New Developments in Cardiology with Implications in Clinical Practice

This series endeavors to provide a bird’s eye view of the latest literature and developments in cardiology, which has potentially practice-changing implications.

Consequently, the elephant in the room is addressed first – the DELIVER trial.

Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Solomon SD, McMurray JJV, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al., DELIVER Trial Committees and Investigators

Indian Heart J. 2022 Jul-Aug;74(4):275–281. doi: 10.1016/j.ihj.2022.07.002. Epub 2022 Aug 3. PMID: 36027570

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain.

Methods: We randomly assigned 6,263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis.

Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3,131 patients (16.4%) in the dapagliflozin group and in 610 of 3,132 patients (19.5%) in the placebo group (hazard ratio: 0.82; 95% confidence interval [CI], 0.73−0.92; P < .001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio: 0.79; 95% CI: 0.69−0.91); cardiovascular death occurred in 231 (7.4%) and 261 (8.3%) patients, respectively (hazard ratio: 0.88; 95% CI: 0.74−1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups.

Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.).

Comments: The DELIVER trial can be considered a landmark trial in the therapy of heart failure. While the role of dapagliflozin in heart failure with reduced ejection fraction (HFrEF) was well established by the DAPA-HF trial, its role in heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) was undetermined.

The EMPEROR trials demonstrated the benefits of empagliflozin in HFrEF (EMPEROR-Reduced) and HFpEF (EMPEROR-Preserved). However, while EMPEROR-Preserved showed a mortality reduction and symptom benefit in HFmrEF, only symptom benefit was demonstrated in HFpEF.

On the other hand, the DELIVER trial has demonstrated, for the first time, a mortality benefit in HFpEF and HFmrEF patients with dapagliflozin. The benefits of dapagliflozin were the same in patients with EF < 60% and EF > 60%.

Strengths: The trial evaluated a large sample size and a diverse population, demonstrating the benefits in a variety of patient populations seen in clinical practice. While dapagliflozin (like all agents) remains more useful in HFrEF, this is the first agent which has shown a mortality benefit in HFpEF, which is otherwise a difficult-to-treat population.

Implications: As a consequence of the EMPEROR-Reduced and the DELIVER trials, the ACC/AHA/HFSA Heart Failure guidelines 2022 recommend the use of SGLT2 inhibitors in HFpEF with a Class 2A recommendation. For day-to-day practice, it is now possible to prescribe an evidence-based and effective agent in patients with HFpEF, something which was not possible before.

The following trials demonstrate the conflicting evidence available in deciding targets for preventive cardiology. To start, the completely Indian MERIFACS study gives an interesting insight into the concept of the “Metabolic Syndrome”.

Metabolic Risk Factors in First Acute Coronary Syndrome (MERIFACS) Study

Rao BH, Raju NR, Raju CS, Patel P, Korabathina R, Raj JP, Azam MS, Rao BA, Shivakumar Y, Abdullakutty J, Raju PK.

Indian Heart J. 2022 Sep-Oct;74(5):430. doi: 10.1016/j.ihj.2022.10.003. PMID: 36347596

Abstract

Objectives: In acute coronary syndrome (ACS) patients, the focus is on major conventional risk factors – CRF (diabetes, hypertension, elevated low-density cholesterol [LDL-C], and smoking) whereas others – specific metabolic risk factors – MRF (high-density lipoprotein cholesterol [HDL-C], body-mass index [BMI], waist–hip ratio [WHR], and triglycerides, and HbA1c get less attention).

Methods: This is a prospective case-control observational study from 15 tertiary care hospitals in India. CRF and MRF in patients presenting with the first incidence of ACS (n = 2,153) were compared with matched controls (n = 1,210).

