Natriuretic peptides in acute decompensated heart failure: insights from the DAPA ACT HF-TIMI 68 Trial
E O'Meara, S M Patel, M G Palazzolo, J Belohlavek, A S Desai, J Drozdz, S E Inzucchi, J J V McMurray, B Merkely, S Verma, S D Wiviott, M S Sabatine, D D BergAbstract
Background
The prognostic value of natriuretic peptide (NP) levels is established in chronic heart failure (HF), but less is known about the prognostic associations between admission NP levels and early outcomes in acute decompensated heart failure (ADHF). Moreover, some contemporary HF therapies appear to be less efficacious in patients with markedly elevated NP levels, and whether there exists a threshold NP value above which the clinical benefits of SGLT2i are diminished is of interest.
Purpose
DAPA ACT HF-TIMI 68 was a randomized, double-blind, placebo-controlled trial of in-hospital initiation of dapagliflozin in patients hospitalized for ADHF. We examined: (1) correlations between baseline NP levels and markers of congestion, (2) associations between baseline NP levels and early clinical outcomes, and (3) comparative treatment effects of dapagliflozin vs. placebo by baseline NP levels.
Methods
Patients enrolled in DAPA ACT HF-TIMI 68 were required to have elevated NP levels (either NT-proBNP or BNP). For this analysis, baseline NP values (measured locally) were log-transformed and normalized as Z-scores based on the distribution within the trial cohort. Tertiles of normalized NP values were compared. Congestion markers included dyspnea, orthopnea, fatigue, JVD, pulmonary rales, and peripheral edema. The primary outcome was adjudicated cardiovascular death or worsening heart failure (CVD/WHF) through 2 months. Symptomatic hypotension was a key safety outcome. Cox models were adjusted for age, eGFR, LVEF, prior HF hospitalization, prior stroke, atrial fibrillation, and use of non-invasive ventilation.
Results
Of 2400 participants, the median age was 69 years, 34% were women, and 72% had HFrEF. Median NT-proBNP levels for each tertile were 2366 (Q1-Q3, 1882-2843), 4888 (4123-5820), and 11,717 (8888-17,883) pg/ml, and respective median BNP levels were 617 (500-717), 1090 (957-1259), and 2322 (1820-2994) pg/ml. Clinical congestion parameters were poorly correlated with baseline NP levels (all correlation coefficients <0.1). There was a direct monotonic relationship between baseline NP level and risk of the primary outcome, with an apparent upward inflection with values above the mean (Z-scores >0) (Fig A). This risk relationship persisted after multivariable adjustment (adj-HR for T3 vs. T1, 1.64 [95% CI, 1.20-2.25]; p=0.002). Rates of symptomatic hypotension were also higher across increasing NP tertiles (T3 vs. T1: 3.9% vs. 1.8%; p=0.01). The relative treatment effect of dapagliflozin vs. placebo on CVD/WHF over 2 months appeared generally consistent across NP tertiles (Fig B).
Conclusions
In a large contemporary ADHF trial, baseline NP levels were minimally associated with congestion markers but strongly associated with early risk of clinical outcomes. While participants with higher baseline NP levels are at higher risk of adverse events, they may also derive greater absolute treatment benefit from dapagliflozin.Figures A-B-NP DAPA-ACT