Do We Have a Breakthrough Drug for Patients with Heart Failure?

Finerenone is a new dug that blocks the mineralocorticoid receptor. We have such a drug now, called spironolactone. How do they compare?

Last Monday I wrote about one of the most positive drug trials in all of cardiology. In the RALES trial, the mineralocorticoid receptor antagonist (MRA) spironolactone substantially reduced death rates in patients with heart failure due to a weak heart.

There were two big limitations to the RALES story. One was that the most common kind of heart failure now is heart failure with preserved heart function. (In medical jargon, this is called HFpEF or heart failure with preserved ejection fraction). HFpEF is especially challenging because it has proven much harder to treat with medical therapy than HFrEF.

The second RALES limitation is that spironolactone has two adverse effects: it raises potassium levels, which can be hazardous, and it has steroidal side effects; chiefly, it causes men to develop (often painful) breasts, a condition called gynecomastia. Uptake of spironolactone, therefore, is much lower than other heart failure drugs.

Twenty years on, drug makers have developed a new kind of MRA—one without steroidal side effects, and potentially with less tendency to cause high potassium levels.

The drug is called finerenone. Two trials (FIDELIO-DKD and FIGARO-DKD) have shown it has the ability to improve outcomes in patients with chronic kidney disease.

Last month, the New England Journal of Medicine published the FINEHEARTS-HF study, a randomized placebo-controlled trial of finerenone in patients with HFpEF.

This is a big deal because it studied a new drug in a condition (HFpEF) that has proven hard to treat.

The Trial

About 6000 patients with moderate to severe heart failure symptoms and an LVEF greater than 40% were randomized to finerenone or placebo. Patients were 72 years old on average and the mean LVEF was normal at 53%.

Over 32 months, a primary endpoint of total HF events (first or recurrent hospitalization or urgent visit) and CV death occurred in 14.9 per 100 patient years in the finerenone arm vs 17.7 per 100 patient years in the placebo arm. This was a 16% reduction with a HR of 0.84 (95% CI 0.75-0.95).

The composite endpoint was driven by an 18% reduction (HR 0.82 (95% CI 0.71-0.94) in HF events, but the slightly lower rate of CV death (8.1% vs 8.7% ) did not reach statistical significance. There was also no difference in overall death rates.

Total adverse effects were similar in both groups but more patients in the finerenone group had a potassium level greater than 6.0 mmol per liter (3% vs 1.4%). Though no episodes of high K led to death.

Comments

FINEHEARTS-HF was a positive trial. Finerenone did better than placebo in the composite outcome now used for heart failure trials—cardiovascular death and heart failure events. But it was driven by the softer endpoint of heart failure events. The big and important outcome of death or cardiovascular death were not different. It’s hard, therefore, to call finerenone a disease-modifying therapy.

I now need to tell you a brief story on how the other MRA drug—spironolactone—affects patients with HFpEF. It is indeed a story.

When you look up the TOPCAT trial in the NEJM, in 2014, you will find that spironolactone did not reduce the primary outcome of CV death, aborted cardiac arrest or hospitalization for heart failure vs placebo in patients with HFpEF. The 11% reduction in the primary endpoint with spironolactone did not meet statistical significance.

But there is a huge caveat. Nearly half the patients in this trial were enrolled in Russia and Georgia. And studies done after the main trial noted that event rates were four-fold less than patients from other regions. And spironolactone had no effect in Russia and Georgia. A subsequent study done on drug metabolites in a fraction of patients in the trial found that large percentages of patients from Russia/Georgia were likely not taking spironolactone.

The take-home of this TOPCAT story is that if you exclude half the patients in the trial—spironolactone had an 18% statistically significant reduction in the primary outcome.

People in cardiology are super conflicted about how to interpret TOPCAT. On the one hand, there are obvious regional differences—the p-value for interaction is very low. But on the other hand, people do not want to accuse centers in Russia and Georgia of malfeasance.

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Yet how we think about TOPCAT bears on how we interpret FINEHEARTS-HF.

If we stick to the main results of TOPCAT, then finerenone, is a novel new drug that we should prefer over spironolactone. Plus, finerenone has less hormonal side effects.

If we interpret TOPCAT as the authors urge us to do with their multiple re-analyses, then spironolactone is a low-cost effective agent that reduced outcomes to the same degree as finerenone. What is more, spironolactone actually reduced CV death in the America’s subgroup from TOPCAT. See highlighted outcomes from TOPCAT below.

Can we defer to experts who do meta-analyses?

Numerous authors did a complex meta-analysis of the trials of MRA drugs in heart failure. LANCET published the study.

They find that MRA drugs work amazingly well in patients with lower heart function (HFrEF). That is expected. We knew that from RALES.

They also combine the TOPCAT and FINEHEARTS-HF trials and show that the results are similar in patients with HFpEF but then mysteriously conclude that

Steroidal MRAs reduce the risk of cardiovascular death or heart failure hospitalisation in patients with HFrEF and non-steroidal MRAs reduce this risk in patients with HFmrEF or HFpEF.

That conclusion confuses me. It seems like they ignore their findings that spironolactone (steroidal) and finerenone (non-steroidal) performed similarly in their respective trials in HFpEF.

The matter could be solved with a head-to-head trial of the two drugs. But that would be costly. And unlikely to occur.

Instead, we will have marketing to use finerenone in the large population of patients with HFpEF. It is a huge market.

While finerenone has less hormonal side effects than spironolactone, the efficacy seems similar. My guess is that will not be the message. We shall see. JMM