FDA panel votes down Bystolic as heart failure treatment
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According to briefing materials provided by Forest, during the SENIORS trial (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) of 2,135 patients who were 70 years or older with “reduced or relatively preserved systolic function,” those treated with the drug had a 14 percent reduction in mortality and cardiovascular hospital admission.
However, during the FDA's evaluation of the trial, reviewers alleged that results of the SENIORS trial "lack robustness" and that “approval is not recommended for nebivolol for the treatment of heart failure.”
According to the FDA, although the drug was approved in the U.S. as a treatment for hypertension in 2007, the drug did not exhibit a significant reduction in its endpoints of mortality or cardiovascular hospitalizations to be considered for treatment of chronic heart failure.
Primary endpoints were cited as the first event of cardiovascular hospitalization or death. According to the New York City-based Forest, during the study 332 patients treated with nebivolol (31 percent) and 375 patients treated with placebo (35 percent) experienced an event of death or cardiovascular hospital admission. According to the FDA, these results did not show a significant reduction.
The FDA reportedly had concerns with the SENIORS trial due to late changes that were made regarding study design. “There were several changes made to the protocol, including extension of the minimum follow-up period from six months to 12 months, adjustment of the primary endpoint for covariates of age, sex and LVEF and, finally, adding the deaths collected by phone call/inquiry to the all-cause mortality component of the primary endpoint,” wrote the FDA.
“Changes to the study design while the trial was ongoing, neither component of the primary endpoint significant alone and the lack of enrollment from the U.S. tend to weaken the results,” wrote the reviewer.
“Despite changes, the p-value for the primary endpoint hovers around 0.05 after March 2003, ranging from 0.058 at the six month follow-up time point as originally planned, to 0.048 at the 12 month extended follow-up time point,” wrote the reviewer. In addition, the FDA said, “For a single study, the FDA normally needs a small p-value, say less than 0.01, and internal consistency to support the claim.”
According to Forest, nebivolol is approved for use in 79 countries for the treatment of hypertension and 71 countries for chronic heart failure.
While the panel suggests that the use of nebivolol as a drug to treat heart failure be rejected by the FDA, a final decision is due by March 1.