Abstract
Background
Coronary vasospasm is highly prevalent in patients with angina and no obstructive coronary arteries (ANOCA). In the pathophysiology of coronary vasospasm, endothelial dysfunction and vascular smooth muscle cell hyperreactivity may cause an imbalance between vasodilation and vasoconstriction. Within this pathophysiology, nitric oxide is crucial. Nitric oxide activates soluble guanylate cyclase, which through the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, reduces intracellular calcium levels in vascular smooth muscle cells, resulting in vasodilation. sGC stimulators, such as vericiguat, enhance the sensitivity of soluble guanylate cyclase to nitric oxide. Vericiguat was shown to be well tolerated, safe, and clinically effective in both heart failure patients as well as in patients with coronary artery disease. We hypothesize that vericiguat restores the balance between vasodilation and vasoconstriction and thereby reduces coronary spasm episodes in ANOCA patients.
Methods
In the Vericiguat in Vasospastic Angina trial, we will assess the impact of vericiguat on endothelial function and microvascular vasodilator responses, angina and quality of life. Additionally, we will evaluate the tolerability and safety of vericiguat in patients with coronary vasospasm as the pathophysiological substrate of ANOCA. 50 patients will be included in the trial, and will be randomized in a 1:1 ratio to placebo treatment first, followed by vericiguat treatment, or vericiguat treatment first, followed by placebo treatment.
Trial Registration
The Vericiguat in Vasospastic Angina trial is registered at ClinicalTrials.gov ID NCT06415227 .
Background
Around half of patients with angina undergoing coronary angiography for suspected coronary artery disease have nonobstructed epicardial coronary arteries. Many of these patients with angina and no obstructive coronary arteries (ANOCA) have a form of coronary vasomotor dysfunction. This includes abnormal susceptibility to vasospasm in the epicardial coronary arteries and/or the coronary microvasculature, and/or coronary microvascular dysfunction: a reduced vasodilator reserve capacity of the coronary microcirculation due to structural and/or functional alterations in the microvasculature. ,, Of these ANOCA endotypes, the presence of epicardial and/or microvascular vasospasm is the most common. ,,
Coronary vasospasm is considered to arise from a disturbed balance between endothelial vasodilator and vasoconstrictor influences, where nitric oxide (NO) and soluble guanylate cyclase (sGC) play a central role. In healthy vessels, endothelium-derived NO maintains the basal vasodilator tone and prevents spontaneous or stimulus-induced vasoconstriction by inducing smooth muscle cell relaxation through activation of sGC. Activation of sGC is required to elicit a vast increase in the conversion of guanosine triphosphate (GTP) to the second messenger cyclic guanosine monophosphate (cGMP), in turn leading to a decrease in intracellular calcium and consequent vasodilation. In vasospasm-prone vessels, endothelial dysfunction reduces NO-bioavailability, while oxidative stress further scavenges NO. In addition, sGC loses responsiveness to NO under oxidative stress in the setting of chronic exposure to cardiovascular risk factors. As a result, the smooth muscle-relaxing effects of NO through sGC and cGMP generation are blunted, predisposing to inappropriate vasoconstriction. This impaired NO-sGC-cGMP pathway not only contributes to vasospasm but may also explain the heterogeneous response to nitrate treatment in patients with vasospasm. Restoring sGC responsiveness, either by enhancing NO sensitivity or directly activating oxidized sGC, therefore represents a rational therapeutic target in coronary vasospasm (see Figure 1 ). ,,,,,,,,,,
NO-sGC-cGMP pathway.
In patients with endothelial dysfunction, triggered by oxidative stress and inflammation, eNOS and NO availability is reduced, decreasing sGC activity and cGMP levels, which contributes to myocardial and vascular dysfunction. Vericiguat enhances sGC sensitivity to NO and directly stimulates sGC, which increases cGMP production. This activates protein kinase G, resulting in vascular smooth muscle cell relaxation and consequently reduction of arterial vasoconstriction. cGMP, cyclic guanosine monophosphate; eNOS, endothelial nitric oxide synthase; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase.
