Pifenidone in heart failure with preserved ejection fraction – The PIROUETTE Trial

Presented at ACC.21 by Chris Miller, MD (Manchester, UK)

Introduction and methods

HFpEF is a heterogenous syndrome and involves a range of pathogenic mechanisms. One of them is heart muscle scarring (fibrosis), which is associated with death and hospitalization for HF. Cardiac fibrosis can be measured using cardiac MRI, assessing myocardial extracellular volume (ECV).

Pirfenidone is an anti-fibrotic medication, licensed for long fibrosis.

In the PIROUETTE trial was examined whether pirfenidone resulted in regression of myocardial fibrosis in patients with HFpEF and myocardial fibrosis. It was a predictive enrichment, randomized, double-blind, placebo-controlled, phase 2 trial of 94 patients with EF≥45% and elevated NT-proBNP or BNP. Patients underwent cardiac MRI scanning and those with evidence of myocardial fibrosis were randomized to pirfenidone or placebo for 52 weeks. Primary outcome was change in ECV from baseline to 52 weeks.

Main results

• There was a reduction in ECV in the pirfenidone group vs. an increase in ECV in the placebo group (% change in ECV was -0.7 ± 1.4 vs. 0.5 ± 2.4, respectively, with a between-group difference of -1.21, 95%CI: -2.12 to -0.31, P=0.009).
• There was a greater reduction in log NT-proBNP in the pirfenidone group compared to the placebo group (P=0.02).
• No differences were observed in diastolic function, atrial size and function, or right ventricular size or function.

Conclusion

This phase 2 trial showed that treatment with pirfenidone for 52 weeks reduced myocardial fibrosis compared to placebo in patients with HFpEF and evidence of myocardial fibrosis. These findings suggest that pirfenidone has beneficial clinical effects in patients with HFpEF.

Discussion

The discussant Ileana Piña, MD (Mount Pleasant, MI, USA) said we often think about HFpEF in terms of diastolic dysfunction and fibrosis in the extracellular matrix, but don’t think about reversing fibrosis to improve outcomes. Therefore, the premise of this study was beautiful, according to Piña. The findings are sufficient to go further with a large RCT that is powered for outcomes, especially HF hospitalization. She will be interested to look at sex differences in a future trial. HF is a heterogenous disorder in which many comorbidities play a role, particularly hypertension, which may be a trigger for fibrosis.

- Our coverage of ACC.21 is based on the information provided during the congress –