Mandrola Previews the Virtual AHA 2021

John Mandrola, MD


November 09, 2021

For the second year in a row, the American Heart Association (AHA) meeting is virtual. AHA is a huge international affair, so the decision is understandable.

Yet I hope this is the last year for virtual meetings. Zoom has some positives, but it cannot replace the learning that comes from meeting with colleagues in person.

Let's go to the studies.

Aortic Stenosis

Dogma has long held that you wait to operate on stenotic aortic valves until there are symptoms. This always seemed strange to me: why wait for disaster? There is the flipside, though: always be afraid to treat an image. People aren't images.

Last year, the RECOVERY trial reported that early surgery was far superior to watchful waiting in asymptomatic patients with severe aortic stenosis (AS). That trial seemed to garner only modest attention.

AVATAR will be the second randomized controlled trial (RCT) to test watchful waiting vs early surgery in asymptomatic patients. And it has a twist: patients will have to be truly asymptomatic—meaning they must achieve 80% of maximal heart rate on exercise testing. This is important because AS occurs slowly, and patients may acclimate to progressively lower exercise tolerance by reducing what they do. Some even attribute the lower vigor to aging.

I'd be surprised if AVATAR doesn't favor surgery, but we will have to study the components of the primary endpoint of death or major cardiac adverse outcomes of acute myocardial infarction (MI), stroke, or heart failure hospitalization.

If benefits are driven by fewer deaths, I will be convinced. If, however, the endpoint is driven by reduced MI, which may be a poor surrogate for survival, or heart failure hospitalization, which is susceptible to bias in an unblinded trial, I will be less convinced.

The other issue: the active arm was surgical aortic valve replacement. If positive, will the results apply to transcatheter aortic valve replacement? I am asking. I don't know.

Surrogate Endpoints

The second RCT in the first late-breaking session will assess the value of tricuspid valve repair done as an add-on to mitral surgery. The uncertainty surrounding the value of tricuspid repair makes this a good topic for an RCT.

But that is not why I highlight the trial. I mention it because its composite primary endpoint of death, reoperation for tricuspid regurgitation (TR), and the degree of TR is a problematic endpoint. It's problematic because regurgitant lesions are difficult to quantify and patients cannot possibly care about Doppler signals on an ultrasound.

I worry that if this is a positive trial, and the significance is driven by an ultrasound image, the top-line conclusion will read that tricuspid valve repair "delivers benefits."

If you want to show a surgical add-on procedure has benefits, you do what Richard Whitlock, MD, did with LAAOS-III: you measure a single hard clinical endpoint, such as stroke.

Another learning point: the tricuspid valve trial has 22 secondary outcomes. The likelihood of a positive outcome is high.

Atrial Fibrillation

  • AF Triggers

Greg Marcus, MD, and his team from the University of California, San Francisco, are back with two elegant experiments looking at atrial fibrillation (AF) triggers. The CRAVE trial uses an n-of-1 design to assess the change in atrial or ventricular ectopy with caffeine. It will be 2 days with caffeine and 2 days without; patients are their own control.

Although alcohol has a clear association with AF, oodles of observational studies, and even RCTs, have not shown caffeine to be hazardous or arrhythmogenic. If this is another negative caffeine trial, I hope we can put coffee studies to rest. If it is "positive," well, that complicates matters.

In the I-STOP-Afib study, the question is how best to help patients identify their triggers for AF episodes. Both groups of symptomatic patients have mobile apps and AliveCor electrocardiograms. The control group uses the devices for symptom surveillance. The active treatment arm does that plus a series of n-of-1 trials that will include up to 3 periods of trigger exposure and 3 periods of trigger elimination, with each exposure/elimination period lasting 1 week. In other words, the active arm gets direct feedback on possible causal factors. The primary endpoint is quality of life.

  • Post–Cardiac Surgery AF

The quest to reduce post–cardiac surgery AF gets another try in the PALACS trial, which randomly assigns patients who have had cardiac surgery to posterior left pericardiotomy or to standard care.

Performing a posterior left pericardiotomy is thought to prevent AF after surgery by allowing the posterior pericardial space to drain into the left side of the chest and be evacuated by a chest tube, preventing blood and fluid from accumulating behind the left atrium. Downsides include longer procedure time and a potentially higher incidence of left pleural effusion.

Epicardial Left Atrial Appendage Closure

The aMAZE trial assessed outcomes of AF ablation using adjunctive left atrial appendage ligation with the LARIAT device compared with pulmonary vein isolation alone.