Two new drug classes, sGC stimulators and sGC activators, offer promise by either enhancing NO sensitivity or activating oxidized/heme-free sGC independently of NO, resulting in vasodilation. , While use of sGC activators was previously limited due to side effects, sGC stimulators like vericiguat have demonstrated safety and efficacy in patients with heart failure and pulmonary hypertension. ,, The VISOR and VENICE clinical trials have shown that vericiguat is well tolerated in coronary artery disease patients, even in combination with nitrates. , Vericiguat’s favorable pharmacokinetics, high tolerability, and vasodilatory properties make it a promising candidate for targeting vasospastic angina.
The vericiguat in vasospastic angina (ViVA) trial aims to evaluate the effect of vericiguat on anginal symptoms, as well as on endothelial function and peripheral microvascular vasodilator responses in patients with abnormal vasoconstriction as the pathophysiological substrate of ANOCA. Furthermore, the ViVA trial aims to assess the tolerability and safety of vericiguat in these patients. The ViVA trial is registered at ClinicalTrials.gov ID NCT06415227 .
Hypothesis
Our hypothesis is that administration of vericiguat improves microvascular function and angina symptoms compared with placebo in patients with persisting angina due to epicardial and/or microvascular coronary vasospasm.
Methods
Trial design
The ViVA trial is a prospective, double-blind, placebo-controlled randomized cross-over trial testing the efficacy of vericiguat vs placebo as add-on therapy in patients with epicardial and/or microvascular coronary vasospasm and persisting angina pectoris on guideline-directed medical therapy.
Study setting
The ViVA trial is embedded in the Netherlands Registry of Invasive Coronary Vasomotor Function Testing (NL-CFT; NCT06083155). NL-CFT is a national collaboration, collecting data on clinically indicated coronary function tests (CFT) performed across 16 hospitals in the Netherlands performing CFT according to a standardized protocol. The trial will be conducted in the Amsterdam UMC (Amsterdam, The Netherlands), where specific expertise regarding laser speckle contrast imaging is available. All centers participating in NL-CFT can refer patients to participate in this trial, adding to the generalizability of our study outcome.
Study population
Patients are eligible for participation if they are diagnosed with epicardial and/or microvascular vasospastic angina (according to the COVADIS criteria), documented using comprehensive invasive CFT, and have persistent anginal symptoms on guideline-directed medical therapy. Persistent angina is defined as at least 1 episode of chest pain per week on either a minimum of 2 antianginal drugs targeted to coronary vasospasm according to the treatment recommendations of the 2024 ESC Guidelines for the management of chronic coronary syndromes, or on the maximally tolerated number of antianginal drugs when less than 2. The full list of in and exclusion criteria is presented in Table 1 .
Table 1
Inclusion and exclusion criteria.
| Inclusion criteria |
| 1. Age > 18 y. |
| 2. Recurrent angina symptoms provoked by exercise and/or repeated attacks of angina at rest at least once weekly despite current medical treatment. |
| 3. Absence of (coexisting) 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). |
| 4. Unambiguous epicardial and/or microvascular coronary vasospasm according to the COVADIS criteria, documented by invasive acetylcholine provocation testing. |
| 5. A female participant is eligible to participate if at least one of the following conditions applies: women with a confirmed postmenopausal state (defined as amenorrhea for at least 12 mo 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 h 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 1 mo after the last dose of study intervention: progestogen-only subdermal contraceptive implant, intrauterine system (progestin releasing intrauterine device), nonhormonal intrauterine device, bilateral tubal occlusion, azoospermic partner (vasectomized or secondary to medical cause), or heterosexual abstinence. |
| Exclusion criteria |
| 1. Impaired left ventricular function (LVEF < 50%). |
| 2. Significant valvular pathology. |
| 3. Contraindication for treatment with sublingual nitrates as background medication only, at the discretion of the treating cardiologist. |
| 4. Contraindications for treatment with vericiguat: resting systolic blood pressure <100 mmHg, severe renal impairment (estimated glomerular filtration rate <15mL/min), severe hepatic impairment. |
| 5. Known hypersensitivity to the active substance or to any of the excipients (microcrystalline cellulose, croscarmellose sodium, hypromellose 2910, lactose monohydrate, magnesium stearate, and sodium laurilsulfate). |
| 6. Concomitant use of other soluble guanylate cyclase (sGC) stimulators, such as riociguat. |
| 7. Concomitant use PDE5 inhibitors, such as sildenafil. |
| 8. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. |
| 9. Patients who are pregnant or nursing and those who plan pregnancy in the period up to 1 mo after the study. |
| 10. Patients with a limited life expectancy less than 1 y. |
| 11. Patients unable to provide written informed consent or are otherwise not suitable for inclusion according to the investigator. |
Enrolment and randomization
All patients meeting the study criteria are invited to participate. After providing written informed consent, patients are randomized in a 1:1 ratio to placebo treatment first, followed by vericiguat treatment, or vericiguat treatment first, followed by placebo treatment. Randomization is performed using a web-based system (Castor Electronic Data Capture, Amsterdam, The Netherlands). The randomization allocation is only accessible to the trial pharmacy distributing the medication, located at Amsterdam UMC, while the rest of the research team and the treating physician remain blinded to the study allocation. The randomization allocation is stratified for sex and type of coronary vasospasm (epicardial, microvascular, or a combination of both).
