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Sponsors and Collaborators: |
Haukeland University Hospital The Research Council of Norway Norwegian Foundation for Health and Rehabilitation Norwegian Heart and Lung Patient Organisation The Royal Norwegian Ministry of Health Locus for Homocysteine and Related Vitamins, University of Bergen, Norway Locus for Cardiac Research, University of Bergen, Norway Foundation to Promote Research into Functional Vitamin B12 Deficiency, Bergen, Norway Alpharma Inc. |
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Information provided by: | Haukeland University Hospital |
ClinicalTrials.gov Identifier: | NCT00354081 |
PURPOSE OF STUDY Observational studies have demonstrated that elevated levels of plasma total homocysteine is a risk factor for cardiovascular disease. The purpose of this trial is to evaluate the clinical effects of homocysteine lowering treatment with B vitamins during 3-5 years follow-up of patients undergoing cardiac catheterization for suspected coronary artery disease (CAD). Special attention will be given to complication rates among patients needing subsequent percutaneous transluminal coronary angioplasty (PCI) or coronary artery by-pass grafting (CABG).
HYPOTHESIS The primary hypothesis of this study is that, among patients with CAD, a daily supplement with B vitamins will reduce the risk for cardiovascular mortality and serious cardiovascular events with at least 20%. The secondary hypothesis of this study is that, among patients with CAD, a daily supplement with B vitamins will reduce the risk for total mortality, coronary events, cerebrovascular events and other cardiovascular events. The hypothesis will be tested for an effect of any of the treatments (folic acid / vitamin B12 or B6), and the effect will be evaluated according to initial total homocysteine levels and B vitamin levels as well as to the change in these levels after 1 and 6 months. The sample size has been calculated to 3088 patients using a two-sided chi-square test with significance 0.05 and at an 80% power level, presumed event rate of 22% over 4 years, and event rate reduction of 20%, adjusted for non-compliance/drop-out of 20%.
STUDY DESIGN This is a controlled, double-blind two-centre trial with 3090 included men and women who underwent coronary angiography at Haukeland University Hospital or Stavanger University Hospital between April 1999 and April 2004. At baseline about 1300 patients underwent PCI and 600 underwent CABG. The patients were randomized into 4 groups in a 2 x 2 factorial design to receive one of the following four treatments: A, folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg per day; B, folic acid 0.8 mg plus vitamin B12 0.4 mg per day; C, vitamin B6 40 mg per day; D, placebo. The active drug and the placebo tablets had identical appearance and taste. Treatment was started as soon as the patients were randomized after the coronary angiography procedure. The patients have been undergoing interviews, clinical examination and blood-sampling at baseline, at follow-up after 1 month and 1 year, and at a final study visit. In addition, information on dietary habits was obtained from 2400 patients at baseline. Among 350 patients that have undergone PCI at baseline, a full clinical examination, blood sampling and repeat coronary angiography to assess re-stenosis has been performed about 9 (6-12) months after the PCI procedure. For these patients, angiograms suitable for quantitative coronary angiography (QCA) analysis have been obtained at the baseline and follow-up invasive procedures.
The follow-up was terminated ahead of schedule in October 2005 due to lack of compliance of the participants caused by media reports from the NORVIT study (NCT00266487) on potential increased cancer risk associated by B vitamin supplementation. The patients had then been followed for 1.5 - 5 years.
STUDY END POINTS Primary clinical endpoints during follow-up are all cause death, non-fatal acute myocardial infarction, acute hospitalization for unstable angina and non-fatal thromboembolic stroke (infarction). Secondary endpoints are fatal and non-fatal acute myocardial infarction (including procedure related myocardial infarction), acute hospitalization for angina, stable angina with angiographic verified progression, myocardial revascularization, fatal and non-fatal thromboembolic stroke.
Condition | Intervention | Phase |
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Coronary Artery Disease Myocardial Infarction Cerebrovascular Stroke |
Drug: folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine) Drug: folic acid, vitamin B12 (cyanocobalamin) Drug: vitamin B6 (pyridoxine) Drug: placebo |
Phase III |
Study Type: | Interventional |
Study Design: | Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efficacy Study |
Official Title: | A Randomised Double Blind Study of the Effects of Homocysteine Lowering Therapy on Mortality and Cardiac Events in Patients Undergoing Coronary Angiography |
Enrollment: | 3096 |
Study Start Date: | April 1999 |
Study Completion Date: | February 2008 |
Primary Completion Date: | June 2007 (Final data collection date for primary outcome measure) |
Arms | Assigned Interventions |
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1: Active Comparator
folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg)
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Drug: folic acid, vitamin B12 (cyanocobalamin), vitamin B6 (pyridoxine)
folic acid 0.8 mg plus vitamin B12 0.4 mg and vitamin B6 40 mg, in a capsule, taken orally once a day
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2: Active Comparator
folic acid (0.8 mg) plus vitamin B12 (0.4 mg)
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Drug: folic acid, vitamin B12 (cyanocobalamin)
folic acid 0.8 mg plus vitamin B12 0.4 mg, in a capsule, taken orally once a day
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3: Active Comparator
vitamin B6 (40 mg)
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Drug: vitamin B6 (pyridoxine)
vitamin B6 40 mg, in a capsule, taken orally once a day
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4: Placebo Comparator
placebo
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Drug: placebo
placebo, in a capsule, taken orally once a day
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Ages Eligible for Study: | 18 Years and older |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
Exclusion Criteria:
Norway | |
Department of Cardiology, Stavanger University Hospital | |
Stavanger, Norway, 4011 | |
Department of Heart Disease, Haukeland University Hospital | |
Bergen, Norway, 5021 |
Principal Investigator: | Ottar Nygård, MD, PhD | Department of Heart Disease, Haukeland University Hospital |
Responsible Party: | Department of Heart Disease, Haukeland University Hospital, Bergen, Norway ( Ottar Nygård, MD, PhD, Project leader ) |
Study ID Numbers: | NSD-14154 |
Study First Received: | July 19, 2006 |
Last Updated: | July 25, 2008 |
ClinicalTrials.gov Identifier: | NCT00354081 |
Health Authority: | Norway: Norwegian Medicines Agency; Norway: Data Inspectorate; Norway: Norwegian Social Science Data Services |
Coronary Artery Disease Myocardial Infarction Cerebrovascular Stroke Homocysteine |
Folic Acid Vitamin B 12 Vitamin B 6 |
Arterial Occlusive Diseases Heart Diseases Cerebral Infarction Myocardial Ischemia Hydroxocobalamin Stroke Vascular Diseases Vitamin B 12 Central Nervous System Diseases Ischemia Arteriosclerosis Brain Diseases |
Cerebrovascular Disorders Vitamin B 6 Folic Acid Coronary Disease Necrosis Brain Ischemia Pyridoxine Brain Infarction Infarction Myocardial Infarction Coronary Artery Disease |
Vitamin B Complex Pathologic Processes Hematinics Therapeutic Uses Growth Substances Vitamins |
Hematologic Agents Physiological Effects of Drugs Nervous System Diseases Cardiovascular Diseases Micronutrients Pharmacologic Actions |