Antifibrotic Drug Shows Promise in HFpEF

A novel approach to heart failure with preserved ejection fraction (HFpEF) that takes a page from fibrotic lung disease appeared to pay off, with a reduction in myocardial fibrosis, the phase II PIROUETTE trial showed.

The antifibrotic drug pirfenidone (Esbriet, approved for idiopathic pulmonary fibrosis) reduced myocardial extracellular volume by 1.21 percentage points more than placebo over 52 weeks (0.7% decline vs 0.5% increase, P=0.009).

A treatment effect of that magnitude would be expected to translate to a 9% to 28% reduction in heart failure hospitalization or death, based on recent observational studies, reported Christopher Miller, MBChB, PhD, of the University of Manchester in England, at the virtual American College of Cardiology (ACC) meeting.

The 94 patients randomized in the trial didn’t provide sufficient power to really look at clinical outcomes. However, there were encouraging signals with a significant reduction in N-terminal pro-B-type natriuretic peptides (NT-proBNP) and nonsignificantly better 6-minute walk distance and Kansas City Cardiomyopathy Questionnaire (KCCQ) scores.

No significant differences were seen in diastolic function, atrial size and function, or right ventricular size and function between groups, nor were there any differences in serious or cardiac adverse events.

“The findings suggest that pirfenidone could have favorable clinical effects in patients with HFpEF, but further clinical trials are necessary to determine the clinical effectiveness and safety,” Miller concluded.

“This is fantastic. We’re all looking for something for these HFpEF patients,” commented ACC President and session co-chair Dipti Itchhaporia, MD, of the University of California Irvine.

Session discussant Biykem Bozkurt, MD, PhD, of Baylor College of Medicine in Houston, pointed out, though, that the NT-proBNP findings could have been a direct effect of pirfenidone, which is “known to reduce the expression mRNA of BNP and natriuretic peptides,” rather than reverse remodeling.

However, the quality-of-life findings were notable, said Mary Norine Walsh, MD, of St. Vincent Heart Center in Indianapolis and a past president of the ACC.

“Patients felt better, and in HFpEF that’s the number one result, although obviously we want to impact survival as well,” she told MedPage Today. “Improvements in KCCQ can’t be ignored. But it’s really clear a lot more work has to be done before we can be sure that a change in imaging outcomes translates to a true biologic effect.”

Fibrosis has been documented in half to two-thirds of heart failure patients but has not yet been a target of therapy in HFpEF.

Given the heterogeneity in HFpEF, Miller’s group designed the trial for predictive enrichment of the population most likely to gain from an antifibrotic drug. Out of the HFpEF population with elevated natriuretic peptides approached, they enrolled only patients for whom cardiac MRI (CMR) showed myocardial fibrosis with at least 27% myocardial extracellular volume. Other patients with less fibrosis were shunted to a registry.

After randomization to pirfenidone or placebo, repeat CMR was done at 12 months.

CMR is fairly accessible and already routine in HFpEF to help evaluate for infiltrative disease, Walsh noted, although not all can tolerate it due to claustrophobia.

Miller agreed that a clinical parameter screening tool would be needed, perhaps incorporating smoking status and other factors. His group is actively investigating such a tool.

In addition to the need for more study, Walsh suggested future studies will need to include more women. She said she was disappointed that women didn’t account for even half of the study population, despite HFpEF being a prevalent disease in women.