The primary objective of the VERA trial (trialregister.nl, Identifier: NL7546) is to assess whether the ETA receptor antagonist macitentan at a dose of 10 mg once daily will reduce the frequency and severity of anginal complaints in patients diagnosed with VSA due to epicardial spasm or MVA due to microvascular spasm (i.e. functional CMD), together defined as coronary artery spasm (CAS).
This proof-of-concept study with a prospective, randomized, double-blind, placebo-controlled, sequential cross-over design will include multiple centers in the Netherlands (Amsterdam University Medical Centers, Radboud University Medical Center, HeartLife Clinics). A total of 30 symptomatic participants with CAS despite background anti-anginal therapy (at least treatment with CCB and/or long-acting nitrates, angiotensin converting enzyme inhibitors or angiotensin receptor antagonists) will be included. Participants will be randomized to double-blind treatment with either 10 mg of macitentan once daily for 4 weeks, and subsequently placebo for 4 weeks, or vice versa. In between treatment with macitentan or placebo, there is a 2-week wash-out period. (Fig. 1.)
A potential candidate will be identified at the outpatient clinic and have had invasive coronary vasomotor function testing to diagnose VSA due to epicardial vasospasm or MVA due to microvascular spasm as per the COVADIS guidelines (Table 1). For MVA patients, only those with evidence of microvascular spasm defined as coronary microvascular spasm, defined as reproduction of symptoms, ischemic ECG shifts but no epicardial spasm during ACh testing (Table 1. MVA criteria: 4b) will be included. The diagnostic classification of VSA and MVA are endorsed by the European Society of Cardiology practice guidelines of 2019 . Other inclusion criteria are: (1) age ≥ 18 and < 75 years old; (2) absence of significant obstructive coronary artery disease (defined as stenosis > 50% in an epicardial coronary artery) documented by invasive coronary angiography; (3) persistent anginal complaints with a frequency of at least 3 times per week despite anti-anginal treatment; (4) anginal complaints for at least 3 months despite optimal anti-anginal treatment, which is at the discretion of the treating cardiologist; (5) able to comply with the study procedures; (6) able to provide written informed consent. The exclusion criteria are listed in Table 2. MVA patients who meet the MVA criteria 4a, b or d (see Table 1) will be excluded as they are diagnosed with structural CMD.
The primary endpoint of the VERA trial is to determine whether the macitentan reduces the burden of anginal symptoms in patients with CAS, calculated as:
- The frequency of angina attacks * severity (on a VAS scale 1-10) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication.
- The duration (in minutes) * severity (on a Visual Analogue Scale (VAS) pain scale 1-10) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication.
The VAS score is widely used to measure pain intensity and has been found to be valid, reliable and appropriate for use in clinical practice, using black lines and a numeric scale .
The pre-specified secondary efficacy endpoints include (1) incidence and severity of angina complaints as obtained on a weekly basis by the Seattle Angina Questionnaire (SAQ) during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication, and (2) patients reported outcomes measures (PROMS) via an angina diary. The SAQ is a valid and reliable, disease-specific 19-item self-administered questionnaire that quantifies the physical limitation caused by angina, the frequency of angina, treatment satisfaction, and subjective perception of quality of life . The SAQ is sensitive to subtle clinical change, as seen among outpatients treated with pharmacotherapy as well as in patients with VSA and MVA [20,21]. SAQ scores are independently associated with hospitalization and mortality [22–24]. In the angina diary patients are asked to report on a daily basis the frequency, duration, and severity (on a VAS scale 1-10) of angina episodes, as well as under which circumstances the complaints developed, and use of sublingual nitroglycerin tablets or sprays.
The pre-specified secondary safety outcomes include (1) detrimental changes in physical, laboratory or ECG parameters during medication use (macitentan or placebo) up to 2 weeks after discontinuation of the study medication, and (2) the occurrence of adverse events (i.e. hospitalization for anginal symptoms and/or myocardial infarction) during the study period. All possible side effects associated with macitentan will be recorded during the study period.
