Introduction
By John L. Jefferies, MD, FACC
University of Tennessee Health Science Center
Memphis, TN

The ACC.org Heart Failure, Noninvasive Imaging, and Acute Coronary Syndromes editorial teams have developed additional education from the American College of Cardiology's 70th Annual Scientific Session & Expo (ACC.21) Virtual late-breaking clinical science. This education focuses on high-impact recommendations that can be potential areas of confusion or controversy or simply new evidence that represents a significant change from former standard of care. This review covers the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness), LAAOS III (Left Atrial Appendage Occlusion Study), GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure), EXPLORER-HCM (Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy), and FLOWER-MI (Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction) trials.

Video: HF, ACS, and Imaging Perspectives on ACC.21 Hot Trials

Focus on Heart Failure and Cardiomyopathies

ADAPTABLE
By Richard K. Cheng, MD, MSc
University of Washington
Seattle, WA

The ADAPTABLE trial randomized participants with established atherosclerotic cardiovascular disease (ASCVD) enriched for a number of factors,¹ which may include left ventricular (LV) ejection fraction (EF) <50% or chronic heart failure (HF), to aspirin 81 mg or 325 mg daily.² Although the study did not directly address aspirin use in HF, 22.8% of those in the 81 mg group and 23.8% in the 325 mg group had prevalent HF. The study found no significant differences in cardiovascular events or major bleeding between the 2 groups. Aspirin discontinuation was 7.0% in the 81 mg group and 11.1% in the 325 mg group. Additionally, 41.6% of patients assigned to 325 mg crossed over to 81 mg during the study.²

Data are inconclusive regarding aspirin use for primary prevention in HF.^3-7 Both American College of Cardiology (ACC)/American Heart Association (AHA)⁸ and European Society of Cardiology (ESC)⁹ guidance documents state that there is insufficient evidence to recommend aspirin for HF in the absence of other indications. For HF patients without a separate indication, the ADAPTABLE trial does not provide guidance because inclusion criteria required ASCVD. However, for HF patients with a specific indication, the ADAPTABLE trial suggests that aspirin 81 mg may be preferred due to higher adherence and equivalent efficacy to aspirin 325 mg.

A separate major take-home point was the study design itself that provides an attractive framework for future studies, including in HF cohorts. This was the first clinical trial to use the PCORnet® electronic data infrastructure, which allowed identification of participants via electronic health records, who were e-consented and directly randomized to open-label aspirin use with no in-person visits during follow-up. Potential benefits include more pragmatic identification of participants, lower study costs, and the ability to obtain real-world data and permit more inclusive enrollment of diverse populations. Trade-offs include the open-label nature of the study and potential for misclassification or underreporting outcomes.^2,10

LAAOS III
By Kevin S. Shah MD, FACC
University of Utah Health
Salt Lake City, UT

The LAAOS III randomized controlled trial tested whether surgical left atrial appendage occlusion (LAAO) compared with no occlusion among patients with atrial fibrillation (AF) undergoing open heart surgery was beneficial. The investigators from over 100 centers tested whether this procedure, which is commonly performed at the time of cardiac surgery, can lower the long-term risk of the primary outcome of ischemic stroke or systemic embolism. They found that the performance of LAAO at time of surgery reduced the long-term (3.8 years) risk of the primary outcome (4.8% vs. 7.0%; p = 0.001). Importantly, of patients enrolled in the study, over 50% had a history of HF, and the majority of surgeries were either valve intervention, coronary artery bypass grafting, or AF ablation.

Patients with HF commonly are referred for cardiac surgery, including revascularization via coronary artery bypass grafting, AF ablation, or valvular intervention. AF is a common comorbidity seen in patients with HF, which does increase the long-term risk of stroke. Although this study did not investigate whether anticoagulation can be withheld in these patients, it did demonstrate the efficacy of LAAO to reduce the risk of stroke. Those taking care of patients with HF should consider LAAO superior to no occlusion to reduce the long-term risk of ischemic stroke or systemic embolism in patients with AF who are being considered for open heart surgery.

