note, the Kaplan-Meier curves examining the main endpoint are unusual in that all the events seemed to occur immediately after the index procedure, and well before 30 days, with few events between then and the 12-month timepoint. Looking back at the definitions of the primary endpoint, it turns out that this must have comprised peri-procedural infarcts (defined according to enzyme rise or ECG change) or angiography defined vessel failure. This rather important aspect of the study is not explored in the prose of the results or the discussion.

 

DK-crush may be the optimal bifurcation strategy??

Clinical Outcomes Following Coronary Bifurcation PCI Techniques. A Systematic Review and Network Meta-Analysis Comprising 5,711 Patients.

JACC Cardiovasc Interv. 2020; 13:1432-44

Despite robust randomized data favouring a provisional one stent strategy, the optimal technique for bifurcation lesions remains unresolved. The current meta-analysis of 21 randomized controlled trials including 5711 patients treated using 5 bifurcation techniques (provisional (N=1952), T stenting/T and protrusion (N=392), crush (1361), culotte (N=1101), and DK-crush (N=905)) studied MACE, cardiac death, MI, target vessel or lesion revascularization and stent thrombosis. Patients had a mean age of 64±10 years, 71% were men, 22% had diabetes, and 50% presented with stable angina. Over a median follow-up of 12 months, DK-crush was associated with a lower rate of MACE compared with other techniques (OR vs. provisional: 0.39; 95% CI: 0.26-0.55). This was driven by a reduction in target vessel revascularization (OR vs. provisional 0.39; 95% CI: 0.26-0.55) and target lesion revascularization (OR vs. provisional: 0.36; 95% CI: 0.22-0.57). There were no differences in the rates of all-cause death, cardiovascular death, MI and stent thrombosis among the five techniques studied. DK-crush was associated with significantly fewer MIs compared to classic crush (OR: 0.38; 95% CI: 0.1400.86). DK-crushed ranked first in probability of being the best treatment for all outcomes, followed by culotte and provisional stenting. T/TAP and crush were least likely to be the best treatment. Pairewise meta-analyses showed that the benefit of 2-stent techniques was observed in bifurcation lesions with side branch length ≥ 10mm whereas no difference was observed in outcomes between 1 and 2 stent techniques in bifurcation lesions with side branch lesion length < 10mm.

 

MIRACLE₂ may streamline management for OOHCA

A practical risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest: MIRACLE₂

EHJ 2020 Online

The management of patients presenting with an out-of-hospital cardiac arrest (OOHCA) is variable depending upon the presence or absence of ST-elevation on the presenting ECG and the patient’s premorbid status. Despite many approaches that may improve survival, a significant proportion of patients still sustain poor outcomes due to hypoxic brain injury. The purpose of this study was to develop a practical point-based risk score that can be applied to patients with OOHCA on arrival to a Heart Attack Centre (HAC) to reflect long-term prognosis and support clinical decision making. The study included 1055 patients aged ≥ 18 years presenting with an OOHCA and return of spontaneous circulation between May 2012-December 2017 of whom 373 were included in the King’s Out of Hospital Cardiac Arrest Registry. Inclusion criteria were the presence of ST-elevation on the ECG and patients without ST-elevation if there if there was absence of a noncardiac aetiology. Prediction modelling and multivariable logistic regression were used to identify predictors of poor neurological outcome classified as Cerebral Performance Category 3-5 (severe disability-death) at 6-month follow-up. This was externally validated in two independent cohorts comprising 473 patients. Seven independent predictors of outcome were identified: missed (unwitnessed) arrest, initial non shockable rhythm, nonreactive pupils, age (60-80 years: 1 point; >80 years: 3 points), changing intra-arrest rhythms, low pH < 7.20, and epinephrine administration (2 points). The MIRACLE₂ score had an AUC=0.90 in the development and 0.84/0.91 in the validation cohorts. Three risk score were identified: MIRACLE₂ ≤ 2: 5.6%risk of poor outcome;  MIRACLE₂ 3-4: 55.4% risk of poor outcome; MIRACLE₂ ≥ 5: 92.3% risk of poor outcome. The MIRACLE₂ had a superior discrimination to the OHCA score and the Cardiac Arrest Hospital Prognosis Score, but it performed as well as the Target Temperature Management score. These findings help define subgroup of patients where an early invasive strategy may be futile. Since the risk score was derived and validated in retrospective populations, there is now a requirement to prospectively validate it in larger cohorts and across different health care systems prior to its routine use.