Results: Propensity score matching (PSM) yielded 1,193 cases and matched 1,210 controls. Risk factor prevalence in cases vs controls was CRF: hypertension – 39.4% vs. 16.4% (p < .0001), diabetes – 42.6% vs. 12.7% (p < .0001), smoking − 28.3% vs. 9.3% (p < .0001), and elevated LDL-C – 70.2% vs. 57.9% (p < .0001). MRF: High BMI – 54.7% vs 55.1% (p = .84), increased waist: hip ratio 79.5% vs. 63.6% (p < .0001), high HbA1c – 37.8% vs. 14.9% (p < .0001), low HDL-C – 56.2% vs. 42.8% (p < .0001), and elevated triglycerides – 49.7% vs. 44.2% (p = .007). Adjusted odds ratios by multivariate analysis were CRF: hypertension – 2.3 (p < .001), diabetes – 4.7 (p < .001), high LDL-C – 3.3 (p < .001), and smoking – 6.3 (p < .001). MRF: High waist: hip ratio – 2.4 (p < .001), high HbA1c – 3.2 (p < .001), low HDL-C − 2.2 (p < .001), and elevated triglycerides – 0.878 (p = .17).

Conclusion: In India, the risk of ACS conferred by specific metabolic risk factors (High waist: hip ratio, low HDL-C, and high HbA1c) is comparable to that caused by CRF.

Comments: Metabolic Syndrome is a heterogenous collection of parameters and is proven to be an unconventional risk factor for atherogenesis. The Indian population, especially, has been demonstrated to have a disproportionate incidence of metabolic syndrome as a cardiac risk factor. Unfortunately, most studies on this causation have treated the syndrome as a single entity.

This study is notable for evaluating the components of metabolic syndrome separately and comparing them to traditional risk factors. As a result, it clarifies certain aspects of cardiac risk factors in the Indian population.

First, the study underlines the importance of traditional risk factors. Thus, control of diabetes, hypertension and LDL-C, and smoking cessation are as important in Indians as in the rest of humanity.

Second, it demonstrates that all the components of metabolic syndrome are not born equal. A high waist–hip ratio is more important as a risk factor than the body-mass index (BMI). The level of HbA1c, i.e., diabetes control, is as important as the presence of diabetes. Low HDL-C is as important as high LDL-C (albeit, currently not effectively modifiable).

By contrast, triglyceride (TG) levels were not shown to be an important risk factor. While the data on triglyceride control are conflicting, this study does show that the claim that TG control is as important or even more important than LDL-C control is just a hype.

Strengths: This a very well-designed study with a decent sample size and endeavors to answer some of the persisting questions about metabolic syndrome. Since it is a purely Indian study, the results can be used in the Indian population without reservation.

Implications: The MERIFACS study gives us four major takeaway points for clinical practice. First, the importance of traditional risk factors remains undiminished, and they should be targeted as per global guidelines as far as possible. Second, the waist–hip ratio should be added to routine patient risk evaluation. Third, while it is impossible to reduce the risk in diabetic patients to the level of non-diabetics, control of diabetes is important and should not be neglected, especially now that we have several cardio-safe and even cardio-protective options for diabetes management. Fourth, aggressive control of TG is quite clearly unnecessary and should not be separately pursued unless TG levels are very high (targets remain unclear).

The confusion regarding the importance (or lack thereof) of TG control can be seen by the conflicting evidence provided by the following two papers, one which suggests that TG control is important, but needs novel agents, and another which suggests that TG control does not provide any real benefit.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention

Quispe R, Sweeney T, Varma B, Agarwala A, Michos ED.

Curr Atheroscler Rep. 2022 Oct;24(10):767–778. doi: 10.1007/s11883-022-01052-4. Epub 2022 Jul 27.

Purpose of Review: Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia.

Recent Findings: The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in the metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed a significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefits on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Comments: This review highlights the evidence which suggests that TG levels are atherosclerotic risk factors beyond LDL-C levels, especially in people whose TG remains high even after effective control of LDL-C. It also acknowledges that fibrates have not demonstrated any benefit when added to statins even when TG levels reduce.