Randomization will occur during visit 2, but only if they have experienced anginal complaints during the run-in period of 4 weeks on background anti-anginal therapy. Randomization will be performed using a computerized randomization tool. Eligible and consenting patients will be randomized with equal probability to the two groups reflecting the sequential order of macitentan or placebo in Phase 1 and Phase 2, respectively: Group 1 = macitentan in Phase 1 then placebo in Phase 2; Group 2 = placebo in Phase 1 then macitentan in Phase 2.
Study Visit and Follow-up
The study visits are shown in Fig. 1. After obtaining informed consent, during visit 1, we check the inclusion and exclusion criteria and collect baseline information (including pharmacological therapy, clinical examination and laboratory measurements). Visit 2 takes place after 4 weeks of background anti-anginal therapy (at least treatment with CCB and/or long-acting nitrates, angiotensin converting enzyme inhibitors or angiotensin receptor antagonists). Symptomatic participants, despite background anti-anginal therapy, will be randomized to double-blinded treatment with either 10 mg of macitentan once daily for 4 weeks. Visit 3 takes place after 8 weeks: after 4 weeks of study medication (macitentan or placebo); visit 4 takes place after 10 weeks: after 2 weeks wash-out, cross-over of treatment allocation; visit 5 takes place at 14 weeks: after 4 weeks study medication (macitentan or placebo); and visit 6 takes place at 16 weeks: after 2 weeks wash-out, end of the study. At visit 3, 4, 5 and 6 the patient’s well-being and the occurrence of adverse events (including hospitalization) are assessed. At visit 3 and 5 a blood sample is drawn and analyzed to check haemoglobin, haematocrit, erythrocytes, leucocyte, thrombocytes, sodium, potassium, high-sensitive troponin T, creatinine, urea, ALAT, ASAT, gamma-GT and AF, bilirubin, and NT-proBNP.
Sample Size Determination and Statistical Analysis
The VERA trial is a crossover trial design in which each patient will serve as his/her own control thus controlling for confounding variables (e.g., age and sex) requiring a lower sample size than parallel-group trials to meet the same criteria in terms of type I and type II error risks. As this is a proof-of-concept study no formal sample size calculation is performed. In this study, we aim to include 30 patients.
Analyses will be done by intention-to-treat and on-treatment principle. Descriptive data are summarized as numbers with percentages for categorical variables, as mean with standard deviation for continuous variables with normal distribution and as median with (interquartile) range for continuous data with skewed distribution. Potential imbalances in protocol violation, lost-to-follow-up are evaluated with a Student independent T test, or a Chi-Square test if appropriate. The level of significance to be used for tests will be 0.05.
Study administration and Management
The trial is registered as trialregister.nl, Identifier: NL7546. The VERA trial is approved by the Dutch Medical Ethics Committee of the Amsterdam University Medical Centers (Reference 2018_213). The VERA trial is an investigator-initiated clinical trial. Actelion Pharmaceuticals Nederland B.V. has provided the investigational medicinal product. Actelion Pharmaceuticals reviewed and approved the protocol. The company did not have any role in the conduct of the trial, analysis of the data, or publication of the results.
An independent Data Safety Monitoring Board (DSMB) including two independent medical experts (one interventional cardiologist and one general cardiologist) and a statistician is established to assure the safety of participants in this trial. The DSMB will review the trial for safety and overall trial conduct. At the end of the trial, the DSMB may adjudicate final outcome based on clinical information.
Since the trial is a crossover proof-of-concept trial, and is not designed to assess between-group differences in clinical endpoints, a Clinical Event Committee is not required. The trial management team is solely responsible for the design and conduct of this trial, all study analyses, the drafting and editing of the manuscript and its final content. Monitoring of the trial will be performed by an independent Clinical Research Unit with Clinical Research Associates.
The study is currently ongoing and recruited 17 patients. Patient mean (SD) age is 55.5 (8.5) years, 82% are female, and 8 have VSA whereas 9 have MVA due to microvascular spasm. Due to SARS-COVID19 inclusion of participants was temporarily halted between February 2020 and August 2020.