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Dose-Response to Sacubitril/Valsartan in Patients With HFrEF
Quick Takes
- In a post hoc analysis of data from the PROVE-HF study, patients receiving sacubitril/valsartan had similar change in biomarkers including NT-proBNP, hs-cTnT, and sST2 and echocardiographic parameters of remodeling irrespective of dose attained.
- Patients receiving a low dose of sacubitril/valsartan showed comparable improvement in health status, as measured by the KCCQ, compared with a high dose of sacubitril/valsartan.
Study Questions:
What is the association between dose of sacubitril/valsartan and health status, biomarkers, and cardiac remodeling among patients with heart failure with reduced ejection fraction (HFrEF)?
Methods:
This was a post hoc analysis of data collected for the PROVE-HF study: an open-label, single-arm study of HFrEF patients with left ventricular ejection fraction (LVEF) ≤40% initiated on sacubitril/valsartan, titrated per usual care over 60 days. Average daily dose was calculated and patients divided into tertiles based on this. Outcomes of interest included change in N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), Kansas City Cardiomyopathy Questionnaire (KCCQ), and echocardiograms at 6 and 12 months of follow-up.
Results:
Overall, 794 patients were included in these analyses. Patients receiving the highest dose of sacubitril/valsartan were younger, more likely to be male, Black, with a higher body mass index, and have higher baseline blood pressure with better renal function and lower NT-proBNP. Patients receiving the lowest dose of the medication had higher baseline NT-proBNP, and treatment resulted in greater absolute reduction compared to the higher dose group. Decreases in hs-cTnT and sST2 were similar across dose tertiles.
Increase in KCCQ scores at 12-month follow-up were observed regardless of dose category. Increase in LVEF, reduction of LV and left atrial volumes, lowering of E/e’, and reduction in LV mass index was observed across all three dose groups. Hypotension, hyperkalemia, and dizziness were more reported in the lowest dose group.
Conclusions:
In a post hoc analysis of the PROVE-HF study, patients with HFrEF showed improvement in biomarkers, echocardiographic markers of remodeling, and health status with sacubitril/valsartan regardless of dose achieved.
Perspective:
Efficacy of sacubitril/valsartan over angiotensin-converting enzyme (ACE) inhibitors in HFrEF patients was established by the PARADIGM-HF trial. However, this trial had a run-in period where patients had to tolerate the maximal dose of enalapril to continue further. This has led to ambiguity about efficacy of lower doses of angiotensin receptor/neprilysin inhibitor (ARNI) in HFrEF patients and if it continues to provide a benefit over ACE inhibitors at lower doses. In this study, ARNI was effective in HFrEF patients regardless of dose achieved and patients across all dose groups showed improvements in health status, remodeling, and biomarkers. Real-world observational data show that a small proportion of patients are able to tolerate high-dose ARNI. These data support that, while reaching target maximal dose of ARNI may not be possible for all, patients benefit to a similar extent regardless of ARNI dose.
Clinical Topics: Heart Failure and Cardiomyopathies, Noninvasive Imaging, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Echocardiography/Ultrasound
Keywords: Angiotensin-Converting Enzyme Inhibitors, Biomarkers, Blood Pressure, Body Mass Index, Echocardiography, Health Status, Heart Failure, Hyperkalemia, Hypotension, Natriuretic Peptide, Brain, Neprilysin, Stroke Volume, Troponin T, Valsartan, Ventricular Function, Left, Ventricular Remodeling
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