Baseline N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were found to predict hospitalizations for heart failure (HF) and cardiovascular death in patients with HF with preserved ejection fraction (HFpEF), not to modify the effect of sacubitril/valsartan treatment in these patients, according to study results published in JACC: Heart Failure.

In the Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction (PARAGON-HF; ClinicalTrials.gov identifier: NCT01920711) randomized, double-blind trial, 4796 patients with HFpEF were randomly assigned to receive 97 mg sacubitril/103 mg valsartan twice daily or 160 mg valsartan twice daily after a run-in period during which participants received valsartan and sacubitril/valsartan sequentially. NT-proBNP levels were measured in >2700 patients at 5 different time points: before the run-in phase, between run-in periods, at the beginning of the randomization period, and at 16 and 48 weeks after randomization.

The study’s primary endpoint was a composite of total HF hospitalizations and cardiovascular deaths. Secondary endpoints included individual components of the primary outcome and all-cause mortality.


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Median NT-proBNP was 911 pg/mL (25th to 75th percentile, 464-1613 pg/mL) at baseline. Baseline NT-proBNP levels were associated with the primary endpoint (adjusted risk ratio [aRR], 1.68 per natural log increase in NT-proBNP; 95% CI, 1.53-1.85; P <.001). This association was stronger in patients with vs without atrial fibrillation (aRR, 2.33; 95% CI, 1.89-2.87and aRR, 1.58; 95% CI, 1.42-1.75; P <.001, respectively).

Elevated baseline NT-proBNP was associated with all-cause mortality (adjusted hazard ratio [aHR], 1.71; 95% CI, 1.55-1.89; P <.001), cardiovascular death (aHR, 1.93; 95% CI, 1.71-2.18; P <.001), and total HF hospitalizations (aRR, 1.61; 95% CI, 1.46-1.79; P <.001). Baseline NT-proBNP levels were not found to modify the effect of sacubitril/valsartan compared with valsartan alone on the primary endpoint (Pinteraction =.96).

Geometric mean NT-proBNP levels declined by 5% and 25% during the valsartan run-in period and the subsequent sacubitril/valsartan run-in period. After adjusting for baseline NT-proBNP levels, sacubitril/valsartan vs valsartan decreased NT-proBNP levels by 19% at 16 weeks (95% CI, 14% to 23%; P <.001), and by 17% at 48 weeks (17%; 95% CI, 11% to 22%; P <.001). Decreases were similar in patients with left ventricular ejection fraction below and above the median (reductions, 20% and 18%, respectively).

Patients for whom NT-proBNP levels declined the most were at lower subsequent risk for primary endpoints: at 16 weeks (RR, 0.62 per log decrease in NT-proBNP; 95% CI, 0.54-0.71; P <.001).

Study limitations include a lack of heterogeneity (2% Blacks), which may limit the generalizability of results.

“Data from the PARAGON-HF trial affirm the strong prognostic significance of NT-proBNP in forecasting future risk [for] HF events in patients with HFpEF,” the study authors concluded. “The mechanisms by which neprilysin inhibition lowers NT-proBNP in HFpEF require further study and may be distinct from those that explain therapeutic benefits on clinical outcomes.”

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Disclosure: Funding for the study was provided by Novartis. Several authors declare affiliations with the pharmaceutical industry. Please see the original reference for a full list of disclosures.

Reference

Cunningham JW, Vaduganathan M, Claggett BL, et al. Effects of sacubitril/valsartan on N-terminal pro-B-type natriuretic peptide in heart failure with preserved ejection fraction [published online March 26, 2020]. JACC Heart Fail. doi:10.1016/j.jchf.2020.03.002