Physicians' Academy for Cardiovascular Education

Soluble guanylate cyclase (sGC) stimulator did not meet primary endpoint in HFpEF

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

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


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!’


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Find this article online at Eur Heart J