Vericiguat and NT‐proBNP in patients with heart failure with reduced ejection fraction: analyses from the VICTORIA trial

AIMS: Treatment response to vericiguat, based on baseline N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) subgroups specified in the protocol, was evaluated in the heart failure (HF) VICTORIA trial population by post hoc analysis of combined lower three quartiles [Q1–Q3] vs. the upper quartile [Q4]. METHODS AND RESULTS: VICTORIA participants with available baseline NT‐proBNP levels (n = 4805; 95.1% of total) were included. Compared with patients in Q1–Q3 (NT‐proBNP: Q1, ≤1556 pg/mL; Q2, >1556–2816 pg/mL; and Q3, >2816–5314 pg/mL), patients in Q4 (NT‐proBNP: >5314 pg/mL) were older (69.2 ± 12.0 vs. 66.6 ± 12.1 years), had lower mean ejection fraction (27.2 ± 8.3% vs. 29.5 ± 8.2%; P < 0.0001), and were more likely to be in New York Heart Association (NYHA) Class III (51.8 vs. 35.6%) or IV (2.4 vs. 1.0%). Compared with Q1–Q3, patients in Q4 had higher mean Meta‐Analysis Global Group in Chronic Heart Failure risk score (27.3 ± 6.6 vs. 23.5 ± 6.4; P < 0.0001), had lower mean estimated glomerular filtration rate (eGFR; 51.5 ± 25.5 vs. 65.0 ± 26.8 mL/min/1.73 m(2); P < 0.0001) and haemoglobin (12.8 ± 2.0 vs. 13.6 ± 1.9 g/dL; P < 0.0001), and more had atrial fibrillation (48.7% vs. 43.1%; P = 0.0007) and were randomized while hospitalized for HF (14.8 vs. 9.9%; P < 0.0001). Target dose was achieved in 72.3 and 63.7% of patients in Q1–Q3 and Q4, respectively (P < 0.0001). Primary outcome (composite of time to cardiovascular death or first HF hospitalization) rates were 24.5 and 31.7 per 100 patient‐years for vericiguat and placebo in Q1–Q3 [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.69–0.88, P < 0.001] and 73.6 and 63.6 in Q4 (HR 1.15; 95% CI 0.99–1.34, P = 0.070). Serious adverse events were more frequent in NT‐proBNP Q4 (total population) compared with Q1–Q3 (38.3 vs. 32.3%; P = 0.0001), driven mainly by the placebo group. Adverse events leading to death were more frequent in Q4 than Q1–Q3 (5.8 vs. 2.4%; P < 0.0001). CONCLUSIONS: Plasma NT‐proBNP may help identify patients with worsening HF with reduced ejection fraction, in whom the beneficial effects of vericiguat may be highest. Patients with highest NT‐proBNP values are probably too far advanced, suffering more co‐morbidities, or still clinically unstable after decompensation to derive benefit from vericiguat.