Oct 30 2020 This Week in Cardiology – Medscape

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.

For the week ending October 30, 2020, John Mandrola, MD comments on the following news and features stories.

Im no fan of a lax US Food and Drug Administration (FDA); the decision on Watchman was horrific and my friend Vinay Prasad talks often about cancer drugs that are approved on terrible evidence, cost oodles, and may extend life only weeks to months, or not at all. With that, I was surprised to witness the Remdesivir nihilism and sharp criticism of FDAs decision.

Here is the thing: I agree with the FDAs decision. The drug has biologic plausibility; it has known antiviral activity.

The ACTT trial is compelling. It is a well-done, government sponsored, double-blind placebo-controlled trial that met its primary endpoint. Remdesivir decreased hospital stays by 5 days;59 patients of 541 or 11% died on remdesivir vs 77 patients of 521 or 15% who died on placebo. The absolute risk reduction is a massive 3.8%.

On Twitter, Sanjay Kaul wrote, If one considers 10% relative risk reduction (1.5% ARD) to be clinically relevant, then these data suggest an 89% probability of a risk reduction. In death! Not bad! Using the null mortality rate in the Lancet study by Wang and colleagues, the relative risk reduction is still 82%.

The World Health Organization (WHO) sponsored Solidarity Trial, which is published only in preprint form, had 2750 allocated to remdesivir. This trial was carried out in 405 hospitals and 30 countries and it complicates the matter of remdesivir net benefits. Remdesivir had only a 5% reduction in mortality. Also, the trial did not find that remdesivir led to any reduction in hospital stay.

But Solidarity did not have a placebo arm; instead it was compared against standard of care. Also, the trial was carried out in vastly different countries around the world with different health care standards.

Now we have to look deeper into the possibility that there may have been heterogenous treatment effect of remdesivir. The last figure in the Solidarity preprint is a meta-analysis of the Wuhan, American (ACTT), and WHO remdesivir trials. Its broken up by oxygen subgroups, which is a surrogate for how sick patients are.

In the Solidarity, ACTT, and Wuhan studies the point estimate for mortality in patients with low-flow oxygen trends favorable for remdesivir. Taken together, the hazard ratio for this combined subgroup is 0.80 [0.63-1.01]. Prof Landray from Oxford points out that if you posit patients in the low-flow oxygen arm do better, than you have to posit that remdesivir harms those who are sicker.

Now to adverse effects: the Solidarity trial did not report on side effects. ACTT found no significant difference. In sum, you have a drug with minimal safety issues that probably has a modest effect. There may be a benefit if given early before serious respiratory failure.

At the current price, I agree that it is low-value care. However, the FDA is not charged with pricing. The FDA concerns itself with efficacy and safety.

This week, JAMA Cardiology published a consensus document on COVID and the heart relative to athletics. Led by Jonathan Kim from Emory, a group of authors reviewed what is known about the effects of the virus in athletes. Their paper is a much-needed antidote to the excess of fear-mongering surrounding COVID myocarditis.

The authors point out that markers that can be used as myocardial injury, such as troponin, can overlap with athletic hearts. It is well-known that bouts of intense exercise can cause troponin release and edema and inflammation on cardiac magnetic resonance (CMR) imaging. The authors criticize the Puntmann (German) paper as having included patients with co-morbid conditions, or ongoing COVID-19 symptoms. This study had little applicability to athletes.

They criticize the Ohio State 26-patient study based on the fact that little is known about what is normal on the CMR scans in athletes who have recovered from any viral disease. They call for carefully standardized, CMR-based phenotypic studies of athletes with COVID-19 that include appropriate control participants and clinically relevant outcomes.

In discussing the role of CMR in the diagnosis of myocarditis, the authors write that athletes with low clinical pretest probability of myocarditis and isolated abnormal CMR findings should not be presumed to have myocardial injury attributable to COVID-19.

They caution against screening athletes with COVID-19 with CMR based on inconsistency of CMR parameters; a dearth of normative CMR data; the current data lacks appropriate control groups; and no current agreement on the CMR myocarditis criteria in asymptomatic healthy patients. They even cite the dangers of downstream cascades from ECG screening to show how overuse of CMR could lead to iatrogenic harm.