The REDUCE-IT trial demonstrated that the addition of icosapent ethyl to statins reduces TG levels and provides incremental reduction in cardiovascular risk. Other omega-3 fatty acids have not shown a similar response.

The authors feel that ongoing research into novel molecules may cover this unmet need.

Implications: TG control remains controversial and problematic. As of now, icosapent ethyl may be considered, since it has some supportive data.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk

Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al.; PROMINENT Investigators.

N Engl J Med. 2022 Nov 24;387(21):1923–1934. doi: 10.1056/NEJMoa2210645. Epub 2022 Nov 5.

Abstract

Background: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels.

Methods: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy endpoint was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes.

Results: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, −25.8% for very-low-density lipoprotein (VLDL) cholesterol, −25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), −27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 patients of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease.

Conclusions: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Comments: The PROMINENT trial evaluated a new agent, pemafibrate, for the control of TG levels. While the TG levels reduced, there was no risk reduction in terms of cardiovascular outcome. There was a lower incidence of non-alcoholic fatty liver disease at the cost of an increase in the incidence of adverse renal events and venous thromboembolism. This trial, once again, demonstrates that unproven targets should not be chased based on “it can’t hurt”. Drug adverse events and adverse interactions are real and dangerous and should always be considered even when using proven therapy. There is no justification for subjecting a patient to adverse drug reactions for unproven indications.

To conclude, while TG levels may or may not be important risk factors, effective risk-reducing therapy is still lacking.

To conclude the discussion on preventive cardiology, the next trial is 3 years old, but as bempedoic acid has been approved in India only in the last few months and is being aggressively marketed, it is only appropriate to review the data about the agent.

Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol

Kausik K Ray, Harold E Bays, Alberico L Catapano, Narendra D Lalwani, LeAnne T Bloedon, Lulu R Sterling, et al.; CLEAR Harmony Trial

N Engl J Med. 2019 Mar 14;380(11):1022–1032. doi: 10.1056/NEJMoa1803917. PMID: 30865796

Abstract

Background: Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein cholesterol (LDL-C). Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.

Methods: We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary endpoint was safety, and the principal secondary endpoint (principal efficacy endpoint) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.

Results: The trial involved 2,230 patients, of whom 1,488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL-C level at baseline was 103.2 ± 29.4 mg per deciliter. The incidence of adverse events (1,167 of 1,487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of −16.5% from baseline (difference vs. placebo in change from baseline, −18.1 percentage points; 95% confidence interval, −20.0 to −16.1; P < .001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.

Conclusions: In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).

Comments: The importance of lowering LDL-C levels to as low as possible cannot be overestimated. While PCSK9 inhibitors are very effective and safe for the same, their high cost and parenteral route of administration remain barriers in their widespread acceptance. Statin intolerance, especially at high doses, is common, and ezetimibe is a modestly effective agent.

The CLEAR Harmony trial demonstrates both the safety and efficacy of bempedoic acid as an add-on to statin with or without ezetimibe therapy in patients who do not achieve target LDL-C at maximum doses and those who do not tolerate high statin doses. Bempedoic acid was not shown to cause myopathy. The only significant adverse effect was the precipitation of gout.

Strengths: This was a randomized control trial with a large sample size thereby providing convincing results.

Implications: Cost has proven to be a major barrier to the widespread adoption of PCSK9 inhibitors in India. Bempedoic acid provides an effective and safe option in patients where statins do not achieve the target or are not tolerated at full doses.

The next abstract deals with the risk stratification of patients.

Plaque Burden and 1-Year Outcomes in Acute Chest Pain: Results from the Multicenter RAPID-CTCA Trial

Mohammed N Meah, Evangelos Tzolos, Kang-Ling Wang, Anda Bularga, Marc R. Dweck, Nick Curzen, et al.

J Am Coll Cardiol Img. 2022 Nov 15(11):1916–1925.

Abstract

Background: In patients with stable chest pain, computed tomography (CT) plaque burden is an independent predictor of future coronary events.

