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Soluble guanylate cyclase (sGC) stimulator did not meet primary endpoint in HFpEF
Literature - Pieske B, Maggioni AP, Lam CSP, et al. - Eur Heart J. 2017;38(15):1119-112


Vericiguat is a soluble guanylate cyclase (sGC) stimulator. This class of agents are promising for the treatment of heart failure (HF). sGCs positively influence cardiac, vascular and peripheral mechanisms that are associated with worsening HF [1,2]. However, in the first phase 2 study SOCRATES-REDUCED, vericiguat was not associated with a clinically significant reduction in NT-proBNP in patients with HF with reduced ejection fraction (HFrEF) [3].

In this study, the safety, tolerability and pharmacodynamics of once-daily vericiguat on top of standard-of-care was assessed in 477 patients with HF and preserved ejection fraction (HFpEF). The two primary endpoints were NT-proBNP, a marker of short-term wall stress, and left atrial volume (LAV), a measure of chronic elevations in left ventricular filling pressures. In this study, patients were randomized 1:1:1:1:1 to 1.25, 2.5, 5 or 10 mg vericiguat treatment or placebo. 5 and 10 mg were up-titrated treatment arms starting at 2.5 mg.

Main results

  • Patients were randomised at 12.9±9.0 (mean± SD) days after clinical stabilisation following hospitalisation for worsening of chronic HF, or based on outpatient treatment with i.v. diuretics for worsening of chronic HF.
  • Only 72% of total randomised population fulfilled the validity criteria for the per-protocol analysis of NT-proBNP and 71% fulfilled the validity criteria for the per-protocol analysis of LAV.
  • At baseline, NT-proBNP was high with a median of 1174 pg/mL (IQR 433–2576 pg/mL) and LAV was large with a mean of 86±36 mL in the entire group.
  • Changes in logNT-proBNP and LAV from baseline to 12 weeks were small and did not differ in primary analysis between the pooled three highest vericiguat dose arms and placebo, or in the pre-specified secondary analyses between any vericiguat group and placebo.
  • Results for the KCCQ Clinical Summary Score (CSS), which quantifies patients’ perceptions of their symptoms and physical limitations, showed a clinically meaningful difference of ≥5 points in change from baseline to 12 weeks in the 10 mg target dose arm compared with placebo.
  • General trends observed in echocardiographic parameters of cardiac function and structure at rest included increased trans-mitral diastolic left ventricular (LV) inflow (mitral E velocity) and increased LV relaxation (mitral e’ velocity) from baseline to 12 weeks with treatment.
  • The incidence of the composite of HF hospitalisation and cardiovascular death at 12 weeks was 7.5% in the placebo arm and 6.3% in the vericiguat 1.25 mg, 11.5% in 2.5 mg, 7.3% in the 5 mg and 5.2% in the 10 mg target dose arms. There was a numerical increase in deaths with vericiguat.
  • The rates of adverse events were 69.8% in the 10 mg vericiguat arm and 73.1% in the placebo arm and the rates of serious adverse events were 25.0% in the 10 mg vericiguat arm and 28.0% in the placebo arm.


In the phase 2 study SOCRATES-PRESERVED, vericiguat did not change the primary endpoints of NT-proBNP and LAV at 12 weeks compared with placebo in patients with HFpEF.

Editorial comment

In their editorial article [4], Cleland and Mueller note that there were errors in the randomisation process of the study published by Pieske et al. and they discuss the results of both phase 2 studies with vericiguat in HFrEF and HFpEF: ‘Neither study met its primary endpoint.’ ….’Clearly, the published studies of vericiguat do not provide a strong argument for progressing to large outcome trials.’ Going in more detail, the authors comment on the numerical increase in deaths with vericiguat and the improvement in quality of life, which was mainly due to self-reported symptom improvement in the 10 mg group, and they add: ‘Socrates was a classical Greek scholar who had a reputation for teaching by asking questions but not necessarily providing answers. Naming a randomized trial after him is tempting fate. You might just get what you ask for - questions but no clear answers!’


1. van Heerebeek L, Hamdani N, Falcao-Pires I, et al. Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 2012;126:830–839.

2. Greene SJ, Gheorghiade M, Borlaug BA, et al. The cGMP signalling pathway as a therapeutic target in heart failure with preserved ejection fraction. J Am Heart Assoc 2013;2:e000536.

3. Gheorghiade M, Greene SJ, Butler J, et al. Effect of Vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: the SOCRATES-REDUCED randomized trial. JAMA 2015;314:2251–2262.

4. Cleland JGF, Mueller C. What can we learn from SOCRATES: more questions than answers? Eur Heart J 2017; 38 (15): 1128-1131.

Find this article online at Eur Heart J

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