Mandrola's Three Trials to Look For at the 2024 ACC

It boggles my mind that the European Heart Rhythm Association (EHRA) and American College of Cardiology (ACC) meet at the same time. This year, I decided to attend EHRA. That's sad, because there are three trials that I would love to see presented in person at the ACC in Atlanta.

DanGer Shock: Impella Faces the Ultimate Test in Cardiogenic Shock

In the original 1968 paper describing the first left ventricular assist device — the intra-aortic balloon pump (IABP) — Adrian Kantrowitz, MD and colleagues noted that widespread use of a mechanical circulatory support system would require simplicity.

The percutaneous Impella device, which mechanically pumps blood from the left ventricle to the aorta, seems simple when shown in drawings. The device can deliver many liters of cardiac output. It makes sense that it would provide lifesaving temporary support during periods of low cardiac output. Yet the words simple, device, and human body hardly belong in the same sentence.

The problem: The Impella device has failed to demonstrate benefit when tested in randomized trials. And recently, the US Food and Drug Administration issued safety warnings, which have garnered notice in The New York Times.

None of these trial failures, however, have dampened enthusiasm for the device. Proponents have explanations for the tables of nonsignificant results. When the PROTECT II trial of Impella vs IABP for high-risk percutaneous coronary intervention was stopped early for futility and then delivered a nonsignificant primary endpoint result, proponents could argue that there was a trend toward Impella benefit in the per-protocol population and in the 90-day results.

When a 2017 meta-analysis of the three small (n = 95) trials of Impella vs IABP in patients with cardiogenic shock found no difference in mortality, proponents could say the trials were underpowered — and obviously, doctors would not randomize patients whom they knew would benefit from the Impella.

The most curious thing about the Impella vs IABP trials is that both a large, randomized trial (IABP-SHOCK II) and a meta-analysis of IABP vs medical therapy found no benefit of the IABP.

At ACC, Jacob Eifer Møller, MD, PhD, from Odense University, will present the results of the DanGer Shock trial of Impella vs standard of care in patients with cardiogenic shock due to acute myocardial infarction (MI).

DanGer Shock will report a primary endpoint of death at 180 days. The trial is powered to detect an 18% absolute difference in death, assuming a death rate of 60% in the control arm. I hope it's not underpowered. Thankfully the control arm will not include a device (IABP) shown to have no benefit.

Interventional cardiologists have placed the Impella device in tens of thousands of patients, at great expense, and risk, for 18 years since its approval. No randomized trial has shown it to be beneficial. Observational studies are mixed, and without randomization, there is difficulty sorting out selection bias.

If this trial does not show clear benefit, I see two major consequences: It will have exposed the danger of lax regulatory approval, and it will have — sadly — shown that doctors are far too susceptible to industry marketing.

The Four Stories of the TACT2 Trial

I am deeply curious about this placebo-controlled 2 × 2 factorial design trial of chelation and multivitamins for the prevention of major adverse cardiac events in patients with diabetes and previous MI. Four parts of my brain can't wait for TACT2.

As a writer, I like the potential of this story. Unlike Impella, chelation has few proponents. You don't see chelation banners at the expo of major medical meetings, or adverts in science journals. When the original TACT trial came out, the editors-in-chief of JAMA wrote a long explanatory letter defending their decision to publish the positive trial. And Steven Nissen, MD, wrote a letter of concern regarding the "reliability" of the trial. It's fair to say that the medical establishment had very low opinions about chelation. TACT2, therefore, has the potential to infuse lots of people with good doses of humility.

As a doctor who cares for people with vascular disease, I hope for another disease-modifying therapy. TACT2 will measure an important composite outcome of death, stroke, coronary revascularization, or hospitalization for unstable angina. If either chelation or vitamins work, medicine will have been advanced.

As a fan of medical science, I would be fascinated by a newly discovered causal pathway for atherosclerosis — via heavy metals. One of the reasons the medical establishment struggled with accepting TACT is that heavy metals have not been established as a cause of atherosclerosis. A positive TACT2 result would provide not only a new therapy but also open new thinking about prevention of atherosclerosis via limiting exposure to toxic metals — specifically lead and cadmium. Major discoveries are rare these days.

The final part story of TACT2 is the matter of subgroup analyses. TACT had a clinically important but statistically fragile result. The hazard ratio (HR) of chelation vs placebo for the primary composite outcome was 0.82; however, the CI was close to 1.0 (95% CI, 0.69-0.99). But the HR for the 633 patients with diabetes was far better: 0.61 (95% CI, 0.45-0.83). The tension with any subgroup analysis is always noise vs signal. The proper way to resolve this is another trial — that is, TACT2.

REDUCE-AMI and the Value of Retesting Established Therapy

As I get older, I think more about trials having expiration dates. I can remember the excitement when we heard about the potential of streptokinase in patients with acute MI.

That is exactly the era in which beta-blockers were established as foundational therapy. But even then, the benefit of beta-blockers was debatable. In BHAT (1982), oral propranolol modestly reduced death in post-MI patients, but these patients were highly selected and the drug was started on average 14 days after presentation. In the ISIS-1 trial (1986), intravenous then oral atenolol reduced mortality by less than 1%. And in COMMIT (2005), intravenous then oral metoprolol did not significantly reduce either a composite outcome or all-cause death.

Rapid revascularization of acutely occluded coronary arteries is one of cardiology's best discoveries. Most post-MI patients now leave the hospital with normal or near-normal left ventricular function. The lack of injury to the myocardium makes beta-blocker therapy less likely to modify outcomes. A meta-analysis from 10 years ago of beta-blocker trials done in the era after reperfusion therapy found no effect.

In the REDUCE-AMI trial, Swedish investigators will randomize about 5000 patients with acute MI to standard oral beta-blocker vs no beta-blockers. The primary endpoint will be similar to the original trials: death or MI. I am also interested in the secondary outcomes of symptoms, functional status, and health-related quality of life. Because the only way to sort out true beta-blocker side effects is with a proper placebo design.

I would be shocked if this trial is positive for beta-blocker. A nonsignificant REDUCE-AMI result should have important consequences. First, it will lead to lower pill burden for patients who have normal ventricular function after MI. More important, though, is that it will have taught the medical establishment the crucial value in retesting established therapies when enough time has passed.

There will be many more trials from ACC. I will be in Berlin next week with my electrophysiology colleagues but will write about the most important trials from ACC. And, of course, I will have critical appraisal on This Week in 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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