Objectives: The purpose of this study was to determine whether plaque burden and characteristics can predict subsequent death or myocardial infarction in patients with acute chest pain.

Methods: In a post-hoc analysis of a multicenter trial of early coronary CT angiography, the authors performed quantitative plaque analysis to assess the association between primary endpoint of 1-year all-cause death or nonfatal myocardial infarction and the GRACE (Global Registry of Acute Coronary Events) score, presence of obstructive coronary artery disease, and plaque burden in 404 patients with suspected acute coronary syndrome.

Results: Following the index event, 25 patients had a primary event that was associated with a higher GRACE score (134 ± 44 vs. 113 ± 35; P = .012), larger burdens of total (46% [IQR: 43%−50%] vs. 36% [IQR: 21%−46%]; P < .001), noncalcified (41% [IQR: 37%−%47] vs. 33% [IQR: 20%−41%]; P < .001), and low-attenuation plaque (4.22% [IQR: 3.3% to 5.68%] vs. 2.14% [IQR: 0.5% to 4.88%]; P < .001), but not obstructive coronary artery disease (P = .065). Total, noncalcified, and low-attenuation plaque burden were the strongest predictors of future events independent of GRACE score and obstructive coronary artery disease (P ≤ .002 for all). Patients with a low-attenuation burden above the median had nearly an 8-fold increased risk of the primary endpoint (HR: 7.80 [95% CI: 2.33−26.0]; P < .001), outperforming either a GRACE score of >140 (HR: 3.80 [95% CI: 1.45−.98]; P = .004) or obstructive coronary artery disease (HR: 2.07 [95% CI: 0.94−4.53]; P = .07).

Conclusions: In patients with suspected acute coronary syndrome, low-attenuation plaque burden is a major predictor of 1-year death or recurrent myocardial infarction. (Rapid Assessment of Potential Ischaemic Heart Disease With CTCA [RAPID-CTCA]; NCT02284191).

Comments: The RAPID-CTCA trial evaluated the cardiac risk predicted by the presence of plaques by CTCA and the effect of plaque composition. The study is important because it demonstrates the ability of CTCA to distinguish between lipid-rich and lipid-poor plaques without the need for invasive intravascular imaging. Total, noncalcified, and low-attenuation plaque burden proved to be very strong predictors of future events. This study adds to the growing body of evidence that suggests that while stenosis severity may determine the need for coronary intervention or surgery, vulnerable plaque burden determines the required aggressiveness of medical therapy.

The following studies deal with therapeutic strategies.

Transcatheter Edge-to-Edge Mitral Valve Repair in Patients With Severe Mitral Regurgitation and Cardiogenic Shock

Trevor Simard, Sreek Vemulapalli, Richard G. Jung, Andrew Vekstein, Amanda Stebbins, David R. Holmes, et al.

J Am Coll Cardiol. 2022 Nov 80(22):2072–2084.

Abstract

Background: Data on the efficacy of transcatheter edge-to-edge repair (TEER) in patients with cardiogenic shock (CS) are limited.

Objectives: This study investigated the characteristics and outcomes of consecutive patients with significant mitral regurgitation (MR) and CS who underwent TEER.

Methods: The Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry was assessed from November 22, 2013, to December 31, 2021. CS was defined as the coding of (1) CS; (2) inotrope use; or (3) mechanical circulatory support before TEER. Device success was defined as an MR reduction of ≥ 1 grade and a final MR grade ≤ 2+. The primary outcome was the impact of device success on 1-year mortality or heart failure (HF) readmissions. Cox proportional hazards models were used to report the risk-adjusted association between device success and 1-year outcomes.

