Dear stakeholder

Launch of Acute Aortic Dissection Pathway Toolkit

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

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

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

Kind regards,

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

BCIS R&D Group Literature Update

January 2022

Prepared by Michael Mahmoudi, Julian Gunn & Natalia Briceno
Edited by Michael Mahmoudi

Stable CAD & ACS

FFR-guided PCI not noninferior to CABG in patients with MVD

Fractional flow reserve-guided PCI as compared with coronary bypass surgery.

NEJM 2022; 386:128-137

Coronary artery bypass grafting (CABG) has been shown to improve outcomes in patients with three vessel coronary artery disease (CAD). FFR-guided revascularization with current generation drug-eluting stents (DES) has not been compared with CABG in such patients. The FAME-3 investigators evaluated whether a strategy of FFR-guided PCI with current generation DES is noninferior as compared to CABG with respect to the incidence of MACCE (defined as death from any cause, MI, stroke, or repeat revascularization) in 1500 patients with three vessel CAD. Secondary endpoints included a composite of death, MI, or stroke. Major inclusion criteria were angiographic ≥ 50% stenosis in three major epicardial vessels (without left main involvement) amenable to revascularization by both PCI and CABG. Major exclusion criteria were cardiogenic shock, STEMI within 5 days, and LV ejection fraction < 30%. The mean age of patients was 65 years, 29% had diabetes, 39% presented with an ACS, 13% had undergone previous PCI, patients had an average of 4.3 lesions, 22% of patients had at least one vessel with chronic total occlusion, 68% had at least one bifurcation lesion and the mean SYNTAX score was 26. In the FFR-guided PCI group, the mean number of lesions per patient was 4.3, the mean number of DES implanted per patient was 3.7, and the median stented length was 80mm. FFR was measured in 82% of lesions; the most common reasons for not measuring FFR were sub-totally or completely occluded vessels. The mean FFR was 0.70, and 24% of the lesions intended for treatment had an FFR >0.80. Patients undergoing CABG had a mean of 4.2 lesions and received a mean of 3.4 distal anastomoses.; 97% received a LIMA graft and 25% received multiple arterial grafts. The 1-year incidence of the composite primary endpoint was 10.6% in the PCI group and 6.9% in the CABG group (HR 1.5; 95% CI: 1.1-2.2; p_{for noninferiority} =0.35). The incidence of death, MI, or stroke was 7.3% in the PCI group and 5.2% in the CABG group (HR 1.4; 95% CI:0.9-2.1. The rates of BARC 3-5 bleeding (1.6% vs. 3.8%; p<0.01), and acute kidney injury (0.1% vs. 0.9%; p<0.04), atrial arrythmia (2.4% vs. 14.1%; p<0.001) were greater in the CABG group. Based on these findings FFR-guided PCI using current generation DES did not meet criteria for noninferiority compared with CABG in patients with three vessel CABG.

A novel risk score for contrast nephropathy

A contemporary simple risk score for prediction of contrast-associated acute kidney injury after percutaneous coronary intervention: derivation and validation from an observational registry.

Lancet 2021; 398:1974-81

Contrast administration is routinely performed in many interventional procedures that use x-ray. The development of contrast associated acute kidney injury (AKI) is one of the major potential complications following contrast administration, and in previous studies has been shown to be associated with development of chronic renal impairment, need for renal replacement therapy and mortality. What has been debated are the risk factors that are associated with it’s development. The current study sought to develop a new risk score from a contemporary PCI cohort. Consecutive patients undergoing PCI in a single centre between 2012 to 2020 with available creatinine measurements pre-PCI and within 48 hours after the procedure were included, and those on chronic renal replacement therapy and undergoing multiple procedures were excluded. The derivation cohort were those having undergone PCI between 2012 and 2017 (14,616 patients) and the validation cohort were those having undergone PCI between 2018 and 2020 (5606 patients). A multivariate logistic regression analysis was performed to assess for independent predictors of contract associated AKI, with two regression models developed. Model 1 included only pre procedural variables, and Model 2 included pre procedural and procedural variables. The final risk score was categorised into four groups: low risk, moderate risk, high risk and very high risk. The primary endpoint was contrast induced AKI defined as an increase in the serum creatinine by at least 50% or at least 0.3mg/dL within 48 hours after PCI. The secondary endpoint was all cause deaths. All patients had IV pre and post-hydration and low osmolar non-anionic contrast medium was used. Overall there was a 4.3% rate of contrast associated AKI. Model 1 predictors included clinical presentation (stable versus acute), estimated GFR, LVEF, diabetes, haemoglobin, basal glucose levels, age and congestive cardiac failure. Model 2 included the pre procedural variables alongside procedural variables including contrast volume, peri procedural bleeding, nonflow or slow flow and complex PCI anatomy. Both models resulted in high discriminatory power, which was not impacted with the inclusion of the procedural variables (C-statistic 0.72 in Model 1 and 0.74 in Model 2).  High discriminatory power was also seen in the validation cohort. The observed and predicted rates of contrast associated AKI increased with an increment in the risk group. The development of contrast associated AKI was associated with increased deaths at one year, with a significant separation in the Kaplan-Meier curves within a month following PCI. Salient features include a single centre study, and a relatively small percentage of patients with an eGFR<30.

How late is late for PCI in STEMI?

Percutaneous Myocardial Revascularization in Late-Presenting Patients With STEMI

JACC 2021; 78:1291-1305

The clinical benefits of coronary revascularization in patients presenting late with a STEMI remain controversial and are given a Class IIa recommendation by the American and European societies. The FAST-MI investigators examined the long-term outcome of revascularization in patients presenting with a STEMI between 12-48 hours after symptom onset using the three FAST-MI registries undertaken over a 1-month period in 2005, 2010, and 2015. The three registries included 13,129 patients of whom 1,169 were STEMI latecomer and 1,077 were alive at 48 hours after hospital admission (32 deceased within 48 hours, 59 had undergone fibrinolysis, and 1 patient had no data about reperfusion therapy). In comparison, 5,105 STEMI patients presented within 12 hours of symptom onset. Median time from symptom onset to ICU admission was 3.5 hours in the early comers versus 20.2 hours in the latecomers (p<0.001). From 2005 to 2015, the proportion of latecomers decreased from 22.7% to 16.1% (p<0.001). Latecomer patients were more frequently women (30.8% vs. 25.2%; p<0.001), significantly older (65.2 years ± 14.8 years vs. 62.6 ± 14.1 years; p<0.001), more likely to be diabetic (21.3% vs. 15.5%; p<0.001), and hypertensive (53.2% vs. 46.1%; p<0.001). Multivariate analysis identified age, diabetes, atypical chest pain, prior heart failure, and admission via emergency medical service as characteristics independently related to late presentation. In the latecomer population, 67.7% underwent revascularization within 48 hours following hospital admission (99.6% with PCI and 0.4% with CABG). At 30-day follow-up, all cause death was significantly lower among revascularized latecomers (2.1% vs. 7.2%; p<0.0001). After a median follow-up of 58 months, the rate of all cause death was 30.4 per 1,000 patient-years in the revascularized latecomers versus 78.7 per 1,000 patient-years in the non-revascularized latecomers (p<0.001). In multivariate analysis, revascularization of latecomer STEMI patients was independently associated with a reduction in mortality (HR: 0.65; 95% CI: 0.50-0.84; p=0.001). Accepting the limitations of observational studies, several lines of evidence support the benefit of PCI in latecomers. Firstly, the assumption that the IRA may be completely occluded is not correct as evidenced by the BRAVE-2 study in which 43.4% of patients in the invasive arm had TIMI flow ≥ 2 in the IRA at the time of intervention and 29% had some degree of collateralization. Secondly, imaging studies have shown the presence of significant volume of viable myocardium in late STEMI presenters which may be salvaged with PCI. Finally, a meta-analysis of 10 studies enrolling 3,560 patients with a median time from AMI to randomization of 12 days and follow-up of 2.8 years demonstrated that compared to medical therapy PCI of the IRA was associated with significant improvements in cardiac function and survival.

Is routine therapeutic hypothermia justified in survivors of OOHCA?

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest. The CAPITAL CHILL Randomized Clinical Trial.

JAMA 2021; 326:1494-1503

The overall evidence supporting targeted temperature management in survivors of out-of-hospital cardiac arrest (OOHCA) is of low certainty. We recently highlighted the results of the TTM2 trial which did not support targeted hypothermia in this patient population. The CAPITAL CHILL investigators examined whether moderate therapeutic hypothermia below 31°C was associated with an improvement in clinical outcomes compared with guideline-recommended mild hypothermia below 34°C in a cohort of 367 patients. In the moderate hypothermia arm, targeted temperature was maintained for 24 hours, followed by rewarming over 24 hours and normothermia for 24 hours. In the mild hypothermia arm, targeted temperature was maintained for 24 hours followed by rewarming over 12 hours and normothermia for 24 hours. Cooling was undertaken utilising an endovascular cooling device. The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. There were 19 secondary outcomes including mortality at 180 days and length of stay in the ICU. Neurologic outcome was assessed using the Disability Rating Scale with poor neurologic outcome defined as a score >5. The mean age was 61 years, 19% were female, bystander CPR was performed in 76%, there was an initial shockable rhythm in 86%, and 38% of patients had ST-elevation MI. The primary outcome was similar in the moderate and mild hypothermia groups (48.4% vs. 45.4%; risk difference 3.0%; 95% CI: 7.2%-13.2%; RR 1.07; 95% CI:0.86-1.33; p=0.56). Of the 17 secondary outcomes, the only difference was observed in the length of ICU stay (10 vs. 7 days; p=0.004). Modified Rankin Scale, pneumonia, need for renal replacement therapy, seizures, and TIMI major bleed were all similar in both groups.

FFR_CT does not reduce cost nor does it improve clinical outcomes

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial.

EHJ 2021; 42:3844-52

FFR_CT is a well validated method for determining the presence and extent of CAD combined with physiological assessment of vessel specific ischaemia in patients presenting with chest pain. The clinical effectiveness and economic impact of using FFR_CT instead of other tests in the initial evaluation of patients with stable chest pain had not been tested in a randomized trial. The FORECAST trial randomized 1,400 patients with stable chest pain to either undergo FFR_CT or routine assessment as directed by NICE CG95- guideline for chest pain of recent onset in 11 UK centres and examined whether an evaluation strategy based on FFR_CT would improve economic and clinical outcomes. Patients randomized to the routine arm (n=700) were scheduled for the test recommended by the clinical pathway and the supervising physician then decided upon the clinical management. Patients randomized to the FFR_CT arm were referred for CTCA; any CTCA demonstrating a coronary stenosis ≥40% in at least one major epicardial vessel of a diameter suitable for revascularization was referred for FFR_CT. The primary endpoint was total cardiac cost at 9 months. Secondary endpoints were angina status, quality of life, MACCE and use of invasive coronary angiography. Most patients had an initial CTCA: 63% in the routine arm and 96% in the FFR_CT arm. FFR_CT was undertaken in 38%. Mean age was 60 years, 48% were female, and 13% had diabetes. Median cost was £285 in both arms (p=0.96). MACCE was similar in the routine and FFR_CT arms (10.2% vs. 10.6%; >0.05). Use of invasive angiography was lower in the FFR_CT arm (19.4% vs. 25%; p=0.01). FORECAST thus concluded that a strategy of routine FFR_CT was not associated with reductions in cost or clinical outcomes but reduced the use of invasive coronary angiography.

Optimal medical therapy remains first choice in diabetic patients

Outcome of participants with diabetes in the ISCHEMIA trial.

Circ 2021; 144:1380-1395

It is well established that patients with diabetes have poorer outcomes compared with non-diabetic patients with coronary disease. In the ISCHEMIA and ISCHEMIA-CKD trials ~45% of all cases had diabetes, and in this study these cases underwent a pooled-analysis. The main outcome was to compare the rates of death and MI with a routine invasive strategy against guideline-directed medical therapy for patients with diabetes (n=2553) (including high-risk diabetes subgroups), relative to the outcomes in those without diabetes (n=3347). As a quick aide memoir, ISCHEMIA recruited patients with known or suspected CAD if they had moderate or severe reversible ischemia by imaging or exercise testing. Those with eGFR ≥30 entered the main trial and those <30 were enrolled into ISCHEMIA-CKD.  Over a median of 3.1 years, diabetics had a 12% absolute reduction in event-free survival compared with non-diabetics. However, the main finding was that there was no reduction in death or MI for an initial invasive approach compared with a conservative approach in either the diabetics or non-diabetics. Insulin-dependent diabetics had a poorer event-free survival than non-insulin-dependent diabetics, but even in this group there was no improvement in outcome with an initial invasive strategy. This was all despite the fact that diabetics had more severe CAD, MVD and LV dysfunction. In short, an initial invasive approach was not associated with a reduction in death /MI compared with an initial conservative approach in diabetic (or high-risk diabetic) patients with moderate or severe inducible ischaemia. This study included those with more severe CKD. It is important to remember that these results may not extend to those groups excluded from the ISCHEMIA trials including those with unstable angina, ACS, left main disease, LVSD (<35%). This study highlights the importance of lifestyle changes, weight loss and optimal diabetic control in diabetics with coronary disease – something that is very hard to achieve in everyday clinical practice.

Similar all-cause death at 10 years for SYNTAX patients

Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease.

EHJ 2021; 43:56-67

The debate over how best to revascularize patients with diabetes has been confounded by many factors such as continuously evolving interventional techniques, old pharmacology, & methodological limitations. The key messages have been that as compared to non-diabetic patients, those with diabetes have a worse prognosis regardless of the revascularization technique and CABG has the edge over PCI in terms of repeat revascularisation. The current manuscript analysed the 10-year survival of all-cause death according to diabetic status and revascularization strategy in diabetics (n=452) and non-diabetics (n=1,348) in the landmark SYNTAX trial. In diabetic patients, the risk of mortality was numerically higher with PCI compared with surgery at 5 years (19.6% vs. 13.3%; HR: 1.53; 95% CI: 0.96-2.43; p=0.075), with the opposite seen between 5 and 10 years (20.8% vs. 24.4%; HR: 0.82; 95% CI: 0.52-1.27; p=0.366). Irrespective of diabetic status, there was no difference in all-cause death at 10 years between patients receiving PCI or CABG. In insulin treated patients (n=182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%; difference: 8.2%; 95% CI: -6.5-22.5; p=0.227). The current study did not examine repeat revascularization which one would expect to be greater in the PCI group. Salient features include lack of adequate statistical power and subgroup analyses may have increased the risk of types 1 and 2 error, lack of formal correction for multiple testing, and application of results to those with de novo 3VD and/or LM disease rather than general CAD patients.

Antiplatelet Therapy

Ticagrelor monotherapy beats DAPT in HBR patients

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HB

EHJ 2021; 42:4624-4634

The TWIGHLIGHT study has indicated that early cessation of aspirin at three months (i.e. ticagrelor monotherapy) is superior to continuing DAPT (i.e. aspirin and ticagrelor) in terms of bleeding, but with no apparent increase in the secondary outcome measure of death, MI or stroke. In this pre-specified TWIGHLIGHT sub-analysis, the investigators studied the effect of cessation of DAPT at three months, but only in those with high bleeding risk (HBR). HBR was defined as at least one Academic Research Consortium major criterion (eGFR <30, platelets <100, previous major bleeding, significant liver disease) or two minor criteria (age ≥75 years, eGFR 30-60, Hb 11-13/12 men /women, regular NSAID use). 1,064 patients met the inclusion criteria. Ticagrelor monotherapy was associated with a 5.1% reduction in BARC class 2 (‘actionable’ bleeding requiring investigation and hospitalisation), 3 (overt bleeding with Hb drop of ≥3g/dL or intracranial haemorrhage), or 5 (probable or definite fatal bleeding) bleeding in those with HBR. The magnitude of the reduction in BARC 2, 3 or 5 bleeding associated with early DAPT cessation was similar in HBR patients (HR 0.53) and non-HBR patients. However, the magnitude of effect of monotherapy was greater on more major bleeding (BARC 3 or 5) (HR 0.31 vs 0.62). Ticagrelor monotherapy was not associated with a significant increase in ischaemic events (death, MI, stroke). However, this was a sub-study and was underpowered to detect clinically relevant differences in ischaemic events. The main findings were (a) HBR patients experienced higher rates of both bleeding and ischaemic events than non-HBR patients, (b) early cessation of aspirin at three months with continuing ticagrelor monotherapy reduced bleeding and especially major bleeding comparted with longer term DAPT and (c) the magnitude if this effect was greater in HBR patients than non-HBR patients. As the trial literature regarding dual antiplatelet therapy accumulates there seems to be evidence to support both longer and shorter duration DAPT, depending on the clinical context. Broadly, longer duration and more potent DAPT protects against ischaemic events, but at the expense of increased bleeding risk. Although this study is underpowered to be completely relaxed about the effects on ischaemic risk, the results do appear to support that ticagrelor monotherapy from three months onwards is effective in reducing bleeding events, especially major bleeding events, compared with longer term DAPT with ticagrelor and aspirin.

