St. Louis, MO—A common drug combination did not improve outcomes for patients with heart failure with reduced ejection fraction (HFrEF) compared with a single component, according to a new study.
A presentation at the American College of Cardiology’s 70th Annual Scientific Session compared the use of sacubitril/valsartan combination therapy with valsartan alone. Washington University–led researchers point out that the major clinical trial leading to FDA approval of sacubitril/valsartan for treatment of heart failure, PARADIGM-HF, had relatively few participants with New York Heart Association (NYHA) Class IV heart failure, the most severe form of the disease.
The conference presentation was on results of a new trial, LIFE, which was designed to determine whether sacubitril/valsartan is superior to valsartan alone in patients with severe HFrEF.
Results suggest no significant improvements with the combination drug when compared with valsartan, based on a primary endpoint of change in heart failure severity as measured by the area under the curve for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. Clinical outcomes also showed no significant differences, although the authors point out that results for some secondary and tertiary endpoints showed benefit for using valsartan alone. That included a finding that hyperkalemia was less likely in those on the single agent.
“The results of the LIFE trial show that sacubitril/valsartan is not superior to valsartan for lowering NT-proBNP levels in patients with advanced heart failure,” explained lead author Douglas L. Mann, MD, Lewin Distinguished Professor of Cardiovascular Disease at Washington University School of Medicine. “This is important because the type of heart failure patients studied in the LIFE trial were sicker than the patients in PARADIGM-HF. Although the trial did not have the statistical power to evaluate endpoints such as cardiovascular death and heart failure hospitalization, when you look at the totality of the data, everything was in favor of valsartan.”
The trial included 335 participants with advanced heart failure—defined as having reduced pumping capacity with an ejection fraction of less than 35%, as well as other physiological and functional markers of severe heart failure. The patients were randomly assigned to take either sacubitril/valsartan or valsartan alone for 24 weeks.
The study notes that about a third of patients assigned to take sacubitril/valsartan were unable to tolerate the combination drug at the full dose used in previous trials because of hypotension and worsening renal function and took a reduced dose.
“Patients with advanced heart failure are a very difficult group of patients to treat. It has been widely assumed that sacubitril/valsartan would be effective in all patients with heart failure,” Dr. Mann said. “I think the drug works very effectively in patients with milder heart failure, but the results of the LIFE trial indicate that there is no evidence that sacubitril/valsartan is better than valsartan for more advanced heart failure, and there appears to be less hyperkalemia with valsartan.”
The sacubitril/valsartan combination appears to reduce the size of the heart and improving its pumping ability, but that might not be optimal in all cases, Dr. Mann suggests, adding, “We make the assumption that all heart failure patients are the same and therefore will respond the same to all therapies. However, the patient population with advanced heart failure is different from patients with less advanced heart failure because of the end organ changes that occur in the heart and kidneys. These end organ changes limit the ability of the failing heart to respond to conventional therapies to the same extent as occurs in patients with milder forms of heart failure. This is one of the lessons we learned from the LIFE trial.”
Limitations include the relatively short duration of the study and that its sample size was smaller than the planned enrollment of 400 patients because of discontinuation due to the COVID-19 pandemic.
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