Concerns about cardiac issues in COVID19 should not constitute a primary justification for the cancellation or postponement of sports. Regarding return to play, in high school or young athletes, they write that in the absence of systemic symptoms or persistent CV complaints, CV risk stratification is unnecessary after CDC-recommended self-isolation.

In masters-aged athletes they write, routine, return to play, CV assessment in this population is not recommended, but with the caveat that athletes with severe COVID-19, persistent symptoms, or significant co-morbid symptoms may benefit from an assessment.

Regarding the focal late gadolinium enhancement (LGE) in the right ventricular septum in masters-aged athletes with COVID-19, the authors cite the previous data that finds LGE in the right ventricular septum in ultra-endurance athletes. Here is why this is important: If CMR use increases due to the fear and hype of COVID and the heart, the authors write: We anticipate that this nonspecific LGE pattern will be scrutinized as suggestive evidence of myocarditis.

You all know I am a critic of guidelines and expert opinion documents, but here is one that is unusual in its wisdom and candid writing that calls on clinicians to master the obvious and not run off the rails.

Lets now talk about a JACC paper that sought to characterize echo abnormalities associated with myocardial injury and prognosis in patients with COVID-19. A total of 55 authors from New York City and Milan teamed up to publish a chart review study of 305 patients who had COVID-19 and were sick enough to get echocardiograms. Recall that getting an echocardiogram with COVID-19 signifies a serious selection bias. Due to the danger to healthcare workers, at least in our hospital, we have protocols that basically say COVID positive patients only get tests that are felt to be absolutely necessary.

At baseline, of the 305 patients, 190 had biomarker evidence myocardial injury and 115 did not; 72 of the 115 went on to develop positive biomarkers. Those patients who had positive biomarkers had a 6-fold greater risk of having an echo abnormality.

The second big finding was that all-cause mortality was 5% in those with no myocardial injury, 21% in those with myocardial injury but no echo abnormality, and 31% with both myocardial injury and echo abnormalities. In a multivariate model, abnormal enzymes and echo abnormality increased the risk of death nearly 4-fold, which was similar to having acute kidney disease, and ARDS.

Just before I recorded the podcast, the paper has been covered by 30 news organizations, and Tweeted by 106 accounts. The chart review paper comes with a celebratory editorial that includes this sentence: We congratulate the esteemed investigator group from the United States and Italy for this excellent data in this issue of theJournal.

But this paper tells us nothing useful. First of all, it is a select group of sick patientsthey had to be to get an echocardiogram done in the first place. Then you do troponins. Per the fourth universal definition, the presence of an elevated troponin means there is myocardial injury. This is not the same as myocardial infarction.

The treatment of any troponin not due to plaque rupture or type I MI is treatment of the underlying cause, which is the coronavirus infection and its sequalae, and which is being done in all in-patientseverywhere. As for the outcomes in the paper, if you count patients sick enough to have an echo, and those sick enough to have troponins, and sick enough to have echo abnormalities (that could be old or new), then is it any surprise that these are markers for increased risk of death? No.

You could do this same sort of study for any infectious syndrome; you could do it for post-surgical patients, those with pancreatitis, diverticulitis, AF with a rapid response. There are observational studies that at least attempt to have a control group, an attempt at matching these groups. But not here. Its just a chart review of five patients per author that shows the sicker one is, the higher the chance of dying.

Just a quick note before closing on the new drug, finerenone, which is a selective nonsteroidal mineralocorticoid receptor antagonist (MRA).

Journalist Mitchel Zoler has nice coverage of the FIDELO-DKD trial which was published in the New England Journal of Medicine and presented at Kidney Week. FIDELO was an RCT of about 5700 patients with chronic kidney disease (CKD) and type 2 diabetes with a primary endpoint of kidney failure or death from renal causes. The key secondary composite outcome was CV death, MI, stroke, or heart failure.

Finerenone reduced the primary outcome by 3.3% in absolute terms; the hazard ratio was 0.82 with a confidence interval of 0.73 to 0.93 so significant. The drug also reduced the key CV secondary outcomes albeit with a smaller effect size. Hyperkalemia was 2.3% vs 0.9% with placebo, but supposedly this drug has less hyperkalemia-producing tendencies than the other two MRA drugs, spironolactone and eplerenone.

Read more from the original source:
Oct 30 2020 This Week in Cardiology - Medscape