Ticagrelor or prasugrel-the debate rages on!

Ticagrelor or prasugrel for patients with acute coronary syndrome treated with percutaneous coronary intervention: a prespecified subgroup analysis of a randomized clinical trial.

JAMA Cardiol 2021; 6:1121-29

Aspirin in combination with either ticagrelor or prasugrel have become established as the dual antiplatelet therapy of choice. The ISAR REACT 5 trial compared ticagrelor and prasugrel as part of DAPT therapy, both in combination with aspirin, in 4018 patients presenting with ACS in whom an interventional strategy was planned. The cohort was representative of real-world intervention: 12% unstable angina, 46% NSTEMI and 41% STEMI. 83% were treated with PCI, 2% CABG and 14% conservatively. Patients were randomised 1:1 and the 12-month primary outcome was a composite of death, nonfatal MI, or stroke. The secondary (safety) outcome was BARC major (3-5) bleeding. There was a 2.4% absolute reduction in the primary outcome with prasugrel (6.9% vs 9.3%) driven by a reduction in non-fatal MI. There was no associated increase in major bleeding. In fact, major bleeding was numerically lower with prasugrel (4.8% vs 5.4%). Stent thrombosis rates were low overall but numerically lower with prasugrel (0.6% vs 1.1%). The study was open-label, but outcomes adjudication was blinded. Importantly, those taking ticagrelor were more likely to discontinue therapy before 12 months (15% vs 12%). The twice daily dosing regime of ticagrelor is likely to have influenced this, and overall compliance. The current study is a  pre-specified analysis of the 3377 patients who, after randomisation, underwent PCI. Again, the primary outcome measure was death, MI, or stroke at 12 months and the safety end point was BARC 3-5 bleeding. 1676 were treated with ticagrelor and 1701 with prasugrel. Compared with the main study, rates of the primary endpoint were similar but again, this was lower in the prasugrel group (9.8% vs 7.1%, HR 1.41). Rates of bleeding were again non-significantly different with a slight trend to lower bleeding with prasugrel (5.3% vs 4.9%). The results of both analyses are similar overall, perhaps not surprising given that the second study was a sub-analysis of >80% of those in the first study. The results appear slightly counter-intuitive given that, with appropriate administration, chronic ticagrelor therapy is thought to offer slightly higher levels of, and more stable platelet inhibition than prasugrel. Moreover, these differences were not replicated in the recent SWEDEHEART registry analysis of nearly 38,000 MI patients managed with PCI, in which there were no differences in MACE or bleeding between ticagrelor or prasugrel treatment. Ticagrelor also offers the advantage of being a reversible P2Y12 inhibitor with shorter offset of action. In short, it seems that ticagrelor offers slightly greater and more predictable platelet inhibition and is reversible, but its twice daily regime may impair compliance and this may explain the findings in both ISAR-REACT 5 analyses. Whether or not these differences are strong enough to influence what becomes considered first and second line treatment remain to be seen.

TALOS-AMI supports unguided de-escalation

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator initiated, open-label, multicentre, non-inferiority, randomised trial.

Lancet 2021; 389:1803-10

It is well established that anti-platelets are essential in reducing recurrent thrombotic events. With the advent of more potent P2Y₁₂ inhibition and following favourable trial data, guidelines now recommend the use of ticagrelor or prasugrel in patients with AMI to further reduce ischaemic events and stent thrombosis. However, both major RCTs of ticagrelor and prasugrel found increased bleeding rates, which occurs more frequently during the maintenance phase. This open label, assessor masked, multi-centre non-inferiority randomised controlled trial (TALOS-AMI) sought to test the hypothesis that unguided (without platelet function testing or genomic testing) de-escalation of ticagrelor to clopidogrel in stabilized AMI patients is non-inferior to ticagrelor based dual antiplatelet therapy (DAPT). Patients who had biomarker positive acute myocardial infarction who underwent successful PCI and with no significant ischaemic or bleeding events within the first month were selected and enrolled. Exclusion criteria included cardiogenic shock, active bleeding and coagulopathy within two months. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke or bleeding type 2,3,5 (BARC criteria). A total of 2,697 patients were randomly assigned 30 days after PCI to undergo de-escalation therapy to clopidogrel up to 12 months (n=1,349) or continued ticagrelor treatment (n=1,348) across 32 centres in South Korea. 90% of the patients randomised received the allocated treatment in the de-escalation arm, and 87% in the active control arm. There was no significant difference in demographic, clinical and procedural data. 53% presented as a STEMI, and there was overall a high rate of femoral access used during index PCI. Approximately a quarter of patients had multi-vessel disease. Following one year, the primary end point occurred in 4.6% of the de-escalation group and 8.2% in the active control group (P_{non-inferiority} <0.001; HR 0.55 [95% CI 0.40-0.76]. There was an absolute risk reduction of 3.6%, driven by reduced bleeding rates. Of note in the pre-specified secondary end point of composite of CV death, stroke, and myocardial infarction no difference was observed. There was also a reduction in the more severe BARC 3 and 5 bleeding events observed. Of note there was also no difference seen in repeat revascularisation or stent thrombosis rates between groups. The de-escalation strategy also met superiority requirements in the intention to treat as well as the per protocol and as treated populations. This trial appears to indicate that in patients that have surpassed their most at-risk period following PCI, unguided de-escalation can be performed safely with a reduction in significant bleeding events.

Valvular Intervention

TA at the time of mitral surgery reduces TR progression

Concomitant tricuspid repair in patients with degenerative mitral regurgitation.

NEJM 2021 Online

The optimal management of concomitant mild or moderate tricuspid regurgitation (TR) at the time of surgical intervention for degenerative mitral regurgitation (MR) is uncertain. The CTSN investigators examined the benefits and risks of tricuspid valve repair at the time mitral valve surgery in 401 patients with moderate or less than moderate TR who were undergoing surgery for degenerative MR. 203 patients were randomized to mitral valve surgery alone (surgery alone) and 198 patients were randomized ratio to undergo mitral surgery and tricuspid annuloplasty (surgery plus TA). Major exclusion criteria were secondary MR, primary tricuspid valve disease and suboptimal volume management. The primary endpoint at 2 years was a composite of reoperation for TR, progression of TR from baseline by two grades or the presence of severe TR, or death. Secondary endpoints included death, MACCE (defined as a composite of death, stroke, MI, or serious heart failure events), permanent pacemaker implantation (PPM), length of hospital stay, and cost effectiveness. The core laboratory confirmed moderate TR in 37.3%, RV systolic function was normal 90.5%, and 30% had NYHA class III or IV heart failure. In the tricuspid annuloplasty recipients, the average annuloplasty ring size was 29.0±1.9mm in men and 27.8±1.6mm in women. The primary endpoint was significantly greater in the surgery-alone group (10.2%) than in the surgery plus TA group (3.9%) (RR 0.37; 95% CI: 0.16-0.86; p=0.02). Death occurred in 4.5% in the surgery-alone group and 3.2% in the surgery plus TA group (RR 0.69; 95% CI: 0.25-1.88). No patients underwent tricuspid valve reoperation within 2 years after randomization. More patients in the surgery-alone group had progression of TR at 2 years (6.1% vs 0.6%; RR 0.09; 95% CI:0.01-0.69). The frequencies of MACCE, functional status, and quality of life were similar in both groups at 2 years although the incidence of PPM was higher in the surgery plus TA group (14.1% vs. 2.5%; RR 5.75; 95% CI:2.27-14.60). The rate of heart failure events was 0.11 per 24 patient-months in the surgery-alone group and 0.07 per 24 patient-months in the surgery plus TA group (RR 0.68; 95% CI: 0.25-1.85). The median length of stay during the index hospitalization was 2 days shorter in the surgery-alone group. The trial concluded that concomitant tricuspid valve repair at the time of mitral valve surgery in patients with less than severe TR at baseline results in improved outcomes at 2 years primarily in reducing the progression to worse/severe TR. The PPM rate was 5x higher in the surgery plus TR group and it is conceivable that over the long-term this can result in lead-related TR and potentially nullify these benefits.

To treat or not treat CAD prior to TAVI

ACTIVATION (percutaneous coronary intervention prior to transcatheter aortic valve implantation). A randomized clinical trial.

JACC Cardiol Intv 2021; 14:1965-74

The role of PCI in patients with concomitant significant coronary artery disease (CAD) and severe aortic stenosis who are due to undergo TAVR is unclear. The ACTIVATION trial was a randomized, open-label, noninferiority clinical trial undertaken in 17 European centres, included 235 patients, and designed to determine if PCI prior to TAVR in patients with significant CAD would produce noninferior clinical outcomes when compared to no PCI. Key inclusion criteria were severe AS deemed suitable for TAVR following heart team discussion and at least 1 stenosis of ≥70% stenosis in a major epicardial artery or ≥50% in a protected left main stem or vein graft suitable for PCI. Key exclusion criteria were ACS within 30 days of enrolment, CCS angina class III or greater, unprotected left main stem disease, or clinical features that would prohibit dual antiplatelet therapy. The primary endpoint was a composite of all-cause death or rehospitalization at 1 year. Noninferiority testing was performed in the intention-to-treat population. Eligible patients were randomised to undergo either PCI  or no PCI prior to TAVR. Based on reduced recruitment rates the Trial Steering Committee recommended early termination of the trial (the study was powered for 310 patients). Baseline characteristics were similar in both groups. Significant angiographic stenosis in the LAD was identified in 61.3% of those randomized to PCI and 60.5% randomized to no PCI. In those randomized to PCI, PCI was indicated for single vessel disease in 71.4% patients with a mean angiographic stenosis of 80±15%. The median number of lesions treated was 1. Mean treated lesion length was 17.4±6.6mm. A BMS was used in 18.1% of patients. At 1 year the primary endpoint occurred in 41.5% of the PCI arm and 44% of the no-PCI arm. The requirement for noninferiority was not met with a difference of -2.5% and 1-sided 95% confidence limit reaching 8.5%. Mortality was 13.4% in the PCI arm and 12.1% in the no PCI arm (p=0.99). The rates of MI (6.7% vs. 3.4%; p-0.30), stroke (5.9% vs. 6.9%; p=0.55), and acute kidney injury (10.1% vs. 4.3%; p=0.11) were similar in the PCI and no PCI group. Bleeding events at 1 year was greater in the PCI group (44.5% vs. 28.4%; p=0.021). Salient features of the trial include smaller-than-planned population, the noninferiority design (no PCI with potential advantages of no bleeding or kidney injury risk, single procedure and lower cost to be tested for noninferiority versus PCI and not vice versa), visual estimation of coronary stenosis, lack of predefined antithrombotic protocol, and the use of BMS.

Encouraging durability for TAVI

Native aortic valve disease progression and bioprosthetic valve degeneration in patient with transcatheter aortic valve implantation.

Circ 2021; 144:1396-1408

Despite the widespread adoption of TAVI in clinical practice, a number of questions including valve durability and ongoing disease activity within the retained aortic valve leaflets remain unanswered. The current study sought to answer these questions using ¹⁸F-sodium fluoride positron emission tomography (¹⁸F-NaF PET), which has been shown to be a marker of calcification activity and vascular injury across several cardiovascular conditions. Patients (n=47) were recruited into this study that had had a TAVI at one month, two years and five years prior, without significant haemodynamic evidence of valve degeneration. Each patient underwent a CT angiogram, echocardiogram and ¹⁸F-NaF PET at baseline, followed by an annual repeat echo. These were compared with a cohort of surgical aortic valve replacement (SAVR) patients (n=51) recruited into a similar study with the same imaging protocol. The investigators also performed an ex vivo assessment using histological immunohistochemistry and ¹⁸F-NaF autoradiography of explanted native valves and bioprosthetic valves obtained from patients with degenerative TAVI valves. The imaging protocol was performed at one month (n=9, 19%), 2 years (n=22, 47%) and 5 years (n=16, 34%). The patients with prior TAVI were older and were more likely to have co-morbidities such as diabetes, with a greater effective orifice area. In the ex vivo study calcified native aortic valve tissue was present around the perimeter of TAVI bioprosthesis, with evidence of ongoing calcification activity in the native valve. ¹⁸F-NaF uptake was seen on the explanted TAVI bioprosthesis, with colocalization of this signal to regions of calcification seen on histological immunohistochemistry analyses.  In the TAVI cohort, native valve uptake was highest in patients imaged 5 years after their TAVI, with a modest positive correlation with time from TAVI (r=0.36, p=0.023). At baseline all but 3 patients had normal valve function. All three had five year old TAVIs. Overall, 8 patients had imaging evidence on echo or CT of valve degeneration, 7 of which were imaged 5 years after TAVI. Seven patients were seen to have ¹⁸F-NaF uptake, all with five-year-old valves. The three highest uptake values were observed in patients with echo evidence of haemodynamic structural valve degeneration. During follow up echo the investigators observed a strong correlation between baseline ¹⁸F-NaF uptake and change in bioprosthetic valve peak velocity. On multivariable analysis ¹⁸F-NaF uptake was the only predictor of annualized change in peak velocity. There was no significant difference in degeneration on CT or echo between the SAVR and TAVI cohorts. ¹⁸F-NaF uptake was numerically almost doubled in the SAVR cohort, which did not reach statistical significance.  Although a small non-randomised observational study, this has given some insight into the mechanisms of aortic stenosis, suggesting that it is an active disease process which is independent of valve movement and mechanical ‘wear and tear’. ¹⁸F-NaF as a tracer for PET has been identified as a marker of subclinical valve degeneration and predicting subsequent development of valve dysfunction, which will need to be evaluated in larger studies. TAVI and SAVR had similar rates of degeneration in this study.

miscellaneous

Myocarditis is most common in the young post Pfizer vaccine

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.

NEJM 2021; 385:2132-39

Several reports have shown an association between the development of myocarditis and the mRNA vaccines against COVID-19. The current study examined this association using the database of the Clalit Health Services, the largest health care organization in Israel in patients who had received at least one dose of the Pfizer-BioNTech vaccine. This health care system provides care for 52% of the total population in Israel. The cohort were patients who had been vaccinated between December 20, 2020 through May 24, 2021. A follow-up period of 42 days after the first dose was chosen to allow at least 21 days of follow-up after each of the two vaccine doses. A patient was considered to have myocarditis if the Centers for Disease Control and Prevention (CDC) case definition for suspected, probable, or confirmed myocarditis had been met. During the study period, 2,558,421 patients had received at least one dose of the vaccine and 94% of these had received two doses. 54 cases were diagnosed with myocarditis of whom 41 were classified as mild, 12 as intermediate, and 1 as fulminant. The median age of patients with myocarditis was 27 years, 94% were male, 83% had no coexisting medical condition, 13% were receiving treatment for chronic diseases, 69% were diagnosed with myocarditis after the second dose of the vaccine with a median interval of 21 days between doses. The presenting symptom was chest pain in 82% of cases. Vital signs on admission were generally normal; 1 patient presented with hemodynamic instability and non-required circulatory support. The most common ECG abnormality was ST elevation, median peak troponin was 680 ng/L, 5% had non-sustained VT, 3% had AF, and 29% had left ventricular systolic dysfunction (LVSD) on echocardiography (17% were classified as mild, 4% mild to moderate, 4% moderate, 2% moderate to severe, and 2% as severe). The overall incidence of myocarditis within 42 days after having the first dose per 100,000 vaccinated persons was 2.13 cases (95% CI:1.56-2.70). The highest incidence of myocarditis was observed in male patients aged between 16 and 29 years (10.69 cases per 100,000 persons; 95% CI: 6.93-14.46). Salient features include a modest proportion of patients with myocarditis undergoing cardiac MRI (28%), myocardial biopsy undertaken in only one patient, and a short follow-up period to determine the long-term clinical implications of myocarditis post vaccination.

