BARCELONA — Greater fragility of patients with heart failure with preserved ejection fraction (HFpEF) should not influence whether those patients receive sacubitril/valsartan (Entresto), based on the results of a post hoc analysis of data from a pivotal trial.
Furthermore, a recently reported prespecified analysis of data from a different pivotal trial shows that the same rule applies to HFpEF patients receiving treatment with dapagliflozin (farciga). A couple of previous reports showed similar findings for dapagliflozin and sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF).
“There appears to be a greater reduction in primary outcome and hospitalizations for heart failure with sacubitril/valsartan compared with valsartan with increasing frailty, and sacubitril/valsartan was safe and well tolerated regardless of frailty status” in the post hoc analysis of the data of the PARAGON HF lawsuits, Jawad H. Butt, MDreported at the annual congress of the European Society of Cardiology.
Analysis of the treatment effect of sacubitril/valsartan compared to valsartan in patients with HFpEF in PARAGON-HF showed that sacubitril/valsartan actually benefited patients more as their frailty increased when the investigators applied severity of frailty as a measure of frailty. Continuous variable.
When they analyzed the effect of frailty by dividing the study cohort into three subgroups according to the severity of frailty (not frail, more frail, and more frail), the statistical analysis did not show significant heterogeneity of effect, although the point estimates for each subgroup showed by far the greatest benefit among the most frail patients. A safety analysis showed consistent safety of sacubitril/valsartan compared with valsartan in all three frailty subgroups, Butt reported.
Simultaneously with his report to the congress, the results appeared online in the Journal of the American College of Cardiology.
Do not discontinue sacubitril/valsartan due to frailty
“We must not refuse [sacubitril/valsartan] treatment in patients perceived as frail,” Butt said in an interview. “There are no safety or efficacy concerns,” although he cautioned that sacubitril/valsartan is not indicated for all patients with congestive heart failure. “If you think sacubitril/valsartan is indicated for a patient with HFpEF, don’t stop it just because of frailty,” said Butt, a cardiologist at Copenhagen University Hospital.
Butt went a step further, emphasizing, “I don’t think we should measure frailty” when considering heart failure patients for treatment with sacubitril/valsartan, or dapagliflozin, which had shown safety and maintained efficacy in a prespecified group. . recently reported analysis for patients with HFpEF, and in a separate recent report on a post hoc analysis of the use of dapagliflozin in patients with HFrEF in the DAPA-HF trial.
The issue of the safety and efficacy of treatment for patients considered frail is especially noteworthy because “clinicians may be more reluctant to initiate new therapies due to doubts about the benefit of treatments in frail patients and fears of predisposing them to possible new side effects,” Butt said. .
“We should not postpone these treatments because of the frailty of the patient,” he said. Maja Cikes, MD, cardiologist at the Zagreb University Hospital Center, Croatia. Butt’s report “shows the safety” of sacubitril/valsartan use in most HFpEF patients regardless of their frailty status, Cikes added in an interview.
“Benefits without increasing the risk of frailty”
The data reported by Butt “suggest that although frail older people with HFpEF are at increased risk of adverse outcomes overall, prescribing sacubitril/valsartan appears to confer benefit without increasing the risk of frailty-related adverse events.” George A. Heckman, M.D.geriatrician from the University of Waterloo (Canada), and Dr Kenneth Rockwoodprofessor of geriatric medicine at Dalhousie University in Halifax, NS, wrote in a editorial accompanying the published version of the Butt report.
the PARADIGM-HF assay enrolled 4,822 patients with heart failure and a left ventricular ejection fraction of at least 45% at 848 centers in 43 countries during 2014-2016, and followed them for a median of 35 months, with a primary endpoint of rate combined hospitalization for heart disease failure or cardiovascular death. Sacubitril/valsartan treatment reduced the incidence of the primary endpoint by 13% compared with control patients receiving valsartan, a difference that narrowly missed significance (P = .06).
Despite this statistically neutral result, the Food and Drug Administration subsequently, based on these results, changed the indication for the use of sacubitril/valsartan from patients exclusively with HFrEF to patients with higher left ventricular ejection fractions, including at least some patients diagnosed with HFpEF.
To run the frailty analysis, Butt and his associates designed a 41-item frailty index, which identified 45% of the study cohort as not frail, 44% as most frail, and 11% as very frail. Their analyzes also showed that the severity of frailty was not significantly related to the effect of sacubitrile valsartan treatment on improving quality of life or improving functional status. Frailty also did not play an apparent role in the impact of sacubitril/valsartan compared to valsartan on treatment discontinuations or adverse effects.
PARAGON-HF and PARADIGM-HF were sponsored by Novartis, the company that markets sacubitril/valsartan (Entresto). Butt has been an adviser to Bayer. Cikes has received travel or honoraria support from Novartis, as well as Amicus, AstraZeneca, Bayer, Boehringer Ingelheim, GE Healthcare, Krka, LivaNova, Pfizer, Sanofi, and Teva, and research or contract support from Novartis, as well as Abbott, Corvia and Pfizer.
Heckman made no disclosures. Rockwood is a co-founder of Ardea Outcomes, an advisor to Nutricia, and owns a copyright through Dalhousie University to the Clinical Frailty Scale (allowing free use for nonprofit healthcare, research, and educational purposes) .
This article originally appeared on MDedge.compart of the Medscape professional network.