 

Novel markers of plaque instability

Progression of ultrasound plaque attenuation and low echogenicity associates with major adverse cardiovascular events.

EHJ 2020; 41:2695-73

Although several pathological features of atherosclerotic plaque are known to be associated with instability and ACS, accurately identifying lesions likely to erode or rupture remains a scientific and clinical ambition. It is challenging because neither the anatomical (angiography, OCT, IVUS) nor physiological (FFR, iFR, CFR) tests that we use, and rely upon, can accurately characterise or predict plaque behaviour. In this study two specific IVUS ‘signature’ appearances were studied: (a) attenuated plaque (AP) characterized by a hypoechoic area with deep ultrasonic attenuation in the absence of calcium and (b) echolucent plaque (ELP) characterized by an intraplaque zone of absent or low echogenicity. The authors sought to associate these imaging biomarkers with clinical outcomes in a post hoc analysis of patients with one or more stenosis (≥20%) at invasive angiography.  Patients underwent IVUS at baseline and again after two years of medical therapy. IVUS was performed in arteries with no stenoses >50%, and no previous revascularisation and with no evidence that it was the culprit of a previous MI. Core laboratory, manually traced, AP and ELP, were performed at 1mm intervals. Of the 1497 patients studied, 18.8% had AP or ELP at baseline. These tended to be males, with an ACS history, diabetic, and had higher percentage stenoses and total atheroma volumes. These patients had a twofold increase in MACE compared with those without AP/ELP at baseline (8.2% vs. 3.9% p<0.01). 10.7% experienced either new or increased AP/ELP. In these patients MACE was even higher compared to those that did not experience progression (10.0% vs. 4.1%, p<0.001). Differences were driven by MI, revascularisation and stroke, as there were no deaths. Interestingly, many patients experienced a decrease in AP/ELP, demonstrating that vulnerable plaque can heal or regress with OMT. The focus on signature appearances appears to be a pragmatic approach that could aid translation into real world practice. Although the criteria and algorithms for calculating the ELP and AP indices appears complicated, the algorithms could likely be automated if this is commercially opportune. However, the proverbial ‘elephant in the room’ is the relevance to real-world clinical practice?  It will be fascinating to see if the results of studies like this one will translate into clear clinical benefit, i.e. will any medical or interventional treatment strategies be shown to improve clinical outcomes when targeted specifically at patients with high risk imaging appearances?

 

ACE inhibitors are safe in the COVID-19 era

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

Lancet 2020; 395:1705-14

The SARS-CoV-2 virus uses the angiotensin-converting enzyme 2 (ACE2) as the receptor for its spike protein to invade host cells and replicate. There is a high degree of homology between ACE2 and ACE, and so naturally there was concern that those taking ACE inhibitors or angiotensin receptor blockers (ARBs) may be predisposed to a more severe episode of COVID-19 if infected. Renin-angiotensin-aldosterone system (RAAS) inhibitors also upregulate the expression of ACE2. Impromptu cessation of these drugs, however, could cause inadvertent harm to those patients with ischaemic heart disease, hypertension, heart failure, or chronic kidney disease secondary to diabetes, already taking them. The very conditions which are notably prevalent in patients with the most severe COVID-19 infections. To study the putative detrimental effect of RAAS inhibitors, investigators from seven hospitals in Madrid performed a case-population study in which 1139 PCR-confirmed cases of COVID-19 were compared against 10 controls per case (N=11390), individually matched for age, sex, region, and date of hospital admission extracted from a primary healthcare database. The study found no significant increase in the risk of COVID-19 requiring hospital admission associated with the administration of ACE inhibitors or ARBs, either as monotherapy or in combination with other drugs. When stratified according to age, sex, diabetes, hypertension, and baseline cardiovascular risk, no significant interaction was observed with any of these variables, other than diabetes, for which RAAS inhibitors were associated with a significantly reduced risk of hospital admission in the context of COVID-19 infection. The investigators have postulated a possible imbalance of ACE:ACE2 in favour of ACE in the lungs of diabetics underpinning this interesting result. This would mean greater ACE activity with simultaneous downregulation of ACE2 by SARS-CoV-2 which would lead to a more serious infection unless there was RAAS inhibitor protection opposing this.