Results: A total of 3,797 patients met the inclusion criteria. The mean age was 73.0 ± 11.9 years, and 59.5% were male. The mean Society of Thoracic Surgery score (MV repair) was 14.9% ± 15.3%. MR etiology was degenerative (53.4%) and functional (27.5%). Device success was achieved in 3,249 (85.6%) patients given the successful achievement of final MR grade ≤ 2+ (88.2%) and MR reduction ≥ 1 absolute grade (91.4%). At 1 year after TEER, device success was associated with significantly lower all-cause mortality (34.6% vs 55.5%; adjusted HR: 0.49; 95% CI: 0.41−0.59; P < .001) and a composite of mortality or HF admissions (29.6% vs. 45.2%; adjusted HR: 0.51; 95% CI: 0.42−0.62; P < .001).

Conclusions: Successful MR reduction is achievable in most patients with CS and is associated with significantly lower mortality and HF hospitalization in 1 year. Randomized trials assessing TEER in CS are needed to establish this potential therapeutic approach.

Comments: Treatment of patients with mechanical complications of ischaemic or non-ischaemic heart disease remains a problem with no easy answers. If such a patient has CS, therapy is even more difficult as emergency surgery in these patients has a very high risk.

TEER is an evolving technique that has shown excellent results in MR related to LV dilatation due to heart failure, and severe symptomatic MR due to non-rheumatic valvular disease (like MVP or flail mitral valve).

This study has evaluated TEER for use in patients with severe MR with CS and suitable anatomy. Device success was achieved in around 85% of patients and resulted in an excellent reduction in mortality and HF admissions at the end of one year.

Strengths: This study is remarkable in that more than 3,700 patients with MR and CS were enrolled and evaluated for response to TEER. Not only was device success achieved in a very large proportion of patients (85%), there was a fantastic reduction in mortality at the end of one year (34% vs. 55%). Given the persistently high mortality of CS, this study shows the promise of TEER in this high-mortality group.

Implications: While cost and availability of TEER limit its usage, this study provides a strong argument to improve availability and reduce the cost of this potentially life-saving procedure. Patients with severe MR and CS should be offered TEER whenever possible.

Defibrillation Strategies for Refractory Ventricular Fibrillation

Sheldon Cheskes, P Richard Verbeek, Ian R Drennan, Shelley L McLeod, Linda Turner, Ruxandra Pinto, et al.

N Engl J Med. 2022 Nov 24;387(21):1947–1956. doi: 10.1056/NEJMoa2207304. Epub 2022 Nov 6.

Abstract

Background: Despite advances in defibrillation technology, shock-refractory ventricular fibrillation remains common during out-of-hospital cardiac arrest. Double sequential external defibrillation (DSED; rapid sequential shocks from two defibrillators) and vector-change (VC) defibrillation (switching defibrillation pads to an anterior-posterior position) have been proposed as defibrillation strategies to improve outcomes in patients with refractory ventricular fibrillation.

Methods: We conducted a cluster-randomized trial with crossover among six Canadian paramedic services to evaluate DSED and VC defibrillation as compared with standard defibrillation in adult patients with refractory ventricular fibrillation during out-of-hospital cardiac arrest. Patients were treated with one of these three techniques according to the strategy that was randomly assigned to the paramedic service. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a good neurologic outcome, defined as a modified Rankin scale score of 2 or lower (indicating no symptoms to slight disability) at hospital discharge.

Results: A total of 405 patients were enrolled before the data and safety monitoring board stopped the trial because of the coronavirus disease 2019 pandemic. A total of 136 patients (33.6%) were assigned to receive standard defibrillation, 144 (35.6%) to receive VC defibrillation, and 125 (30.9%) to receive DSED. Survival to hospital discharge was more common in the DSED group than in the standard group (30.4% vs. 13.3%; relative risk, 2.21; 95% CI, 1.33−3.67) and more common in the VC group than in the standard group (21.7% vs. 13.3%; relative risk, 1.71; 95% CI, 1.01−2.88). DSED but not VC defibrillation was associated with a higher percentage of patients having a good neurologic outcome than standard defibrillation (relative risk, 2.21 [95% CI, 1.26−3.88] and 1.48 [95% CI, 0.81−2.71], respectively).