Treatment
Figure 2 shows the study flowchart. After randomization, the starting dose of 2.5 mg vericiguat or placebo is provided for 2 weeks as add-on to the current medication regime. Treatment will be uptitrated provided that the patient’s mean sitting systolic blood pressure permits this adjustment (systolic blood pressure ≥100 mmHg). The first uptitration to 5 mg will occur at 14 ± 4 days after randomization, and the second uptitration to the target dose of 10 mg will occur at 28 ± 4 days after randomization. The target dose will be maintained for a total of 6 weeks until end point assessment scheduled at 70 ± 4 days. Following end point assessments, a 2-week washout period occurs after which patients cross over to the next study phase, depending on the concealed randomization sequence. Matching placebo is uptitrated in the same manner to maintain blinding.
Study flowchart.
Peripheral microvascular function testing
Peripheral microvascular function testing for the assessment of systemic endothelial function and vasodilation will be performed with the techniques described below. Baseline measurements will be performed at the baseline visit, before study medication intake.
Laser speckle contrast imaging (LASCA)
Microvascular reactivity is measured by iontophoresis of vasoactive agents during continuous monitoring using a laser speckle contrast imaging system (PeriCam PSI, Perimed, Järfälla, Sweden). This noninvasive optical imaging technique projects coherent laser light onto the skin surface and records the resulting speckle pattern. Movement of red blood cells within the skin microcirculation causes fluctuations in the recorded speckle pattern, which is quantified to provide a relative index of microvascular perfusion. Measurements are performed under standardized conditions to minimize motion artefacts and ensure comparability across participants. A dedicated iontophoresis electrode chamber (PeriIont, Perimed, Järfälla, Sweden) is attached to the forearm skin and a dispersive electrode is placed nearby to complete the electrical circuit. This creates an electric field that propels the vasoactive drugs into the skin and allows precise and controlled delivery of vasoactive drugs. Using this technique, laser speckle contrast imaging is performed throughout the application of acetylcholine and insulin to study endothelium-dependent vasodilatation, and nitroprusside to study endothelium-independent vasodilatation (see Figure 3 ). The system therefore allows for simultaneous quantification of these 3 microvascular responses, enabling comprehensive noninvasive evaluation of endothelial function with good reproducibility. Both PeriCam and PeriIont are CE-marked medical devices (certification numbers: 4131087 and 41310877-01) and are used according to their intended purpose. Dedicated software (PIMSoft, Perimed, Järfälla, Sweden) is used to analyze the images. The results of the pharmacological test are expressed both as peak values, representing the maximal vasodilation observed in response to acetylcholine, insulin, and nitroprusside, and as the area under the vasodilation curve for each of the drugs. The measurements of skin blood flow will be divided by mean arterial pressure to provide cutaneous vascular conductance. Previous studies using laser speckle contrast imaging have demonstrated that this technique can assess microvascular function in patients with ANOCA, particularly those with coronary vasospasm, as well as in patients with heart failure with preserved ejection fraction. ,, Furthermore, a prior in vitro wire myography study showed that patients with coronary vasospasm exhibit impaired peripheral vasorelaxation in response to acetylcholine. Together, these findings support our hypothesis that patients with coronary vasospasm also exhibit peripheral endothelial dysfunction, which can be assessed noninvasively using LASCA.
