Cardiology · Medical Literature
Randomized controlled trial of vericiguat in patients with coronary microvascular dysfunction causing stable chest pain (V-COM): study protocol for a randomized control trial.
Abstract
Previous studies have shown that ∼50% of patients with stable chest pain have no obstructive coronary artery disease (CAD), yet remain at higher risk of major adverse cardiovascular events (MACE) compared to patients without chest pain. Coronary microvascular dysfunction (CMD) is a major cause of ischemia with no obstructive coronary arteries (INOCA). While therapies for CMD are lacking, Vericiguat, a soluble guanylate cyclase stimulator, has shown improvement in coronary microvascular circulation in animal studies. Quantitative stress cardiovascular magnetic resonance (CMR) allows the quantification of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR). This study aims to conduct a randomized controlled trial to determine if Vericiguat improves MBF and MPR in patients with stable chest pain and INOCA caused by CMD. V-COM is a single-blind, randomized controlled trial. Ninety-four patients aged 40-80 years with recurrent stable chest pain, nonobstructive coronary arteries on recent coronary computed tomography (CT) or invasive angiography, and CMD defined by stress CMR (MPR <2.19 or stress MBF <2.19 mL/g/min) will be recruited across six centers in Hong Kong. Participants will be randomized 1:1 to vericiguat plus optimal medical therapy (intervention) or optimal medical therapy alone (control). Vericiguat will be prescribed once daily for 6 months, starting at 2.5 mg and titrated up to a target dose of 10 mg based on systolic blood pressure and tolerability. CMR (including quantitative stress perfusion) will be performed at baseline and 6 months. The primary outcome is the between-group difference in change in stress MBF and MPR from baseline to 6 months. Secondary outcomes include change in six-minute walk distance and Seattle Angina Questionnaire-7 (SAQ-7) scores. This study will provide evidence on whether Vericiguat can improve myocardial perfusion in patients with CMD and offer insights into its potential as a novel therapy for CMD.
Clinical relevance
Does vericiguat, a soluble guanylate cyclase stimulator, improve stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) compared with optimal medical therapy alone in patients aged 40–80 years with stable chest pain and coronary microvascular dysfunction (CMD) in the setting of ischemia with no obstructive coronary arteries (INOCA)? __SNAPSHOT__ {"studyDesign":"Randomized controlled trial — study protocol publication (prospective, single-blind, parallel-group, 1:1 allocation; this publication describes the protocol, not results)","setting":"Six centers in Hong Kong (multicenter)","sampleSize":"Planned n=94 (intervention: 47, control: 47)","population":"Adults aged 40–80 years with recurrent stable chest pain, nonobstructive coronary arteries confirmed by CT coronary angiography or invasive angiography within 6 months ( 0.80), and CMR-defined CMD (MPR <2.19 or stress MBF <2.19 mL/g/min). Key exclusion criteria include systolic BP <100 mmHg, eGFR <30 mL/min/1.73m², concurrent sGC stimulator use, MRI-incompatible implanted devices, malignancy or non-cardiac condition limiting life expectancy to <3 years, and recent stroke/TIA within 60 days.","intervention":"Vericiguat once daily for 6 months, initiated at 2.5 mg and titrated to a target dose of 10 mg (doubling every 2 weeks) based on systolic blood pressure and tolerability, added to background optimal medical therapy","comparator":"Optimal medical therapy alone (no placebo arm; control patients receive standard follow-up appointments every 3 months)","primaryOutcome":"Between-group difference in change from baseline to 6 months in stress MBF (mL/g/min) and MPR, measured by quantitative stress CMR","followUp":"6 months (CMR performed at baseline and 6 months)","fundingSource":"Health and Medical Research Fund (government). Lead investigator (Ming-Yen Ng) has received educational grants and speaker's fees from Bayer (manufacturer of vericiguat), among other imaging industry sponsors; this represents a potential conflict of interest."}
Key findings
This publication reports a study protocol, not efficacy or safety results. No primary or secondary outcome data are available. The planned primary outcome is the between-group difference in change in stress MBF and MPR from baseline to 6 months as measured by quantitative stress CMR. Secondary outcomes include change in six-minute walk distance and Seattle Angina Questionnaire-7 (SAQ-7) scores. No effect sizes, confidence intervals, p-values, NNT, NNH, or adverse event frequencies from the V-COM trial itself are reported, as the trial is ongoing at the time of this protocol publication. The biological rationale for vericiguat in CMD rests on preclinical animal data showing improvement in coronary microvascular circulation with sGC stimulation; no efficacy data in humans with CMD are available from this study.
