Mandrola's Top 5 Picks From AHA 2022 Previewed

John Mandrola, MD


October 31, 2022

Here are the 5 studies to be presented at the American Heart Association (AHA) scientific sessions in Chicago that I find most worthy of comment.

Torsemide vs Furosemide: Battle of the Commoners

I favor torsemide over furosemide. It's a gut feeling honed over years of giving diuretics to patients with heart failure. Torsemide has greater potency, better gastrointestinal absorption, and a longer half-life.

During the first late-breaking session at AHA, we will hear results of the TRANSFORM-HF trial, which randomly assigned a broad and inclusive group of patients with heart failure to the oral formulation of either of the two drugs.

Unlike typical heart failure trials, TRANSFORM-HF is designed to be easy on patients and centers; follow-up occurs through phone interviews and standard care with usual providers.

Perhaps the best part is the endpoints: mortality is the primary endpoint, and total hospitalizations (not just those for heart failure) is a secondary endpoint. Total hospitalizations should always be the endpoint in heart failure trials because patients want to avoid any hospitalizations.

I doubt torsemide can affect total mortality, but the way to find out is to study it. This is my choice of top study because doctors use these drugs almost every day.

Expert's vs Practitioner's Diuretic Choice

Guideline writers (experts) recommend chlorthalidone over hydrochlorothiazide as first-line therapy for hypertension. Yet there has never been a head-to-head trial of the two drugs.

Nearly every clinician I know uses hydrochlorothiazide over chlorthalidone. Do practicing doctors know more than guideline writers?

We will find out when the Veterans Affairs Diuretic Comparison Project (DCP) reports results of a pragmatic randomized trial comparing the two drugs. The primary endpoint is a composite of nonfatal cardiovascular events and noncancer death.

In addition to testing whether the expert's favorite diuretic is superior, the other reason to like this trial is that it is embedded in the electronic health record (EHR) and all the data are collected via administrative claims.

If a clinician is going to prescribe a diuretic, and there are many choices, it makes sense to simply randomly assign patients at the point of care. Then, instead of gut feelings of older doctors, we get data. Our EHRs ought to do more than maximize billing.

I look forward to both the results and the discussion of the methods of the DCP trial.

Hurry Up and Ablate PROGRESSIVE-AF

AHA will feature yet another study of early ablation in patients with new atrial fibrillation (AF). PROGRESSIVE-AF compares cryoballoon pulmonary vein isolation with antiarrhythmic drugs for the prevention of persistent AF. Secondary endpoints include the time in AF, quality of life, and healthcare utilization.

I have great respect for primary author Jason Andrade and his colleagues. My critique should not be taken personally, but early AF ablation trials are not advancing the field. We already know that pulmonary vein isolation leads to less AF than do antiarrhythmic drugs.

Our 20-year-long plateau in AF treatment is not about how early or how well we destroy atrial myocardium. It is a knowledge problem.

We urgently need to sort out the causes of AF. For all we know, AF episodes on an ECG are a symptom, not a disease. Ablation may simply be targeting a symptom, which would be fine if we knew it was better than a placebo. But we don't.

We also don't know how early ablation would fare against a multidisciplinary AF clinic—one that uses education, reassurance, risk factor management, and a tincture of time before opening catheters.

PROGRESSIVE-AF will likely deliver positive results. Then, early ablation will gather even more momentum. Industry will sell more products; doctors and hospitals will earn more revenue.

Yet I fear that the ablate-early therapeutic fashion will further ossify a field that used to be known for its ability to understand the pathophysiology of arrhythmia.

IRONMAN Tests Things That Make Sense

Patients with heart failure often have low iron levels, which are associated with worse symptoms and a poor prognosis—even in the absence of overt anemia. Iron is essential in oxygen transfer, so it makes sense to replace low levels.

Yet smaller trials have found only modest improvement in symptoms. AFFIRM-AHF, a trial of one-time iron dosing before discharge, barely failed to meet its primary endpoint of cardiovascular (CV) death and hospitalizations for heart failure.

The nicely named IRONMAN open-label trial randomly assigned patients with heart failure with a reduced ejection fraction who had iron deficiency to intravenous ferric derisomaltose or no infusion in addition to guideline-recommended therapy. Infusions were done every 4 months if iron deficiency persisted.

The primary endpoint is a composite of hospitalizations for heart failure and CV death. The trial was done in 70 hospitals in the United Kingdom. The investigators aimed to keep patients repleted with iron throughout—which distinguishes it from previous iron replacement trials.

I make note of IRONMAN because any result would further our knowledge: it would be nice if iron led to clinically meaningful benefits. The problem, of course, is that heart failure therapy is already quite good. Nonsignificant results or net harm would also add to our knowledge by reinforcing the notion that therapies that make sense don't always pass muster in randomized trials.

CRISPR/Cas9 for TTR Amyloidosis: The Promise of Big Science

The final study I mention is a report of a first-in-human CRISPR/Cas9 editing of the TTR gene in patients with transthyretin amyloidosis with cardiomyopathy.

Transthyretin amyloid cardiomyopathy is an increasingly recognized cause of restrictive cardiomyopathy. The problem is the accumulation of misfolded transthyretin fibrils within the myocardium.

Transthyretin is a circulating protein carrier for vitamin A and thyroxine and is mostly made in the liver. Transthyretin normally travels through the body in tetrameric form composed of 4 β sheet–rich monomers.

In hereditary transthyretin amyloid (hATTR), mutations in the TTR gene, which resides on chromosome 18, can lead to structural changes in TTR that then predispose to misfolding. This abnormal folding leads to deposition in the skin and heart, which then causes the clinical manifestations. Wild-type ATTR, the more common form of ATTR, occurs when the normal aging process causes misfolding of the TTR protein.

Last year, a large group of researchers showed that they could alter the gene coding for abnormal TTR proteins and reduce its concentration in a patient with hereditary transthyretin neuropathy.

This is made possible by the CRISPR/Cas9 system. It comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 and single-guide RNA targeting TTR.

At AHA, we will hear results of this DNA-modifying technique in patients with hATTR cardiomyopathy. This study will not affect practice tomorrow, but the potential of modifying genes to cure disease feels like we may be on the cusp of something big.

Remember, no one could have imagined the time after the discovery of antibiotics, or after the Internet. Are we in such a moment with gene-rewriting technology?

AHA features too many trials and studies to cover in a preview. I'll be attending in person and hope to see some of you there. Please say hello if you see me in the hallways.

And, as always, follow the team of journalists from | Medscape Cardiology.

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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