John Mandrola, MD


November 10, 2020

Finally, THE Answer on Statin Side Effects

Well over 100,000 patients have been enrolled in blinded randomized controlled trials (RCTs) of statin drugs. Yet we still don't know whether the drugs cause myalgia.

According to blinded data, the rate of adverse effects with statins is similar to that seen with placebo; in observational studies, the rate of adverse effects is higher with statins. The nocebo effect looms large.

To me, the highlight of this year's AHA virtual meeting will be when the Imperial College London group presents results of the SAMSON trial. It has only 60 participants, but with a crossover design, each patient is their own control arm. Such designs are called n-of-1 trials.

SAMSON enrolled patients who had previously stopped statins because of side effects. Each participant was enrolled in 12 randomly assigned 1-month periods consisting of no medications, placebo, and statin.

The primary outcome is the individual nocebo proportion. The authors will calculate the mean symptom scores for the 4 months on statin or placebo and then divide the symptoms occurring during placebo use by those occurring during drug use. This is an especially neat trial because it will also factor in any symptoms experienced during the time with no medications. Remember, to truly define a placebo or nocebo effect, you need an arm with no intervention because merely taking a tablet can affect symptom perception.

SAMSON will inform us about one class of drugs, but I think the results may transcend statins and speak to the everyday notion of how our brains play into therapeutic effects. I strongly believe a clinician's words can alter the probability of whether an intervention works.

AF Gets an Entire Session

Numerous studies have found that the more you look for atrial fibrillation (AF), the more you find.

Researchers at the Massachusetts General Hospital will add to this literature when they report their pragmatic VITAL-AF trial. One group of patients in primary care clinics will be screened using the KARDIA handheld smartphone ECG device, and another group will get standard of care. (An aside: maybe I am old-fashioned, but I would think a basic exam from a clinician would detect AF; we feel the pulse, don't we?)

VITAL-AF will enroll 35,000 patients, but, sadly, the primary endpoint is not stroke or bleeding but incident AF. I sound like a broken record, but the point of screening for disease—of any sort—is not to pick up the disease; it is to improve an important outcome. Without the latter, screening may line the pockets of the screeners, but it does not help the screened.

Speaking of outcomes, the mSToPS study, 3-year clinical outcomes (emphasis mine), is a nationwide, randomized, pragmatic clinical trial of AF screening that will also be presented at this year's AHA. That could be interesting. Back in 2018, the mSToPS researchers reported in JAMA that an ECG monitoring patch in older patients led to higher rates of an AF diagnosis, more initiation of anticoagulant therapy, and increased healthcare utilization.

Current practice holds that before ablation is tried, a trial of antiarrhythmic should have failed in (most) patients with symptomatic AF amenable to rhythm control. The multicenter Canadian EARLY-AF trial will test this dogma. About 300 patients will be randomly assigned to pulmonary vein ablation using the cryoballoon vs antiarrhythmic drugs. The primary outcome is time to recurrence of symptomatic or asymptomatic AF.

Early ablation worries me because AF can abate on its own, and, although the risks of the procedure are small in absolute terms, the asymmetry of having an atrial-esophageal fistula or stroke is substantial.

Boosting the Squeeze

When I began medical school, the cardiology world had been stunned by the discovery that β-blockers, a drug that reduces contractility, actually improved outcomes in patients with already reduced contractility. At the time, this was confusing; it made more sense to use drugs that increased contractility—say, with dobutamine. That plausible strategy did not improve outcomes.

The first late-breaking clinical trial at this year's AHA features a novel oral agent called omecamtiv mecarbil, a cardiac myosin activator that has been shown to improve parameters of systolic function. GALACTIC-HF is a placebo-controlled RCT that enrolled more than 8000 patients with heart failure with reduced ejection fraction (HFrEF) and measured a primary endpoint of time to cardiovascular death or first heart failure event.

We learned by press release that omecamtiv mecarbil met its primary composite efficacy endpoint. Alas, the drug did not reduce the key secondary endpoint of cardiovascular (CV) death.

We will have to see the details, but a modest relative risk reduction without a CV death reduction is going to be tough to spin as a breakthrough. Given cost constraints and the already significant pill burden for the four drug classes known to reduce mortality in HFrEF, I doubt this agent makes it. The larger question, though, is whether this class of drugs is a fertile area of research.

A Novel MRA?

I call spironolactone my secret weapon; mineralocorticoid receptor agonists (MRAs) are underappreciated. The problems with spironolactone are hyperkalemia and androgen blockade effects.

A few weeks before AHA, at the Kidney Week meeting, we learned that finerenone, a novel nonsteroidal MRA, resulted in lower risks for chronic kidney disease progression and CV events in the FIDELIO-DKD trial. This RCT enrolled more than 5700 patients with chronic kidney disease and type 2 diabetes. The primary endpoint was a renal composite, but the secondary outcomes were CV death, myocardial infarction (MI), stroke, and hospital admissions for heart failure.

