Various Doses of Sacubitril/Valsartan Have Similar Efficacy for HFrEF

All 3 dosing regimens of sal/vac produced similar reductions in stress biomarkers, health status, and cardiac remodeling.

The efficacy of sacubitril/valsartan (sac/val) in lowering prognostic biomarkers, improving health status, and reversing cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF) was similar in 3 dose categories, according to findings from a  study published in the Journal of the American College of Cardiology.

The Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sac/Val Therapy for Heart Failure (PROVE-HF) was a phase 4, 52-week, open-label, single-group study of patients with HFrEF (left ventricular ejection fraction [LVEF] ≤40%) who initiated sac/val treatment per usual care at 78 US sites.

After initiation of sac/val treatment, the participants returned for visits and drug titration about every 2 weeks through day 60, with a sac/val goal dose of 97/103 mg twice daily (or highest tolerated dose). Treatment continued for up to 12 months. Based on data from the study visits, the researchers calculated an average daily sac/val dose and grouped the participants into dose tertiles.

At each visit, measurement was obtained for plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) with use of electrochemiluminescence immunoassays. Health status was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ)-23.

We characterized different sac/val dose trajectories in HFrEF, finding similar reduction in stress biomarkers, similar improvement in health status, and comparable reversal in cardiac remodeling process across all 3 dose categories.

A total of 794 patients with HFrEF were included and categorized into the following groups: low-dose (tertile 1, 112-mg daily dose; n=286; mean age, 66.37±13.1 years; 66.4% men), moderate-dose (tertile 2, 342-mg daily dose; n=272; mean age, 65.00±11.6 years; 75.4% men), and high-dose (tertile 3, 379-mg daily dose, n=236; mean age, 63.76±12.2 years; 73.3% men).

Sac/val was associated with a greater absolute reduction of NT-proBNP in patients who received lower doses (tertile 1, -318 pg/mL; tertile 2, -307 pg/mL; tertile 3, -237 pg/mL; P =.02), although the relative NT-proBNP decrease was the same among the dose categories. Similar patterns of decrease were observed regarding hs-cTnT change at 12 months (tertile 1, -3 ng/L; tertile 2, -3 ng/L, tertile 3, -2 ng/L; P =.27). Changes in soluble suppressor of tumorigenicity-2 also were comparable among the dose tertiles.

Increases in KCCQ-23 score in the 12-month follow-up were observed regardless of dose category, although no statistical difference occurred in summary scores across dose tertiles. Similar categorical changes were observed in health status across dose tertiles: 71 (32.6%) patients in tertile 1, 79 (34.8%) patients in tertile 2, and 67 (32.8%) patients in tertile 3 had a 20 or more increase in KCCQ-23 score.

LVEF was significantly increased in all dose categories: from 28.7% to 38.0% in tertile 1, from 28.9% to 37.7% in tertile 2, and from 29.5% to 39.7% in tertile 3. The corresponding median absolute LVEF improvement in these categories at 12 months was 9.35% (interquartile range [IQR], 5.35%-13.63%), 8.80% (IQR, 4.40%-12.80%), and 9.55 (IQR, 5.67%-14.07%), respectively.

Left atrial volume index, transmitral E wave velocity/early diastolic mitral tissue Doppler velocity, and left ventricular mass index improved in all dose tertile categories after 12 months.

Dizziness (22.4%), hypotension (27.6%), and hyperkalemia (13.3%) occurred significantly more frequently in tertile 1 vs the other tertiles.

Among several study limitations, more than 70% of participants were White and a minority were women. Also, randomized placebo-controlled, phase 2-type dose-ranging trials would be necessary to more rigorously assess the benefit of different dose levels. Furthermore, the impact of various doses on survival was not evaluated.

“We characterized different sac/val dose trajectories in HFrEF, finding similar reduction in stress biomarkers, similar improvement in health status, and comparable reversal in cardiac remodeling process across all 3 dose categories,” stated the researchers. “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: The PROVE-HF study was funded by Novartis Pharmaceuticals. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


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(16):1529-1541. doi:10.1016/j.jacc.2022.08.737