Conclusions: Among patients with refractory ventricular fibrillation, survival to hospital discharge occurred more frequently among those who received DSED or VC defibrillation than among those who received standard defibrillation. (Funded by the Heart and Stroke Foundation of Canada; DOSE VF ClinicalTrials.gov number, NCT04080986.).

Comments: Refractory ventricular fibrillation remains a major cause of mortality in both, in-hospital and out-of-hospital cardiac arrest. This study randomly evaluated response to DSED or VC defibrillation versus standard fibrillation and found a clear-cut survival advantage.

Implications: This study makes a strong case for a switch in our method of defibrillation for improving survival in cardiac arrest patients. VC defibrillation especially does not even need a change in equipment and can be easily adopted. Perhaps, it is time to change our defibrillation strategy as per available evidence.

Everolimus-Eluting Stents or Bypass Surgery for Multivessel Coronary Artery Disease: Extended Follow-Up Outcomes of Multicenter Randomized Controlled BEST Trial

https://doi.org/10.1161/CIRCULATIONAHA.122.062188

Jung-Min Ahn, Do-Yoon Kang, Sung-Cheol Yun, Seung Ho Hur, Hun-Jun Park, Damras Tresukosol, et al.; BEST Extended Follow-Up Study Investigators

Circulation. 2022;146:1581–1590. https://doi.org/10.1161/CIRCULATIONAHA.122.062188

Abstract

Background: Long-term comparative outcomes after percutaneous coronary intervention (PCI) with everolimus-eluting stents and coronary artery bypass grafting (CABG) are limited in patients with multivessel coronary artery disease.

Methods: This prospective, multicenter, randomized controlled trial was conducted in 27 international heart centers and was designed to randomly assign 1,776 patients with angiographic multivessel coronary artery disease to receive PCI with everolimus-eluting stents or CABG. After inclusion of 880 patients (438 in the PCI group and 442 in the CABG group) between July 2008 and September 2013, the study was terminated early because of slow enrollment. The primary endpoint was the composite of death from any cause, myocardial infarction, or target vessel revascularization.

Results: During a median follow-up of 11.8 years (interquartile range, 10.6–12.5 years; maximum, 13.7 years), the primary endpoint occurred in 151 patients (34.5%) in the PCI group and 134 patients (30.3%) in the CABG group (hazard ratio [HR], 1.18 [95% CI, 0.88−1.56]; P = .26). No significant differences were seen in the occurrence of a safety composite of death, myocardial infarction, or stroke between groups (28.8% and 27.1%; HR, 1.07 [95% CI, 0.75−1.53]; P = .70), as well as the occurrence of death from any cause (20.5% and 19.9%; HR, 1.04 [95% CI, 0.65−1.67]; P = .86). However, spontaneous myocardial infarction (7.1% and 3.8%; HR, 1.86 [95% CI, 1.06−3.27]; P = .031) and any repeat revascularization (22.6% and 12.7%; HR, 1.92 [95% CI, 1.58−2.32]; P < .001) were more frequent after PCI than after CABG.

Conclusions: In patients with multivessel coronary artery disease, there were no significant differences between PCI and CABG in the incidence of major adverse cardiac events, the safety composite endpoint, and all-cause mortality during the extended follow-up.

Comments: This study evaluates long-term results of everolimus-eluting stents (EES) versus CAGB in patients with multi-vessel disease. Unlike older trials, this study used new-generation EES in the PCI arm. While the study was unfortunately terminated early due to slow recruitment, it demonstrated equivalent survival in both arms even though the PCI arm had higher spontaneous myocardial infarction and repeat revascularizations.

Strengths: This study was a multicentre study with a long median follow-up of 11.8 years. Therefore, the study answers the question regarding the long-term results of multi-vessel PCI. It used EES which is the most common stent variety used currently. This is one of the few studies that demonstrate a similar survival advantage of complex PCI versus CABG, at least in selected cases.

Limitations: Due to early termination, a relatively small sample size was evaluated. Consequently, the results should be interpreted with caution.