Blood pressure linked to the development of diabetes mellitus

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis.

Lancet 2021; 398:1974-83

In type 2 diabetes, blood pressure management is a well-established therapeutic strategy to reduce both macrovascular and microvascular complications. However, whether blood pressure lowering can prevent the development of type 2 diabetes is unknown. Previous observational studies have had conflicting results and have been unable to tease out the drug class specific effects. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) provided individual participant data for this meta-analysis. All primary and secondary prevention RCTs between 1973 and 2008 that used a specific class/classes of antihypertensive drug versus placebo, or other classes of anti-hypertensives who had at least 1000 person years of follow up were included. Those participants with known diabetes at baseline or trials that were conducted in populations with high prevalence of diabetes were excluded. 19 trials (203,368 patients, 60.6% men) were included in the one-stage individual participant data meta-analysis to test the hypothesis that BP lowering leads to reduced incidence of type 2 diabetes. A Bayesian fixed effect network analysis model was used to compare the effect of different classes of anti-hypertensives in 22 trials. A stratified cox proportional hazards model with fixed treatment effects and participants as the unit of analysis was used to adjust for confounders, with standardised effect sizes for 5mmHg reduction in systolic blood pressure used. Median follow up was 4.5 years. The incidence rate for developing type 2 diabetes per 1000 person years was 16.4 (95% CI 16.01-16.87) in the comparator arm and 15.94 (95% CI 15.47-16.42), with a hazard ratio of new onset diabetes for a 5mmHg reduction in systolic blood pressure of 0.89 (95% CI 0.84-0.95).  In the Bayesian network meta-analysis of 22 RCTs, ACEIs and ARBs reduced the risk of diabetes compared with placebo (risk ratio 0.84 for both). Beta-blockers and thiazide diuretics were found to increase the risk of diabetes compared with placebo (RR 1.48 and 1.20 respectively), whilst calcium channels blockers had no impact.   No significant change in the results was seen after adjustment for baseline characteristics and after accounting for random effects in the Cox model. Interestingly baseline body mass index also had no impact on treatment effects. This was a large meta-analysis involving individual patient data with robust statistical tests used in the data analysis, including assessment of acquisition bias and undertaking sensitivity analyses. The key findings were that a reduction of SBP by 5mmHg resulted in lower numbers of new onset type 2 diabetes, and in terms of pharmacotherapy, ACEIs and ARBs had the greatest impact. This suggests that blood pressure is a modifiable risk factor in the development of diabetes, and therefore should be a target in primary prevention, particularly for those with other risk factors for diabetes. It also suggests that renin-angiotensin-aldosterone pathway deactivation may be involved in reducing the risk of diabetes. Further pre-clinical studies and randomised trials with the development of diabetes as a main outcome should be conducted to investigate this further.

BCIS R&D Group Literature Update

January 2022

Prepared by Michael Mahmoudi, Julian Gunn & Natalia Briceno
Edited by Michael Mahmoudi

Stable CAD & ACS

FFR-guided PCI not noninferior to CABG in patients with MVD

Fractional flow reserve-guided PCI as compared with coronary bypass surgery.

NEJM 2022; 386:128-137

Coronary artery bypass grafting (CABG) has been shown to improve outcomes in patients with three vessel coronary artery disease (CAD). FFR-guided revascularization with current generation drug-eluting stents (DES) has not been compared with CABG in such patients. The FAME-3 investigators evaluated whether a strategy of FFR-guided PCI with current generation DES is noninferior as compared to CABG with respect to the incidence of MACCE (defined as death from any cause, MI, stroke, or repeat revascularization) in 1500 patients with three vessel CAD. Secondary endpoints included a composite of death, MI, or stroke. Major inclusion criteria were angiographic ≥ 50% stenosis in three major epicardial vessels (without left main involvement) amenable to revascularization by both PCI and CABG. Major exclusion criteria were cardiogenic shock, STEMI within 5 days, and LV ejection fraction < 30%. The mean age of patients was 65 years, 29% had diabetes, 39% presented with an ACS, 13% had undergone previous PCI, patients had an average of 4.3 lesions, 22% of patients had at least one vessel with chronic total occlusion, 68% had at least one bifurcation lesion and the mean SYNTAX score was 26. In the FFR-guided PCI group, the mean number of lesions per patient was 4.3, the mean number of DES implanted per patient was 3.7, and the median stented length was 80mm. FFR was measured in 82% of lesions; the most common reasons for not measuring FFR were sub-totally or completely occluded vessels. The mean FFR was 0.70, and 24% of the lesions intended for treatment had an FFR >0.80. Patients undergoing CABG had a mean of 4.2 lesions and received a mean of 3.4 distal anastomoses.; 97% received a LIMA graft and 25% received multiple arterial grafts. The 1-year incidence of the composite primary endpoint was 10.6% in the PCI group and 6.9% in the CABG group (HR 1.5; 95% CI: 1.1-2.2; p_{for noninferiority} =0.35). The incidence of death, MI, or stroke was 7.3% in the PCI group and 5.2% in the CABG group (HR 1.4; 95% CI:0.9-2.1. The rates of BARC 3-5 bleeding (1.6% vs. 3.8%; p<0.01), and acute kidney injury (0.1% vs. 0.9%; p<0.04), atrial arrythmia (2.4% vs. 14.1%; p<0.001) were greater in the CABG group. Based on these findings FFR-guided PCI using current generation DES did not meet criteria for noninferiority compared with CABG in patients with three vessel CABG.

A novel risk score for contrast nephropathy

A contemporary simple risk score for prediction of contrast-associated acute kidney injury after percutaneous coronary intervention: derivation and validation from an observational registry.

Lancet 2021; 398:1974-81

Contrast administration is routinely performed in many interventional procedures that use x-ray. The development of contrast associated acute kidney injury (AKI) is one of the major potential complications following contrast administration, and in previous studies has been shown to be associated with development of chronic renal impairment, need for renal replacement therapy and mortality. What has been debated are the risk factors that are associated with it’s development. The current study sought to develop a new risk score from a contemporary PCI cohort. Consecutive patients undergoing PCI in a single centre between 2012 to 2020 with available creatinine measurements pre-PCI and within 48 hours after the procedure were included, and those on chronic renal replacement therapy and undergoing multiple procedures were excluded. The derivation cohort were those having undergone PCI between 2012 and 2017 (14,616 patients) and the validation cohort were those having undergone PCI between 2018 and 2020 (5606 patients). A multivariate logistic regression analysis was performed to assess for independent predictors of contract associated AKI, with two regression models developed. Model 1 included only pre procedural variables, and Model 2 included pre procedural and procedural variables. The final risk score was categorised into four groups: low risk, moderate risk, high risk and very high risk. The primary endpoint was contrast induced AKI defined as an increase in the serum creatinine by at least 50% or at least 0.3mg/dL within 48 hours after PCI. The secondary endpoint was all cause deaths. All patients had IV pre and post-hydration and low osmolar non-anionic contrast medium was used. Overall there was a 4.3% rate of contrast associated AKI. Model 1 predictors included clinical presentation (stable versus acute), estimated GFR, LVEF, diabetes, haemoglobin, basal glucose levels, age and congestive cardiac failure. Model 2 included the pre procedural variables alongside procedural variables including contrast volume, peri procedural bleeding, nonflow or slow flow and complex PCI anatomy. Both models resulted in high discriminatory power, which was not impacted with the inclusion of the procedural variables (C-statistic 0.72 in Model 1 and 0.74 in Model 2).  High discriminatory power was also seen in the validation cohort. The observed and predicted rates of contrast associated AKI increased with an increment in the risk group. The development of contrast associated AKI was associated with increased deaths at one year, with a significant separation in the Kaplan-Meier curves within a month following PCI. Salient features include a single centre study, and a relatively small percentage of patients with an eGFR<30.

How late is late for PCI in STEMI?

Percutaneous Myocardial Revascularization in Late-Presenting Patients With STEMI

JACC 2021; 78:1291-1305

The clinical benefits of coronary revascularization in patients presenting late with a STEMI remain controversial and are given a Class IIa recommendation by the American and European societies. The FAST-MI investigators examined the long-term outcome of revascularization in patients presenting with a STEMI between 12-48 hours after symptom onset using the three FAST-MI registries undertaken over a 1-month period in 2005, 2010, and 2015. The three registries included 13,129 patients of whom 1,169 were STEMI latecomer and 1,077 were alive at 48 hours after hospital admission (32 deceased within 48 hours, 59 had undergone fibrinolysis, and 1 patient had no data about reperfusion therapy). In comparison, 5,105 STEMI patients presented within 12 hours of symptom onset. Median time from symptom onset to ICU admission was 3.5 hours in the early comers versus 20.2 hours in the latecomers (p<0.001). From 2005 to 2015, the proportion of latecomers decreased from 22.7% to 16.1% (p<0.001). Latecomer patients were more frequently women (30.8% vs. 25.2%; p<0.001), significantly older (65.2 years ± 14.8 years vs. 62.6 ± 14.1 years; p<0.001), more likely to be diabetic (21.3% vs. 15.5%; p<0.001), and hypertensive (53.2% vs. 46.1%; p<0.001). Multivariate analysis identified age, diabetes, atypical chest pain, prior heart failure, and admission via emergency medical service as characteristics independently related to late presentation. In the latecomer population, 67.7% underwent revascularization within 48 hours following hospital admission (99.6% with PCI and 0.4% with CABG). At 30-day follow-up, all cause death was significantly lower among revascularized latecomers (2.1% vs. 7.2%; p<0.0001). After a median follow-up of 58 months, the rate of all cause death was 30.4 per 1,000 patient-years in the revascularized latecomers versus 78.7 per 1,000 patient-years in the non-revascularized latecomers (p<0.001). In multivariate analysis, revascularization of latecomer STEMI patients was independently associated with a reduction in mortality (HR: 0.65; 95% CI: 0.50-0.84; p=0.001). Accepting the limitations of observational studies, several lines of evidence support the benefit of PCI in latecomers. Firstly, the assumption that the IRA may be completely occluded is not correct as evidenced by the BRAVE-2 study in which 43.4% of patients in the invasive arm had TIMI flow ≥ 2 in the IRA at the time of intervention and 29% had some degree of collateralization. Secondly, imaging studies have shown the presence of significant volume of viable myocardium in late STEMI presenters which may be salvaged with PCI. Finally, a meta-analysis of 10 studies enrolling 3,560 patients with a median time from AMI to randomization of 12 days and follow-up of 2.8 years demonstrated that compared to medical therapy PCI of the IRA was associated with significant improvements in cardiac function and survival.

Is routine therapeutic hypothermia justified in survivors of OOHCA?

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest. The CAPITAL CHILL Randomized Clinical Trial.

JAMA 2021; 326:1494-1503

The overall evidence supporting targeted temperature management in survivors of out-of-hospital cardiac arrest (OOHCA) is of low certainty. We recently highlighted the results of the TTM2 trial which did not support targeted hypothermia in this patient population. The CAPITAL CHILL investigators examined whether moderate therapeutic hypothermia below 31°C was associated with an improvement in clinical outcomes compared with guideline-recommended mild hypothermia below 34°C in a cohort of 367 patients. In the moderate hypothermia arm, targeted temperature was maintained for 24 hours, followed by rewarming over 24 hours and normothermia for 24 hours. In the mild hypothermia arm, targeted temperature was maintained for 24 hours followed by rewarming over 12 hours and normothermia for 24 hours. Cooling was undertaken utilising an endovascular cooling device. The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. There were 19 secondary outcomes including mortality at 180 days and length of stay in the ICU. Neurologic outcome was assessed using the Disability Rating Scale with poor neurologic outcome defined as a score >5. The mean age was 61 years, 19% were female, bystander CPR was performed in 76%, there was an initial shockable rhythm in 86%, and 38% of patients had ST-elevation MI. The primary outcome was similar in the moderate and mild hypothermia groups (48.4% vs. 45.4%; risk difference 3.0%; 95% CI: 7.2%-13.2%; RR 1.07; 95% CI:0.86-1.33; p=0.56). Of the 17 secondary outcomes, the only difference was observed in the length of ICU stay (10 vs. 7 days; p=0.004). Modified Rankin Scale, pneumonia, need for renal replacement therapy, seizures, and TIMI major bleed were all similar in both groups.

FFR_CT does not reduce cost nor does it improve clinical outcomes

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial.

EHJ 2021; 42:3844-52

FFR_CT is a well validated method for determining the presence and extent of CAD combined with physiological assessment of vessel specific ischaemia in patients presenting with chest pain. The clinical effectiveness and economic impact of using FFR_CT instead of other tests in the initial evaluation of patients with stable chest pain had not been tested in a randomized trial. The FORECAST trial randomized 1,400 patients with stable chest pain to either undergo FFR_CT or routine assessment as directed by NICE CG95- guideline for chest pain of recent onset in 11 UK centres and examined whether an evaluation strategy based on FFR_CT would improve economic and clinical outcomes. Patients randomized to the routine arm (n=700) were scheduled for the test recommended by the clinical pathway and the supervising physician then decided upon the clinical management. Patients randomized to the FFR_CT arm were referred for CTCA; any CTCA demonstrating a coronary stenosis ≥40% in at least one major epicardial vessel of a diameter suitable for revascularization was referred for FFR_CT. The primary endpoint was total cardiac cost at 9 months. Secondary endpoints were angina status, quality of life, MACCE and use of invasive coronary angiography. Most patients had an initial CTCA: 63% in the routine arm and 96% in the FFR_CT arm. FFR_CT was undertaken in 38%. Mean age was 60 years, 48% were female, and 13% had diabetes. Median cost was £285 in both arms (p=0.96). MACCE was similar in the routine and FFR_CT arms (10.2% vs. 10.6%; >0.05). Use of invasive angiography was lower in the FFR_CT arm (19.4% vs. 25%; p=0.01). FORECAST thus concluded that a strategy of routine FFR_CT was not associated with reductions in cost or clinical outcomes but reduced the use of invasive coronary angiography.

Optimal medical therapy remains first choice in diabetic patients

Outcome of participants with diabetes in the ISCHEMIA trial.

Circ 2021; 144:1380-1395

It is well established that patients with diabetes have poorer outcomes compared with non-diabetic patients with coronary disease. In the ISCHEMIA and ISCHEMIA-CKD trials ~45% of all cases had diabetes, and in this study these cases underwent a pooled-analysis. The main outcome was to compare the rates of death and MI with a routine invasive strategy against guideline-directed medical therapy for patients with diabetes (n=2553) (including high-risk diabetes subgroups), relative to the outcomes in those without diabetes (n=3347). As a quick aide memoir, ISCHEMIA recruited patients with known or suspected CAD if they had moderate or severe reversible ischemia by imaging or exercise testing. Those with eGFR ≥30 entered the main trial and those <30 were enrolled into ISCHEMIA-CKD.  Over a median of 3.1 years, diabetics had a 12% absolute reduction in event-free survival compared with non-diabetics. However, the main finding was that there was no reduction in death or MI for an initial invasive approach compared with a conservative approach in either the diabetics or non-diabetics. Insulin-dependent diabetics had a poorer event-free survival than non-insulin-dependent diabetics, but even in this group there was no improvement in outcome with an initial invasive strategy. This was all despite the fact that diabetics had more severe CAD, MVD and LV dysfunction. In short, an initial invasive approach was not associated with a reduction in death /MI compared with an initial conservative approach in diabetic (or high-risk diabetic) patients with moderate or severe inducible ischaemia. This study included those with more severe CKD. It is important to remember that these results may not extend to those groups excluded from the ISCHEMIA trials including those with unstable angina, ACS, left main disease, LVSD (<35%). This study highlights the importance of lifestyle changes, weight loss and optimal diabetic control in diabetics with coronary disease – something that is very hard to achieve in everyday clinical practice.

