COMMENTARY

May 14, 2021 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

May 14, 2021

Please note that the text below is not a full transcript and has not been copyedited. For more insight and commentary on these stories, subscribe to the This Week in Cardiology podcast.

In This Week’s Podcast

For the week ending May 14, 2021, John Mandrola, MD comments on the following news and features stories.

A quick comment on COVID-19: It’s getting better. We are almost there. I renewed my passport this week.

ACC Preview

The American College of Cardiology (ACC) annual meeting starts this weekend. Here are some potentially interesting trials.

  • PARADISE MI

PARADISE MI is one of those big multicenter industry-sponsored trials that compared sacubitril/valsartan to ramipril in post-MI patients with an ejection fraction (EF) less than 40% and clinical evidence of heart failure. Depending on dosing, ramipril is a legitimate comparator. But as I’ve said before, I do not understand why these trials are not designed to compare sacubitril/valsartan to valsartan alone.

Shortly before the ACC, Novartis announced in a press release that although numeric trends favored sacubitril/valsartan, it did not meet its primary endpoint of reducing cardiovascular death and heart failure. My friends, pay close attention to this presentation at ACC. Numeric trends favored the drug but it did not reach statistical difference.

I’ve published previously on the presence of spin in the cardiovascular (CV) literature. Spin occurs when trialists emphasize something other than the primary endpoint. As I wrote in my preview piece, the highly marketed drug sacubitril/valsartan is now one for three in big clinical trials. Recall that in patients with heart failure with preserved EF (HFpEF), sacubitril/valsartan did not reach statistical significance vs valsartan alone. 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.

  • ADAPTABLE

At ACC, we will also hear about the results of ADAPTABLE, a truly pragmatic trial comparing 81mg vs 325 mg of ASA for secondary prevention—that is, to prevent another cardiac event in patients who have established coronary artery disease (CAD).

The trial features quite special methods, in that patients were enrolled and followed with a direct-to-patient randomization and data collection using a novel web-based patient portal format. ASA 81 mg vs 325 mg is a super important question. If there is no difference in efficacy (and/or bleeding) and the trial’s methods pass muster, then we can just go with the lower dose.

  • LAAOS III

The LAAOS III trial compares left atrial appendage (LAA) closure at the time of heart surgery vs no closure. These were patients with atrial fibrillation (AF) who had to undergo surgery for CAD or valvular heart disease. Surgeons love to clip off the LAA, but to date, no one knows if it helps. Observational studies have been fatally flawed. LAAOS III authors have published their rationale paper, and I love it because it is a simple trial that has a simple outcome – stroke or systemic embolism. It’s so refreshing not to have to parse out a bloated composite endpoint. Or complex randomization groups. Closure or not; count up strokes. The most important thing to remember about this trial is the study question: does LAA occlusion reduced stroke in addition to baseline therapy with anticoagulation.

  • New SGLT1/2 inhibitor

ACC will feature an important meta-analysis involving the novel, yet-to-be-approved, novel SGLT1/2 inhibitor sotagliflozin. Deepak Bhatt, MD will present the effects of the drug across the full spectrum of EF, including heart failure with preserved ejection fraction (HFpEF). Bhatt is on record as saying, "I think sotagliflozin has the potential to be the best in class." The drug class seems amazing, but we also heard in a pre-ACC release of the DARE-19 trial—an RCT comparing dapagliflozin with placebo in patients recovering from COVID-19—that there was not a statistically significant difference in the primary outcome.

  • Heart Failure Therapy

Much of heart failure therapeutics focuses on medical and device therapy. Trials enroll ambulatory, mostly male patients. But that’s not like the real-world. Out here in practice, many or most of our patients with HF have co-morbidities that limit that their physical functioning.

The REHAB-HF trial assessed a novel physical rehabilitation intervention for older adults with acute decompensated heart failure and measured physical functioning as its outcome. Kudos to the team and I hope this one shows benefit because there is more to HF care than mindless algorithmic titration of meds.