Schematic representation of the LASCA measurements.
Using iontophoresis, various stimuli (acetylcholine, nitroprusside, and insulin) are administered to the skin on the ventral side of the forearm. The PeriCam PSI imaging system then monitors the real-time movement of erythrocyte flow within the cutaneous microcirculation. This is achieved by illuminating the skin with an infrared laser, which produces backscattered light that forms a speckle pattern, captured by the PeriCam camera. This figure was created using BioRender. LASCA, laser speckle contrast imaging.
EndoPAT
Microvascular reactivity and systemic endothelial function are further assessed using postocclusive reactive hyperemia. The EndoPAT (Peripheral Artery Tonometer, Itamar Medical, Israel) is a device used to noninvasively assess peripheral microvascular function. This operator-independent device records skin blood flow (peripheral arterial tone, or PAT) signals using plethysmographic probes placed on the index finger of both hands. A baseline flow signal is recorded for 5 minutes, followed by 5 minutes of ischemia induced by brachial artery occlusion with a blood pressure cuff. After cuff deflation, reactive hyperemia occurs. The EndoPAT device then calculates the Reactive Hyperemia Index (RHI), which partially reflects postischemic vasodilation mediated by endothelium-derived NO. RHI is the ratio of postocclusion to preocclusion PAT in the occluded arm, compared to the control arm. A RHI < 1.67 indicates peripheral endothelial dysfunction. ,,
Symptom assessment
To assess the effect of treatment on symptoms, daily angina burden will be recorded using the ORBITA-app (ORBITA Systems Ltd., London, United Kingdom). Using the ORBITA-app, participants record the daily occurrence and severity of angina episodes from 2 weeks prior to randomization until end of study. In addition, participants will be requested to fill out the Seattle Angina Questionnaire, Rose Dyspnea Scale, EQ-5D-5L, and iPCQ and iMCQ questionnaires at baseline and at 10-, 12-, and 22-week follow-up.
Blood sampling
To investigate the systemic exposure to vericiguat and its relationship with treatment effects, the plasma concentrations of vericiguat will be determined at different timepoints throughout the study. Table 2 displays an overview of the sampling timepoints. Determination of the concentration of vericiguat in plasma will be performed at an independent central laboratory (Syneos Health, Montreal, Canada) blinded to treatment allocation. Detailed pharmacokinetic and pharmacodynamics modeling will be performed as a secondary analysis when an overall clinical benefit of vericiguat over placebo is demonstrated.
Table 2
Schedule of events.
| Procedure/test | Screening | Baseline | Uptitration visits | 10-wk follow-up | 12-wk cross-over | 22-wk follow-up | 24-wk study exit |
|---|---|---|---|---|---|---|---|
| Physical assessment and patient interview | |||||||
| General eligibility criteria | ✓ | ✓ | |||||
| Informed consent | ✓ | ||||||
| Medical history | ✓ | ||||||
| Biomarkers (hemoglobin, creatinine, hs-troponin, NT-proBNP, and CRP) and hCG | ✓ | ✓ | ✓ | ||||
| Sitting blood pressure | ✓ | ✓ | ✓ | ✓ | ✓ | ||
| Antianginal medication use | ✓ | ✓ | ✓ | ✓ | ✓ | ✓ | |
| Event assessment | ✓ | ✓ | ✓ | ✓ | ✓ | ||
| Blood samples for vericiguat plasma concentration | ✓ | ✓ | ✓ | ✓ | ✓ | ||
| Noninvasive testing | |||||||
| LASCA | ✓ | ✓ | ✓ | ||||
| EndoPAT | ✓ | ✓ | ✓ | ||||
| Questionnaires | |||||||
| Seattle Angina Questionnaire | ✓ | ✓ | ✓ | ✓ | |||
| Rose Dyspnea Score | ✓ | ✓ | ✓ | ✓ | |||
| EQ-5D-5L | ✓ | ✓ | ✓ | ✓ | |||
| iPCQ and iMCQ | ✓ | ✓ | ✓ | ✓ | |||
| Daily angina documentation through the ORBITA-2 app | ✓ | ||||||
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