Similar all-cause death at 10 years for SYNTAX patients

Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease.

EHJ 2021; 43:56-67

The debate over how best to revascularize patients with diabetes has been confounded by many factors such as continuously evolving interventional techniques, old pharmacology, & methodological limitations. The key messages have been that as compared to non-diabetic patients, those with diabetes have a worse prognosis regardless of the revascularization technique and CABG has the edge over PCI in terms of repeat revascularisation. The current manuscript analysed the 10-year survival of all-cause death according to diabetic status and revascularization strategy in diabetics (n=452) and non-diabetics (n=1,348) in the landmark SYNTAX trial. In diabetic patients, the risk of mortality was numerically higher with PCI compared with surgery at 5 years (19.6% vs. 13.3%; HR: 1.53; 95% CI: 0.96-2.43; p=0.075), with the opposite seen between 5 and 10 years (20.8% vs. 24.4%; HR: 0.82; 95% CI: 0.52-1.27; p=0.366). Irrespective of diabetic status, there was no difference in all-cause death at 10 years between patients receiving PCI or CABG. In insulin treated patients (n=182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%; difference: 8.2%; 95% CI: -6.5-22.5; p=0.227). The current study did not examine repeat revascularization which one would expect to be greater in the PCI group. Salient features include lack of adequate statistical power and subgroup analyses may have increased the risk of types 1 and 2 error, lack of formal correction for multiple testing, and application of results to those with de novo 3VD and/or LM disease rather than general CAD patients.

Antiplatelet Therapy

Ticagrelor monotherapy beats DAPT in HBR patients

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HB

EHJ 2021; 42:4624-4634

The TWIGHLIGHT study has indicated that early cessation of aspirin at three months (i.e. ticagrelor monotherapy) is superior to continuing DAPT (i.e. aspirin and ticagrelor) in terms of bleeding, but with no apparent increase in the secondary outcome measure of death, MI or stroke. In this pre-specified TWIGHLIGHT sub-analysis, the investigators studied the effect of cessation of DAPT at three months, but only in those with high bleeding risk (HBR). HBR was defined as at least one Academic Research Consortium major criterion (eGFR <30, platelets <100, previous major bleeding, significant liver disease) or two minor criteria (age ≥75 years, eGFR 30-60, Hb 11-13/12 men /women, regular NSAID use). 1,064 patients met the inclusion criteria. Ticagrelor monotherapy was associated with a 5.1% reduction in BARC class 2 (‘actionable’ bleeding requiring investigation and hospitalisation), 3 (overt bleeding with Hb drop of ≥3g/dL or intracranial haemorrhage), or 5 (probable or definite fatal bleeding) bleeding in those with HBR. The magnitude of the reduction in BARC 2, 3 or 5 bleeding associated with early DAPT cessation was similar in HBR patients (HR 0.53) and non-HBR patients. However, the magnitude of effect of monotherapy was greater on more major bleeding (BARC 3 or 5) (HR 0.31 vs 0.62). Ticagrelor monotherapy was not associated with a significant increase in ischaemic events (death, MI, stroke). However, this was a sub-study and was underpowered to detect clinically relevant differences in ischaemic events. The main findings were (a) HBR patients experienced higher rates of both bleeding and ischaemic events than non-HBR patients, (b) early cessation of aspirin at three months with continuing ticagrelor monotherapy reduced bleeding and especially major bleeding comparted with longer term DAPT and (c) the magnitude if this effect was greater in HBR patients than non-HBR patients. As the trial literature regarding dual antiplatelet therapy accumulates there seems to be evidence to support both longer and shorter duration DAPT, depending on the clinical context. Broadly, longer duration and more potent DAPT protects against ischaemic events, but at the expense of increased bleeding risk. Although this study is underpowered to be completely relaxed about the effects on ischaemic risk, the results do appear to support that ticagrelor monotherapy from three months onwards is effective in reducing bleeding events, especially major bleeding events, compared with longer term DAPT with ticagrelor and aspirin.

Ticagrelor or prasugrel-the debate rages on!

Ticagrelor or prasugrel for patients with acute coronary syndrome treated with percutaneous coronary intervention: a prespecified subgroup analysis of a randomized clinical trial.

JAMA Cardiol 2021; 6:1121-29

Aspirin in combination with either ticagrelor or prasugrel have become established as the dual antiplatelet therapy of choice. The ISAR REACT 5 trial compared ticagrelor and prasugrel as part of DAPT therapy, both in combination with aspirin, in 4018 patients presenting with ACS in whom an interventional strategy was planned. The cohort was representative of real-world intervention: 12% unstable angina, 46% NSTEMI and 41% STEMI. 83% were treated with PCI, 2% CABG and 14% conservatively. Patients were randomised 1:1 and the 12-month primary outcome was a composite of death, nonfatal MI, or stroke. The secondary (safety) outcome was BARC major (3-5) bleeding. There was a 2.4% absolute reduction in the primary outcome with prasugrel (6.9% vs 9.3%) driven by a reduction in non-fatal MI. There was no associated increase in major bleeding. In fact, major bleeding was numerically lower with prasugrel (4.8% vs 5.4%). Stent thrombosis rates were low overall but numerically lower with prasugrel (0.6% vs 1.1%). The study was open-label, but outcomes adjudication was blinded. Importantly, those taking ticagrelor were more likely to discontinue therapy before 12 months (15% vs 12%). The twice daily dosing regime of ticagrelor is likely to have influenced this, and overall compliance. The current study is a  pre-specified analysis of the 3377 patients who, after randomisation, underwent PCI. Again, the primary outcome measure was death, MI, or stroke at 12 months and the safety end point was BARC 3-5 bleeding. 1676 were treated with ticagrelor and 1701 with prasugrel. Compared with the main study, rates of the primary endpoint were similar but again, this was lower in the prasugrel group (9.8% vs 7.1%, HR 1.41). Rates of bleeding were again non-significantly different with a slight trend to lower bleeding with prasugrel (5.3% vs 4.9%). The results of both analyses are similar overall, perhaps not surprising given that the second study was a sub-analysis of >80% of those in the first study. The results appear slightly counter-intuitive given that, with appropriate administration, chronic ticagrelor therapy is thought to offer slightly higher levels of, and more stable platelet inhibition than prasugrel. Moreover, these differences were not replicated in the recent SWEDEHEART registry analysis of nearly 38,000 MI patients managed with PCI, in which there were no differences in MACE or bleeding between ticagrelor or prasugrel treatment. Ticagrelor also offers the advantage of being a reversible P2Y12 inhibitor with shorter offset of action. In short, it seems that ticagrelor offers slightly greater and more predictable platelet inhibition and is reversible, but its twice daily regime may impair compliance and this may explain the findings in both ISAR-REACT 5 analyses. Whether or not these differences are strong enough to influence what becomes considered first and second line treatment remain to be seen.

TALOS-AMI supports unguided de-escalation

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator initiated, open-label, multicentre, non-inferiority, randomised trial.

Lancet 2021; 389:1803-10

It is well established that anti-platelets are essential in reducing recurrent thrombotic events. With the advent of more potent P2Y₁₂ inhibition and following favourable trial data, guidelines now recommend the use of ticagrelor or prasugrel in patients with AMI to further reduce ischaemic events and stent thrombosis. However, both major RCTs of ticagrelor and prasugrel found increased bleeding rates, which occurs more frequently during the maintenance phase. This open label, assessor masked, multi-centre non-inferiority randomised controlled trial (TALOS-AMI) sought to test the hypothesis that unguided (without platelet function testing or genomic testing) de-escalation of ticagrelor to clopidogrel in stabilized AMI patients is non-inferior to ticagrelor based dual antiplatelet therapy (DAPT). Patients who had biomarker positive acute myocardial infarction who underwent successful PCI and with no significant ischaemic or bleeding events within the first month were selected and enrolled. Exclusion criteria included cardiogenic shock, active bleeding and coagulopathy within two months. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke or bleeding type 2,3,5 (BARC criteria). A total of 2,697 patients were randomly assigned 30 days after PCI to undergo de-escalation therapy to clopidogrel up to 12 months (n=1,349) or continued ticagrelor treatment (n=1,348) across 32 centres in South Korea. 90% of the patients randomised received the allocated treatment in the de-escalation arm, and 87% in the active control arm. There was no significant difference in demographic, clinical and procedural data. 53% presented as a STEMI, and there was overall a high rate of femoral access used during index PCI. Approximately a quarter of patients had multi-vessel disease. Following one year, the primary end point occurred in 4.6% of the de-escalation group and 8.2% in the active control group (P_{non-inferiority} <0.001; HR 0.55 [95% CI 0.40-0.76]. There was an absolute risk reduction of 3.6%, driven by reduced bleeding rates. Of note in the pre-specified secondary end point of composite of CV death, stroke, and myocardial infarction no difference was observed. There was also a reduction in the more severe BARC 3 and 5 bleeding events observed. Of note there was also no difference seen in repeat revascularisation or stent thrombosis rates between groups. The de-escalation strategy also met superiority requirements in the intention to treat as well as the per protocol and as treated populations. This trial appears to indicate that in patients that have surpassed their most at-risk period following PCI, unguided de-escalation can be performed safely with a reduction in significant bleeding events.

Valvular Intervention

TA at the time of mitral surgery reduces TR progression

Concomitant tricuspid repair in patients with degenerative mitral regurgitation.

NEJM 2021 Online

The optimal management of concomitant mild or moderate tricuspid regurgitation (TR) at the time of surgical intervention for degenerative mitral regurgitation (MR) is uncertain. The CTSN investigators examined the benefits and risks of tricuspid valve repair at the time mitral valve surgery in 401 patients with moderate or less than moderate TR who were undergoing surgery for degenerative MR. 203 patients were randomized to mitral valve surgery alone (surgery alone) and 198 patients were randomized ratio to undergo mitral surgery and tricuspid annuloplasty (surgery plus TA). Major exclusion criteria were secondary MR, primary tricuspid valve disease and suboptimal volume management. The primary endpoint at 2 years was a composite of reoperation for TR, progression of TR from baseline by two grades or the presence of severe TR, or death. Secondary endpoints included death, MACCE (defined as a composite of death, stroke, MI, or serious heart failure events), permanent pacemaker implantation (PPM), length of hospital stay, and cost effectiveness. The core laboratory confirmed moderate TR in 37.3%, RV systolic function was normal 90.5%, and 30% had NYHA class III or IV heart failure. In the tricuspid annuloplasty recipients, the average annuloplasty ring size was 29.0±1.9mm in men and 27.8±1.6mm in women. The primary endpoint was significantly greater in the surgery-alone group (10.2%) than in the surgery plus TA group (3.9%) (RR 0.37; 95% CI: 0.16-0.86; p=0.02). Death occurred in 4.5% in the surgery-alone group and 3.2% in the surgery plus TA group (RR 0.69; 95% CI: 0.25-1.88). No patients underwent tricuspid valve reoperation within 2 years after randomization. More patients in the surgery-alone group had progression of TR at 2 years (6.1% vs 0.6%; RR 0.09; 95% CI:0.01-0.69). The frequencies of MACCE, functional status, and quality of life were similar in both groups at 2 years although the incidence of PPM was higher in the surgery plus TA group (14.1% vs. 2.5%; RR 5.75; 95% CI:2.27-14.60). The rate of heart failure events was 0.11 per 24 patient-months in the surgery-alone group and 0.07 per 24 patient-months in the surgery plus TA group (RR 0.68; 95% CI: 0.25-1.85). The median length of stay during the index hospitalization was 2 days shorter in the surgery-alone group. The trial concluded that concomitant tricuspid valve repair at the time of mitral valve surgery in patients with less than severe TR at baseline results in improved outcomes at 2 years primarily in reducing the progression to worse/severe TR. The PPM rate was 5x higher in the surgery plus TR group and it is conceivable that over the long-term this can result in lead-related TR and potentially nullify these benefits.

To treat or not treat CAD prior to TAVI

ACTIVATION (percutaneous coronary intervention prior to transcatheter aortic valve implantation). A randomized clinical trial.

JACC Cardiol Intv 2021; 14:1965-74

The role of PCI in patients with concomitant significant coronary artery disease (CAD) and severe aortic stenosis who are due to undergo TAVR is unclear. The ACTIVATION trial was a randomized, open-label, noninferiority clinical trial undertaken in 17 European centres, included 235 patients, and designed to determine if PCI prior to TAVR in patients with significant CAD would produce noninferior clinical outcomes when compared to no PCI. Key inclusion criteria were severe AS deemed suitable for TAVR following heart team discussion and at least 1 stenosis of ≥70% stenosis in a major epicardial artery or ≥50% in a protected left main stem or vein graft suitable for PCI. Key exclusion criteria were ACS within 30 days of enrolment, CCS angina class III or greater, unprotected left main stem disease, or clinical features that would prohibit dual antiplatelet therapy. The primary endpoint was a composite of all-cause death or rehospitalization at 1 year. Noninferiority testing was performed in the intention-to-treat population. Eligible patients were randomised to undergo either PCI  or no PCI prior to TAVR. Based on reduced recruitment rates the Trial Steering Committee recommended early termination of the trial (the study was powered for 310 patients). Baseline characteristics were similar in both groups. Significant angiographic stenosis in the LAD was identified in 61.3% of those randomized to PCI and 60.5% randomized to no PCI. In those randomized to PCI, PCI was indicated for single vessel disease in 71.4% patients with a mean angiographic stenosis of 80±15%. The median number of lesions treated was 1. Mean treated lesion length was 17.4±6.6mm. A BMS was used in 18.1% of patients. At 1 year the primary endpoint occurred in 41.5% of the PCI arm and 44% of the no-PCI arm. The requirement for noninferiority was not met with a difference of -2.5% and 1-sided 95% confidence limit reaching 8.5%. Mortality was 13.4% in the PCI arm and 12.1% in the no PCI arm (p=0.99). The rates of MI (6.7% vs. 3.4%; p-0.30), stroke (5.9% vs. 6.9%; p=0.55), and acute kidney injury (10.1% vs. 4.3%; p=0.11) were similar in the PCI and no PCI group. Bleeding events at 1 year was greater in the PCI group (44.5% vs. 28.4%; p=0.021). Salient features of the trial include smaller-than-planned population, the noninferiority design (no PCI with potential advantages of no bleeding or kidney injury risk, single procedure and lower cost to be tested for noninferiority versus PCI and not vice versa), visual estimation of coronary stenosis, lack of predefined antithrombotic protocol, and the use of BMS.

Encouraging durability for TAVI

Native aortic valve disease progression and bioprosthetic valve degeneration in patient with transcatheter aortic valve implantation.

