Vericiguat in patients with worsening chronic heart failure and preserved ejection fraction: results of the SOluble guanylate Cyclase stimulatoR in heArT failurE patientS with PRESERVED EF (SOCRATES-PRESERVED) study

Abstract

Aims: To determine tolerability and the optimal dose regimen of the soluble guanylate cyclase stimulator vericiguat in patients with chronic heart failure and preserved ejection fraction (HFpEF).

Methods and results: SOCRATES-PRESERVED was a prospective, randomized, placebo-controlled double-blind, Phase 2b dose-finding study in patients with HFpEF (ejection fraction ≥ 45%). Patients received vericiguat once daily at 1.25 or 2.5 mg fixed doses, or 5 or 10 mg titrated from a 2.5 mg starting dose, or placebo for 12 weeks. The two primary endpoints were change from baseline in log-transformed N-terminal pro-B-type natriuretic peptide (NT-ProBNP) and left atrial volume (LAV) at 12 weeks. Patients (N = 477; 48% women; mean age 73 ± 10 years; baseline atrial fibrillation 40%) were randomized within 4 weeks of HF hospitalization (75%) or outpatient treatment with intravenous diuretics for HF (25%) to vericiguat (n = 384) or placebo (n = 93). In the pooled three highest dose arms change in logNT-proBNP (vericiguat: +0.038 ± 0.782 log(pg/mL), n = 195; placebo: -0.098 ± 0.778 log(pg/mL), n = 73; one-sided P = 0.8991, two-sided P = 0.2017), and change in LAV [vericiguat: -1.7 ± 12.8 mL (n = 194); placebo: -3.4 ± 12.7 mL (n = 67), one-sided P = 0.8156, two-sided P = 0.3688] were not different from placebo. Vericiguat was well tolerated (adverse events: vericiguat 10 mg arm, 69.8%; placebo, 73.1%), with low discontinuation rates in all groups, and no changes in blood pressure at 10 mg compared with placebo. The pre-specified exploratory endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score improved in the vericiguat 10 mg arm by mean 19.3 ± 16.3 points [median 19.8 (interquartile range 10.4-30.7)] from baseline (mean difference from placebo 9.2 points).

Conclusion: Vericiguat was well tolerated, did not change NT-proBNP and LAV at 12 weeks compared with placebo but was associated with improvements in quality of life in patients with HFpEF. Given the encouraging results on quality of life, the effects of vericiguat in patients with HFpEF warrant further study, possibly with higher doses, longer follow-up and additional endpoints.

Keywords: Heart failure with preserved ejection fraction; Soluble guanylate cyclase stimulator; Vericiguat.

Figure 1

Patient flow and validity of analysis sets. Detailed reasons for exclusion from per protocol sets are provided in Supplementary material online, Table S1. BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; FAS, full analysis set; LAV, left atrial volume; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SAF, safety analysis set.

Figure 2

Echocardiography at rest. Full analysis set excluding patients with incorrectly assigned doses. Data are displayed as mean ± standard error. (A) E wave peak velocity antegrade flow (mitral valve early diastolic filling, Doppler echo of LV diastolic inflow pattern),*¹ difference relative to placebo: 9 cm/s (95% CI 2 to 17 cm/s); (B) medial e′ (mitral valve medial annular peak early diastolic tissue velocity, tissue Doppler imaging of LV relaxation),*² baseline-adjusted linear regression slope 0.08 cm/s (95% CI 0.02 to 0.14 cm/s); (C) lateral e′ (mitral valve lateral annular peak early diastolic tissue velocity). CI, confidence interval; LV, left ventricular.

Figure 3

Blood pressure and heart rate at given time points. Safety analysis set excluding patients with incorrectly assigned doses. Data are displayed as mean ± standard error. (A) systolic blood pressure; (B) diastolic blood pressure; (C) heart rate, difference in heart rate between the placebo and 2.5 mg vericiguat groups at 12 weeks was −3.7 bpm (95% CI −7.32 to 0.00 bpm), and between the 10 mg and placebo groups −5.9 bpm (95% CI −10.0 to −1.9 bpm). Baseline-adjusted linear regression slope −0.34 bpm (95% CI −0.66 to −0.02 bpm). bpm, beats per minute; CI, confidence interval.