The Impact of Vericiguat on Microvascular Function in Patients with Documented Vasospastic Angina Pectoris
- Registration Number
- NCT06415227
- Brief Summary
Vasospastic angina is increasingly recognized as an important contributor to anginal symptoms in patients with non-obstructive coronary artery disease (ANOCA). Endothelial dysfunction and smooth muscle cell dysfunction are considered elementary in the development of vasospastic angina. As one of many functions, the vascular endothelium regulates local vascular tone, mainly through the vasodilatory effect of endothelium-derived nitric oxide (NO). Vericiguat is a soluble guanylate cyclase (sGC) stimulator and thereby acts directly on the NO signalling pathway from the endothelium towards the vascular smooth muscle cells. As such, Vericiguat potentially has an beneficial therapeutic effect in patients with vasospastic angina.The VIVA study aims to demonstrate the effect of Vericiguat on endothelial function and microvascular vasodilator responses, as well as its tolerability and safety in patients with vasospastic angina as the pathophysiological substrate of ANOCA.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 55
- Age >18 years
- Recurrent angina symptoms provoked by exercise and/or repeated attacks of angina at rest at least once weekly despite current medical treatment.
- Absence of (co-existing) flow-limiting coronary artery stenosis (as defined by any coronary artery diameter reduction >50%, or fractional flow reserve≤0.80, or instantaneous wave-free ratio/resting full cycle ratio ≤0.89).
- Unambiguous epicardial and/or microvascular coronary vasospasm according to the COVADIS criteria, documented by invasive acetylcholine provocation testing.
- A female participant is eligible to participate if at least one of the following conditions applies: Women with a confirmed post-menopausal state (defined as amenorrhea for at least 12 months without an alternative medical cause); or premenopausal women with documented hysterectomy, documented bilateral salpingectomy or documented bilateral oophorectomy; or for women of childbearing potential: Negative highly sensitive urine or serum pregnancy test within 24 hours the first dose of study intervention and practicing a highly effective birth control method (failure rate of less than 1%) during the study intervention period / and for at least one month after the last dose of study intervention: progestogen-only subdermal contraceptive implant, intrauterine system (progestin releasing intrauterine device), non-hormonal intrauterine device, bilateral tubal occlusion, azoospermic partner (vasectomized or secondary to medical cause) or heterosexual abstinence.
- Impaired left ventricular function (LVEF<50%)
- Significant valvular pathology
- Contraindication for treatment with sublingual nitrates as background medication only, at the discretion of the treating cardiologist.
- Contraindications for treatment with vericiguat: resting systolic blood pressure<100mmHg, severe renal impairment (estimated glomerular filtration rate <15ml/min), severe hepatic impairment.
- Known hypersensitivity to the active substance or to any of the excipients (Microcrystalline cellulose, croscarmellose sodium, hypromellose 2910, lactose monohydrate, magnesium stearate, sodium laurilsulfate).
- Concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat.
- Concomitant use PDE5 inhibitors, such as sildenafil.
- Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.
- Patients who are pregnant or nursing and those who plan pregnancy in the period up to 1 month after the study;
- Patients with a limited life expectancy less than one year;
- Patients unable to provide written informed consent, or are otherwise not suitable for inclusion according to the investigator
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Vericiguat (2.5 mg, 5 mg and 10 mg) first; placebo second Vericiguat Treatment with Vericiguat will be uptitrated every two weeks to the highest tolerated dose, with a target maintenance dose of maximum 10 mg once daily. After a washout period of 2 weeks, matching placebo will be started and is uptitrated every two weeks to maintain double blinding. Placebo first; Vericiguat (2.5 mg, 5 mg and 10 mg) second Vericiguat Matching placebo is uptitrated every two weeks to maintain double blinding. After a washout period of 2 weeks, treatment with Vericiguat will be started and is uptitrated every two weeks to the highest tolerated dose, with a target maintenance dose of maximum 10 mg once daily.