  • Alcohol and AF

Greg Marcus and his clever team at University of California San Francisco will present a study looking at alcohol ingestion and AF. His team published a small but elegant study earlier this year on the matter. We know alcohol associates with AF events in some populations; Voskobonik has shown in an RCT that abstinence reduces AF burden. Work underpinning these observations is important and may also give clues to AF pathophysiology.

  • Renal Denervation

Ablation in the kidneys is making a comeback and at ACC we will hear more about ReCor Medical’s Paradise Ultrasound system, which was used in the RADIANCE-HTN Trio study. This was a sham-controlled study of about 300 patients who had uncontrolled hypertension on three anti-hypertensive drugs. The company announced months ago that it had met its primary endpoint of control of daytime blood pressure. At ACC we hear the details.

In 2018, the RADIANCE-HTN Solo study, which used the same device and sham control design, studied patients controlled on one or two antihypertensive medications or uncontrolled on up to two antihypertensives produced positive results. The device has earned breakthrough device designation from the US Food and Drug Administration for the treatment of hypertensive patients who are unable to sufficiently respond to or are intolerant of antihypertensive therapy.

Already Published from ACC; Polypharmacy

Big meetings often feature a handful of papers released early. A group at Beth Israel Hospital in Boston studied the prevalence of use of meds that may increase blood pressure. They used the data from the NHANES longitudinal study, which is broadly representative of a US adult population, a middle-aged group (56 years) and nearly half with hypertension.

Of all adults with hypertension, 19.0% (nearly 1 in 5) reported using one or more blood pressure-raising medications and 3.3% reported using multiple. The most common classes of blood pressure-raising meds were: antidepressants 9%, NSAID 7.2%, and steroids 2.2%. Predictive models estimated that stopping a single blood pressure-raising medication could improve population hypertension control rates by 4.8%.

This sort of data isn’t new. I learned about the CV dangers of NSAIDs in the 1990s. But I still think it’s worth mention because my thinking on the matter has changed. Yes, clinicians should always be aware of BP-raising meds and reduce or stop them when we can. Where my mind has changed is that NSAIDS and antidepressants sometimes allow patients to live more active fuller lives. And for them, the probabilistic increase in risk is worth it.

More Good News From Finerenone

Finerenone is a first-in-class investigational nonsteroidal, selective mineralocorticoid receptor antagonist (MRA). It acts like spironolactone and eplerenone but without the steroidal side effects such as gynecomastia. In 2020, in the large FIDELIO-DKD trial, published in the New England Journal of Medicine, the drug lowered the risk of chronic kidney disease (CKD) progression (the primary endpoint) and CV events (secondary endpoints) vs placebo in patients with type 2 diabetes and CKD.

As part of the regulatory approval process, there is another trial, called FIGARO-DKD, and here the endpoints are switched, with major adverse cardiac events (MACE) as the primary endpoint and prevention of diabetic kidney disease (DKD) as the secondary. The drug maker, Bayer, announced in a press release that finerenone significantly reduced the composite risk of time to first occurrence of CV death or non-fatal CV events (myocardial infarction, stroke, or hospitalization for heart failure). The drug is under review at FDA. Obviously, we need to see the details. But I think we will have a new and novel MRA on the market.

Ethics and Professionalism

Multiple authors representing the American Heart Association (AHA) and ACC have published a long document on ethics and professionalism. I am always perplexed about these sorts of efforts.

The document is finely written and there is nothing to disagree with. I may be wrong, but I don’t see any need for a guiding document, nor do I think the morals of a cardiologist should differ from a worker in a factory or a carpenter. There is right behavior and right thinking. Period. Honesty is super straightforward.

Being a doctor isn’t as hard as rocket science, or statistics, but it does require attention to detail, humility, dedication, and practice. Lots and lots of practice. By being good at our craft we help people and this makes the world a much better place. Indeed, that is what gives this job so much meaning.

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