The first trial presented on the opening day of late-breaking clinical trials often brings big news.
Post-MI Renin-Angiotensin Blockade
The PARADISE-MI trial comparing sacubitril/valsartan to ramipril in patients with a left ventricular ejection fraction of 40% or less after myocardial infarction (MI) and clinical evidence of heart failure might have given Novartis another market for their angiotensin receptor neprilysin inhibitor drug.
But it isn't to be. Novartis announced in an earnings statement that although numeric trends favored sacubitril/valsartan, it did not meet its primary endpoint of reducing cardiovascular death and heart failure.
We will hear the numbers at ACC, but the highly marketed drug is now 1 for 3 in big clinical trials. And its only win, in PARADIGM-HF, was against the medium-dose angiotensin-converting enzyme inhibitor enalapril. I wonder what would happen if we repeated that trial with equal-dose valsartan as the comparator. Be alert for spin with this trial.
Aspirin Dosing in Secondary Prevention
The ADAPTABLE trial will compare a daily aspirin dose of 81 mg vs 325 mg in patients with established coronary artery disease for the reduction of the primary endpoint of all-cause death and hospitalization for MI or stroke.
The trial, which is publicly funded by the Patient-Centered Outcomes Research Institute (PCORI), features new ways of conducting research. These include electronic informed consent, direct-to-patient randomization, and data-collection via a novel format using a web-based patient portal to collect patient-reported outcomes.
ADAPTABLE enrolled approximately 15,000 patients and measures a broad composite endpoint. I suspect this will answer the question of which dose to use. The subgroup results might also be interesting; will we see heterogeneity in effects, say in obesity or sex?
Surgical Left Atrial Appendage Occlusion
I estimate that hundreds of thousands, maybe millions, of patients undergo heart surgery each year. Many of these patients have atrial fibrillation (AF). The left atrial appendage is an area where stasis of blood can promote thrombus. Surgeons can close the appendage relatively easily while the chest is open.
The Canadian-led global LAAOS III trial randomly assigned nearly 5000 patients to have appendage closure or not. The primary endpoint is stroke.
As one of the trial discussants, I will have more to say about this study, but it's crucial to remember that LAAOS III studied appendage closure as an adjunct to anticoagulation, not as a replacement for anticoagulation. This is different from the strategy of percutaneous left atrial appendage closure with endocardial devices.
SGLT2 Inhibitor for COVID-19?
As a class of drugs, the sodium-glucose cotransporter-2 (SGLT2) Inhibitors look impressive. They reduce cardiac outcomes in patients with diabetes, improve renal outcomes in patients with chronic kidney disease, and prevent recurrent heart failure in patients with left ventricular dysfunction.
Why not try them in patients who have had respiratory failure due to COVID-19?
Sadly, we learned in an AstraZeneca press release that the DARE-19 trial of dapagliflozin vs placebo in patients recovering from COVID-19 did not achieve statistical significance for either of its primary endpoints.
But it won't be all bad news for this class of drugs at ACC. Look for a report on the novel SGLT-1/2 Inhibitor sotagliflozin in the fourth late-breaking clinical trial session.
Deepak Bhatt, MD, and colleagues will report a meta-analysis of the effects of the drug across the full spectrum of ejection fraction, including heart failure with preserved ejection fraction. Bhatt is on record as saying, "I think sotagliflozin has the potential to be the best in class."
Surgical Intervention for Obesity
It hardly needs stating that obesity is not letting up as a global health problem. The pandemic hasn't helped; I estimate that 9 of 10 patients in my clinic have gained weight during the pandemic.
In 2017, the New England Journal of Medicine published the 5-year results of the STAMPEDE trial comparing intensive medical therapy alone vs intensive medical therapy plus either Roux-en-Y gastric bypass or sleeve gastrectomy in patients with type 2 diabetes. The primary endpoint was a glycated hemoglobin level of 6.0% or less. At 5 years, more patients in the surgical group met that goal, but, technically, the results failed to reach statistical significance.