It is the view of the BCIS Council that the assessment of a PCI service should continue to be site-specific. BCIS will therefore continue to assess each site as a separate entity in terms of granting professional approval for its suitability to offer PCI.

This recommendation will apply to merged trusts and to any new PCI centre that is to be supported by clinicians from another site.

BCIS R&D Group

Literature Review January 2020

Prepared by: Michael Mahmoudi, Julian Gunn, Paul Morris & Aung Myat

 

STABLE CAD & ACS

 

Benefits of complete revascularization in STEMI patients are long lasting

Long-term follow-up of complete versus lesion-only revascularization in STEMI and multivessel disease. The CvLPRIT Trial.

JACC 2019; 74:3083-94
Multivessel coronary artery disease (CAD) may be present in up to 50% of patients presenting with STEMI. In such patients, there is increasing evidence that complete revascularization of both the infarct related artery (IRA) and non-culprit lesion(s) either at the time of PPCI or within a relatively short time frame of the index procedure will provide prognostic benefits. The CvLPRIT (Complete Versus Lesion-Only Primary PCI Trial) is the first study to provide data regarding the long-term efficacy of such an approach. The original study recruited 296 patients, with 150 randomized to complete revascularization (CR), and 146 randomized to IRA-only PCI. At a median follow-up of 5.6 years, the primary MACE (all-cause death, MI, heart failure, and ischemia-driven revascularization) endpoint was lower in the CR group (24% vs. 37.7%; HR: 0.57; 95% CI: 0.37-0.87; p=0.0079). The composite endpoint of all cause death/MI was lower in the CR group (10% vs. 18.5%; HR: 0.47; 95% CI: 0.25-0.89; p=0.0175). In a landmark analysis from 12 months to final follow-up, there was no significant difference between MACE, death/MI, and individual components of the primary endpoint suggesting that the majority of the benefits occurred in the early phase and was maintained during longer-term follow-up. It is noteworthy that the vast majority of new revascularization that occurred between 12 months and long-term follow-up in the IRA group were located in the original non-IRA lesion.

 

Left main PCI remains the Achilles heel of interventional cardiology

Percutaneous coronary angioplasty versus coronary artery bypass grafting in the treatment of unprotected left main stenosis: updated 5-year outcomes from the randomised non-inferiority NOBLE trial

Lancet 2020; 395:191-199
Hot on the heels of EXCEL reporting its 5-year outcomes in September 2019, the NOBLE trial published its own 5-year results in December 2019. In brief, NOBLE was a prospective, randomised, open-label, non-inferiority trial which randomised patients 1:1 with left main coronary artery disease (LMCAD) to either PCI or CABG. Patients were recruited from 36 centres in northern Europe, whereas EXCEL recruited from Europe, North and South America, and the Asia Pacific region. EXCEL also recruited patients with low to moderate anatomic complexity (SYNTAX score ≤32), whereas NOBLE did not stipulate a SYNTAX score level of complexity but instead recruited patients with left main lesions visually assessed as >50% or ≤0.80 by fractional flow reserve in the ostium, mid-shaft, or bifurcation, with no more than 3 additional complex lesions (i.e. CTOs, bifurcation lesions needing a 2-stent strategy or lesions with calcified or tortuous vessel morphology). At 3 years, the primary composite endpoint of MACCE (consisting of all-cause mortality, non-procedural MI, any repeat coronary revascularisation, and stroke) were 28% for PCI (121 events) and 18% for CABG (80 events), HR 1.51 (95% CI 1.13-2.00), exceeding the limit for non-inferiority, with CABG shown to be significantly better than PCI (p=0.0044). At 5 years, the Kaplan-Meier estimates of MACCE were 28% (165 events) for PCI and 19% (110 events) for CABG, HR 1.58 (95% CI 1.24-2.01). The difference was driven by significantly higher rates of non-procedural MI (p=0.0002) and repeat revascularisation (p=0.0009) seen in the PCI arm. Therefore CABG was again found to be superior for the primary composite endpoint (p=0.0002).
How prognostically significant is repeat revascularization as an endpoint in this context? EXCEL did not include ischemia driven revascularization (IDR) as a component of the primary endpoint. The principal investigators considered IDR undeserving of parity with critical outcomes such as death, stroke or extensive MI. The justification being repeat revascularization was of no greater clinical consequence than many other adverse perioperative outcomes that would have favoured PCI (when compared to CABG), such as major bleeding, acute kidney injury, arrhythmia, or serious wound infection. Indeed, without repeat revascularization as the major driving force, PCI would have reached equipoise with CABG for the management of symptomatic LMCAD in the NOBLE trial. Moreover, patients may be more willing to accept the likelihood of a repeat percutaneous intervention in the medium to long term over the invasive nature of CABG and the inherently higher risk of perioperative complications. NOBLE also excluded peri-procedural MI from its primary endpoint despite general acceptance that the prognostic implications of an MI tend not to be predicated by when it occurs, but the territorial extent to which it occurs. Greater harmonisation of individual and combined endpoint definitions for future trials is required.

