COMMENTARY

Dec 18, 2020 This Week in Cardiology Podcast

John M. Mandrola, MD

Disclosures

December 18, 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 December 18, 2020, John Mandrola, MD comments on the following news and features stories.

Announcement

Christmas and New Year’s both fall on Friday, so TWIC will take two weeks off and return on January 8, 2021. I hope everyone has a peaceful and happy holiday.

COVID: Two Nuggets of Good News

While I see news reports of severe situations in some cities, the Johns Hopkins site showed a flattening of the peak in US cases. Since this is a 7-day rolling average, it is a good sign that maybe the surge has eased. Thank goodness.

Of course, the biggest news is the rollout of the Pfizer-BioNTech vaccine. Yesterday, the US Food and Drug Administration (FDA) heard from the advisory committee about the Moderna vaccine. Approval is likely so soon there will be even more vaccine.

Heart Failure With Preserved Ejection Fraction (HFpEF)

An advisory committee at FDA met this week to discuss expanding the indication for sacubitril/valsartan (S/V) to patients with HFpEF. Recall that S/V is already approved for patients with heart failure with reduced ejection fraction (HFrEF). This was based on the PARADIGM HF trial that compared S/V and enalapril and found a 20% reduction in the primary endpoint of cardiovascular (CV) death or HF. The median EF of enrolled patients was 29%

But HFpEF is much more common. The discussion at FDA centered on the PARAGON HF trial, published late last year in the New England Journal of Medicine (NEJM). PARAGON compared S/V with valsartan alone in patients with HFpEF. The results are super complicated.

While overshadowed by the pandemic, this FDA decision is a big one because there are many more patients with HFpEF than those with HFrEF, and HFpEF is far less well understood.

The discussion at FDA centered on PARAGON HF, which was a large RCT comparing S/V vs valsartan alone in 4800 patients with HFpEF. The primary endpoint was a composite of total HF hospitalizations and CV death. The choice to use total HF hospitalizations is notable because four previous trials in HFpEF used time to first heart failure hospitalization or CV death. The counting of total HF hospitalizations will accrue more events and increase the statistical power.

The results: There were 894 primary events (37.1%) in the S/V group and 1009 primary events (42,2%) in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P=0.06). The lower rates of HF hospitalizations drove the trend towards improvement. There was really no difference in CV death. Staying true to the frequentist approach, the P value above the threshold of 0.05 means that we do not reject the null hypothesis that there is no difference the two drugs.

FDA reviewers dug deep into the weeds of the adjudication of HF events and found that if you add in urgent HF visits, say to an HF clinic that can give diuretics, that would add enough events so as to tighten the confidence interval and now the rate ratio of 0.86 for the primary endpoint would be significant at a P value of 0.04. Another way they could make the main trial results significant is to count investigator-reported events rather than what was done in the trial—central committee adjudication. The trial was blinded, so the FDA reviewers argued that using investigator reported events is legitimate. This analysis does not much change the ratio of primary endpoint events (still about 14% reduction) but by adding more events, it tightens the confidence interval further and now it meets the threshold of a P value of 0.01. And if you use total HF events including urgent visits and investigator-reported HF events, you get a rate ratio of 0.83 with even tighter confidence interval and a P of 0.006.

The committee said: “The study failed to reject the null hypothesis for the prospectively planned primary efficacy endpoint; however, reasonable exploratory analyses, planned and unplanned, were able to reject the null hypothesis.”

When PARAGON was published, there was much discussion of subgroups within the main trial, the question being: were there groups of patients that do better? A large chunk of the discussion at FDA focused on the possibility of heterogenous effects in two subgroups—female patients, and patients with EFs lower than the median of 57%. In the NEJM paper, we see that female patients had a 27% risk reduction with V/S but in male patients the risk reduction was 1.03 and so, no reduction at all. The authors also separated out events in those with a median EF < 57% vs those > 57%. In the lower EF group the risk reduction was 0.78 so a 22% reduction but in those with an EF > 57% the risk reduction was no reduction.

The FDA advisory committee combined the two subgroups and looked at event rates and found the risk reduction for female patients and EF < 57% to be a massive 0.57, or 43% reduction. They also cited a prominent paper from PARAGON and PARADIGM authors that combined the two trials looking at S/V effects across the spectrum of EF in the two trials. They showed that the drug has its greatest risk reduction at a left ventricular EF of 30%-45%, but the benefits seem to extend to higher EFs in women vs men. In sum then we have a trial that did not meets its primary endpoint but there appears to be subgroup effects.

The FDA committee voted on the question: Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support any indication? Twelve voted yes, and one voted no.

I have several questions:

  1. Is the effect size worth the cost?

  2. What about subgroups?

  3. What are the implications of approval?

If the FDA approves this drug for such a broad class, I worry that it will get into guidelines, and if that happens, then the drug’s use could be deemed “evidence-based-practice.” The next step might even be codifying its use with performance measures.

Spirinolactone for HFpEF

Spirinolactone was also on the FDA’s docket this week, to consider a formal label adding spironolactone for patients with HFpEF. The advisory committee debate focused on the controversial TOPCAT trial.

The TOPCAT trial enrolled 3400 patients; primary endpoint was CV death, HF hospitalization, or cardiac arrest. Results failed to show a significant benefit of spironolactone over placebo.

The controversy centers on regional differences in the data from the Americas vs that of Russia/Georgia. For example, compared with patients in the Americas, patients in Russia/Georgia were younger and had more ischemic heart disease. They also were less likely to have been enrolled because of elevated natriuretic peptide levels. Event rates also were substantially lower in this population. And there were questions about medication compliance in these patients.

Read Patrice Wendling’s excellent news story about the FDA’s deliberations for more details.

Top Stories/Research of 2020

Check out Bob Harrington’s and Michael Gibson’s excellent discussion of the top trials of 2020, as well as my recap of the most important stories and themes of 2020.

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