EXPLORER-HCM
By Deirdre M. Mooney, MD, MPH
Providence Center for Advanced Heart Disease & Transplant
Spokane, WA

Until recently, there has been no disease-specific therapy for patients with obstructive hypertrophic cardiomyopathy (HCM), and most therapies have been poorly tolerated. Mavacamten, the first-in-class cardiac myosin inhibitor, was studied in the EXPLORER-HCM trial, which demonstrated an increase in peak oxygen consumption with stable or improved New York Heart Association functional class in adults with symptomatic obstructive HCM.¹¹ Most HCM therapies are poorly tolerated, and HCM patients with HF report moderately reduced quality of life.¹² In this secondary analysis, Professor Spertus and colleagues assessed the impact of mavacamten on patients' disease-specific health status as measured by change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score at week 30 from baseline.¹² Change was greater with mavacamten than placebo (mean score 14.9 [standard deviation 15.8] vs. 5.4 [13.7]; difference +9.1 [95% confidence interval (CI), 5.5-12.8]; p < 0.0001). Similar benefits were seen across all KCCQ subscales. A very large improvement in KCCQ-OS (≥20 points) was much more common in the mavacamten group (36%) than placebo (15%), with an estimated absolute difference of 21% (95% CI, 8.8-33.4). This suggests mavacamten is well tolerated and associated with improved symptoms, physical and social function, and quality of life with a low number needed to treat of 5 (95% CI, 3-11). Mavacamten may become the first disease-specific pharmacologic option for HCM; however, it remains to be seen if these benefits will be seen in a broader HCM population, including reduced LVEF, history of syncope, or recent sustained ventricular tachycardia.

GALACTIC-HF
By Christopher V. Chien, MD, FACC
UNC School of Medicine
Chapel Hill, NC

Omecamtiv mecarbil is a first-in-class myotrope that increases systolic function by augmenting cardiac sarcomere function through cardiac myosin activation. In the GALACTIC-HF study, treatment with omecamtiv mecarbil (vs. placebo) lowered the incidence of time to first HF event or cardiovascular death in subjects with an LVEF ≤35% (hazard ratio [HR] 0.92; 95% CI, 0.86-0.99).¹³ The impact of baseline LVEF on clinical outcomes in the GALACTIC-HF trial was studied and presented at ACC.21.¹⁴ This analysis found that LVEF was the strongest modifier of treatment effect, such that patients in the lowest quartile of LVEF (≤22%) treated with omecamtiv mecarbil (vs. placebo) had a greater reduction in first HF event or cardiovascular death (HR 0.83; 95% CI, 0.73-0.95) than patients with the highest quartile of LVEF (≥33%) (HR 0.99; 95% CI, 0.84-1.16). The absolute reduction in the primary outcome was 7.4 events per 100 patient-years.

This study demonstrates the clinical benefit of omecamtiv mecarbil in HF patients with the lowest LVEF, a population at the highest risk for adverse events. This finding is congruent with the omecamtiv mecarbil's mechanism of action to improve systolic function through cardiac myosin activation. This is a particularly notable finding because previous studies failed to show benefit of systolic augmentation with oral inotropes in patients with systolic HF.¹⁵ This stresses the important and novel nature of omecamtiv mecarbil's mechanism of action¹⁶ and its potential role in clinical management of patients with severely reduced LVEF.

Focus on Noninvasive Imaging
By Smadar Kort, MD, FACC
Stony Brook University Medical Center
Stony Brook, NY

LAAOS III
Multiple randomized trials support use of anticoagulation for stroke prevention in patients with non-valvular AF and high risk determined by the CHA2DS2-VASc score. For those who have contraindications to long-term anticoagulation, percutaneous occlusion is an alternative treatment. Surgical occlusion of the left atrial appendage at the time of cardiac surgery is a Class IIb recommendation.