 

The lipid content of coronary lesions may be a novel marker of vulnerability

Identification of patients and plaques vulnerable to future coronary events with near-infrared spectroscopy intravascular ultrasound imaging, a prospective cohort study

Lancet 2019; 394:1629-1637
The desire to accurately detect vulnerable plaques in non-obstructed coronary arteries and be able to predict their likelihood of causing a major adverse cardiovascular event has long been seen as the Holy Grail of interventional cardiology. Identification of thin cap fibroatheroma (TCF) was previously regarded as the most likely substrate for vulnerable plaques. Attempts to image TCF using intravascular ultrasound (IVUS) have, however, been hampered by its inability to identify lipid core and the need for high-level core laboratory support. Focus has thus shifted to detection of lipid-rich plaques (LRP), which are known to cause the majority of coronary deaths from autopsy studies. Near-infrared spectroscopy (NIRS) has been developed to impart unique spectral differences between cholesterol and collagen to readily differentiate LRP from normal vessels or fibrotic and calcified plaques. It is incorporated with IVUS in a dual modality probe, allowing simultaneous analysis of structure and plaque composition. NIRS provides both a graphical result as a yellow area on a red background and a numerical value to indicate LRP size (known as the Lipid Core Burden Index which has a maximum level of 4mm [maxLCBI4mm]). According to previous validation studies, a maxLCBI4mm of >400 is associated with vulnerable plaque causing MI. NIRS is FDA approved.
The LRP study enrolled 1563 patients with suspected CAD proceeding to cardiac catheterization ± PCI and scanned non-culprit lesion segments using NIRS-IVUS. Patient- and plaque-level hierarchical hypotheses were set, each assessing the association between maximum LCBI4mm with non-culprit major adverse cardiovascular events (NC-MACE). Of the 1271 patients with evaluable LCBI4mm, the mean number of arteries scanned per patient was 2.1 with ≥50 mm of eligible vessel in 89% (1135/1271) of patients. Over a 2-year follow-up, the cumulative incidence of NC-MACE was 9%. In patients with max LCBI4mm >400, the unadjusted hazard ratio (HR) was 2.18 (95% CI 1.48–3.22; p<0.0001) and adjusted HR was 1.89 (1.26–2.83; p=0.0021) on a patient level. On a plaque level for segments with a max LCBI4mm > 400, the unadjusted HR increased to 4.22 (95% CI 2.39–7.45; p<0.0001) and the adjusted HR to 3.39 (1.85–6.20; p<0.0001). There were few periprocedural complications (<0.5%). The LRP study is the largest prospective intracoronary imaging study to demonstrate that NIRS-IVUS is a safe and clinically user-friendly tool to appropriately identify patients and coronary segments at greater risk of future adverse coronary events.
But how do we use this information? On a patient level it might identify individuals that require a more intensive lipid-lowering regime and may stimulate greater focus on lifestyle modification. On the other hand such information could be incendiary to a patient that might now feel they are walking around with a ticking time bomb. Good communication will be essential in this scenario. On a plaque-level, prophylactic stenting of vulnerable segments in the absence of haemodynamic compromise may do more harm than good. We await the results of the PROSPECT II (NCT02171065) and PREVENT (NCT02316886) randomised studies comparing optimal medical therapy versus focal stenting plus optimal medical therapy to reduce NC-MACE using IC imaging.

