COMMENTARY

Oct 9, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

October 09, 2020

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 October 9, 2020, John Mandrola, MD comments on the following news and features stories.

COVID-19: Hydroxychloroquine, Remdesivir, and What to Do About Unproven Therapies

The New England Journal of Medicine (NEJM) published two important studies yesterday. From the RECOVERY group in the UK, a 4500-patient RCT of hospitalized patients with COVID-19, found no mortality benefit to hydroxychloroquine (HCQ). No subgroup had even a hint of benefit. It’s good to know for sure that HCQ does not help patients ill with COVID. But more important is the epistemology. The only way to know if a non-parachute-like treatment works is randomization.

The NEJM also published the final 28-results of the NIH-funded adaptive RCT of remdesivir called ACTT-1. Recall that the 14-day results found benefit in that a shorter time to recovery and death was numerically lower in the remdesivir arm, but the p-value was not-significant at 0.05. In the 29-day and final report, the end-results were similar, with improved time to recovery and again, the 27% relative risk reduction in death did not reach significance. The confidence interval for mortality ranged from a 0.52 to 1.03—meaning a 50% reduction to a 3% increase in death. Thus, we don’t know whether the mortality reduction was due to chance.

On Twitter you could see people who dichotomized the result: essentially, they said it wasn’t significant so remdesivir does not reduce death. I used to think that way too, but not anymore. If you think like a Bayesian you have to consider the nearly 4% absolute risk reduction in death given other information. What makes me think it is real and not chance is that the drug has documented anti-viral activity and time to recovery was better in the 14-day results. What makes me worried that it was a chance finding was the RCT by Wang and colleagues, which found no mortality benefit.

The teaching point: The Data Safety Monitoring Board met after a total of 482 recoveries (exceeding the estimated number of recoveries needed for the trial) and 81 deaths had been entered in the database. They had a great result in time to recovery and a close to significant result in mortality. It was the middle of a pandemic and they chose to stop randomizing remdesivir. I totally understand the decision, but had they let more patients recruit, they would have increased (or decreased) confidence in the mortality signal.

A 2010 JAMA systematic review found that, “...Truncated RCTs were associated with greater effect sizes than RCTs not stopped early. This difference was independent of the presence of statistical stopping rules and was greatest in smaller studies.”

After our president famously received a monoclonal antibody infusion and seemingly recovered, social and regular media has exploded with enthusiasm. This includes a glowing Wall Street Journal opinion piece from Dr. Scott Gottleib. Two companies have put out press releases saying their brand of monoclonal antibody looks great. But that is all the data we have. By press release. Nothing else. This is crazy. While I hope this drug works great, I could find no human data published with clinical endpoints. I couldn’t even find preprints of clinical data. The first two NEJM papers show exactly how we should learn whether these treatments work. COVID-19 is not a long disease. Proper trials could be done quickly and that is the only way to know if this works.

The EXCEL Trial (Again)

The European Society of Cardiology and the European Association for Cardiothoracic Surgery (ESC/EACTS) announced this week that they will review their joint recommendations for revascularization of patients with left main coronary artery disease (LMCA). Obviously, this stems from the controversies surrounding the EXCEL trial, which I discussed last week.

In 2018, European guideline writers based their recommendation for PCI for LMCA on the 3-year results of EXCEL published in 2016. In light of that 3-year EXCEL data, the old guideline document upgraded PCI to a class IA indication for patients with a low SYNTAX score and gave a class IIA and III recommendation for those with intermediate and high SYNTAX scores. But a basic critical appraisal of EXCEL data, caused the EACTS council to withdraw its support for the LMCA chapter of the guidelines.

Several subsequent publications, including a recent post hoc analysis zeroing in on how MI was defined in EXCEL, have failed to quell the controversy. So now the two groups will work together. And the collaboration will include “completely fresh” people. They will strive to make it completely independent. This is an important step forward.

Empagliflozin

The EMPEROR-Reduced trial was still simmering after its presentation a month ago at ESC and publication in the NEJM, and we already have a post-hoc analysis.

Recall first that EMPEROR-Reduced was a large RCT of empagliflozin vs placebo in patients with heart failure with reduced ejection fraction (HFrEF) who were on guideline-directed medical therapy. Empagliflozin reduced a composite of cardiovascular (CV) death or heart failure hospitalization (HFH) by 5% in absolute terms. Most of benefit was driven by fewer HFH rather than CV death. In the main trial, the empagliflozin effect was seen in patients with and without diabetes.

One important subgroup not shown the main trial were patients currently taking the sacubitril/valasartan (S/V) and the effect of empagliflozin on them. At the virtual Heart Failure Society of America sessions, the EMPEROR-Reduced principal investigator Milton Packer presented the results in this subgroup.

Of the nearly 3800 patients in the main trial, 727 or 19% were taking S/V at baseline. The primary endpoint CV death or HFH fell by 36% relative to placebo in patients who received empagliflozin on top of S/V, and by 23% relative to placebo among the remaining patients who received empagliflozin on top of a different type of RAS inhibitor drug or no RAS inhibition. The p for interaction was not significant.

Empagliflozin was also as effective for improving a quality-of-life measure in patients compared with placebo regardless of the type of RAS inhibition used. For all four outcomes, the point-estimate of empagliflozin's benefit was higher when used along with S/V.

The trial discussant, a biostats person, said that you can’t say empagliflozin works better in the S/V group; but rather, that empagliflozin effect overall is not diminished in the S/V group.

This is an important question we will face in the clinic: S/V has a lofted status in the minds of doctors. It is a big new drug that has shown to be very effective. Now we have another hot drug, the SGLT2i drugs. Should we add two hot new drugs or is one enough? This analysis suggests that empagliflozin still stands to benefit patients even when they are taking the big guns of HF.

Class EFFECT?

Another side note on SGLT2 inhibitors, one that has come up here at our hospital, is whether they have a class effect or should we stick with the drugs studied in the trials. It would be easier for hospital formularies to not include each one.

The VERTIS trial of ertugliflozin vs placebo in diabetic patients found no reduction in CV outcomes, although a secondary endpoint of HFH had a 30% reduction. But last month on Twitter, nephrologist Cristos Agryroupoulus sent out an informal meta-analysis of the big SGLT2 inhibitor trials. All-cause death, CV death, HFH, and worsening renal function all looked better.

We have the class effect debate in heart failure. Only metoprolol XL, carvediolol, bisoprolol have been studied in RCTs. But it’s hard to believe other similar beta -blockers would not exert similar effects. Same with ACEs and ARBs. ACEI has much stronger data in HF than ARB. Captopril, ramipril, peridopril all have strong post MI data. And enalapril for Class 4 HF. We give the other ACEI a pass for HF; but not so much with beta blockers. That seems inconsistent.

Have I erred in my enthusiasm for the SGLT2 inhibitors? Let me know in the comments or on Twitter.

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