From the paper published in the New England Journal of Medicine, the CV outcomes trended in favor of finerenone. At AHA, we will learn more of the details. The key thing with this drug is that it had lower rates of hyperkalemia than seen with spironolactone in previous trials. And it's nonsteroidal, a serious advantage because it avoids the antiandrogen effects of current MRA drugs.

Iron: If It's Low, Replace It

Iron deficiency often coexists with HFrEF. Because iron is important for many bodily processes, plausibility holds that if it's low, replacing it may help. The AFFIRM-AHF RCT, conducted in Poland, will test whether an intravenous infusion of ferric carboxymaltose reduces a composite primary outcome of recurrent heart failure hospital admissions and mortality. A press release announced that the trial narrowly missed statistical significance on its composite primary endpoint.

The sentence after the primary outcome caught my eye: "A pre-specified sensitivity analysis considering the impact of the COVID-19 pandemic revealed a statistically significant difference in favor of the [infusion]." To which I reply: Spin is defined by language designed to detract from nonsignificant primary endpoints.

Another Mulligan for Vitamin D and Fish Pills?

At the 2018 AHA, JoAnn Manson, MD, presented the null results of the VITAL (Vitamin D and Omega-3) trial. This RCT of more than 25,000 adults found no reduction in CV events or cancer incidence. At this year's AHA, we will learn the results of VITAL Rhythm, a continuation of the trial looking at the incidence of AF over 7 years of follow-up in an older population. 

I doubt vitamin D will have any effect. As for the fish oil tablet, keep in mind that in REDUCE-IT, a placebo-controlled trial of icosapent ethyl (a pill with a higher dose of purified eicosapentaenoic acid [EPA] and no docosahexaenoic acid [DHA]), the incidence of AF was 47% higher in the fish oil arm.

The rub with the placebo-controlled OMEMI trial of Pikasol (Pronova Biocare)  (1.8 g EPA plus DHA) is that it enrolled older patients after MI. The thinking here is that these patients will have higher event rates, and, thus, a beneficial signal may be easier to detect. Still, though, no previous trials of EPA plus DHA fish oil supplements have found significant benefits.

The Polypill Is Back Up to the Plate

Two facts: Taking numerous pills each day, especially ones that don't make you feel any better, is a burden, and medicines to prevent cardiac events can't work unless people take them.

The idea behind the polypill is to combine four tablets into one. The upside is it is easier to take; the downside is that it's four chemicals—all of which have diverse actions. In this case, the polypill is potent; it has 25 mg of a thiazide, 100 mg of atenolol, 10 mg of ramipril, and 40 mg of simvastatin.

The group led by Salim Yusuf will present the results of the International Polycap Study 3 (TIPS-3), an RCT that also includes an aspirin and vitamin D arm. The primary outcome of the 5-year trial is a composite of major adverse cardiac events.

Imaging in the Emergency Department

I now have yet another bias: When I visited Edinburgh, Scotland, last year, the famous team of SCOT-HEART investigators were extremely kind. I toured their National Health Service hospital, had a beautiful dinner, and went on a run with Marc Dweck, after which we watched South Africa defeat England in the 2019 Rugby World Cup.

Yet I remain skeptical of imaging in the emergency department—at least in the fee-for-service U.S. system. The problem, of course, is finding incidental coronary artery disease (CAD).

The RAPID-CTCA trial is different from previous CT vs standard-of-care trials in its choice of patients. While SCOT-HEART studied coronary CT angiography in lower-risk patients, RAPID-CTCA will enroll decidedly higher-risk patients who have ischemic ECG changes or troponin elevations, or known CAD. One group gets early CT angiography; the other, standard care. The primary outcome will be all-cause death or MI at 1 year. The authors list 25 secondary outcomes; a high number of outcomes is always a problem because chance alone will lead to some being significant.

Infectious Disease

A medical meeting in 2020 would hardly be complete without studies on COVID-19. This one will feature numerous observations from the AHA's COVID-19 cardiovascular disease registry.

One notable study in the non-COVID infectious disease space is the INVESTED trial, which looks at high-dose vs standard-dose influenza vaccine in patients with high-risk cardiovascular disease. This trial stands out because (a) it looks strong from a methodologic standpoint (n ≈ 9300 over four influenza seasons) and (b) we mustn't forget that there are many respiratory pathogens that can harm our patients with heart disease.

Medscape Coverage

No doubt there will be much more than I have previewed. The team at | Medscape Cardiology will be virtually covering the meeting. They are true professionals.

Stay tuned.

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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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Editor’s Note: An earlier version of this column discussed the ATLANTIS trial which is no longer being presented at the 2020 AHA meeting.


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