The LAAOS III trial is a randomized trial involving 4,811 participants with AF and a CHA2DS2-VASc score of at least 2 who were scheduled to undergo cardiac surgery for another indication. The participants were randomly assigned to undergo or not undergo occlusion of the left atrial appendage during surgery; all the participants were expected to receive usual care, including oral anticoagulation, during follow-up.

The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism.

The primary analysis population included 2,379 participants in the occlusion group and 2,391 in the no-occlusion group, with a mean age of 71 years and a mean CHA2DS2-VASc score of 4.2. The participants were followed for a mean of 3.8 years. A total of 92.1% of the participants received the assigned procedure. At 3 years, 76.8% of the participants continued to receive oral anticoagulation. Stroke or systemic embolism occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the no-occlusion group (HR 0.67; 95% CI, 0.53-0.85; p = 0.001). The incidence of perioperative bleeding, HF, or death did not differ significantly between the trial groups.

Teaching Points

1. Intraoperative transesophageal echocardiography (TEE) during cardiac surgery is currently done routinely and focuses on assessment of valvular disease as well as LV and right ventricular function. Because this trial supports occluding the appendage in all patients with AF and high CHAD2DS2-VASc score at the time of cardiac surgery, it would be critical for the imager who performs that intraoperative TEE to fully assess the left atrial appendage at the time of the pre-pump TEE.
2. During the post-pump TEE, the imager should be able to assess the adequacy of the surgical occlusion and alert the surgeon about any residual communication.
3. Because it is expected that more patients presenting for TEE would have undergone surgical occlusion of the left atrial appendage, it is critical that echocardiographers would be familiar with assessing an appendage post-surgical repair and know how to identify inadequate repair, the presence of a thrombus outside the ligated tissue, and residual communication.

GALACTIC-HF
In the GALACTIC-HF trial (n = 8,256), the cardiac myosin activator omecamtiv mecarbil significantly reduced the primary composite endpoint of time to first HF event or cardiovascular death in patients with HF with reduced EF (EF ≤35%). The objective was to evaluate the influence of baseline EF on the therapeutic effect of omecamtiv mecarbil. Outcomes in patients treated with omecamtiv mecarbil were compared to placebo according to EF.

The risk of the primary composite endpoint in the placebo group was nearly 1.8-fold greater in the lowest (EF ≤22%) compared to the highest (EF ≥33%) EF quartile. Among the pre-specified subgroups, EF was the strongest modifier of the treatment effect of omecamtiv mecarbil on the primary composite endpoint (interaction as continuous variable, p = 0.004). Patients receiving omecamtiv mecarbil had a progressively greater relative and absolute treatment effect as baseline EF decreased with a 17% relative risk reduction for the primary composite endpoint in patients with baseline EF ≤22% (n= 2246; HR 0.83; 95% CI 0.73-0.95) compared to patients with EF ≥33% (n = 1,750; HR 0.99; 95% CI, 0.84-1.16; interaction as EF by quartiles; p = 0.013). The absolute reduction in the primary composite endpoint increased with decreasing EF (EF ≤22%; absolute risk reduction 7.4 events per 100 patient-years; number needed to treat for 3 years = 11.8), compared to no reduction in the highest EF quartile.

In patients with HF with reduced EF, omecamtiv mecarbil produced greater therapeutic benefit as baseline EF decreased. These findings are consistent with the drug's mechanism of selectively improving systolic function and presents an important opportunity to improve the outcomes in a group of patients at greatest risk.