 

Colchicine as a novel, inexpensive secondary prevention therapy post MI?

Efficacy and safety of low-dose colchicine after myocardial infarction.

NEJM 2019; 381:2497-2505
Inflammation is thought to play a central role in the pathogenesis of atherothrombosis. Although pharmacological therapy for secondary prevention (eg. aspirin and statins) appear to have salutary effects on inflammation, the identification of an effective anti-inflammatory agents has remained elusive. The COLCOT investigators evaluated the effects of low dose colchicine (0.5mg OD) on cardiovascular outcomes as well as its long-term safety profile in 4745 patients recruited within 30 days after a MI. The primary efficacy endpoint was a composite of death from cardiovascular causes, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina leading to coronary revascularization. After a median follow-up of 22.6 months, the primary endpoint was lower in the colchicine group than the placebo group (5.5% vs. 7.1%; HR: 0.77; 95% CI: 0.61-0.96; p=0.02). This result was driven predominantly by lower risks for angina and stroke. A significant effect on death from cardiovascular causes or MI was not shown. Overall, the incidence of adverse events was similar in the two groups; however, some gastrointestinal side effects such as nausea were more frequent in the colchicine group as were pneumonias. Of note, 1.9% of the patients were lost to follow-up, 0.6% withdrew consent, and nearly 19% of the patients in both treatment groups stopped receiving colchicine or placebo prematurely. These factors may have obscured the true cardiovascular treatment effect or adverse-event profile.

 

Gender disparity in NSTEMI patients

Outcomes of Women Compared With Men After Non–ST-Segment Elevation Acute Coronary Syndromes.

JACC 2019; 74:3013-22
Women present with CAD at a later age and with a higher burden of comorbidities than men. They are also more likely to present with atypical symptoms and less likely to be treated with guideline-directed medical therapy. Ten TIMI trials including 68,730 patients with NSTEMI, 29% of whom were women, sought to determine whether outcomes differed between women and men after NSTEMI and if any observed differences were due to differences in baseline comorbidities, treatment strategies, or if gender itself was associated with the risk of cardiovascular events during follow-up.
In this study women were older and more frequently had hypertension, diabetes, previous heart failure, and renal disease than men. Women were at similar risk of MACE (CV death, MI, or stroke) compared with men (HR: 1.04; 95% CI 0.99-1.09; p=0.16) but at higher risk of all-cause death (HR: 1.12; 95% CI: 1.01-1.24; p=0.03). After adjustment for baseline differences, risks of MACE ( HR: 0.93; 95% CI: 0.88-0.98; p<0.01) and all-cause death (HR: 0.84; 95% CI: 0.78-0.90; p<0.0001) were lower among women than men.

 

PHYSIOLOGY & IMAGING

 

Moving beyond coronary stenosis in patients with stable chest pain

1-Year Outcomes of Angina Management Guided by Invasive Coronary Function Testing (CoerMicA)

JACC Cardiovasc Interv 2020; 13:33-45
Approximately 50% of patients presenting with stable chest pain may not have significant epicardial coronary stenosis. Coronary microvascular dysfunction has emerged as an important diagnosis in such patients and is associated with an increased risk of MACE independently of conventional risk factors.
The CorMicA trial involving 151 patients with ischemia and no obstructive coronary disease found that an interventional diagnostic procedure (IDP) to rule in or rule out a disorder of coronary vasomotion was feasible and resulted in improved anginal symptoms at 6 months in patients whose IDP results were disclosed compared to the blinded control group. Results at 1 year have shown that the intervention group had improvements in angina by 27% (difference 13.6 units; 95% CI: 7.3-19.9; p<0.001) and EQ-5D index (mean difference 0.11 units; 95% CI: 0.03-0.19; p=0.1). After a median follow-up of 19 months, MACE (mortality, MI, unstable angina, heart failure hospitalization and cerebrovascular events) were similar in both groups (12% vs. 11%; p=0.8).