Practice implications
This protocol publication establishes the design and rationale for the first randomized trial of vericiguat specifically targeting CMD in INOCA. It does not establish efficacy or safety in this population. The findings that approximately 50% of patients with stable chest pain have no obstructive CAD, yet carry elevated MACE risk compared to chest-pain-free individuals, underscore the clinical importance of this therapeutic gap. Vericiguat's mechanism—enhancement of the nitric oxide–soluble guanylate cyclase–cyclic GMP pathway—provides a plausible pathophysiological basis for benefit in CMD, but translational extrapolation from animal data to human CMD remains unvalidated. Patients with HFrEF were not the target population here, and prior vericiguat data from VICTORIA and VICTOR (HFrEF trials) cannot be applied to this INOCA/CMD context. The use of quantitative CMR-derived MBF and MPR as primary endpoints is a methodologically sound surrogate for microvascular function but does not constitute a patient-level clinical outcomes endpoint. Findings—when reported—will apply specifically to patients aged 40–80 years with CMR-confirmed CMD and nonobstructive coronary arteries; broader INOCA populations (including those with coronary vasospasm), patients outside this age range, and those with significant renal impairment were excluded. This summary is based solely on the published abstract and protocol; the full statistical analysis plan, power calculations, and additional methodological details require full-text review. No changes to clinical practice are warranted from a protocol publication alone. __LIMITATIONS__ Protocol-only publication: no efficacy or safety results are available; all conclusions about therapeutic benefit are speculative at this stage.,Single-blind design: investigators are not blinded to treatment allocation, introducing potential for assessment bias particularly in subjective secondary endpoints (SAQ-7).,Surrogate primary endpoints: MBF and MPR are physiological measures, not patient-centered clinical outcomes (MACE, mortality, hospitalization, or quality of life); their clinical relevance as trial endpoints requires validation.,Small sample size (n=94): likely underpowered to detect clinically meaningful differences in secondary or safety endpoints; adequacy for primary CMR endpoints depends on full-text power calculations not available from the abstract alone.,No placebo arm: the control group receives no sham intervention, which does not account for placebo or Hawthorne effects, particularly on symptom-based secondary outcomes.,Single geographic and ethnic cohort (Hong Kong): limits generalizability to other populations, particularly Western, South Asian, or Black patients who may have different CMD phenotypes and comorbidity burden.,Restricted age range (40–80 years) and multiple exclusion criteria (eGFR <30, BP <100 mmHg, MRI-incompatible devices) further limit generalizability.,CMD defined by CMR thresholds (MPR <2.19 or stress MBF <2.19 mL/g/min) without invasive coronary function testing: coronary vasospasm cannot be fully excluded as a contributing mechanism, potentially creating diagnostic heterogeneity.,Short follow-up of 6 months: insufficient to assess durability of any physiological response or impact on clinical events.,Potential conflict of interest: lead investigator has disclosed educational grants and speaker's fees from Bayer, the co-manufacturer of vericiguat, which may influence study conduct or reporting despite government funding. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ V-COM is the first RCT designed to evaluate whether vericiguat improves coronary microvascular physiology—measured by quantitative stress CMR—in patients with stable chest pain and CMR-defined CMD in the INOCA setting; this publication reports only the protocol, and no efficacy or safety data are yet available. Clinicians should not alter current management of CMD/INOCA based on this protocol publication alone, as the preclinical rationale is promising but entirely unvalidated in humans with this condition. Results from V-COM, when reported, will be essential to determine whether vericiguat represents a viable therapeutic option for a patient population with significant unmet need.