Implications: In selected cases at least, complex PCI can be considered to be a useful alternative to CABG in multivessel coronary artery disease.

Efficacy of a Drug-Eluting Stent vs. Bare Metal Stents for Symptomatic Femoropopliteal Peripheral Artery Disease: Primary Results of the EMINENT Randomized Trial

Yann Gouëffic, Giovanni Torsello, Thomas Zeller, Giovanni Esposito, Frank Vermassen, Klaus Armin Hausegger, et al.: on behalf of the EMINENT Investigators

Circulation. 2022;146:1564–1576. https://doi.org/10.1161/CIRCULATIONAHA.122.059606

Abstract

Background: A clear patency benefit of a drug-eluting stent (DES) over bare metal stents (BMSs) for treating peripheral artery disease of the femoropopliteal segment has not been definitively demonstrated. The EMINENT study (Trial Comparing Eluvia Versus Bare Metal Stent in Treatment of Superficial Femoral and/or Proximal Popliteal Artery) was designed to evaluate the patency of the Eluvia DES (Boston Scientific, Marlborough, MA), a polymer-coated paclitaxel-eluting stent, compared with BMSs for the treatment of femoropopliteal artery lesions.

Methods: EMINENT is a prospective, randomized, controlled, multicenter European study with blinded participants. and outcome assessment. Patients with symptomatic peripheral artery disease (Rutherford category 2, 3, or 4) of the native superficial femoral artery or proximal popliteal artery with stenosis ≥ 70%, vessel diameter of 4 to 6 mm, and total lesion length of 30 to 210 mm were randomly assigned 2:1 to treatment with DES or BMS. The primary effectiveness outcome was primary patency at 12 months, defined as an independent core laboratory-assessed duplex ultrasound peak systolic velocity ratio ≤ 2.4 in the absence of clinically driven target lesion revascularization or surgical bypass of the target lesion. Primary sustained clinical improvement was a secondary outcome defined as a decrease in Rutherford classification of ≥ 1 category compared with the baseline without a repeat target lesion revascularization. Health-related quality of life and walking function were assessed.

Results: A total of 775 patients were randomly assigned to treatment with DES (n = 508) or commercially available BMSs (n = 267). Baseline clinical, demographic, and lesion characteristics were similar between the study groups. The mean lesion length was 75.6 ± 50.3 and 72.2 ± 47.0 mm in the DES and BMS groups, respectively. The 12-month incidence of primary patency for DES treatment (83.2% [337 of 405]) was significantly greater than for BMS (74.3% [165 of 222]; P < .01). The incidence of primary sustained clinical improvement was greater among patients treated with the DES than among those who received a BMS (83.0% vs. 76.6%; P = .045). The health-related quality of life dimensions of mobility and pain/discomfort improved for the majority of patients in both groups (for 66.4% and 53.6% of DES-treated and for 64.2% and 58.1% of BMS-treated patients, respectively) but did not differ significantly. At 12 months, no statistical difference was observed in all-cause mortality between patients treated with the DES or BMS (2.7% [13 of 474] vs. 1.1% [3 of 263]; relative risk, 2.4 [95% CI, 0.69−8.36]; P = .15).

Conclusions: By demonstrating superior 1-year primary patency, the results of the EMINENT randomized study support the benefit of using a polymer-based paclitaxel-eluting stent as a first-line stent-based intervention for patients with symptomatic peripheral artery disease attributable to femoropopliteal lesions.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02921230.

Comments: Unlike coronary artery disease, the advantage of drug-eluting stents in peripheral arterial disease is unproven. The EMINENT study compared paclitaxel-eluting stents (PES) versus bare-metal stents in peripheral artery disease. It demonstrated a superior 1-year patency of PES in femoropopliteal lesions with no increase in complications.

Implications: The EMINENT study has finally demonstrated an advantage of PES over standard stents in femoropopliteal disease. The use of PES should increase after these results.