ANti-Oxidant in Variant Angina (ANOVA) Trial

Seoul National University Hospital300 enrolled

Overview

Purpose Objectives 1. To evaluate the anti-oxidant effect of long-term Vitamin C+E therapy on coronary vasospasm improvement. 2. To evaluate the anti-oxidant effect of long-term statin therapy on coronary vasospasm improvement. 3. To evaluate the effect of long-term Vitamin C+E and statin therapy on regression of atheroma in target coronary vessels via intravascular ultrasound. 4. To find out the role of vascular endothelium in variant angina via evaluating long-term Vitamin C+E and statin therapy on improvement in vascular endothelial function by assessing brachial arterial expansion capability. 5. To find out the role of vascular endothelium in variant angina via evaluating long-term Vitamin C+E and statin therapy on improvement in arterial stiffness by assessing pulse wave velocity(PWV)

Study Design: Prospective, open label, Four-arm, randomized single-center trial to test the effect long-term Vitamin C+E and Statin therapy on vasospasm improvement and regression of atheroma in patients with variant angina. After provocation test, patients will be classified into three groups.(See below) 1. Negative group : Patients who have symptoms that are consistent with vasospastic angina but only show luminal narrowing less than 50% on coronary angiography during provocation test. 2. Mild Spastic group : Patients who have symptoms that are consistent with vasospastic angina and show luminal narrowing over 50% to less than 90% on coronary angiography during provocation test. 3. Severe Spastic group : Patients who have symptoms that are consistent with vasospastic angina and show luminal narrowing over 90% on coronary angiography during provocation test. In each group (except for patient in Negative group), patients will be randomized in a two by two factorial manner according to the study drug therapy (Vitamin C+E vs. no Vitamin C+E) (Statin vs. no Statin) As a result, patients in each group(except for patient in Negative group) will be randomized to 4 treatment subgroups, which are 1. Control subgroup : Standard medication for Variant angina only 2. Vitamin subgroup : Standard medication + Vitamin C+E 3. Statin subgroup : Standard medication + Statin 4. Dual subgroup : Standard medication + Vitamin C+E + Statin Patients in Negative group will be prescribed only for standard medication for variant angina. Patient Enrollment: Recruiting 300 patients(100 patients for each group, as 25 patients for each subgroups) from September 2014 through February 2021 at single center in Korea(Seoul National University Hospital) Patient Follow-Up: Clinical follow-up will occur at 1, and 6 months, and at 2, 4, and 6 years. Investigator or designee may conduct follow-up as telephone contacts or office visits.

Eligibility

Sex: ALLMin age: 30 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Subject must be at least 30 years of age. 2. Subject is able to verbally confirm understandings of risks, benefits and treatment alternatives of receiving the Vitamin C+E or Statin or Dual, and he/she or his/her legally authorized representative provides written informed consent prior to any study related procedure. 3. Subject must have symptoms that are consistent with vasospastic angina with planned Coronary angiography and Provocation test. Exclusion Criteria: 1. Patient who has organic coronary stenosis in main coronary branch at least 50% luminal narrowing after intracoronary nitroglycerin injection 2. Patient who has continuously taken Vitamin C or Vitamin E or Statin within 3months before Admission 3. Creatinine level ≥ 2.0mg/dL or dependence on dialysis. 4. Severe hepatic dysfunction (AST and ALT: 3 times upper normal reference values). 5. Active Myopathy or elevated Creatine kinase enzyme level (3 times upper normal reference values). 6. History of Severe hepatic dysfunction or Rhabdomyolysis due to statin side effect 7. Female of childbearing potential, unless a recent pregnancy test is negative, who possibly plan to become pregnant any time after enrollment into this study. 8. History of Urolithiasis 9. Non-cardiac co-morbid conditions are present with life expectancy \<1 year or that may result in protocol non-compliance (per site investigator's medical judgment).

Outcomes

Primary Outcomes

Vasospasm at 6months

Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.

Time frame: at 6 months

Vasospasm at 2 years

Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.

Time frame: at 2 years

Vasospasm at 4 years

Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.

Time frame: at 4 years

Vasospasm at 6 years

Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.

Time frame: at 6 years

Secondary Outcomes

Changes from baseline in Vasospasm

Changes of Vasospasm in Control subgroup, Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline vasospasm assessed by provocation test.