- Primary Outcome Measures
Name Time Method Microvascular function assessed with LASCA : Area under the curve for cutaneous microvascular conductance during acetylcholine iontophoresis 10-week and 22-week follow-up Difference in area under the curve for cutaneous microvascular conductance in APU/s during acetylcholine iontophoresis after 10-week placebo- versus 10-week vericiguat treatment periods
- Secondary Outcome Measures
Name Time Method Microvascular function assessed with LASCA : Peak cutaneous microvascular conductance during acetylcholine iontophoresis 10-week and 22-week follow-up Difference in peak cutaneous microvascular conductance in APU/mmHg during acetylcholine iontophoresis after 10-week placebo- versus 10-week vericiguat treatment periods
Microvascular function assessed with LASCA : Absolute and relative change in cutaneous microvascular conductance (peak-baseline) during acetylcholine iontophoresis. 10-week and 22-week follow-up Difference in the absolute and relative change in cutaneous microvascular conductance from baseline conditions to peak conductance during acetylcholine iontophoresis in APU/mmHg after 10-week placebo- versus 10-week vericiguat treatment.
Vasodilator function assessed with EndoPAT. 10-week and 22-week follow-up Difference in vasodilator function assessed with EndoPAT after 10-week placebo versus 10-week vericiguat treatment expressed by the Reactive hyperemia index (RHI), calculated as the index of signal amplitude pre-to-post occlusion in the occluded arm, divided by the same ratio in the control arm.
Microvascular function assessed with LASCA on placebo versus vericiguat treatment using SNP and insulin. 10-week and 22-week follow-up Difference in the area under the curve for cutaneous microvascular conductance in APU/s during SNP or insulin iontophoresis after 10-week placebo- versus 10-week vericiguat treatment periods
Microvascular function assessed with LASCA stratified by the vericiguat dose reached during the treatment 10-week and 22-week follow-up Difference in absolute and relative changes in cutaneous microvascular conductance in APU/mmHg after 10-week placebo versus 10-week vericiguat treatment stratified by the vericiguat dose reached during the treatment phase (5 or 10mg).
Vasodilator function assessed with EndoPAT stratified by the vericiguat dose reached during the treatment 10-week and 22-week follow-up Difference in reactive hyperemia index (RHI) after 10-week placebo versus 10-week vericiguat treatment stratified by the vericiguat dose reached during the treatment phase (5 or 10mg). RHI is calculated as the index of signal amplitude pre-to-post occlusion in the occluded arm, divided by the same ratio in the control arm.
Microvascular function assessed with LASCA stratified by epicardial or microvascular vasospasm endotype. 10-week and 22-week follow-up Difference in absolute and relative changes in cutaneous microvascular conductance in APU/mmHg after 10-week placebo versus 10-week vericiguat treatment stratified by epicardial or microvascular vasospasm endotype.
Vasodilator function assessed with EndoPAT stratified by epicardial or microvascular vasospasm endotype. 10-week and 22-week follow-up Difference in reactive hyperemia index (RHI) after 10-week placebo versus 10-week vericiguat treatment stratified by epicardial or microvascular vasospasm endotype. RHI is calculated as the index of signal amplitude pre-to-post occlusion in the occluded arm, divided by the same ratio in the control arm.
Quality of life between vericiguat treatment and placebo 10-week and 22-week follow-up Difference in quality of life measured by iMCQ (iMTA (Institute for Medical Technology Assessment) Medical Consumption Questionnaire) index score after 10-week placebo versus 10-week vericiguat treatment periods. The scoring of the iMCQ questionnaire involves calculating medical consumption by assessing respondents' answers to relevant questions, which inquire about various forms of care and the frequency of their utilization. A higher score indicates higher health care consumption.
Quality of life between baseline and end of treatment 10-week and 22-week follow-up Difference in the change of quality of life measured by the iMCQ (iMTA (Institute for Medical Technology Assessment) Medical Consumption Questionnaire) index score from baseline (prior to randomization) to 10-week placebo and 10-week vericiguat treatment periods. The scoring of the iMCQ questionnaire involves calculating medical consumption by assessing respondents' answers to relevant questions, which inquire about various forms of care and the frequency of their utilization. A higher score indicates higher health care consumption.
Angina burden 10-week and 22-week follow-up Angina burden calculated by the frequency of angina attacks for placebo versus vericiguat treatment periods
The occurrence of major adverse cardiac events 24 weeks The occurrence of major adverse cardiac events (hospitalization for angina, spontaneous myocardial infarction, unplanned revascularization, death) during the study period.