Among patients with heart failure with reduced ejection fraction (HFrEF), various doses of sacubitril/valsartan therapy showed similar improvement in prognostic biomarkers, health status, and cardiac remodeling, according to new study results. Reza Mohebi, MD, of Massachusetts General Hospital and Harvard Medical School, Boston, and colleagues reported these findings from a post hoc analysis of the PROVE-HF study in a manuscript published Monday online and in the Oct. 18 issue of the Journal of the American College of Cardiology. Sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNI), has been established as a medical therapy for HFrEF. Since its release and incorporation into clinical practice guidelines, the doses of sacubitril/valsartan given in usual care have been considerably lower than those given in clinical trials, and relatively few patients in clinical practice reach the target guideline-directed medical therapy (GDMT) doses. The study, funded by the drug’s manufacturer, Novartis Pharmaceuticals, included 794 persons who were followed for 12 months. The study hypothesized that the mechanistic effects of sacubitril/valsartan would be largely consistent across dose levels. The patients were categorized according to average daily doses of sacubitril/valsartan divided into tertiles. Change from baseline to 12 months in biomarkers (N-terminal pro–B-type natriuretic peptide, high-sensitivity cardiac troponin T, soluble ST2, atrial natriuretic peptide, urinary cyclic guanosine monophosphate), Kansas City Cardiomyopathy Questionnaire (KCCQ)-23 scores, and parameters of cardiac reverse remodeling (left ventricular ejection fraction [LVEF], indexed left atrial and ventricular volumes, and E/e’) were assessed. The average daily dose was 112 mg in Tertile 1 (low dose), 342 mg in Tertile 2 (moderate dose) and 379 mg in Tertile 3 (high dose). Similar changes in prognostic biomarkers were observed across all dose tertiles. Gains in KCCQ-23 scores were comparable regardless of dose category. Consistent reverse cardiac remodeling in all dose categories occurred; the median absolute LVEF improvement across dose groups was 9.3%, 8.7%, and 10.2%, for low, moderate, and high doses, respectively; similar improvements in left atrial and ventricular volumes and E/e’ were also observed across dose categories. The results of this study have immediate applicability to recent clinical practice guidelines and consensus recommendations regarding application and titration of GDMT in HFrEF, the authors wrote. “When reaching target ARNI dose is not possible, our results suggest that favorable mechanistic outcomes may be expected from even low doses of [sacubitril/valsartan] and provide reassurance that the most commonly used dose of the drug in clinical practice (24/26 mg twice daily) provides substantial clinical benefit,” Mohebi and colleagues wrote. However, the authors added that further data are needed regarding the optimal dose of sacubitril/valsartan, including the degree of neprilysin and angiotensin receptor inhibition needed to accrue greatest benefits from the drug. In an accompanying editorial, Mary Norine Walsh, MD, of Ascension St Vincent Cardiovascular Research Institute, Indianapolis, wrote that these results “prove to be very encouraging.” She noted that the study does not report whether the lower doses of sacubitril/valsartan improve survival. She added that the preponderance of white (70%) and male (72%) patients in the study is “disappointing,” especially given that the study enrolled participants from 78 U.S. sites, meaning that future studies are needed to determine whether women and minorities would gain the same benefits. “Mohebi et al rightly conclude that although achieving target GDMT doses in HFrEF should always be attempted, their results suggest that for those unable to achieve maximum doses of sacubitril/valsartan, mechanistic benefits and improvement in health status may be expected, even at lower doses,” Walsh wrote. “The findings of this study send a very strong and reassuring message for patients — and their clinicians — who are unable to tolerate maximum-dose sacubitril/ valsartan.” Sources: Mohebi R, Liu Y, Piña IL, et al. Dose-Response to Sacubitril/Valsartan in Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol 2022;80:1529–1541. Walsh MN. Guideline-Directed Medical Therapy: Even a Little Is Better Than None. J Am Coll Cardiol 2022;80:1542–1544. Image Credit: tashatuvango – stock.adobe.com