Patients with heart failure with preserved ejection fraction who took the antifibrotic drug pirfenidone saw a significant reduction in a marker of heart muscle scarring compared with patients who received a placebo, based on findings from an early-phase trial presented at the American College of Cardiology's 70th Annual Scientific Session.
"Observational data suggests that heart muscle scarring, or fibrosis, is an important disease process for heart failure prognosis," said Chris Miller, MD, a cardiologist and National Institute for Health Research Clinician Scientist at the University of Manchester and Manchester University NHS Foundation Trust and the study's lead author. "With cardiac MRI, we were able to select a group of patients in whom fibrosis appears to be important and then reduce that scarring. While further investigation is needed, it suggests that fibrosis is an effective treatment target."
Heart failure means that the heart is no longer able to pump blood around the body properly, causing shortness of breath, swelling and fatigue. In about half of patients with heart failure, the forward pumping function of the heart, or ejection fraction, is normal. This is called heart failure with preserved ejection fraction, or HFpEF. While heart failure can involve multiple factors, scarring of the heart muscle is thought to be an important contributing factor in up to two-thirds of patients with HFpEF. This new trial suggests clinicians could one day use a personalized approach to prevent or reverse scarring in those individuals, thereby slowing the progression of heart failure, Miller said.
Pirfenidone is currently approved for treating adults with idiopathic lung fibrosis, or scarring in the lungs that makes it hard to breathe. While the mechanism of action has not been fully established, the drug is thought to work by inhibiting biological processes involved in scar formation. Preclinical studies suggest pirfenidone can both reduce scar tissue formation and reduce existing scarring in the heart.
Researchers enrolled patients with heart failure, an ejection fraction of 45% or higher and elevated natriuretic peptides (markers of fluid retention). Eligible patients underwent cardiac MRI scanning. Those who had evidence of scarring in the heart muscle, as indicated by an extracellular volume (a measurement of heart muscle scaring) of 27% or greater, were randomly assigned to take pirfenidone or a placebo daily. In total, 94 patients were randomized, with 47 assigned to each treatment group.
At one year, patients underwent a second cardiac MRI to measure change in heart muscle extracellular volume, the primary endpoint. Extracellular volume declined by 1.21% on average in patients who took pirfenidone compared with those receiving placebo, a reduction Miller said was likely to be clinically significant.
"Based on the data we have from previous observational studies, this amount of change in fibrosis could translate into a significant reduction in death and hospitalization for heart failure, but further work is needed to determine this," Miller said.
The study also found evidence that fluid retention, measured using natriuretic peptides, improved in patients who took pirfenidone compared to those receiving placebo.
"The associated reduction in natriuretic peptides provides support for heart scarring having a causal role in heart failure and being an efficacious therapeutic target," Miller said. "Hopefully this work can lead to further development of therapeutics that target heart fibrosis and scarring, and a phase three trial to see if pirfenidone improves patient outcomes."
The most common adverse events were nausea, insomnia and rash.
The study was funded by the National Institute for Health Research (UK). The investigational medicinal product was gifted by Roche Products Limited. Immunoassay testing equipment and materials were gifted by Roche Diagnostics International Limited. Neither company had any role in study design or conduct, including data collection, management, analysis and interpretation; preparation, approval of, and the decision to submit the abstract/manuscript.
Miller will be available to the media in a virtual press conference on Monday, May 17, at 9:30 a.m. ET / 13:30 UTC.
Miller will present the study, "Pirfenidone in Heart Failure With Preserved Ejection Fraction," on Monday, May 17, at 8 a.m. ET / 12:00 UTC.
ACC.21 will take place May 15-17 virtually, bringing together cardiologists and cardiovascular specialists from around the world to share the newest discoveries in treatment and prevention. Follow @ACCinTouch, @ACCMediaCenter and #ACC21 for the latest news from the meeting.
The American College of Cardiology envisions a world where innovation and knowledge optimize cardiovascular care and outcomes. As the professional home for the entire cardiovascular care team, the mission of the College and its 54,000 members is to transform cardiovascular care and to improve heart health. The ACC bestows credentials upon cardiovascular professionals who meet stringent qualifications and leads in the formation of health policy, standards and guidelines. The College also provides professional medical education, disseminates cardiovascular research through its world-renowned JACC Journals, operates national registries to measure and improve care, and offers cardiovascular accreditation to hospitals and institutions. For more, visit ACC.org.