Circ 2021; 144:1396-1408

Despite the widespread adoption of TAVI in clinical practice, a number of questions including valve durability and ongoing disease activity within the retained aortic valve leaflets remain unanswered. The current study sought to answer these questions using ¹⁸F-sodium fluoride positron emission tomography (¹⁸F-NaF PET), which has been shown to be a marker of calcification activity and vascular injury across several cardiovascular conditions. Patients (n=47) were recruited into this study that had had a TAVI at one month, two years and five years prior, without significant haemodynamic evidence of valve degeneration. Each patient underwent a CT angiogram, echocardiogram and ¹⁸F-NaF PET at baseline, followed by an annual repeat echo. These were compared with a cohort of surgical aortic valve replacement (SAVR) patients (n=51) recruited into a similar study with the same imaging protocol. The investigators also performed an ex vivo assessment using histological immunohistochemistry and ¹⁸F-NaF autoradiography of explanted native valves and bioprosthetic valves obtained from patients with degenerative TAVI valves. The imaging protocol was performed at one month (n=9, 19%), 2 years (n=22, 47%) and 5 years (n=16, 34%). The patients with prior TAVI were older and were more likely to have co-morbidities such as diabetes, with a greater effective orifice area. In the ex vivo study calcified native aortic valve tissue was present around the perimeter of TAVI bioprosthesis, with evidence of ongoing calcification activity in the native valve. ¹⁸F-NaF uptake was seen on the explanted TAVI bioprosthesis, with colocalization of this signal to regions of calcification seen on histological immunohistochemistry analyses.  In the TAVI cohort, native valve uptake was highest in patients imaged 5 years after their TAVI, with a modest positive correlation with time from TAVI (r=0.36, p=0.023). At baseline all but 3 patients had normal valve function. All three had five year old TAVIs. Overall, 8 patients had imaging evidence on echo or CT of valve degeneration, 7 of which were imaged 5 years after TAVI. Seven patients were seen to have ¹⁸F-NaF uptake, all with five-year-old valves. The three highest uptake values were observed in patients with echo evidence of haemodynamic structural valve degeneration. During follow up echo the investigators observed a strong correlation between baseline ¹⁸F-NaF uptake and change in bioprosthetic valve peak velocity. On multivariable analysis ¹⁸F-NaF uptake was the only predictor of annualized change in peak velocity. There was no significant difference in degeneration on CT or echo between the SAVR and TAVI cohorts. ¹⁸F-NaF uptake was numerically almost doubled in the SAVR cohort, which did not reach statistical significance.  Although a small non-randomised observational study, this has given some insight into the mechanisms of aortic stenosis, suggesting that it is an active disease process which is independent of valve movement and mechanical ‘wear and tear’. ¹⁸F-NaF as a tracer for PET has been identified as a marker of subclinical valve degeneration and predicting subsequent development of valve dysfunction, which will need to be evaluated in larger studies. TAVI and SAVR had similar rates of degeneration in this study.

miscellaneous

Myocarditis is most common in the young post Pfizer vaccine

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.

NEJM 2021; 385:2132-39

Several reports have shown an association between the development of myocarditis and the mRNA vaccines against COVID-19. The current study examined this association using the database of the Clalit Health Services, the largest health care organization in Israel in patients who had received at least one dose of the Pfizer-BioNTech vaccine. This health care system provides care for 52% of the total population in Israel. The cohort were patients who had been vaccinated between December 20, 2020 through May 24, 2021. A follow-up period of 42 days after the first dose was chosen to allow at least 21 days of follow-up after each of the two vaccine doses. A patient was considered to have myocarditis if the Centers for Disease Control and Prevention (CDC) case definition for suspected, probable, or confirmed myocarditis had been met. During the study period, 2,558,421 patients had received at least one dose of the vaccine and 94% of these had received two doses. 54 cases were diagnosed with myocarditis of whom 41 were classified as mild, 12 as intermediate, and 1 as fulminant. The median age of patients with myocarditis was 27 years, 94% were male, 83% had no coexisting medical condition, 13% were receiving treatment for chronic diseases, 69% were diagnosed with myocarditis after the second dose of the vaccine with a median interval of 21 days between doses. The presenting symptom was chest pain in 82% of cases. Vital signs on admission were generally normal; 1 patient presented with hemodynamic instability and non-required circulatory support. The most common ECG abnormality was ST elevation, median peak troponin was 680 ng/L, 5% had non-sustained VT, 3% had AF, and 29% had left ventricular systolic dysfunction (LVSD) on echocardiography (17% were classified as mild, 4% mild to moderate, 4% moderate, 2% moderate to severe, and 2% as severe). The overall incidence of myocarditis within 42 days after having the first dose per 100,000 vaccinated persons was 2.13 cases (95% CI:1.56-2.70). The highest incidence of myocarditis was observed in male patients aged between 16 and 29 years (10.69 cases per 100,000 persons; 95% CI: 6.93-14.46). Salient features include a modest proportion of patients with myocarditis undergoing cardiac MRI (28%), myocardial biopsy undertaken in only one patient, and a short follow-up period to determine the long-term clinical implications of myocarditis post vaccination.

Blood pressure linked to the development of diabetes mellitus

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis.

Lancet 2021; 398:1974-83

In type 2 diabetes, blood pressure management is a well-established therapeutic strategy to reduce both macrovascular and microvascular complications. However, whether blood pressure lowering can prevent the development of type 2 diabetes is unknown. Previous observational studies have had conflicting results and have been unable to tease out the drug class specific effects. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) provided individual participant data for this meta-analysis. All primary and secondary prevention RCTs between 1973 and 2008 that used a specific class/classes of antihypertensive drug versus placebo, or other classes of anti-hypertensives who had at least 1000 person years of follow up were included. Those participants with known diabetes at baseline or trials that were conducted in populations with high prevalence of diabetes were excluded. 19 trials (203,368 patients, 60.6% men) were included in the one-stage individual participant data meta-analysis to test the hypothesis that BP lowering leads to reduced incidence of type 2 diabetes. A Bayesian fixed effect network analysis model was used to compare the effect of different classes of anti-hypertensives in 22 trials. A stratified cox proportional hazards model with fixed treatment effects and participants as the unit of analysis was used to adjust for confounders, with standardised effect sizes for 5mmHg reduction in systolic blood pressure used. Median follow up was 4.5 years. The incidence rate for developing type 2 diabetes per 1000 person years was 16.4 (95% CI 16.01-16.87) in the comparator arm and 15.94 (95% CI 15.47-16.42), with a hazard ratio of new onset diabetes for a 5mmHg reduction in systolic blood pressure of 0.89 (95% CI 0.84-0.95).  In the Bayesian network meta-analysis of 22 RCTs, ACEIs and ARBs reduced the risk of diabetes compared with placebo (risk ratio 0.84 for both). Beta-blockers and thiazide diuretics were found to increase the risk of diabetes compared with placebo (RR 1.48 and 1.20 respectively), whilst calcium channels blockers had no impact.   No significant change in the results was seen after adjustment for baseline characteristics and after accounting for random effects in the Cox model. Interestingly baseline body mass index also had no impact on treatment effects. This was a large meta-analysis involving individual patient data with robust statistical tests used in the data analysis, including assessment of acquisition bias and undertaking sensitivity analyses. The key findings were that a reduction of SBP by 5mmHg resulted in lower numbers of new onset type 2 diabetes, and in terms of pharmacotherapy, ACEIs and ARBs had the greatest impact. This suggests that blood pressure is a modifiable risk factor in the development of diabetes, and therefore should be a target in primary prevention, particularly for those with other risk factors for diabetes. It also suggests that renin-angiotensin-aldosterone pathway deactivation may be involved in reducing the risk of diabetes. Further pre-clinical studies and randomised trials with the development of diabetes as a main outcome should be conducted to investigate this further.

BCIS R&D Group Literature Update

January 2022

Prepared by Michael Mahmoudi, Julian Gunn & Natalia Briceno
Edited by Michael Mahmoudi

Stable CAD & ACS

FFR-guided PCI not noninferior to CABG in patients with MVD

Fractional flow reserve-guided PCI as compared with coronary bypass surgery.

NEJM 2022; 386:128-137

Coronary artery bypass grafting (CABG) has been shown to improve outcomes in patients with three vessel coronary artery disease (CAD). FFR-guided revascularization with current generation drug-eluting stents (DES) has not been compared with CABG in such patients. The FAME-3 investigators evaluated whether a strategy of FFR-guided PCI with current generation DES is noninferior as compared to CABG with respect to the incidence of MACCE (defined as death from any cause, MI, stroke, or repeat revascularization) in 1500 patients with three vessel CAD. Secondary endpoints included a composite of death, MI, or stroke. Major inclusion criteria were angiographic ≥ 50% stenosis in three major epicardial vessels (without left main involvement) amenable to revascularization by both PCI and CABG. Major exclusion criteria were cardiogenic shock, STEMI within 5 days, and LV ejection fraction < 30%. The mean age of patients was 65 years, 29% had diabetes, 39% presented with an ACS, 13% had undergone previous PCI, patients had an average of 4.3 lesions, 22% of patients had at least one vessel with chronic total occlusion, 68% had at least one bifurcation lesion and the mean SYNTAX score was 26. In the FFR-guided PCI group, the mean number of lesions per patient was 4.3, the mean number of DES implanted per patient was 3.7, and the median stented length was 80mm. FFR was measured in 82% of lesions; the most common reasons for not measuring FFR were sub-totally or completely occluded vessels. The mean FFR was 0.70, and 24% of the lesions intended for treatment had an FFR >0.80. Patients undergoing CABG had a mean of 4.2 lesions and received a mean of 3.4 distal anastomoses.; 97% received a LIMA graft and 25% received multiple arterial grafts. The 1-year incidence of the composite primary endpoint was 10.6% in the PCI group and 6.9% in the CABG group (HR 1.5; 95% CI: 1.1-2.2; p_{for noninferiority} =0.35). The incidence of death, MI, or stroke was 7.3% in the PCI group and 5.2% in the CABG group (HR 1.4; 95% CI:0.9-2.1. The rates of BARC 3-5 bleeding (1.6% vs. 3.8%; p<0.01), and acute kidney injury (0.1% vs. 0.9%; p<0.04), atrial arrythmia (2.4% vs. 14.1%; p<0.001) were greater in the CABG group. Based on these findings FFR-guided PCI using current generation DES did not meet criteria for noninferiority compared with CABG in patients with three vessel CABG.

A novel risk score for contrast nephropathy

A contemporary simple risk score for prediction of contrast-associated acute kidney injury after percutaneous coronary intervention: derivation and validation from an observational registry.

Lancet 2021; 398:1974-81

Contrast administration is routinely performed in many interventional procedures that use x-ray. The development of contrast associated acute kidney injury (AKI) is one of the major potential complications following contrast administration, and in previous studies has been shown to be associated with development of chronic renal impairment, need for renal replacement therapy and mortality. What has been debated are the risk factors that are associated with it’s development. The current study sought to develop a new risk score from a contemporary PCI cohort. Consecutive patients undergoing PCI in a single centre between 2012 to 2020 with available creatinine measurements pre-PCI and within 48 hours after the procedure were included, and those on chronic renal replacement therapy and undergoing multiple procedures were excluded. The derivation cohort were those having undergone PCI between 2012 and 2017 (14,616 patients) and the validation cohort were those having undergone PCI between 2018 and 2020 (5606 patients). A multivariate logistic regression analysis was performed to assess for independent predictors of contract associated AKI, with two regression models developed. Model 1 included only pre procedural variables, and Model 2 included pre procedural and procedural variables. The final risk score was categorised into four groups: low risk, moderate risk, high risk and very high risk. The primary endpoint was contrast induced AKI defined as an increase in the serum creatinine by at least 50% or at least 0.3mg/dL within 48 hours after PCI. The secondary endpoint was all cause deaths. All patients had IV pre and post-hydration and low osmolar non-anionic contrast medium was used. Overall there was a 4.3% rate of contrast associated AKI. Model 1 predictors included clinical presentation (stable versus acute), estimated GFR, LVEF, diabetes, haemoglobin, basal glucose levels, age and congestive cardiac failure. Model 2 included the pre procedural variables alongside procedural variables including contrast volume, peri procedural bleeding, nonflow or slow flow and complex PCI anatomy. Both models resulted in high discriminatory power, which was not impacted with the inclusion of the procedural variables (C-statistic 0.72 in Model 1 and 0.74 in Model 2).  High discriminatory power was also seen in the validation cohort. The observed and predicted rates of contrast associated AKI increased with an increment in the risk group. The development of contrast associated AKI was associated with increased deaths at one year, with a significant separation in the Kaplan-Meier curves within a month following PCI. Salient features include a single centre study, and a relatively small percentage of patients with an eGFR<30.

How late is late for PCI in STEMI?

Percutaneous Myocardial Revascularization in Late-Presenting Patients With STEMI

JACC 2021; 78:1291-1305

The clinical benefits of coronary revascularization in patients presenting late with a STEMI remain controversial and are given a Class IIa recommendation by the American and European societies. The FAST-MI investigators examined the long-term outcome of revascularization in patients presenting with a STEMI between 12-48 hours after symptom onset using the three FAST-MI registries undertaken over a 1-month period in 2005, 2010, and 2015. The three registries included 13,129 patients of whom 1,169 were STEMI latecomer and 1,077 were alive at 48 hours after hospital admission (32 deceased within 48 hours, 59 had undergone fibrinolysis, and 1 patient had no data about reperfusion therapy). In comparison, 5,105 STEMI patients presented within 12 hours of symptom onset. Median time from symptom onset to ICU admission was 3.5 hours in the early comers versus 20.2 hours in the latecomers (p<0.001). From 2005 to 2015, the proportion of latecomers decreased from 22.7% to 16.1% (p<0.001). Latecomer patients were more frequently women (30.8% vs. 25.2%; p<0.001), significantly older (65.2 years ± 14.8 years vs. 62.6 ± 14.1 years; p<0.001), more likely to be diabetic (21.3% vs. 15.5%; p<0.001), and hypertensive (53.2% vs. 46.1%; p<0.001). Multivariate analysis identified age, diabetes, atypical chest pain, prior heart failure, and admission via emergency medical service as characteristics independently related to late presentation. In the latecomer population, 67.7% underwent revascularization within 48 hours following hospital admission (99.6% with PCI and 0.4% with CABG). At 30-day follow-up, all cause death was significantly lower among revascularized latecomers (2.1% vs. 7.2%; p<0.0001). After a median follow-up of 58 months, the rate of all cause death was 30.4 per 1,000 patient-years in the revascularized latecomers versus 78.7 per 1,000 patient-years in the non-revascularized latecomers (p<0.001). In multivariate analysis, revascularization of latecomer STEMI patients was independently associated with a reduction in mortality (HR: 0.65; 95% CI: 0.50-0.84; p=0.001). Accepting the limitations of observational studies, several lines of evidence support the benefit of PCI in latecomers. Firstly, the assumption that the IRA may be completely occluded is not correct as evidenced by the BRAVE-2 study in which 43.4% of patients in the invasive arm had TIMI flow ≥ 2 in the IRA at the time of intervention and 29% had some degree of collateralization. Secondly, imaging studies have shown the presence of significant volume of viable myocardium in late STEMI presenters which may be salvaged with PCI. Finally, a meta-analysis of 10 studies enrolling 3,560 patients with a median time from AMI to randomization of 12 days and follow-up of 2.8 years demonstrated that compared to medical therapy PCI of the IRA was associated with significant improvements in cardiac function and survival.

Is routine therapeutic hypothermia justified in survivors of OOHCA?

Effect of Moderate vs Mild Therapeutic Hypothermia on Mortality and Neurologic Outcomes in Comatose Survivors of Out-of-Hospital Cardiac Arrest. The CAPITAL CHILL Randomized Clinical Trial.

JAMA 2021; 326:1494-1503

The overall evidence supporting targeted temperature management in survivors of out-of-hospital cardiac arrest (OOHCA) is of low certainty. We recently highlighted the results of the TTM2 trial which did not support targeted hypothermia in this patient population. The CAPITAL CHILL investigators examined whether moderate therapeutic hypothermia below 31°C was associated with an improvement in clinical outcomes compared with guideline-recommended mild hypothermia below 34°C in a cohort of 367 patients. In the moderate hypothermia arm, targeted temperature was maintained for 24 hours, followed by rewarming over 24 hours and normothermia for 24 hours. In the mild hypothermia arm, targeted temperature was maintained for 24 hours followed by rewarming over 12 hours and normothermia for 24 hours. Cooling was undertaken utilising an endovascular cooling device. The primary outcome was all-cause mortality or poor neurologic outcome at 180 days. There were 19 secondary outcomes including mortality at 180 days and length of stay in the ICU. Neurologic outcome was assessed using the Disability Rating Scale with poor neurologic outcome defined as a score >5. The mean age was 61 years, 19% were female, bystander CPR was performed in 76%, there was an initial shockable rhythm in 86%, and 38% of patients had ST-elevation MI. The primary outcome was similar in the moderate and mild hypothermia groups (48.4% vs. 45.4%; risk difference 3.0%; 95% CI: 7.2%-13.2%; RR 1.07; 95% CI:0.86-1.33; p=0.56). Of the 17 secondary outcomes, the only difference was observed in the length of ICU stay (10 vs. 7 days; p=0.004). Modified Rankin Scale, pneumonia, need for renal replacement therapy, seizures, and TIMI major bleed were all similar in both groups.

FFR_CT does not reduce cost nor does it improve clinical outcomes

Fractional flow reserve derived from computed tomography coronary angiography in the assessment and management of stable chest pain: the FORECAST randomized trial.

