Vericiguat for the treatment of coronary vasospasm (ViVA): a double-blind placebo-controlled randomized cross-over trial

BACKGROUND Coronary vasospasm is highly prevalent in patients with angina and no obstructive coronary arteries (ANOCA). A central mechanism of vasospasm in these patients arises from endothelial dysfunction and smooth muscle hyper-reactivity that disrupt the nitric oxide-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway governing vasodilation. Vericiguat, an sGC stimulator that enhances sGC sensitivity to nitric oxide, may therefore be a therapeutic option for patients with coronary vasospasm. OBJECTIVES To evaluate the effects of vericiguat on angina symptoms, endothelial function, peripheral microvascular vasodilator responses, and safety in ANOCA patients with epicardial and/or microvascular vasospasm. METHODS In this double-blind, placebo-controlled, randomized crossover trial, patients were randomized 1:1 to vericiguat followed by placebo, or placebo followed by vericiguat. Each treatment period lasted 10 weeks. The primary functional outcome was the difference in peripheral vasodilator function during acetylcholine iontophoresis using laser speckle contrast imaging; the primary symptom outcome was the difference in daily angina episodes, recorded via the ORBITA-app, between treatments. RESULTS Among the 57 patients enrolled in the trial, the median age was 55 years [50, 61], and 44 (77%) were female. Vericiguat did not improve peripheral vasodilator function, assessed by LASCA during acetylcholine iontophoresis, compared with placebo on AUC (intervention effect estimate -1221 APU•s, 95% CI -4237 to 1796, p=0.42). For the primary symptom endpoint, the final-day odds ratio for reduction in angina episodes recorded via the ORBITA-app, the posterior was distributed more towards the direction favoring placebo (OR 0.84, 95% CrI 0.65 to 1.04); however, it did not meet the prespecified efficacy or harm criterion (posterior probability of benefit with vericiguat versus placebo 0.07).; episode counts and angina-free days over 70 days were similar between arms. Vericiguat was generally tolerated, with modest reductions in blood pressure, no clinically relevant laboratory abnormalities, and no treatment-related serious adverse events. CONCLUSIONS The Vericiguat in Vasospastic Angina trial did not demonstrate evidence of improved peripheral vasodilator function or anginal symptoms in patients with coronary vasospasm. Vericiguat was nonetheless generally tolerated, with no treatment-related serious adverse events. Larger studies with longer treatment exposure could further evaluate the potential clinical effects of vericiguat in patients with coronary vasospasm.