 

FFR based deferral of coronary revascularization remains a safe practice

Two-Year Outcomes After Deferral of Revascularization Based on Fractional Flow Reserve
The J-CONFIRM Registry

Circ Cardiovasc Interv 2020; e008355
There is overwhelming evidence in support of FFR-guided revascularization. Whether deferral of coronary lesions with FFR<0.80 is safe in real world practice is less clear cut. The J-CONFIRM registry (Long-Term Outcomes of Japanese Patients With Deferral of Coronary Intervention Based on Fractional Flow Reserve in Multicentre Registry) prospectively enrolled 1263 patients with 1447 lesions in whom revascularization was deferred based on FFR. The primary endpoint was the cumulative 2-year incidence of target vessel MI and clinically driven TVR. The mean FFR was 0.86±0.06. At 2 years, target vessel failure rate was 5.5% in deferred lesion, driven by a 5.2% rate of clinically driven TVR. The rates of cardiac death and target vessel related MI was 0.41% and 0.41% respectively. Independent predictors of 2-year target vessel failure were FFR value (per 0.01 decrease; HR: 1.07; 95% CI: 1.04-1.11; p<0.001), left main lesion (HR: 5.89; 95% CI: 2.72-12.8; p<0.001), Moderate to severe calcific lesions (HR: 2.49; 95% CI: 1.36-4.58; p=0.003), haemodialysis (HR: 2.9; 95% CI: 1.11-7.58; p=0.03), and right coronary artery lesion (HR: 1.78; 95% CI: 1.02-3.11; p=0.042).

 

Even More data for deferral of coronary lesions

Outcomes with Deferred Versus Performed Revascularization of Coronary Lesions with Gray-Zone Fractional Flow Reserve Values

Circ Cardiovasc Interv 2019;12:e008315
The management of coronary lesions with FFR values in the gray zone (0.75-0.80) has remained debateable. A meta-analysis of 7 observational studies including 2683 patients comparing a strategy of deferred versus performed revascularization of coronary lesions with gray zone FFR values has reported similar rates of MACE (12.54% vs. 11.25%; OR: 1.64; 95% CI: 0.78-3.44; p=0.19), cardiac mortality (1.25% vs. 0.72%; OR: 1.78; 95% CI: 0.58-5.46; p=0.31), and MI (1.28% vs. 2.66%; OR: 0.79; 95% CI: 0.22-2.79; p=0.71). Deferral of revascularization was associated with a higher incidence of TVR (9.12% vs. 5.78%; OR: 1.85; 95% CI: 1.03-3.33; p=0.04).

 

IC or IV Adenosine-Route does not matter

Individual Lesion-Level Meta-Analysis Comparing Various Doses of Intracoronary Bolus Injection of Adenosine with Intravenous Administration of Adenosine for Fractional Flow Reserve Assessment

Circ Cardiovasc Interv 2020; e007893
The current literature is modestly sized and inconclusive with regards to the equivalence of intravenous (IV) versus intracoronary (IC) adenosine for FFR measurement. A lesion-level meta-analysis including 1972 FFR measurements and 1413 lesions comparing IC and IV (140 μg/kg) from 16 studies has shown a strong correlation (correlation coefficient=0.915; p<0.001) between IC-FFR and IV-FFR. Mean FFR was 0.81±0.11 for IC adenosine and 0.81±0.11 for IV adenosine (p<0.001). A non-clinically relevant mean difference of 0.006 between the two methods were noted. When stratified by the IC adenosine dose, mean difference between IC and IV-FFR were 0.004, 0.011, 0r 0.000 FFR units for low dose (<40μg), intermediate dose (40-99μg) and high dose (100μg) IC adenosine respectively.

 

IMR remains the gold standard for assessment of microvascular function

Pressure-bounded coronary flow reserve to assess the extent of microvascular dysfunction in patients with ST-elevation acute myocardial infarction

