Mandrola Previews the 2022 American College of Cardiology Scientific Sessions

John M. Mandrola, MD


March 29, 2022

My bet is that the 2022 American College of Cardiology (ACC) meeting in Washington, DC, will be remembered mostly for happening in-person. The pandemic has taught many lessons. One is surely that virtual meetings are over-rated. (The meeting is hybrid for those who can't attend.)

Hypertrophic Cardiomyopathy

The lead study presented in the first late-breaker session at the ACC meeting is the VALOR-HCM trial comparing mavacamten to placebo in patients with obstructive hypertrophic cardiomyopathy (HCM).  Mavacamten is a capsule containing a small-molecule modulator of β-myosin. It reversibly inhibits binding to actin, directly inhibiting sarcomere force output to reduce contractility and improve ventricular compliance. In other words, it is a disease-modifying agent.

The primary endpoint of VALOR-HCM will be septal reduction therapy at 4 months. Its main strength is the blinding: there is a proper placebo, and both patients and clinicians are blinded.

Most would agree that septal reduction therapy for patients with outflow tract obstruction due to HCM is invasive and less than ideal. Either you have open-heart surgery and hope the surgeon shaves exactly the right amount of cardiac tissue from the septum, or you have an interventionalist create a myocardial infarction (MI) with alcohol injected into a septal perforator off the left anterior descending coronary artery.

Two years ago, the EXPLORER-HCM trial found that mavacamten improved exercise capacity and health status in patients with obstructive HCM. A substudy found that the drug led to salutary effects on echocardiography parameters.

If VALOR-HCM is "positive," here are the questions to ask: What is the effect size? Did it reduce the need for surgery by a little or a lot? Were the results statistically robust? Finally, an economic analysis found that cost efficacy turns on pricing. For new cardiac therapies, the words "pricing" and "reasonable" almost never go together.

Another question related to mavacamten is long-term safety, especially because it reduces sarcomere power. In another late-breaking session, we will hear about the long-term (nearly 5 years) safety extension study of mavacamten in patients who completed the MAVERICK-HCM and EXPLORER-HCM trials.

Omecamtiv Mecarbil

Also at ACC, we will learn the results of the METEORIC-HF trial, which studies the effects of the myosin-activating drug omecamtiv mecarbil on functional capacity in patients with heart failure due to a reduced ejection fraction (HFrEF). It aims to enroll about 300 patients.

I'm pessimistic. The GALACTIC-HF trial enrolled more than 8000 patients, and investigators reported in 2021 that omecamtiv mecarbil led to a statistically significant 8% reduction in a composite primary outcome of first HF event (hospitalization or urgent visit for HF) or cardiovascular (CV) death.

Technically this was a positive trial. But the modest risk reduction was driven by HF events; CV death and all-cause deaths were similar, despite a near 20% death rate over the 21-month trial. The results were also not statistically robust, with a P value of .03. And there were no significant effects on quality of life as measured by the Kansas City Cardiomyopathy Questionnaire.

The clinical translation of METEORIC-HF results must consider that we already have four classes of drugs that definitively reduce clinical outcomes in patients with HFrEF.

Sodium Restriction for HF

Another late-breaking trial tests salt restriction in patients with HF. Although this common recommendation makes sense, the evidence is hardly strong. There may be a J-curve relationship between salt and heart health, with too little salt as bad as too much.

The SODIUM-HF trial, which began in 2014, compares dietary salt restriction (<1500 mg daily) to usual care in patients with HF. The primary endpoint is a composite of hospitalizations or emergency department visits for CV reasons or all-cause death at 1 year.

SODIUM-HF renders possible the chance for a medical reversal of an entrenched dogma. Medical reversals are special not only because they inform the treatment of one specific condition but also because they induce humility in clinicians.

Changing Health Behaviors

The moment you walk into a U.S. airport on return from Western Europe, you see different norms regarding body size. Relative to Europeans, the large size of Americans is striking. To reduce the burden of heart disease, we need more than therapeutics; we need to change dietary behaviors—preferably at younger ages.

A group from the University of Cincinnati in partnership with Kroger food stores has designed the SuperWIN study to compare the efficacy of point-of-purchase strategies for improving food purchase choices. It's a modest pragmatic study with a primary endpoint of a change in Dietary Approaches to Stop Hypertension (DASH) score.

It matters less whether a point-of-purchase approach works; the more important thing about SuperWIN is that it is being done and being presented at a major medical meeting. I hope it gets attention. U.S. heart health turns on a change in norms.

