ANti-Oxidant in Variant Angina (ANOVA) Trial

Effects of Long-term Vitamin C+E and Statin Therapy on Vasospasm Improvement and Regression of Atheroma in Patients With Variant Angina

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 Overview

• Status: Terminated
• Conditions: Variant Angina
• Intervention / Treatment: Drug: Vitamin C and Vitamin E; Drug: Statin; Drug: Standard medication for variant angina

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 4

Contacts and Locations

Study Locations

• South Korea
  • Seoul, South Korea
    • Seoul National University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dual subgroup; Standard medication for variant angina plus Vitamin C+E plus Statin Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU Statin : Atorvastatin calcium 10mg	Drug: Vitamin C and Vitamin E; Ascorbic acid Tablet 1g and Tocopherol Capsule 400IU; Other Names: Ascorbic acid and Tocopherol; Drug: Statin; Atorvastatin calcium 10mg; Other Names: Atorvastatin; Drug: Standard medication for variant angina; Calcium Channel blocker or NG; Other Names: Calcium Channel blocker or NG
Experimental: Statin subgroup; Standard medication for variant angina plus Statin Statin : Atorvastatin calcium 10mg	Drug: Statin; Atorvastatin calcium 10mg; Other Names: Atorvastatin; Drug: Standard medication for variant angina; Calcium Channel blocker or NG; Other Names: Calcium Channel blocker or NG
Experimental: Vitamin subgroup; Standard medication for variant angina plus Vitamin C+E Vitamin C and Vitamin E : Ascorbic acid Tablet 1g / Tocopherol Capsule 400IU	Drug: Vitamin C and Vitamin E; Ascorbic acid Tablet 1g and Tocopherol Capsule 400IU; Other Names: Ascorbic acid and Tocopherol; Drug: Standard medication for variant angina; Calcium Channel blocker or NG; Other Names: Calcium Channel blocker or NG
Active Comparator: Control group; Control subgroup : Standard medication for Variant angina only	Drug: Standard medication for variant angina; Calcium Channel blocker or NG; Other Names: Calcium Channel blocker or NG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vasospasm at 6months	Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.	at 6 months
Vasospasm at 2 years	Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.	at 2 years
Vasospasm at 4 years	Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.	at 4 years
Vasospasm at 6 years	Severity of vasospasm in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup.	at 6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	at 6 months, and at 2, 4, and 6 years follow up period
Composed improvement of Vascular endothelial function(Brachial arterial expansion capability)	in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup	at 6 months, and at 2, 4, and 6 years follow up period
Improvement of Vascular endothelial function(Brachial arterial expansion capability)	in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results	at 6 months, and at 2, 4, and 6 years follow up period
Comparative analysis of improvement of Vascular endothelial function(Brachial arterial expansion capability)	in Vitamin subgroup, Statin subgroup, and Dual subgroup	at 6 months, and at 2, 4, and 6 years follow up period
Composed improvement of Arterial stiffness(Pulse wave velocity(PWV))	in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to control subgroup	at 6 months, and at 2, 4, and 6 years follow up period
Improvement of Arterial stiffness(Pulse wave velocity(PWV))	in Vitamin subgroup, Statin subgroup, and Dual subgroup compared to baseline endothelial function test results	at 6 months, and at 2, 4, and 6 years follow up period
Comparative analysis of improvement of Arterial stiffness(Pulse wave velocity(PWV))	in Vitamin subgroup, Statin subgroup, and Dual subgroup	at 6 months, and at 2, 4, and 6 years follow up period

Collaborators and Investigators

• Sponsor: Seoul National University Hospital
• Investigators: Principal Investigator: Hyo-Soo Kim, Kim, Seoul National University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2014
• Primary Completion (Actual): June 1, 2024
• Study Completion (Actual): June 1, 2024

Study Registration Dates

• First Submitted: July 19, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 24, 2017

Study Record Updates

• Last Update Posted (Actual): April 27, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Myocardial Ischemia; Chest Pain; Angina Pectoris; Angina, Unstable; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Angina Pectoris, Variant; Calcium-Regulating Hormones and Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Membrane Transport Modulators; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pyrans; Fatty Acids; Lipids; Azoles; Pharmacologic Actions; Chemical Actions and Uses; Therapeutic Uses; Carbohydrates; Sugar Acids; Acids, Acyclic; Carboxylic Acids; Hydroxy Acids; Pyrroles; Heptanoic Acids; Benzopyrans; Cardiovascular Agents; Atorvastatin; Vitamin E; Tocopherols; Ascorbic Acid; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Calcium Channel Blockers
• Other Study ID Numbers: ANOVA

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No