EuroIntervention 2019 Dec 24. doi: 10.4244/EIJ-D-19-00674
The importance of microvascular function in both stable and ACS patients is increasingly recognised. In patients with STEMI, elevated microvascular resistance is associated with increased infarct size, complication rates, and adverse prognosis. Given the limitations of current indices of microvascular function (including time and cost), the current study examined whether ‘pressure-bound coronary flow reserve’ (pb-CFR) defined as the interval between the minimum and the maximum possible CFR values would represent a simpler and quicker way for assessing microvascular function at the time of PPCI. In addition to pb-CFR, IMR and CFR were measured with a pressure and temperature sensitive wire. Coronary physiological indices were measured in the infarct-related artery before and /or post-PPCI. Cardiac MRI was performed at 48 hours and six months. In 148 STEMI patients, pb-CFR improved with PCI, was predictive of myocardial injury at 48 hours, demonstrated an association with IMR and was also mildly predictive of microvascular obstruction. However, it was not predictive of LV ejection fraction. IMR outperformed both pb-CFR and CFRthermo in predicting all the key outcomes, prognostic markers and endpoints. Furthermore, pb-CFR was indeterminant in 21% of cases post-PCI. Thus, it seems that in the search for a tool that can provide accurate data regarding microvascular function, IMR remains the current gold standard.

 

Can avoiding IVUS in complex PCI be justified?

Effect of Intravascular Ultrasound–Guided Drug-Eluting Stent Implantation. 5-Year Follow-Up of the IVUS-XPL Randomized Trial.

JACC Cardiovasc Interv 2020; 13:62-71
The advantages of IVUS-guided PCI in reducing cardiac death and repeat revascularization have been confirmed in a multitude of studies. The IVUS-XPL (Impact of Intravascular Ultrasound Guidance on the Outcomes of Xience Prime Stents in Long Lesions) investigators report on the 5 years clinical results of their study in which 1400 patients with long coronary lesions (implanted stent length ≥28mm) were randomised to either IVUS-guided (n=700) or angiography guided (n=700) PCI with an everolimus-eluting stent. The primary outcome was the composite of MACE defined as cardiac death, target lesion-related MI, or ischemia driven TLR. At 5 years follow-up, IVUS-guided PCI was associated with a lower MACE rate (5.6% vs. 10.7%; HR: 0.50; 95% CI: 0.34-0.75; p=0.001). The difference was driven by a lower rate of TLR (4.8% vs. 8.4%; HR: 0.54; 95% CI: 0.33-0.89; p=0.007). By landmark analysis, MACE events between 1 and 5 years was lower in the IVUS-guided PCI group (2.8% vs. 5.2%; HR: 0.53; 95% CI: 0.29-0.95; p=0.03). Of note, the study was originally designed for 2 years follow-up and not 5 years and the optimal IVUS-guided attainment of an expansion index >1.0 is fairly aggressive by most comparisons.

 

CATHETER BASED VALVULAR INTERVENTION

 

Rivaroxaban not appropriate for routine use in patients undergoing TAVI

A Controlled trial of rivaroxaban after transcatheter aortic valve replacement.

NEJM 2020; 382:12-29
Early leaflet thrombosis of TAVI valves has been identified in more than 15% of patients and could be a treatable contributor to future adverse events. Whether routine anticoagulation could prevent leaflet thrombosis and ultimately improve clinical outcomes was the focus of the GALILEO trial. The trial randomized 1644 patients without an established indication for oral anticoagulation following TAVI to either rivaroxaban 10mg daily plus aspirin 75-100mg daily for the first 3 months or aspirin 75-100mg daily plus clopidogrel 75mg daily for the first 3 months. The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated early due to safety concerns.
After a median of 17 months, death or a first thromboembolic event was greater in the rivaroxaban group (incidence rates 9.8 and 7.2 per 100 person-years respectively; HR:1.35; 95% CI: 1.01-1.81; p=0.04). Bleeding was more common in the rivaroxaban group (4.3 and 2.8 per 100 person-years; HR: 1.50; 95% CI: 0.95-2.37; p=0.08) as was death (5.8 and 3.4 per 100 person-years; HR: 1.69; 95% CI: 1.13-2.53). Of note, most of the deaths in the rivaroxaban group were sudden or were due to non- cardiovascular causes, and a minority of the patients who had died had died of a bleeding event. In addition, 37% of the patients discontinued rivaroxaban during the trial, and most deaths occurred long after drug discontinuation.