AtriCure, the makers of LARIAT, said on an earnings call early this year that aMAZE's primary safety goal, 10% freedom from major adverse events, was met, but the primary efficacy endpoint, freedom from episodes of atrial fibrillation lasting at least 30 seconds, was not. We will learn more at the meeting.

The history of LARIAT deserves mention. In July 2015, JAMA Internal Medicine published a systematic review and MAUDE database assessment on LARIAT and found a worrisome incidence of major complications. The authors also noted that LARIAT was approved via the US Food and Drug Administration (FDA) 510(k) clearance for the approximation of soft tissue.

FDA 510(k) clearance does not require clinical testing for a specific indication; rather, clearance is predicated on the demonstration of "substantial equivalence" with existing devices used for suture placement during other types of surgery.

LARIAT's use as a percutaneous epicardial left atrial appendage closure device, therefore, was off label. The aMAZE trial began months after this report.

Digital Health

While the promise of the electronic health record (EHR) was that it would improve care, most clinicians recognize it as a billing device. F. Perry Wilson, MD, and his colleagues from Yale have set out to use the EHR to improve health. Their idea is to show clinicians a 1-year prognosis of patients with heart failure.

The thinking is that knowledge of prognosis may influence care in a positive way. The REVEAL-HF trial will assess this idea. The primary endpoint will be all-cause death or hospitalization for heart failure. Secondary endpoints include length of stay, discharge doses of therapy, and electrophysiology or palliative consults.

I really like this pragmatic trial conception and design. In the care of patients with heart failure, we would do well to reduce both the overtreatment of frail older patients who would benefit most from palliation and the undertreatment of left bundle branch block or underuse of guideline-directed medication.

SGLT2 Inhibitors

What would a cardiac meeting be without sessions on the new class of sodium glucose co-transporter 2 (SGLT2) inhibitors? This week, Eugene Braunwald, MD, likened the drug class to the "the statins of the 21st century."

In addition to meta-analyses and substudies of prior trials in this class, we also get results of two new trials:

The CHIEF-HF trial will assess the effect of canagliflozin on quality of life in patients with heart failure. Patients with any type of heart failure (low or normal left ventricular ejection fraction) will receive canagliflozin or placebo for 12 weeks. The novelty is that they are measuring quality of life with the total symptom score of the Kansas City Cardiomyopathy Questionnaire (KCCQ).

The EMPULSE trial will compare the in-hospital initiation of empagliflozin or placebo in patients with heart failure of any type. The primary outcome is clinical benefit at 90 days, consisting of a composite of all‐cause death, heart failure events, and a 5-point or greater change from baseline on the KCCQ. One novelty of this trial is the use of a win ratio to assess outcomes.

Sorry, readers, statistics appeal to me. The win ratio compares each patient in the trial to every other patient within each stratum (new‐onset heart failure vs  decompensated chronic heart failure) in a pairwise hierarchical fashion. The win ratio is calculated as the total number of wins in the empagliflozin group across all strata divided by the total number of losses.

Ticagrelor Reversal

The increased use of ticagrelor has led to the development of a reversal agent. At AHA, we will learn results of the REVERSE-IT study of bentracimab (PB2452) in patients who present with uncontrolled major or life-threatening bleeding or who require urgent surgery or an invasive procedure.

Sadly, it's a single-arm trial looking only at platelet reversal. I write "sadly" because reversal agents ought to be studied in the same way other drugs are studied—with clinical outcomes. Reversal of drug effect is obviously an important surrogate outcome, but so are the thrombotic complications that may follow.

Other Sessions of Note

Marc Sabatine, MD, of the TIMI-study group at Brigham and Women's Hospital, will present an independent analysis of the left main percutaneous coronary intervention vs coronary artery  bypass grafting trials.

Recall that the EXCEL trial sparked controversy over its choice and reporting of endpoints as well as its interpretation of 5-year data. The TIMI group was assigned the job of neutral judges, and Robert Harrington, MD, from Stanford will be the discussant of this important presentation.

There will be numerous presentations on percutaneous left atrial appendage occlusion, including the effect of peri-device leaks, another on in-hospital outcomes, a network meta-analysis comparing the Watchman device to direct-acting oral anticoagulants (DOACs), and 2-year results of the Amplatzer Amulet Left Atrial Occluder trial of Amulet vs Watchman. The latter trial would have benefited greatly from a DOAC arm.

There will be much more, so stay tuned to our coverage.

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John Mandrola practices cardiac electrophysiology in Louisville, Kentucky, and is a writer and podcaster for Medscape. He espouses a conservative approach to medical practice. He participates in clinical research and writes often about the state of medical evidence. 

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