EHJ 2021; 42:3844-52

FFR_CT is a well validated method for determining the presence and extent of CAD combined with physiological assessment of vessel specific ischaemia in patients presenting with chest pain. The clinical effectiveness and economic impact of using FFR_CT instead of other tests in the initial evaluation of patients with stable chest pain had not been tested in a randomized trial. The FORECAST trial randomized 1,400 patients with stable chest pain to either undergo FFR_CT or routine assessment as directed by NICE CG95- guideline for chest pain of recent onset in 11 UK centres and examined whether an evaluation strategy based on FFR_CT would improve economic and clinical outcomes. Patients randomized to the routine arm (n=700) were scheduled for the test recommended by the clinical pathway and the supervising physician then decided upon the clinical management. Patients randomized to the FFR_CT arm were referred for CTCA; any CTCA demonstrating a coronary stenosis ≥40% in at least one major epicardial vessel of a diameter suitable for revascularization was referred for FFR_CT. The primary endpoint was total cardiac cost at 9 months. Secondary endpoints were angina status, quality of life, MACCE and use of invasive coronary angiography. Most patients had an initial CTCA: 63% in the routine arm and 96% in the FFR_CT arm. FFR_CT was undertaken in 38%. Mean age was 60 years, 48% were female, and 13% had diabetes. Median cost was £285 in both arms (p=0.96). MACCE was similar in the routine and FFR_CT arms (10.2% vs. 10.6%; >0.05). Use of invasive angiography was lower in the FFR_CT arm (19.4% vs. 25%; p=0.01). FORECAST thus concluded that a strategy of routine FFR_CT was not associated with reductions in cost or clinical outcomes but reduced the use of invasive coronary angiography.

Optimal medical therapy remains first choice in diabetic patients

Outcome of participants with diabetes in the ISCHEMIA trial.

Circ 2021; 144:1380-1395

It is well established that patients with diabetes have poorer outcomes compared with non-diabetic patients with coronary disease. In the ISCHEMIA and ISCHEMIA-CKD trials ~45% of all cases had diabetes, and in this study these cases underwent a pooled-analysis. The main outcome was to compare the rates of death and MI with a routine invasive strategy against guideline-directed medical therapy for patients with diabetes (n=2553) (including high-risk diabetes subgroups), relative to the outcomes in those without diabetes (n=3347). As a quick aide memoir, ISCHEMIA recruited patients with known or suspected CAD if they had moderate or severe reversible ischemia by imaging or exercise testing. Those with eGFR ≥30 entered the main trial and those <30 were enrolled into ISCHEMIA-CKD.  Over a median of 3.1 years, diabetics had a 12% absolute reduction in event-free survival compared with non-diabetics. However, the main finding was that there was no reduction in death or MI for an initial invasive approach compared with a conservative approach in either the diabetics or non-diabetics. Insulin-dependent diabetics had a poorer event-free survival than non-insulin-dependent diabetics, but even in this group there was no improvement in outcome with an initial invasive strategy. This was all despite the fact that diabetics had more severe CAD, MVD and LV dysfunction. In short, an initial invasive approach was not associated with a reduction in death /MI compared with an initial conservative approach in diabetic (or high-risk diabetic) patients with moderate or severe inducible ischaemia. This study included those with more severe CKD. It is important to remember that these results may not extend to those groups excluded from the ISCHEMIA trials including those with unstable angina, ACS, left main disease, LVSD (<35%). This study highlights the importance of lifestyle changes, weight loss and optimal diabetic control in diabetics with coronary disease – something that is very hard to achieve in everyday clinical practice.

Similar all-cause death at 10 years for SYNTAX patients

Ten-year all-cause death after percutaneous or surgical revascularization in diabetic patients with complex coronary artery disease.

EHJ 2021; 43:56-67

The debate over how best to revascularize patients with diabetes has been confounded by many factors such as continuously evolving interventional techniques, old pharmacology, & methodological limitations. The key messages have been that as compared to non-diabetic patients, those with diabetes have a worse prognosis regardless of the revascularization technique and CABG has the edge over PCI in terms of repeat revascularisation. The current manuscript analysed the 10-year survival of all-cause death according to diabetic status and revascularization strategy in diabetics (n=452) and non-diabetics (n=1,348) in the landmark SYNTAX trial. In diabetic patients, the risk of mortality was numerically higher with PCI compared with surgery at 5 years (19.6% vs. 13.3%; HR: 1.53; 95% CI: 0.96-2.43; p=0.075), with the opposite seen between 5 and 10 years (20.8% vs. 24.4%; HR: 0.82; 95% CI: 0.52-1.27; p=0.366). Irrespective of diabetic status, there was no difference in all-cause death at 10 years between patients receiving PCI or CABG. In insulin treated patients (n=182), all-cause death at 10 years was numerically higher with PCI (47.9% vs. 39.6%; difference: 8.2%; 95% CI: -6.5-22.5; p=0.227). The current study did not examine repeat revascularization which one would expect to be greater in the PCI group. Salient features include lack of adequate statistical power and subgroup analyses may have increased the risk of types 1 and 2 error, lack of formal correction for multiple testing, and application of results to those with de novo 3VD and/or LM disease rather than general CAD patients.

Antiplatelet Therapy

Ticagrelor monotherapy beats DAPT in HBR patients

Ticagrelor monotherapy in patients at high bleeding risk undergoing percutaneous coronary intervention: TWILIGHT-HB

EHJ 2021; 42:4624-4634

The TWIGHLIGHT study has indicated that early cessation of aspirin at three months (i.e. ticagrelor monotherapy) is superior to continuing DAPT (i.e. aspirin and ticagrelor) in terms of bleeding, but with no apparent increase in the secondary outcome measure of death, MI or stroke. In this pre-specified TWIGHLIGHT sub-analysis, the investigators studied the effect of cessation of DAPT at three months, but only in those with high bleeding risk (HBR). HBR was defined as at least one Academic Research Consortium major criterion (eGFR <30, platelets <100, previous major bleeding, significant liver disease) or two minor criteria (age ≥75 years, eGFR 30-60, Hb 11-13/12 men /women, regular NSAID use). 1,064 patients met the inclusion criteria. Ticagrelor monotherapy was associated with a 5.1% reduction in BARC class 2 (‘actionable’ bleeding requiring investigation and hospitalisation), 3 (overt bleeding with Hb drop of ≥3g/dL or intracranial haemorrhage), or 5 (probable or definite fatal bleeding) bleeding in those with HBR. The magnitude of the reduction in BARC 2, 3 or 5 bleeding associated with early DAPT cessation was similar in HBR patients (HR 0.53) and non-HBR patients. However, the magnitude of effect of monotherapy was greater on more major bleeding (BARC 3 or 5) (HR 0.31 vs 0.62). Ticagrelor monotherapy was not associated with a significant increase in ischaemic events (death, MI, stroke). However, this was a sub-study and was underpowered to detect clinically relevant differences in ischaemic events. The main findings were (a) HBR patients experienced higher rates of both bleeding and ischaemic events than non-HBR patients, (b) early cessation of aspirin at three months with continuing ticagrelor monotherapy reduced bleeding and especially major bleeding comparted with longer term DAPT and (c) the magnitude if this effect was greater in HBR patients than non-HBR patients. As the trial literature regarding dual antiplatelet therapy accumulates there seems to be evidence to support both longer and shorter duration DAPT, depending on the clinical context. Broadly, longer duration and more potent DAPT protects against ischaemic events, but at the expense of increased bleeding risk. Although this study is underpowered to be completely relaxed about the effects on ischaemic risk, the results do appear to support that ticagrelor monotherapy from three months onwards is effective in reducing bleeding events, especially major bleeding events, compared with longer term DAPT with ticagrelor and aspirin.

Ticagrelor or prasugrel-the debate rages on!

Ticagrelor or prasugrel for patients with acute coronary syndrome treated with percutaneous coronary intervention: a prespecified subgroup analysis of a randomized clinical trial.

JAMA Cardiol 2021; 6:1121-29

Aspirin in combination with either ticagrelor or prasugrel have become established as the dual antiplatelet therapy of choice. The ISAR REACT 5 trial compared ticagrelor and prasugrel as part of DAPT therapy, both in combination with aspirin, in 4018 patients presenting with ACS in whom an interventional strategy was planned. The cohort was representative of real-world intervention: 12% unstable angina, 46% NSTEMI and 41% STEMI. 83% were treated with PCI, 2% CABG and 14% conservatively. Patients were randomised 1:1 and the 12-month primary outcome was a composite of death, nonfatal MI, or stroke. The secondary (safety) outcome was BARC major (3-5) bleeding. There was a 2.4% absolute reduction in the primary outcome with prasugrel (6.9% vs 9.3%) driven by a reduction in non-fatal MI. There was no associated increase in major bleeding. In fact, major bleeding was numerically lower with prasugrel (4.8% vs 5.4%). Stent thrombosis rates were low overall but numerically lower with prasugrel (0.6% vs 1.1%). The study was open-label, but outcomes adjudication was blinded. Importantly, those taking ticagrelor were more likely to discontinue therapy before 12 months (15% vs 12%). The twice daily dosing regime of ticagrelor is likely to have influenced this, and overall compliance. The current study is a  pre-specified analysis of the 3377 patients who, after randomisation, underwent PCI. Again, the primary outcome measure was death, MI, or stroke at 12 months and the safety end point was BARC 3-5 bleeding. 1676 were treated with ticagrelor and 1701 with prasugrel. Compared with the main study, rates of the primary endpoint were similar but again, this was lower in the prasugrel group (9.8% vs 7.1%, HR 1.41). Rates of bleeding were again non-significantly different with a slight trend to lower bleeding with prasugrel (5.3% vs 4.9%). The results of both analyses are similar overall, perhaps not surprising given that the second study was a sub-analysis of >80% of those in the first study. The results appear slightly counter-intuitive given that, with appropriate administration, chronic ticagrelor therapy is thought to offer slightly higher levels of, and more stable platelet inhibition than prasugrel. Moreover, these differences were not replicated in the recent SWEDEHEART registry analysis of nearly 38,000 MI patients managed with PCI, in which there were no differences in MACE or bleeding between ticagrelor or prasugrel treatment. Ticagrelor also offers the advantage of being a reversible P2Y12 inhibitor with shorter offset of action. In short, it seems that ticagrelor offers slightly greater and more predictable platelet inhibition and is reversible, but its twice daily regime may impair compliance and this may explain the findings in both ISAR-REACT 5 analyses. Whether or not these differences are strong enough to influence what becomes considered first and second line treatment remain to be seen.

TALOS-AMI supports unguided de-escalation

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator initiated, open-label, multicentre, non-inferiority, randomised trial.

Lancet 2021; 389:1803-10

It is well established that anti-platelets are essential in reducing recurrent thrombotic events. With the advent of more potent P2Y₁₂ inhibition and following favourable trial data, guidelines now recommend the use of ticagrelor or prasugrel in patients with AMI to further reduce ischaemic events and stent thrombosis. However, both major RCTs of ticagrelor and prasugrel found increased bleeding rates, which occurs more frequently during the maintenance phase. This open label, assessor masked, multi-centre non-inferiority randomised controlled trial (TALOS-AMI) sought to test the hypothesis that unguided (without platelet function testing or genomic testing) de-escalation of ticagrelor to clopidogrel in stabilized AMI patients is non-inferior to ticagrelor based dual antiplatelet therapy (DAPT). Patients who had biomarker positive acute myocardial infarction who underwent successful PCI and with no significant ischaemic or bleeding events within the first month were selected and enrolled. Exclusion criteria included cardiogenic shock, active bleeding and coagulopathy within two months. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke or bleeding type 2,3,5 (BARC criteria). A total of 2,697 patients were randomly assigned 30 days after PCI to undergo de-escalation therapy to clopidogrel up to 12 months (n=1,349) or continued ticagrelor treatment (n=1,348) across 32 centres in South Korea. 90% of the patients randomised received the allocated treatment in the de-escalation arm, and 87% in the active control arm. There was no significant difference in demographic, clinical and procedural data. 53% presented as a STEMI, and there was overall a high rate of femoral access used during index PCI. Approximately a quarter of patients had multi-vessel disease. Following one year, the primary end point occurred in 4.6% of the de-escalation group and 8.2% in the active control group (P_{non-inferiority} <0.001; HR 0.55 [95% CI 0.40-0.76]. There was an absolute risk reduction of 3.6%, driven by reduced bleeding rates. Of note in the pre-specified secondary end point of composite of CV death, stroke, and myocardial infarction no difference was observed. There was also a reduction in the more severe BARC 3 and 5 bleeding events observed. Of note there was also no difference seen in repeat revascularisation or stent thrombosis rates between groups. The de-escalation strategy also met superiority requirements in the intention to treat as well as the per protocol and as treated populations. This trial appears to indicate that in patients that have surpassed their most at-risk period following PCI, unguided de-escalation can be performed safely with a reduction in significant bleeding events.

Valvular Intervention

TA at the time of mitral surgery reduces TR progression

Concomitant tricuspid repair in patients with degenerative mitral regurgitation.

NEJM 2021 Online

The optimal management of concomitant mild or moderate tricuspid regurgitation (TR) at the time of surgical intervention for degenerative mitral regurgitation (MR) is uncertain. The CTSN investigators examined the benefits and risks of tricuspid valve repair at the time mitral valve surgery in 401 patients with moderate or less than moderate TR who were undergoing surgery for degenerative MR. 203 patients were randomized to mitral valve surgery alone (surgery alone) and 198 patients were randomized ratio to undergo mitral surgery and tricuspid annuloplasty (surgery plus TA). Major exclusion criteria were secondary MR, primary tricuspid valve disease and suboptimal volume management. The primary endpoint at 2 years was a composite of reoperation for TR, progression of TR from baseline by two grades or the presence of severe TR, or death. Secondary endpoints included death, MACCE (defined as a composite of death, stroke, MI, or serious heart failure events), permanent pacemaker implantation (PPM), length of hospital stay, and cost effectiveness. The core laboratory confirmed moderate TR in 37.3%, RV systolic function was normal 90.5%, and 30% had NYHA class III or IV heart failure. In the tricuspid annuloplasty recipients, the average annuloplasty ring size was 29.0±1.9mm in men and 27.8±1.6mm in women. The primary endpoint was significantly greater in the surgery-alone group (10.2%) than in the surgery plus TA group (3.9%) (RR 0.37; 95% CI: 0.16-0.86; p=0.02). Death occurred in 4.5% in the surgery-alone group and 3.2% in the surgery plus TA group (RR 0.69; 95% CI: 0.25-1.88). No patients underwent tricuspid valve reoperation within 2 years after randomization. More patients in the surgery-alone group had progression of TR at 2 years (6.1% vs 0.6%; RR 0.09; 95% CI:0.01-0.69). The frequencies of MACCE, functional status, and quality of life were similar in both groups at 2 years although the incidence of PPM was higher in the surgery plus TA group (14.1% vs. 2.5%; RR 5.75; 95% CI:2.27-14.60). The rate of heart failure events was 0.11 per 24 patient-months in the surgery-alone group and 0.07 per 24 patient-months in the surgery plus TA group (RR 0.68; 95% CI: 0.25-1.85). The median length of stay during the index hospitalization was 2 days shorter in the surgery-alone group. The trial concluded that concomitant tricuspid valve repair at the time of mitral valve surgery in patients with less than severe TR at baseline results in improved outcomes at 2 years primarily in reducing the progression to worse/severe TR. The PPM rate was 5x higher in the surgery plus TR group and it is conceivable that over the long-term this can result in lead-related TR and potentially nullify these benefits.

To treat or not treat CAD prior to TAVI

ACTIVATION (percutaneous coronary intervention prior to transcatheter aortic valve implantation). A randomized clinical trial.