 

Novel intervention for tricuspid regurgitation

Transcatheter edge-to-edge repair for reduction of tricuspid regurgitation: 6-month outcomes of the TRILUMINATE single-arm study

Lancet 2019; 394:2002-2011
There is a paucity of definitive interventions for severe symptomatic secondary or functional tricuspid regurgitation (TR). Treatment is usually conservative despite an association with adverse outcomes independent of concomitant cardiac or valvular pathology. Only expert-level consensus is available to guide the timing of surgical tricuspid valve repair, which in the main is usually performed in combination with left-sided heart surgery. This has paved the way for the development of transcatheter-based intervention for TR. Given that tricuspid leaflet malcoaptation is the predominant defect in TR, an edge-to-edge clip technique, successfully adopted for treating mitral regurgitation (MitraClip), represents the most promising opportunity to effectively manage functional TR.
The TRILUMINATE study is a prospective multicenter single-arm study aimed at evaluating the safety and effectiveness of the TriClip transcatheter tricuspid valve repair system. Patients were eligible for the study if they had ≥moderate TR, ≥NYHA Class II, and had been adequately treated with optimal medical therapy but were regarded as high risk for surgery. Patients were excluded if they had a pulmonary artery systolic pressure >60 mmHg, prior tricuspid valve intervention or a pacemaker lead implanted in the right ventricle. The primary efficacy endpoint was a reduction in TR by at least one echocardiographic grade by 30 days and the primary safety endpoint was a composite of major adverse events at 6 months. The trial has completed recruiting and the follow-up is ongoing. This paper presented the first 6- month outcomes. From August 2017 to November 2018, 85 patients successfully received TriClip implantation. There was a 100% successful implantation rate. Of those, 71 patients (86%) had achieved a reduction in severity by at least 1 grade at 30 days (p<0.0001). At 6 months, only 3 (4%) of 84 patients had a documented major adverse event. There were, however, no device embolization, MI, or strokes. One patient withdrew prior to 6-month follow-up. Overall, TriClip appears to be a safe and feasible percutaneous method of managing significant functional TR, the caveat being this was not a randomized trial and therefore cannot be definitive regarding any medium- to long-term reduction in morbidity or mortality, for instance in comparison with conservative therapy or surgical intervention.

 

MISCELLANEOUS

 

Troponin rise post PCI confers an adverse prognosis

Peri-procedural elevated myocardial biomarkers predict adverse clinical outcomes following elective percutaneous coronary intervention: a comprehensive dose-response meta-analysis of 24 prospective studies with 44972 patients

Eurointervention 2019 DOI: 10.4244/EIJ-D-19-00737
How many of us request a troponin after PCI? Perhaps we would rather not know. Do we send the patient home, regardless? Do we look at the results or collect the data systematically? In the acute patient, is it just a marker of the underlying condition? In these days of ‘duty of candour’, do we discuss the possible implications of a large troponin rise (‘procedure related’, a ‘troponin blip’) with the patient? Is it meaningful to include peri-procedural markers in composite trial endpoints? This is a particularly important point when dissecting out the results of landmark trials. The authors performed a meta-analysis to evaluate the dose-response relationship between biomarker elevation and the risk of all-cause mortality and MACE following elective PCI. Many of us are not fans of meta-analyses, which have problems associated with publication bias, accessing patient-level data, mixed outcome measures, and variable follow-up periods, to name but four. But the authors worked according to the best standards, known as the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines, and searched for studies between 1979 and 2018. Inevitably, the endpoints shifted from CK-MB to troponin in that study period and, rather than reporting a continuous variable, most studies reported the number in each group (1-3, 3-5, and >5 fold above the upper limit of normal, for example). And there was a lot of data manipulation to express results in a common format. With all those caveats, what they found was a post-procedural troponin >3-fold the 99th centile, and CK-MB > the 99th centile, were associated with increased mortality and MACE. For example, the OR for death if the troponin was 3-5 ULN was 1.5. Of course, it is impossible to correct for every variable, and it is highly likely that the higher marker elevations are found in patients with more extensive, complex or severe disease, and this may well be in the more co-morbid or frail, whose mortality is inevitably going to be higher than the others. Nevertheless, this study serves as a reminder that, on balance, a significant troponin rise at the time of elective PCI is not good for you, and it makes sense to minimise it whenever possible. This may, for instance, have implications for the extent of disease treated, the striving for ‘perfection’, or the drive to complete revascularisation. PCI is a trade-off. One has to know when to stop.