Prompting Clinicians to Do Better

The Yale team is back with another pragmatic cluster randomized trial looking at improving the care of patients with HF. At issue is the underuse of guideline-directed medication. 

The idea behind the PROMPT-HF trial is to "harness the electronic health record (EHR) to create patient-centered 'best practice alerts' that can guide clinicians to prescribe appropriate medical therapies." Their previous trial, CONNECT-HF, found that among patients with HFrEF, an in-hospital and postdischarge quality improvement effort had no effects on important clinical outcomes. But that was in the hospital.

PROMPT-HF focuses on outpatients, and this is where most of the titration of HF meds ought to occur. The primary outcome is the proportion of patients with HFrEF with an increase in prescribed HFrEF therapy.

I laud these efforts because I feel that we understudy practice patterns. But I am not hopeful that EHR alerts will prove effective; there are just too many alerts, and we have become too accustomed to ignoring them. Clicking through alerts has figured prominently in an ongoing criminal medical error case at Vanderbilt.

Tricuspid Valve Repair

Tricuspid valve regurgitation (TR) is everywhere. The question with most cases is whether the TR is causing problems or is simply a marker of HF. If the TR is causal, treatment to reduce the leak is reasonable. Yet surgical repair of TR carries significant risk. Percutaneous repair offers theoretical advantages. But proof of efficacy requires randomized controlled trials.

At ACC, we will learn the 1-year results of CLASP TR  the  early feasibility study  of the PASCAL transcatheter valve repair system in the treatment of TR. (Editor's Note: An earlier version of this column mistakenly reported that  CLASP II TR  would be presented. That trial is ongoing.)

Regarding complications, there is a poster presentation on April 2 looking at in-hospital outcomes of percutaneous tricuspid valve procedures.

Longer-term Results of Transcatheter Aortic Valves

The title says it all: "Five-year Incidence, Timing and Predictors of Hemodynamic Valve Deterioration of Transcatheter and Surgical Aortic Bioprostheses: Insights From the Corevalve US Pivotal and SURTAVI Trials."

Any time we learn longer-term results of bioprosthetic valves, we learn a lot.

Fractional Flow Reserve

At ACC, South Korean investigators will report the results of the FLAVOUR trial, which compares fractional flow reserve (FFR)–guided percutaneous coronary intervention (PCI) with intravascular ultrasound-guided (IVUS) PCI in patients with stable angina. The primary outcome is major adverse cardiac events. There is much to say about the rationale and design of this randomized controlled trial.

My first question is,  Why are patients with intermediate stenosis and stable angina being considered for PCI? It is now clear that PCI on top of medical therapy alone offers no benefit for death or MI reduction and likely has marginal to no benefits for long-term angina relief.

My second question relates to FFR. The authors write, "despite the proven advantage of both adjunctive strategies" but then cite FAME-2 as evidence of the benefits of FFR. That's curious because the benefit in FAME-2 was driven by urgent revascularization, not death or MI. And that can be explained by the trial's unblinded nature: what do you think happens when a patient with an unstented stenosis reports even a twinge of chest pain?

Further, we now have two major trials showing the failure of FFR to improve PCI outcomes. FLOWER-MI compared FFR-guided PCI to angiography-guided PCI in patients with ST-segment elevation MI and found no significant benefit in death, MI, or unplanned hospitalization at 1 year. And in FAME-3, an FFR-guided strategy for multivessel disease was found not to be noninferior to coronary artery bypass grafting for reducing death, MI, stroke, or revascularization at 1 year. (To be fair, FLAVOUR authors started their trial before results of these two trials were reported.)

If FFR underperforms again, we should revisit this commentary on the fallacies of FFR and retire this technology to the museum of dubious medical practices. We should then study how this technique became a therapeutic fashion.

Other Notes

Outside of the late-breaking and featured clinical research, there will be numerous sessions on the CV manifestations of COVID-19 disease and vaccinations. I think (or hope) we are now at a place in the pandemic where we can rationally discuss these issues. I am particularly interested in a session on myocarditis in competitive athletes on April 3.

I am looking forward to walking through the poster session. This is one of the best parts of an in-person meeting.

On a sad note, the European Heart Rhythm Association meeting in Copenhagen will meet on April 3 to 5. This makes it difficult for all but the hardiest travelers to attend both meetings. There looks to be some interesting news in electrophysiology coming from Denmark. I hope society leadership sorts out this conflict in the future.

Check out journalist Steve Stiles' review. And I hope to see some of you in DC.

Meeting hashtag: #ACC2022

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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