JACC Cardiol Intv 2021; 14:1965-74

The role of PCI in patients with concomitant significant coronary artery disease (CAD) and severe aortic stenosis who are due to undergo TAVR is unclear. The ACTIVATION trial was a randomized, open-label, noninferiority clinical trial undertaken in 17 European centres, included 235 patients, and designed to determine if PCI prior to TAVR in patients with significant CAD would produce noninferior clinical outcomes when compared to no PCI. Key inclusion criteria were severe AS deemed suitable for TAVR following heart team discussion and at least 1 stenosis of ≥70% stenosis in a major epicardial artery or ≥50% in a protected left main stem or vein graft suitable for PCI. Key exclusion criteria were ACS within 30 days of enrolment, CCS angina class III or greater, unprotected left main stem disease, or clinical features that would prohibit dual antiplatelet therapy. The primary endpoint was a composite of all-cause death or rehospitalization at 1 year. Noninferiority testing was performed in the intention-to-treat population. Eligible patients were randomised to undergo either PCI  or no PCI prior to TAVR. Based on reduced recruitment rates the Trial Steering Committee recommended early termination of the trial (the study was powered for 310 patients). Baseline characteristics were similar in both groups. Significant angiographic stenosis in the LAD was identified in 61.3% of those randomized to PCI and 60.5% randomized to no PCI. In those randomized to PCI, PCI was indicated for single vessel disease in 71.4% patients with a mean angiographic stenosis of 80±15%. The median number of lesions treated was 1. Mean treated lesion length was 17.4±6.6mm. A BMS was used in 18.1% of patients. At 1 year the primary endpoint occurred in 41.5% of the PCI arm and 44% of the no-PCI arm. The requirement for noninferiority was not met with a difference of -2.5% and 1-sided 95% confidence limit reaching 8.5%. Mortality was 13.4% in the PCI arm and 12.1% in the no PCI arm (p=0.99). The rates of MI (6.7% vs. 3.4%; p-0.30), stroke (5.9% vs. 6.9%; p=0.55), and acute kidney injury (10.1% vs. 4.3%; p=0.11) were similar in the PCI and no PCI group. Bleeding events at 1 year was greater in the PCI group (44.5% vs. 28.4%; p=0.021). Salient features of the trial include smaller-than-planned population, the noninferiority design (no PCI with potential advantages of no bleeding or kidney injury risk, single procedure and lower cost to be tested for noninferiority versus PCI and not vice versa), visual estimation of coronary stenosis, lack of predefined antithrombotic protocol, and the use of BMS.

Encouraging durability for TAVI

Native aortic valve disease progression and bioprosthetic valve degeneration in patient with transcatheter aortic valve implantation.

Circ 2021; 144:1396-1408

Despite the widespread adoption of TAVI in clinical practice, a number of questions including valve durability and ongoing disease activity within the retained aortic valve leaflets remain unanswered. The current study sought to answer these questions using ¹⁸F-sodium fluoride positron emission tomography (¹⁸F-NaF PET), which has been shown to be a marker of calcification activity and vascular injury across several cardiovascular conditions. Patients (n=47) were recruited into this study that had had a TAVI at one month, two years and five years prior, without significant haemodynamic evidence of valve degeneration. Each patient underwent a CT angiogram, echocardiogram and ¹⁸F-NaF PET at baseline, followed by an annual repeat echo. These were compared with a cohort of surgical aortic valve replacement (SAVR) patients (n=51) recruited into a similar study with the same imaging protocol. The investigators also performed an ex vivo assessment using histological immunohistochemistry and ¹⁸F-NaF autoradiography of explanted native valves and bioprosthetic valves obtained from patients with degenerative TAVI valves. The imaging protocol was performed at one month (n=9, 19%), 2 years (n=22, 47%) and 5 years (n=16, 34%). The patients with prior TAVI were older and were more likely to have co-morbidities such as diabetes, with a greater effective orifice area. In the ex vivo study calcified native aortic valve tissue was present around the perimeter of TAVI bioprosthesis, with evidence of ongoing calcification activity in the native valve. ¹⁸F-NaF uptake was seen on the explanted TAVI bioprosthesis, with colocalization of this signal to regions of calcification seen on histological immunohistochemistry analyses.  In the TAVI cohort, native valve uptake was highest in patients imaged 5 years after their TAVI, with a modest positive correlation with time from TAVI (r=0.36, p=0.023). At baseline all but 3 patients had normal valve function. All three had five year old TAVIs. Overall, 8 patients had imaging evidence on echo or CT of valve degeneration, 7 of which were imaged 5 years after TAVI. Seven patients were seen to have ¹⁸F-NaF uptake, all with five-year-old valves. The three highest uptake values were observed in patients with echo evidence of haemodynamic structural valve degeneration. During follow up echo the investigators observed a strong correlation between baseline ¹⁸F-NaF uptake and change in bioprosthetic valve peak velocity. On multivariable analysis ¹⁸F-NaF uptake was the only predictor of annualized change in peak velocity. There was no significant difference in degeneration on CT or echo between the SAVR and TAVI cohorts. ¹⁸F-NaF uptake was numerically almost doubled in the SAVR cohort, which did not reach statistical significance.  Although a small non-randomised observational study, this has given some insight into the mechanisms of aortic stenosis, suggesting that it is an active disease process which is independent of valve movement and mechanical ‘wear and tear’. ¹⁸F-NaF as a tracer for PET has been identified as a marker of subclinical valve degeneration and predicting subsequent development of valve dysfunction, which will need to be evaluated in larger studies. TAVI and SAVR had similar rates of degeneration in this study.

miscellaneous

Myocarditis is most common in the young post Pfizer vaccine

Myocarditis after Covid-19 Vaccination in a Large Health Care Organization.

NEJM 2021; 385:2132-39

Several reports have shown an association between the development of myocarditis and the mRNA vaccines against COVID-19. The current study examined this association using the database of the Clalit Health Services, the largest health care organization in Israel in patients who had received at least one dose of the Pfizer-BioNTech vaccine. This health care system provides care for 52% of the total population in Israel. The cohort were patients who had been vaccinated between December 20, 2020 through May 24, 2021. A follow-up period of 42 days after the first dose was chosen to allow at least 21 days of follow-up after each of the two vaccine doses. A patient was considered to have myocarditis if the Centers for Disease Control and Prevention (CDC) case definition for suspected, probable, or confirmed myocarditis had been met. During the study period, 2,558,421 patients had received at least one dose of the vaccine and 94% of these had received two doses. 54 cases were diagnosed with myocarditis of whom 41 were classified as mild, 12 as intermediate, and 1 as fulminant. The median age of patients with myocarditis was 27 years, 94% were male, 83% had no coexisting medical condition, 13% were receiving treatment for chronic diseases, 69% were diagnosed with myocarditis after the second dose of the vaccine with a median interval of 21 days between doses. The presenting symptom was chest pain in 82% of cases. Vital signs on admission were generally normal; 1 patient presented with hemodynamic instability and non-required circulatory support. The most common ECG abnormality was ST elevation, median peak troponin was 680 ng/L, 5% had non-sustained VT, 3% had AF, and 29% had left ventricular systolic dysfunction (LVSD) on echocardiography (17% were classified as mild, 4% mild to moderate, 4% moderate, 2% moderate to severe, and 2% as severe). The overall incidence of myocarditis within 42 days after having the first dose per 100,000 vaccinated persons was 2.13 cases (95% CI:1.56-2.70). The highest incidence of myocarditis was observed in male patients aged between 16 and 29 years (10.69 cases per 100,000 persons; 95% CI: 6.93-14.46). Salient features include a modest proportion of patients with myocarditis undergoing cardiac MRI (28%), myocardial biopsy undertaken in only one patient, and a short follow-up period to determine the long-term clinical implications of myocarditis post vaccination.

Blood pressure linked to the development of diabetes mellitus

Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis.

Lancet 2021; 398:1974-83

In type 2 diabetes, blood pressure management is a well-established therapeutic strategy to reduce both macrovascular and microvascular complications. However, whether blood pressure lowering can prevent the development of type 2 diabetes is unknown. Previous observational studies have had conflicting results and have been unable to tease out the drug class specific effects. The Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) provided individual participant data for this meta-analysis. All primary and secondary prevention RCTs between 1973 and 2008 that used a specific class/classes of antihypertensive drug versus placebo, or other classes of anti-hypertensives who had at least 1000 person years of follow up were included. Those participants with known diabetes at baseline or trials that were conducted in populations with high prevalence of diabetes were excluded. 19 trials (203,368 patients, 60.6% men) were included in the one-stage individual participant data meta-analysis to test the hypothesis that BP lowering leads to reduced incidence of type 2 diabetes. A Bayesian fixed effect network analysis model was used to compare the effect of different classes of anti-hypertensives in 22 trials. A stratified cox proportional hazards model with fixed treatment effects and participants as the unit of analysis was used to adjust for confounders, with standardised effect sizes for 5mmHg reduction in systolic blood pressure used. Median follow up was 4.5 years. The incidence rate for developing type 2 diabetes per 1000 person years was 16.4 (95% CI 16.01-16.87) in the comparator arm and 15.94 (95% CI 15.47-16.42), with a hazard ratio of new onset diabetes for a 5mmHg reduction in systolic blood pressure of 0.89 (95% CI 0.84-0.95).  In the Bayesian network meta-analysis of 22 RCTs, ACEIs and ARBs reduced the risk of diabetes compared with placebo (risk ratio 0.84 for both). Beta-blockers and thiazide diuretics were found to increase the risk of diabetes compared with placebo (RR 1.48 and 1.20 respectively), whilst calcium channels blockers had no impact.   No significant change in the results was seen after adjustment for baseline characteristics and after accounting for random effects in the Cox model. Interestingly baseline body mass index also had no impact on treatment effects. This was a large meta-analysis involving individual patient data with robust statistical tests used in the data analysis, including assessment of acquisition bias and undertaking sensitivity analyses. The key findings were that a reduction of SBP by 5mmHg resulted in lower numbers of new onset type 2 diabetes, and in terms of pharmacotherapy, ACEIs and ARBs had the greatest impact. This suggests that blood pressure is a modifiable risk factor in the development of diabetes, and therefore should be a target in primary prevention, particularly for those with other risk factors for diabetes. It also suggests that renin-angiotensin-aldosterone pathway deactivation may be involved in reducing the risk of diabetes. Further pre-clinical studies and randomised trials with the development of diabetes as a main outcome should be conducted to investigate this further.

BCIS R&D Group

Literature Review May 2020

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

Edited by Michael Mahmoudi

STABLE CAD & ACS

Is there a role for revascularization in stable angina?

Invasive or conservative strategy for stable coronary artery disease?

NEJM 2020; 382:1395-1407

The preferred contemporary approach to the management of stable angina is not well defined. Two strategies are commonly used: (a) guideline based medical therapy including antianginal drugs as well as disease modifying agents and (b) an invasive strategy consisting of coronary angiography followed by PCI or CABG plus medical therapy.  The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial tested whether an initial invasive strategy would result in better outcomes than a conservative strategy in 5179 patients with stable angina and moderate or severe myocardial ischemia with regards to the primary endpoint of death from cardiovascular causes, MI, or hospitalization for unstable angina, heart failure, resuscitated cardiac arrest. Key exclusion criteria were GFR < 30, recent ACS, unprotected left main stenosis of at least 50%, LV ejection fraction < 35%, NYHA class III or IV heart failure, and “unacceptable angina” despite the use of medical therapy. The majority of patients also underwent CTCA at screening to confirm the presence of obstructive CAD and exclude left main disease. At 6 months, the cumulative event rate was 5.3% in the invasive strategy group and 3.4% in the conservative strategy group (difference 1.9 percentage points; 95% CI: 0.8-3.0); at 5 years, the cumulative event rates were also similar (16.4% vs. 18.2%; difference -1.8 percentage points; 95% CI: -4.7-1.0). The difference in outcomes was driven by results for MI and those results depended on the definition used in the analysis. Of note, patients in the invasive strategy reported fewer angina symptoms than patients in the conservative group although the magnitude of this benefit depended on angina frequency at baseline with 35% having no angina at baseline. The Kaplan-Meier curves showed a trend for a greater number of MI (predominantly procedural) in the invasive strategy group during the first 6 months of the trial but as the trial proceeded the curves crossed and more MI (predominantly spontaneous) occurred in the conservative group. Finally, at 4 years, the cumulative incidence of death from cardiovascular causes or MI based on the primary definition was higher in the conservative strategy group  (13.9% vs. 11.7%). It is possible that ISCHEMIA ended before a substantial difference in favour of the invasive strategy emerged.

Should morphine be replaced by another analgesic agent in ACS patients?

Morphine and cardiovascular outcomes among patients with non-ST-segment elevation acute coronary syndromes undergoing coronary angiography.

JACC 2020; 75:289-300

Morphine is routinely utilised in the management of acute chest pain in patients presenting with ACS. From a pharmacological perspective, morphine and other opiates delay gastric emptying thus compromising intestinal absorption of P2Y₁₂ inhibitors. A number of small studies have demonstrated that morphine reduced active metabolite exposure and antiplatelet effects of clopidogrel, prasugrel, and ticagrelor in stable patients post ACS, in acute MI, and during elective PCI. The current study was designed to explore the association between morphine and ischemic events in 5,438 patients treated with clopidogrel in the context of non-ST-segment elevation ACS in the EARLY-ACS trial. Patients that were not treated with clopidogrel (n=3,462) were used as negative controls. At 96 hours, morphine use was associated with higher rates of the composite endpoint of death, MI, recurrent ischemia, or thrombotic bailout (OR: 1.40; 95% CI: 1.04-1.87; p=0.026). There was a trend for higher rates of death or MI at 30 days (OR: 1.29; 95% CI: 0.98-1.70; p=0.072). The results question a routine strategy of routine morphine use in ACS patients or delaying the administration of clopidogrel loading dose until the time of PCI when the effects of morphine may have subsided.

Antiplatelet therapy in elderly patients presenting with NSTEMI

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label non-inferiority trial.

Lancet 2020;395:1374-81

Landmark trials such as PLATO and TRITON-TIMI 38  have demonstrated the advantage of a more potent antiplatelet effect from ticagrelor or prasugrel versus clopidogrel. The elderly who are often at high risk from thrombotic and bleeding events have been underrepresented in such trials. Investigators from the Netherlands randomised 1002 patients aged ≥70 presenting with NSTE-ACS 1:1 to clopidogrel versus ticagrelor or prasugrel along with standard therapy for 12 months. There were two co-primary endpoints. The safety endpoint was any bleeding requiring medical intervention, defined as PLATO major or minor bleeding. The net clinical benefit outcome was a composite of all-cause death, MI, stroke and PLATO major or minor bleeding. The median age was 77 (IQR 73-81) in the clopidogrel arm (n=500) and 77 (IQR 73-82) in the ticagrelor arm (n=502). There were 64% men and 36% women recruited. Given the open-label construct of the trial, 95% (475/502) of those in the prasugrel/ticagrelor cohort were prescribed ticagrelor. This was to be expected given the contraindications and cautionary advice associated with prasugrel in those ≥75 years old. The primary bleeding endpoint was significantly lower in the clopidogrel arm (HR 0.71, 95% CI 0.54-0.94; p=0.02 for superiority). The net clinical benefit endpoint satisfied the non-inferiority threshold in the clopidogrel arm (absolute risk difference -4%, 95% CI -10.0-1.4; p=0.03) but not for superiority (HR 0.82, 95% CI 0.66-1.03; p=0.11). In essence, treatment with clopidogrel in elderly NSTE-ACS patients resulted in lower bleeding events but not at the cost of greater thrombotic events. The trial was not powered to test for differences in mortality. One of the most important findings of the study was the rate of study drug discontinuation. Only 53% of patients completed their 12-month course of ticagrelor compared to 78% in the clopidogrel cohort, predominantly due to bleeding, dyspnoea and need for chronic oral anticoagulation.

ONYX ONE supports shorter DAPT duration

Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk.

