Mandrola's Top Trials to Look for at AHA 2023

My prediction: a new chapter in medicine starts this weekend at the 2023 American Heart Association (AHA) Scientific Sessions.

SELECT Trial

In recent years, a novel virus distracted us from one of the greatest threats to human health — obesity. AHA refocuses our attention to this side effect of modern living.

The glucagon-like peptide 1 (GLP-1) agonist semaglutide has shown its ability to induce weight loss in patients with obesity and reduce cardiac outcomes in patients with diabetes. The SELECT trial is slated for the first late-breaking trial presentation at AHA. We already know, from a press release, that the trial shows that the drug reduces cardiac outcomes in patients with obesity who do not have diabetes.

I am no fan of the early press release pattern of anchoring us to a positive result. In this case, however, the degree of absolute risk reduction matters less than in other trials. Given the drug’s ability to induce serious weight loss, any amount of reduction in cardiac outcomes will change practice patterns.

Compare semaglutide with statins, for instance. We know that statins reduce cardiac outcomes by about 20%-25%. That is meaningful but patients cannot feel it. Patients who take semaglutide will be able to feel the CV benefits — because losing weight enhances quality of life.

The other thing that may change after AHA is the framing of obesity. Obesity creates a bit of tension. While clinicians treat obesity as a serious health risk, popular culture, with its emphasis on body positivity, takes a more accepting frame. After SELECT, norms regarding body weight may change.

ARTESiA

Technology has ushered in a new way to think about atrial fibrillation (AF). In the past, the diagnosis of AF required a patient to feel unwell and sustain the arrhythmia long enough to get a standard 12-lead ECG. Cardiac devices such as pacemakers and defibrillators require neither of these factors.

The stroke-prevention question that comes up almost every day in our office is whether patients with short-duration asymptomatic AF (subclinical AF) should be treated similarly to those with symptomatic longer-duration AF (clinical AF). That is, with oral anticoagulation.

Many clinicians favor anticoagulation for subclinical AF for two reasons: stroke is a terrible outcome and previous observational studies have found an association between subclinical AF and stroke.

Results of the recent NOAH-AFNET 6 trial upended that default. In this trial of edoxaban vs placebo in patients with subclinical AF, edoxaban not only failed to reduce thrombotic outcomes, it increased bleeding rates enough to warrant early termination of the trial. One of the challenges of NOAH was a very low rate of stroke.

The ARTESiA trial also studied anticoagulation (apixaban) in patients with subclinical AF. Differences in trial design will likely lead to different results. For instance, ARTESiA enrolled more patients and followed them for longer — which will increase the numbers of stroke events. The control arm of ARTESiA will be aspirin, instead of placebo. This may mitigate the higher hazards seen in the edoxaban-placebo pairing in NOAH-AFNET 6.

In the same AHA session, authors of NOAH-AFNET 6 will present a subgroup analysis from their trial looking at patients with AF episodes ≥ 24 hours. I doubt this will clarify much. Stroke rates were low overall, and this subgroup includes only a fraction of the main trial.

I am afraid a "positive" ARTESiA trial and "negative" NOAH trial will complicate stroke-prevention decisions in patients with subclinical AF. Which is fine because it would be bad if algorithms could practice medicine.

ORBITA 2

When the first sham-controlled ORBITA trial showed that percutaneous coronary intervention (PCI) relieved ischemic left ventricular dysfunction but that nearly all of the symptom and exercise improvement stemmed from placebo effect, cardiologists struggled to believe it. Numerous doubtful letters to the editor arrived at The Lancet after trial publication. While ORBITA authors easily answered most of the concerns, some remained.

ORBITA 2 puts the placebo effect of PCI to a much stronger test. This PCI-vs-sham trial will expand the patient population from single vessel disease to include patients with multivessel disease. ORBITA 2 will require both anatomic and functional significance of the lesions; investigators will also stop antianginal medications before randomization to isolate the effect of PCI alone vs PCI as an add-on procedure. The primary endpoint changes from exercise time to an angina score — the latter is relevant to all patients with angina.

I am intensely curious to learn the results of this trial. I predict that PCI will have some degree of placebo-resistant symptom relief. But what if it doesn’t? Gosh, that would change so much — like the last 40 years of belief. 

DAPA MI

The placebo-controlled DAPA MI trial asks a simple question: Does the sodium-glucose reuptake 2 (SGLT2) inhibitor dapagliflozin benefit patients who have evidence of some degree of myocardial damage after a myocardial infarction (MI)? To qualify, post-MI patients must have mild impairment of left ventricular function (those with LVEF ≤ 40% were excluded) or evidence of q-waves on an ECG.

While we always learn from randomization, the problem I foresee will come in the interpretation of the primary endpoint. Post-MI trials used to measure the bias-free endpoint of mortality, but the primary endpoint of DAPA-MI includes death, hospitalization for heart failure, nonfatal MI, atrial fibrillation/flutter, new onset of type 2 diabetes mellitus, HF symptoms as measured by New York Heart Association Functional Classification at last visit, and body weight decrease ≥ 5% at last visit. The statistical plan will use the hierarchical win-ratio.

If DAPA-MI reports a statistically significant result by a win-ratio, the question for practitioners (and perhaps regulators) will be whether this represents a clinically important and cost-effective therapy. We shall see, but I have trouble believing it is possible to further reduce important outcomes on top of current MI therapy.

The Best of the Rest

After these four trials, it’s hard to identify another obvious standount. Here is a brief rundown of potential newsmakers.

The MINT trial tests restrictive vs liberal blood transfusion strategies in post-MI patients. When formally tested, in numerous scenarios, restrictive strategies seem to win out. We shall see if this holds true after MI.

AHA features an entire late-breaking session on hypertension. Two studies that most pique my interest include one on dietary sodium and the other a phase 2 trial of a subcutaneously delivered small-interfering (SiRNA) drug called zilebesiran.

We also learn more details of AZALEA-TIMI 71, a phase 2 trial comparing the Factor XI inhibitor abelacimab vs rivaroxaban in patients with AF. The makers of the drug announced in a press release that the trial was stopped early because of lower rates of bleeding. Factor XI inhibitors have been billed as the ideal anticoagulant. Preliminary data look promising regarding safety (bleeding), but it will take years to determine their efficacy vs direct-acting oral anticoagulants.

If you are attending AHA and see me in the halls, be sure to say hello. 

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.