Elsevier

American Heart Journal

Volume 237, July 2021, Pages 45-53
American Heart Journal

Clinical investigations
Natriuretic peptide plasma concentrations and risk of cardiovascular versus non-cardiovascular events in heart failure with reduced ejection fraction: Insights from the PARADIGM-HF and ATMOSPHERE trials

https://doi.org/10.1016/j.ahj.2021.02.015Get rights and content

Abstract

Background

: N-terminal pro-B-type natriuretic peptide (NT-proBNP) plasma concentrations are independent prognostic markers in patients with heart failure and reduced ejection fraction (HFrEF). Whether a differential risk association between NT-proBNP plasma concentrations and risk of cardiovascular (CV) vs non-CV adverse events exists is not well known.

Objective

: To assess if there is a differential proportional risk of CV vs non-CV adverse events by NT-proBNP plasma concentrations.

Methods

: In this post hoc combined analysis of PARADIGM-HF and ATMOSPHERE trials, proportion of CV vs non-CV mortality and hospitalizations were assessed by NT-proBNP levels (<400, 400-999, 1000-1999, 2000-2999, and >3000 pg/mL) at baseline using Cox regression adjusting for traditional risk factors.

Results

: A total of 14,737 patients with mean age of 62 ± 8 years (24% history of atrial fibrillation [AF]) were studied. For CV deaths, the event rates per 1000 patient-years steeply increased from 33.8 in the ≤400 pg/mL group to 142.3 in the ≥3000 pg/mL group, while the non-CV death event rates modestly increased from 9.0 to 22.7, respectively. Proportion of non-CV deaths decreased across the 5 NT-proBNP groups (21.1%, 18.4%, 17.9%, 17.4%, and 13.7% respectively). Similar trend was observed for non-CV hospitalizations (46.4%, 42.6%, 42.9%, 42.0%, and 36.9% respectively). These results remained similar when stratified according to the presence of AF at baseline and prior HF hospitalization within last 12 months.

Conclusions

: The absolute CV event rates per patient years of follow-up were greater and had higher stepwise increases than non-CV event rates across a broad range of NT-proBNP plasma concentrations indicating a differential risk of CV events at varying baseline NT-proBNP values. These results have implications for future design of clinical trials.

Section snippets

Study design

We conducted a post hoc analysis of the prospective comparison of angiotensin receptor–neprilysin inhibitor (ARNI) with angiotensin-converting–enzyme inhibitor (ACEI) (PARADIGM HF) trial and the aliskiren trial to minimize outcomes in patients with heart failure (ATMOSPHERE) trial. These trials were approved by ethics committees at all 1,043 participating centers in 47 countries in the PARADIGM-HF trial and 789 centers in 43 countries in the ATMOSPHERE trial. All patients provided written

Baseline characteristics

Of the 15,415 patients randomized cumulatively in the two trials, 14,737 patients (96%) had a measured value of NT-pro-BNP plasma concentration at baseline. About a quarter (N = 3,575) of these patients had AF. Median (Q1, Q3) plasma concentrations of NT-proBNP patients with and without AF were 1817 pg/mL (1,095, 3,266) and 1,271 pg/mL (703, 2,569), respectively. Patients with higher NT-proBNP plasma concentrations were older, had lower eGFR and ejection fraction, were less obese, and had worse

Discussion

In this large cohort of ∼15,000 HFrEF patients from two contemporary clinical trials, we found a differential risk for CV vs non-CV events according to baseline NT-proBNP plasma concentrations. The absolute CV event rates per patient-years of follow-up were higher and had greater stepwise increases than non-CV event rates indicating a differential risk of CV events at varying baseline NT-proBNP plasma concentrations. The results remained similar when patients were stratified according to the

Disclosures:

MV has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals and Relypsa, and participates on clinical endpoint committees for studies sponsored by Galmed, Novartis, and the NIH. LK has received a speaker honorarium from Novartis. WTA has done consulting for Abbott and Impulse Dynamics. ASD has received research grant support from Novartis; and has served as a

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