Teaching Points

1. In this trial, the baseline EF was the strongest modifier of the treatment effect of omecamtiv mecarbil.
2. Although all patients had severely reduced EF (EF <35%), those with the lowest EF (EF ≤22%) had significantly greater therapeutic benefit compared with those with the highest EF (EF ≥33%).
3. This trial demonstrates the importance of accurate quantitative assessment of EF in predicting response to therapy. By using qualitative assessment of EF as severely reduced, the ability to predict outcome will be lost.
4. In the vast majority of the patients (97%), the EF was calculated using echocardiography. It is critical for echocardiographers to calculate EF accurately, preferably using three-dimensional algorithms in patients with reduced EF.

Focus on Acute Coronary Syndromes
By Michael C. Kontos, MD, FACC
VCU Health Pauley Heart Center
Richmond, VA

ADAPTABLE
The ADAPTABLE trial was an open-label, pragmatic, randomized controlled trial that evaluated aspirin 81 mg versus 325 mg in patients with ASCVD enriched with additional risk factors.¹⁷ Of the 15,076 patients included, death, hospitalization for myocardial infarction, or stroke occurred in 7.28% of the 81 mg group versus 7.51% of the 325 mg group. Hospitalization for major bleeding was not different between the 2 groups, occurring in 0.63% versus 0.60% in the 81 mg and 325 mg groups, respectively.

Prior studies found minimal to no difference between the efficacy of low-dose and high-dose aspirin.¹⁸ The ESC¹⁹ currently recommends low-dose aspirin; in contrast, the ACC/AHA guidelines²⁰ do not specify a specific dose.

The current trial suggests that lower-dose aspirin is better. The fact that >40% of patients assigned the 325 mg dose quickly changed to the lower dose limits firm conclusions about efficacy but indicates significant differences in tolerability, despite the limitations related to the open-label trial.

All trials come with tradeoffs; the benefits of innovative pragmatic trials such as this one, including the ease of recruitment, enrollment, data collection, and substantially reduced expenses, are offset by the potential for incomplete event ascertainment and biases related to the open-label treatment allocation.²¹ An important advantage of this trial is that it included a relatively inexpensive and commonly used medication, substantially decreasing the complexity of explaining the treatment protocol to patients. The fact that so many patients changed treatment protocol early in the trial provides guidance for others who attempt to perform such trials by considering piloting the protocols prior to implementing the large-scale trial.¹⁰

FLOWER-MI
Prior studies found that a strategy of complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) was associated with decreased risk for later myocardial infarction and repeat revascularization without difference in mortality.^22,23 Whether an angiographic or a physiology-guided revascularization (primarily by measurements of fractional flow reserve [FFR]), strategy is preferred is unclear. To address this, the FLOWER-MI study²⁴ compared complete revascularization guided by FFR with visual assessment in patients with STEMI and multivessel disease. A total of 1,171 patients with STEMI and multivessel disease underwent randomization to FFR-guided or angiography-guided non-infarct artery revascularization.

A physiology-based strategy significantly reduced the number of patients undergoing revascularization, from 91% to 56% with a concomitant reduction in the number of stents used. However, at 1 year, there was a worrisome trend toward increased adverse outcomes (although non-significant), with no difference in mortality. The confidence intervals for the primary outcome were wide and consistent with either a 22% relative benefit or a 123% relative harm associated with the FFR-guided strategy and may not allow conclusive interpretation.

Failure of the FFR-guided approach may have resulted from limitations in assessing the functional significance of non-culprit lesions in the acute or subacute period due to abnormalities in coronary flow reserve.

The timing of the staged procedure has varied in prior studies, being mandated during the initial procedure, as a stage procedure, or at the investigator's discretion (the FLOWER-MI protocol). The FLOWER-MI study indicates that when left to the investigator, the vast majority prefer a staged procedure because this occurred in 95% of patients.