At ACC, we learn the 10-year results, which are important because (1) type 2 diabetes and obesity are chronic conditions, (2) the mean age of patients enrolled in this trial was only 49 years, and (3) the weight loss improvement in the surgical groups looked to be lessening over time.
Heart Failure Rehabilitation
I love the concept behind the REHAB-HF trial of a novel physical rehabilitation intervention for older adults with acute decompensated heart failure (HF).
Here is why: nearly every HF study we hear about in journals and at meetings enrolls relatively healthy ambulatory patient, the type who attends a heart failure clinic. These are not the most common type of patients with HF. The typical patients we see with "heart failure" are older and have many comorbid conditions, including frailty. These patients care as much about their physical function as they do their ejection fraction.
The pilot-REHAB study looked positive. At ACC we will learn whether a physical function intervention in older patients will improve balance, mobility, strength, and endurance, as well as reduce hospitalization.
As a person of science, I am not supposed to root for results, but I am making an exception for REHAB-HF.
Rate vs Rhythm Control in Patients With HF and AF
Most often, I reassure patients with AF that an initial conservative approach is wise. But patients with HF and AF with excessive ventricular rates are different. These patients require prompt action; the question is: Should we act with rate control or primary left atrial ablation?
The Canadian-led RAFT-AF, a randomized controlled trial presented during the last late-breaking session at ACC, compared all-cause mortality and HF events for a strategy of primary AF ablation or one of strict rate control to achieve a resting heart rate less than 80 beats/min and a 6-minute walk heart rate less than 110 beats/min. The rate-control arm allows atrioventricular junction ablation and pacemaker as well as medical therapy.
The results of this trial are important and potentially disruptive to the status quo. The positive results of the CASTLE-AF trial for AF ablation vs medical therapy in patients with HF created significant momentum in the electrophysiology community to prefer primary AF ablation. But CASTLE-AF is one trial, and it had important caveats.
Alcohol and AF
The title of this late-breaking clinical trial, "Acute Alcohol Consumption and Discrete Atrial Fibrillation Events," intrigues me. It's from the electrophysiology group at the University of California San Francisco, led by Gregory Marcus, MD.
Earlier this year, that team published results of an elegant study that randomly assigned 100 patients who were in the lab for AF ablation to a continuous infusion of ethanol (for a blood level of 0.08%) or placebo.
Although they found no differences in the primary endpoint of the proportion of patients with AF induction, they did record significantly lower atrial effective refractory periods in the pulmonary veins of the ethanol group. This is an important observation because it provides a mechanistic link to the well-described association between alcohol intake and AF.
Mineralocorticoid Blockade and AF
Finerenone is a novel nonsteroidal selective mineralocorticoid receptor antagonist (MRA). Last year, the FIDELIO-DKD trial of finerenone vs placebo in patients with chronic kidney disease and type 2 diabetes found lower rates of the primary composite outcome of kidney failure, a sustained decrease of at least 40% in the estimated glomerular filtration rate from baseline, or death from renal causes. Finerenone also produced a statistically significant 14% reduction in a composite of cardiovascular outcomes.
In the last-breaking clinical trial session at ACC, we will learn whether the drug had any effect on new-onset AF in this trial.
You might wonder why an MRA might reduce AF. The first answer to a question like this is: If a drug produces significant and replicable benefits, it doesn't matter why it works. But MRA drugs are plausible AF-reducing agents on the basis of on their blood pressure reduction, potassium-sparing, and potentially antifibrotic effects.
ACC 2021 will obviously include much more science than the above picks. Check out journalist Patrice Wendling’s review.
And if you think I missed an important study, feel free to disagree in the comments.
Meeting hashtag: #ACC2021
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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Cite this: John M. Mandrola. Mandrola Previews the 2021 (Virtual) American College of Cardiology Scientific Sessions - Medscape - May 10, 2021.