NEJM 2020; 382:1208-18

The optimal duration of dual antiplatelet therapy particularly in patients at high bleeding risk who undergo PCI has not been determined. The ONYX ONE trial compared the polymer-based zotarolimus-eluting stent (ZES) (Resolute Onyx; Medtronic; n=1,003) with the polymer-free umirolimus-coated stent (UCS) (Biofreedom; BioSensors; n=993) in patients undergoing PCI and who were deemed at high-bleeding risk. After PCI, patients were treated with 1 month of DAPT, followed by single antiplatelet therapy. The primary outcome was death from cardiac causes, MI, or stent thrombosis. The secondary outcome was target lesion failure, a composite of death from cardiac causes, target vessel MI, or clinically indicated target lesion revascularization. Both outcomes were powered for noninferiority. At 1 year, the primary outcome occurred in 17.1% in the ZES group and 16.9% in the UCS group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI: 3.5; noninferiority margin, 4.1; p=0.01 for noninferiority). The secondary outcome occurred in 17.6% of the ZES group and 17.4% of the UCS group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI: 3.5; noninferiority margin, 4.4; p=0.007 for noninferiority). Important limitations of the trial included its single-blind nature, noninferiority testing of the primary and secondary outcomes, and lack of a control group taking DAPT for a longer duration.

PHYSIOLOGY & IMAGING

Invasive physiology use remains  modest in stable CAD

Utilization and outcomes of measuring fractional flow reserve in patients with stable ischemic heart disease.

JACC 2020; 75:409-19

FFR/iFR guided revascularization is considered the gold standard for invasive assessment of ischemia. Despite evidence from clinical trials and recommendations from the American and European societies FFR/iFR use remains limited with large differences between countries and health systems. The current study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes in patients with stable ischemic heart disease and angiographically intermediate disease (40% to 69% stenosis by visual assessment. A total of 17,989 patients were identified through the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program. Over a period of 8 years (2009-2017), the rate of FFR use gradually increased from 14.8% to 18.5% in patients with intermediate lesions, and from 44% to 75% in patients undergoing PCI. One-year mortality was significantly lower in the FFR group (2.8% vs. 5.9%; p<0.001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization.

IVUS a MUST for left main PCI

Intravascular Imaging and 12-Month Mortality After Unprotected Left Main Stem PCI. An Analysis From the British Cardiovascular Intervention Society Database.

JACC Cardiovasc Interv 2020; 13:346-57

Despite intravascular imaging being shown to improve PCI outcomes in both randomized trials and registries, its use to optimise PCI remains limited. The current study has utilised the UK National PCI Audit to explore temporal changes in and implications of the use of IVUS for unprotected LM PCI in 11,264 patients. Imaging guidance significantly increased from 30.2% of procedures in 2007 to 50.2% in 2014. The factors associated with imaging use included stable angina presentation (OR: 1.2; 95% CI :1.15-1.25; p<0.001), bifurcation LM disease (OR: 1.22; 95% CI: 1.14-1.30; p<0.001), previous PCI (OR: 1.32; 95% CI: 1.22-1.32; p<0.001).  After propensity scoring was performed to adjust for baseline imbalances between groups, imaging guidance was strongly associated with a lower rate of coronary complications, fewer in-hospital major adverse cardiovascular events, and 46% and 34% reductions in 30-day and 12-month mortality respectively. Greater mortality reductions were observed with higher operator LM PCI volume. In logistic regression modelling, imaging use was associated with improved 12-month survival.

CATHETER BASED VALVULAR INTERVENTION

Self-expandable or balloon-expandable TAVI?

Balloon-Expandable Versus Self-Expanding Transcatheter Aortic Valve Replacement. A propensity-Matched Comparison from the FRANCE-TAVI Registry.

Circ 2020; 141:243-59

There are very few randomized head-to-head trials comparing the balloon with the self-expanding transcatheter aortic valve replacement devices. Despite the inherent differences in expansion mode, stent frame, and leaflet characteristics between the device types, which translate into some differences in hemodynamic function, paravalvular sealing, and periprocedural complications have been considered comparable. The FRANCE-TAVI  nationwide registry of 12,141 patients undergoing balloon-expandable (Edwards, n=8,038) or self-expandable (Medtronic, n=4,103) has reported on ≥ moderate paravalvular regurgitation, in-hospital mortality, and 2-year all-cause mortality. In propensity-matched analyses, the self-expandable cohort had higher rates of ≥ moderate paravalvular regurgitation (15.5% vs. 8.3%; RR: 1.9; 95% CI: 1.63-2.22; p<0.0001) and in-hospital mortality (5.6% vs. 4.2%; RR:1.34; 95% CI: 1.07-1.66; p=0.01). 2-year mortality was also higher in the self-expandable group (29.8% vs. 26.6%; HR: 1.17; 95% CI: 1.06-1.29; p=0.003).

The evolution of self-expandable TAVI

Three Generations of Self-Expanding Transcatheter Aortic Valves. A Report From the STS/ACC TVT Registry.

JACC Cardiovasc Interv 2020; 13:170-79

The ever-increasing improvements in transcatheter technology has advanced TAVI to equivalency or superiority to SAVR in multiple studies across the spectrum of surgical risk. The current report focuses on real-world data from the Society of Thoracic Surgeons/American College of Cardiology TVT Registry for patients undergoing TAVI with CoreValve, Evolut R, or Evolut PRO valves for the treatment of tricuspid aortic stenosis between January 2014 to September 2017. The valves analysed included the 23, 26, and 29mm sizes. Propensity matching was performed using the Evolut PRO group as the reference. In 18,874 patients undergoing TAVI, 5,514 patients received the CoreValve, 11, 295 Evolut R, and 2,065 Evolut PRO. At 30-days, there were fewer patients with more than mild AR for the unmatched (7.8% CoreValve, 5.2% Evolut R and 2.8% Evolut PRO; p<0.001) and matched populations (8.3% CoreValve, 5.4% Evolut R and 3.4% Evolut PRO; p=0.03). The mean aortic valve gradients at 30 days in the matched populations were <8 mmHg for all three valves (7.3 mmHg CoreValve, 7.5 mmHg Evolut R, and 7.2 mmHg Evolut PRO).

PARTNER-2 at 5 years

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

NEJM 2020; 382:799-809

To be established as first line therapy for the treatment of symptomatic, severe aortic stenosis, TAVI must prove to be as effective as SAVR in the long term. The PARTNER 2 cohort A trial involved 2,032 patients who were stratified according to intended transfemoral or transthoracic access and randomly assigned to undergo TAVR with the balloon-expandable SAPIENT XT valve or SAVR. TAVR was found to be noninferior to SAVR with regards to the primary outcome of death from any cause or disabling stroke at 2 years. The investigators have now confirmed that at 5 years, there was no difference in the incidence of death or disabling stroke between TAVI and SAVR (47.9% vs. 43.4%; HR: 1.09; 95% CI 0.95-1.25). A landmark analysis of events occurring between 2 and 5 years after the procedure showed a divergence of event rates in favour of surgery (HR: 1.27; 95% CI: 1.06-1.53). This late increase in risk with TAVR has also been reported with the self-expanding TAVI valve. Other salient findings included greater paravalvular regurgitation in the TAVI group, patients in the TAVI group had nearly three times as many valve-related hospitalizations and required 21 aortic valve reinterventions as compared to 6 in the surgery group.

Optimal antithrombotic therapy in TAVI patients

Anticoagulation with or without clopidogrel after transcatheter aortic-valve implantation.

NEJM 2020; 382:1696-1707

Bleeding risk is particularly relevant in patients undergoing TAVI, especially those receiving oral anticoagulation, given the typical age of the patients, the frequent presence of comorbidities, and the use of large-bore access catheters. Expert opinion has indicated that administration of clopidogrel may reduce the risk of stroke and other embolic complications that are due in part to thrombus formation on the bioprosthetic valves. The POPular TAVI trial (cohort B) tested the hypothesis that in patients receiving anticoagulation, the use of oral anticoagulants alone would be safer (n=157) than oral anticoagulants plus 3 months of clopidogrel (n=156). The two coprimary endpoints of the trial were all bleeding and non-procedural related bleeding within 12 months after TAVI. Bleeding was lower in the anticoagulation only group (21.7% vs. 34.6%; RR: 0.63; 95% CI: 0.43-0.90; p=0.01). Most bleeding events were at the access site. Non-procedural related bleeding was also lower in the anticoagulation only group (21.7% vs. 34%; RR: 0.64; 95% CI: 0.44-0.92; p=0.02). Important limitations of the study included the definitions used in the trial with bleeding occurring during TAVI or the index hospitalization being defined as non-procedure related even if it occurred at the access site. Details regarding baseline and procedural characteristics, including aspirin use, the specific direct-acting oral anticoagulant used by patients, and how often oral anticoagulants were withheld periprocedurally, are lacking.

TAVI for bicuspid aortic valve disease

Outcomes of Transcatheter Aortic Valve Replacement in Patients with Bicuspid Aortic Valve Disease. A Report from the Society of Thoracic Surgeons/American College of Cardiology Valve Therapy Registry.

Circ 2020; 141:1071-79

Patients with bicuspid aortic valve stenosis (BAVS) have been excluded from pivotal TAVI trials. The aim of the current study was to compare the outcomes of TAVI in patients with BAVS and tricuspid aortic valve stenosis (TAVS). There were 170,959 eligible procedures in the Society of Thoracic Surgeons/American College of Cardiology Valve Therapy Registry. Of these, 5,412 TAVI procedures were performed in patients with BAVS, including 3,705 with current generation devices. As compared to patients with TAVS, patients with BAVS were younger and had a lower STS score. With current generation devices, device success was 96.3%, and the incidence of 2+ AR was 2.7%. A lower 1-year adjusted risk of mortality was observed in patients with BAVS (HR: 0.88; 95% CI: 0.78-0.99) whereas no difference was observed in the 1-year adjusted risk of stroke (HR: 1.14; 95% CI: 0.94-1.39).

MISCELLANEOUS

Evolution of renal denervation for hypertension

Alcohol-Mediated Renal Denervation Using the Peregrine System Infusion Catheter for Treatment of Hypertension.

JACC Cardiovasc Interv 2020; 13:471-84

The success of catheter-based renal denervation for the treatment of hypertension has remained variable. The Peregrine Catheter system has been developed to deliver small doses of pure dehydrated alcohol into the renal periadventitial space to ablate the afferent and efferent sympathetic nerve bundles. The current study examined the safety and efficacy of the infusion of 0.6ml of alcohol in 45 patients with uncontrolled hypertension taking 3 or more antihypertensive medications. Mean 24-hour ambulatory BP reduction at 6 months versus baseline was -11 mmHg for systolic BP and -7 mmHg for diastolic BP. Office systolic BP was reduced by -18/-10 mmHg at 6 months. Antihypertensive medications were reduced in 23% and increased in 5% of patients at 6 months. The primary safety endpoint, defined as the absence of periprocedural major vascular complications, major bleeding, acute kidney injury, or death within 1 month was met in 96% of patients. Two patients developed access site pseudoaneurysms. There were no death or instances of MI, stroke, TIA, or renal artery stenosis. There were two cases of minor vessel dissection that resolved without treatment.

BP control without the pills?

Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial.

Lancet 2020; 395:1444-51

The SPYRAL HTN-OFF MED (SPYRAL Pivotal) trial was designed to assess the efficacy of renal denervation in the absence of antihypertensive medication. The study randomized 331 patients with office systolic blood pressure of 150-180 mmHg to either renal denervation or a sham procedure. The primary efficacy endpoint was baseline adjusted change in 24-hour systolic BP and the secondary efficacy endpoint was baseline adjusted change in office systolic BP from baseline to 3 months after the procedure. The primary and secondary efficacy endpoints were met, with posterior probability of superiority more than 0.999 for both. The treatment difference between the two groups for systolic BP was -3.9 mmHg and for office systolic BP  the difference was -6.5 mmHg. There were no major device-related or procedural related safety events up to 3 months after the procedure.

Very late stent outcomes

Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention.

JACC 2020; 75:590-604

Many contemporary drug-eluting stent (DES) trials have focused on 1-year outcomes. The frequency and predictors of stent-related major adverse cardiovascular events (MACE) after the first year have not been extensively studied. Individual patient data from patients involved in 19 prospective, randomized metallic stent trials were examined for the frequency and predictors of very-late stent-related events and MACE by stent type. Amongst 25,032 patients, 3718, 7934, and 13380 were treated with bare metal stents (BMS), first generation DES (DES1) and second generation DES (DES2) respectively. MACE rates within 1 year after PCI were progressively lower following treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1% respectively; p<0.0001). Between years 1 and 5, very late MACE occurred in 9.4% of patients including 2.9% cardiac death, 3.1% MI, and 5.1% ischemia driven target lesion revascularization. Very late MACE occurred in 9.7%, 11%, and 8.3% of patients treated with BMS, DES1 and DES2 respectively (p<0.0001), linearly increasing between 1 and 5 years. The use DES1, age, coronary risk factors such as diabetes and smoking, and variables associated with extensive disease (eg. previous revascularization, calcification, multivessel disease) were identified as predictors of very late events.

It’s all about risk factor modification

Modifiable risk factors, cardiovascular disease, and mortality in 155722 individuals from 21 high-income, middle-income, and low-income countries (PURE): a prospective cohort study.

Lancet 2020;395:795-808

The Prospective Urban Rural Epidemiology (PURE) study was designed to standardise the prospective measurement of the effects of 14 modifiable risk factors on cardiovascular disease (CVD) and mortality across 21 countries categorised by different socio-economic strata. Between January 2005 to December 2016, investigators recruited 155,722 participants without a prior history of CVD who were then followed up for a median of 9.5 years. Behavioural risk factors were tobacco use, alcohol intake, diet quality, physical activity, and sodium intake. Metabolic risk factors included hypertension, dysglycaemia (or history of diabetes), non-HDL cholesterol, body mass index and waist-to-hip ratio as a surrogate of centripetal obesity. Education was the primary socioeconomic factor of interest. Symptoms of depression was measured as were grip strength and household and ambient air pollution. Important findings included a mean BMI, waist-to-hip ratio, and non-HDL cholesterol greatest in high-income countries, prevalence of hypertension highest in middle-income countries, and diabetes found most often in low-income countries. Tobacco was most strongly associated with CVD, followed by physical activity and poor diet. Hypertension had a stronger association with CVD than diabetes, elevated non-HDL cholesterol and obesity. In the overall cohort, hypertension was the strongest risk factor for CVD, followed by high non-HDL cholesterol, household air pollution, tobacco use, poor diet, low education, abdominal obesity, and diabetes. Elevated non-HDL cholesterol was the largest risk factor for MI, followed by hypertension and smoking.

Simple measures to reduce radiation exposure

Effectiveness of additional x-ray protection devices in reducing scattered radiation in radial intervention: the ESPRESSO randomized trial.

EuroIntervention 2020 Online

The incidence of radiation associated pathology correlates with length of career and the complexity cases undertaken. Radiation protection practice and training varies considerably between different centres and countries. It is remarkable how simple alterations to practice, can reduce dose, not just to the operator but also to the other staff in the lab. Over a career, these measures make a big difference. Modern interventional trends such as increasing patient BMI, and case complexity are all associated with increased operator x-ray dose. The ESPRESSO trial compared three basic radiation protection measures in the context of radial arterial access. The trial randomised 600 patients undergoing radial access intervention, prospectively, to ‘Shield only’ – a 60*76 cm, 0.5mm Pb, ceiling mounted Mavig shield, ‘Shield + curtain’ – as above, plus an attached 0.5 Pb curtain underhanging the shield, and ‘Shield + curtain + drape’ – as above, plus a 75*40 cm 0.5 Pb drape positioned over the waist. The drape was custom made and covered the patient’s lower abdomen and groin area.  All strategies were all used alongside standard lead apron and thyroid collar. Outcome measures were the radiation dose to the first and second operator and the patient with analysis on an intention to treat basis. There was a mixture of interventional cases including PCI (in 53%), diagnostic studies, left ventriculography and a small percentage of right heart catheterisation and even biopsy.  No cases crossed over. Patient and case characteristics were well balanced between groups. There were no between-group differences in screening or procedure time. The key results were no statistically significant differences in patient dose-area product. As compared with group 1 (shield only), group 2 (+ curtain) was associated with non-significant 3% dose reduction for first operator and 17% dose reduction in the second operator. Group 3 (+ curtain and drape) had a significant 19% dose reduction for first operator and 39% reduction for second operator. Most centres will be familiar with the equipment used in groups 1 and 2 but may not utilise the drape over the patient’s waist. This appears to be a particularly inexpensive (reusable) and simple to use strategy associated with considerable benefit in every case performed.