References

1. Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term (ADAPTABLE). Available at: https://www.clinicaltrials.gov/ct2/show/NCT02697916. Accessed 06/05/2021.
2. Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med 2021;384:1981-90.
3. Cleland JG, Findlay I, Jafri S, et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure. Am Heart J 2004;148:157-64.
4. Homma S, Thompson JLP, Pullicino PM, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859-69.
5. Massie BM, Collins JF, Ammon SE, et al. Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 2009;119:1616-24.
6. Madelaire C, Gislason G, Kristensen SL, et al. Low-dose aspirin in heart failure not complicated by atrial fibrillation: a nationwide propensity-matched study. JACC Heart Fail 2018;6:156-67.
7. Shantsila E, Lip GY. Antiplatelet versus anticoagulation treatment for patients with heart failure in sinus rhythm. Cochrane Database Syst Rev 2016;9:CD003333.
8. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147-239.
9. Lip GYH, Ponikowski P, Andreotti F, et al. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Eur J Heart Fail 2012;14:681-95.
10. Baigent C. Pragmatic trials - need for ADAPTABLE design. N Engl J Med 2021;384:2065-66.
11. Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2020;396:759-69.
12. Capota R, Militaru S, Ionescu AA, et al. Quality of life status determinants in hypertrophic cardiomyopathy as evaluated by the Kansas City Cardiomyopathy Questionnaire. Health Qual Life Outcomes 2020;18:351.
13. Teerlink JR, Diaz R, Felker GM, et al. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med 2021;384:105-16.
14. Teerlink JR, Diaz R, Felker GM, et al. Effect of ejection fraction on clinical outcomes in patients treated with omecamtiv mecarbil in GALATIC-HF. J Am Coll Cardiol 2021;Apr 28:[Epub ahead of print].
15. Packer M, Carve JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med 1991;325:1468-75.
16. Psotka MA, Gottlieb SS, Francis GS, et al. Cardiac calcitropes, myotropes, and mitotropes: JACC Review Topic of the Week. J Am Coll Cardiol 2019;73:2345-53.
17. Jones WS, Mulder H, Wruck LM, et al. Comparative effectiveness of aspirin dosing in cardiovascular disease. N Engl J Med 2021;384:1981-90.
18. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients. BMJ 2002;324:71-86.
19. Collet JP, Thiele H, Barbato E, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021;42:1289-1367.
20. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139-e228.
21. Marquis-Gravel G, Roe MT, Robertson HR, et al. Rationale and design of the aspirin dosing – a patient-centric trial assessing benefits and long-term effectiveness (ADAPTABLE) trial. JAMA Cardiol 2020;5:598-607.
22. Thim T, van der Hoeven NW, Musto C, et al. Evaluation and management of nonculprit lesions in STEMI. JACC Cardiovasc Interv 2020;13:1145-54.
23. Atti V, Gwon Y, Narayanan MA, et al. Multivessel versus culprit-only revascularization in STEMI and multivessel coronary artery disease: meta-analysis of randomized trials. JACC Cardiovasc Interv 2020;13:1571-82.
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Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Valvular Heart Disease, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart Failure, Interventions and ACS, Interventions and Imaging, Interventions and Structural Heart Disease, Echocardiography/Ultrasound

Keywords: ACC21, ACC Annual Scientific Session, Quality of Life, Stroke Volume, Aspirin, Atrial Fibrillation, American Heart Association, Cardiac Myosins, Sarcomeres, Confidence Intervals, Cardiovascular Diseases, Atrial Appendage, Brain Ischemia, Heart Failure, Cardiac Surgical Procedures, Cardiomyopathies, Cardiomyopathy, Hypertrophic, Embolism, Coronary Artery Bypass, Primary Prevention, Comorbidity, Tachycardia, Ventricular, Anticoagulants, Anticoagulants, Oxygen Consumption, Reference Standards, Ischemic Attack, Transient, Ischemic Attack, Transient, Ventricular Function, Right, Echocardiography, Transesophageal, Acute Coronary Syndrome, Risk, Risk Factors, Numbers Needed To Treat, Stroke, Thrombosis, Neuroimaging, Pharmaceutical Preparations, Academic Medical Centers, Heart Valve Diseases

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