Screening for cardiac amyloidosis and excluding patients with cardiac amyloidosis from trials of new therapies for heart failure with preserved ejection fraction (HFpEF) may increase the chances of finding drugs that actually work, a new analysis suggests.
When investigators retrospectively studied a cohort of 317 patients with HFpEF related to cardiac amyloidosis, they found that between 16% and 65% of them would have been eligible for one or more of a series of eight recent failed HFpEF trials, including the PARAGON-HF trial (sacubitril/valsartan), TOPCAT (spironolactone), and CHARM (candesartan).
For PARAGON-HF alone, they found that almost half of the cohort of patients with cardiac amyloidosis would have met inclusion criteria for that trial.
“Our results demonstrate that the patient selection criteria used in clinical trials in patients with HFpEF fail to exclude patients with cardiac amyloidosis,” Silvia Oghina, MD, from the French Referral Center for Cardiac Amyloidosis at Henri Mondor Teaching Hospital, Creteil, France, and colleagues conclude. The group’s study was published online February 3 in JACC: Heart Failure.
There are three main types of cardiac amyloidosis: light-chain amyloidosis, hereditary transthyretin amyloidosis (ATTR), and wild-type ATTR. The cohort studied by Oghina and colleagues included all three types.
“The absence of efficacy of the interventions tested in these trials may be ascribable, at least in part, to the greater refractoriness to treatment and higher mortality that characterize cardiac amyloidosis compared with other causes of HFpEF,” they say.
The history of HFpEF is awash with failed trials in which investigators sought efficacious therapies. Clinical trials involving aldosterone antagonists, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitors, beta blockers, and nitrates all failed to meet primary efficacy endpoints.
That said, in December 2020, on the basis of a new analysis of the PARAGON-HF data, a US Food and Drug Administration (FDA) expert panel backed a bid to expand the indication for the approval for sacubitril/valsartan to include individuals with HFpEF.
Scott D. Solomon, MD, Brigham and Women’s Hospital, Boston, Massachusetts, principal investigator of the PARAGON-HF trial, isn’t convinced the findings would have been different had they formally screened for cardiac amyloidosis, which would have required using techniques that were not yet established at the time the trial was designed. Noting that patients with overt amyloid were excluded from the trial, he had this to say about this new analysis:
“I agree with the authors that patients with unknown amyloid heart disease might contaminate the HFpEF population, including those enrolled in trials. However, the number is likely relatively small, and most likely represented in the higher LVEF patients, and might explain some of the heterogeneity we have seen in recent HFpEF trials,” he said.
Solomon added that, going forward, “it is prudent to consi