Sacubitril/Valsartan Dose-Response in HF With Reduced Ejection Fraction

Patients with HFrEF taking sacubitril/valsartan see improvements in cardiac remodeling, health status, and prognostic biomarkers, regardless of dose.

Similar improvement is found in cardiac remodeling, health status, and prognostic biomarkers among patients with heart failure with reduced ejection fraction (HFrEF) regardless of dose levels of sacubitril/valsartan, according to study findings published in the Journal of the American College of Cardiology.

Investigators aimed to evaluate associations between the level of sacubitril/valsartan doses and changes in cardiac remodeling, health status, and prognostic biomarkers through 12 months of treatment with sacubitril/valsartan among patients with HFrEF.

They conducted a post-hoc analysis using data from the PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure; Identifier: NCT02887183) study to calculate the average daily doses of 794 patients with HFrEF (defined as EF ≤40%) treated with sacubitril/valsartan.

The investigators stratified these patients into low (average daily dose 112 mg), moderate (342 mg), and high (379 mg) dose tertiles. They evaluated the change from baseline to 12 months via cardiac reverse remodeling (left ventricular EF, indexed left atrial and ventricular volumes, and E/e’), health status judged by the Kansas City Cardiomyopathy Questionnaire-23 scores, and biomarkers.

The investigators noted that patients in the high tertile had a higher body mass index, were more likely to be men, were younger, had higher blood pressures, and were more likely to take ACE inhibitors/ARB at baseline.

Further data are needed regarding the optimal dose of Sac/Val, including the degree of neprilysin and angiotensin receptor inhibition needed to accrue greatest benefits from the drug.

The investigators observed consistent reverse cardiac remodeling across all dose categories. They noted median absolute left ventricular EF improvement of 9.3% (low dose), 8.7% (moderate dose), and 10.2% (high dose), along with similar improvements across all dose levels in left atrial and ventricular volumes and E/e’.

Patients in the PROVE-HF study had a target recommended sacubitril/valsartan dosage of 97/103 mg twice daily. Of these patients, 35% did not reach the target dose but still achieved similar degrees of reverse cardiac remodeling at 12 months. The investigators found that 73% of Black patients, 62.2% of White patients, and 52.1% of Hispanic patients reached the target dose by month 12. Those reaching higher doses had better kidney function.

They found the gains in the Kansas City Cardiomyopathy Questionnaire-23 scores to be comparable, regardless of dose level. There was no statistical difference at the end of follow-up between overall scores in any of the dose tertiles. The investigators noted a 20-point or higher increase in scores in tertile 1 (32.6%), tertile 2 (34.8%), and tertile 3 (32.8%).

They observed prognostic biomarkers had similar changes at all dose levels. The relative increase of atrial natriuretic peptide and B-type natriuretic peptide were not significantly different across dose levels. The investigators found decreases in high sensitivity cardiac troponin T and soluble suppressor of tumorigenicity-2 to be similar across dose levels. They noted relative N-terminal pro–B-type natriuretic peptide reduction was the same across dose levels.

Limitations of this study include the majority of patients being White and there being fewer women participants. There is also lack of randomization or use of placebo and the impact of various dose levels on survival is not investigated.

“Among patients with HFrEF, similar improvement in prognostic biomarkers, health status, and cardiac remodeling were observed across various Sac/Val [sacubitril/valsartan] doses,” the study authors wrote. “Further data are needed regarding the optimal dose of Sac/Val, including the degree of neprilysin and angiotensin receptor inhibition needed to accrue greatest benefits from the drug.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. Trial or study (PROVE-HF) supported by industry: Novartis Pharmaceuticals.


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. Published online October 10, 2022. doi:10.1016/j.jacc.2022.08.737