Ignite Creation Date:
2024-05-05 @ 4:56 PM
Last Modification Date:
2024-10-26 @ 9:26 AM
Study NCT ID:
NCT00354081
Status:
COMPLETED
Last Update Posted:
2013-07-12
First Post:
2006-07-19
Brief Title:
WENBIT - Western Norway B Vitamin Intervention Trial
Sponsor:
Haukeland University Hospital
Organization:
Haukeland University Hospital
Study Overview
Official Title:
A Randomised Double Blind Study of the Effects of Homocysteine Lowering Therapy on Mortality and Cardiac Events in Patients Undergoing Coronary Angiography
Status:
COMPLETED
Status Verified Date:
2010-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
WENBIT
Brief Summary:
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 005 and at an 80 power level presumed event rate of 22 over 4 years and event rate reduction of 20 adjusted for non-compliancedrop-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 08 mg plus vitamin B12 04 mg and vitamin B6 40 mg per day B folic acid 08 mg plus vitamin B12 04 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 15 - 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
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 005 and at an 80 power level presumed event rate of 22 over 4 years and event rate reduction of 20 adjusted for non-compliancedrop-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 08 mg plus vitamin B12 04 mg and vitamin B6 40 mg per day B folic acid 08 mg plus vitamin B12 04 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 15 - 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
Detailed Description:
BACKGROUND Coronary artery disease CAD is one of our common diseases and despite the decline in mortality from acute coronary syndromes in the Western world CAD remains the most important cause of death in Norway
HOMOCYSTEINE Homocysteine Hcy is an amino acid and total homocysteine tHcy is the sum of several different forms of Hcy that is present in blood usually measured in serum or plasma A population-based study of plasma tHcy in 18043 individuals in Hordaland Norway demonstrated that plasma tHcy usually is between 5 and 15 micromolL is higher in men than in women and increases with age Nygård et al 1995
FOLIC ACID The most common cause of elevated tHcy is low intake of folic acid a B vitamin that occurs in many fruits vegetables liver products milk and bread Vitamin supplements that are sold without prescription commonly contain folic acid 01 or 02 mg in Norway 04 or 08 mg in other countries In the United States and United Kingdom many food products are fortified with folic acid The Food and Drug administration in the United States has made fortification with folic acid mandatory for some products from 1998 The rationale for this policy is to reduce the occurrence of neural tube defects a class of serious congenital malformations Several studies have also shown a direct relation between serum folic acid and coronary heart disease
MODERATELY ELEVATED tHcy AND CARDIOVASCULAR DISEASE More than twenty retrospective and three prospective studies including two Norwegian Nygård et al 1997 over the past twenty years have demonstrated a relation between tHcy measured in serum or plasma and coronary heart disease peripheral artery disease or stroke Boushey et al 1995 Ueland et al 1992 The meta-analysis performed by Boushey et al Boushey et al 1995 estimated that a 5 micromolL difference in tHcy increase the risk of coronary artery disease with 60 Common causes of moderately elevated tHcy include nutritional deficiency of folic acid vitamin B6 and B12 genetic variation in genes coding key enzymes of the Hcy metabolism eg thermolabile MTHFR and as demonstrated in the Hordaland Homocysteine Study Nygård et al 1995 life-style factors as smoking coffee drinking and exercise
VITAMIN THERAPY A common feature of most individuals with elevated tHcy is responsiveness to folic acid therapy One exception is vitamin B12 deficiency that needs to be corrected with appropriate therapy A recent meta-analysis shows that the mean tHcy lowering effect of folic acid at doses 05-50 mgday is 25 at tHcy levels of 12 micromolL Homocysteine Lowering Trialists Collaboration 1998 1892 The study further shows that the absolute and percentage reduction in tHcy is higher in subjects with higher tHcy levels and particular low folic acid concentrations Moreover additional daily oral therapy with 05 mg B12 seems to have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean dose of 165 mg daily has no effect on basal tHcy levels
RANDOMIZED TRIALS WITH FOLIC ACID There is solid evidence that tHcy is associated with cardiovascular disease We know that tHcy is easily lowered by folic acid in most patients but we cannot know that folic acid will prevent cardiovascular disease or complications of such disease until randomized double-blind trials are carried out The only possible problem with folic acid is that it may correct the anemia but not the neuropathy of vitamin B12 deficiency This necessitates careful screening for B12 deficiency or combining folic acid with B12 in a sufficient oral dose to treat an occasional pernicious anemia
RANDOMIZED TRIALS WITH VITAMIN B6 Data from several studies show that inappropriate vitamin B6 status is a strong risk factor for cardiovascular disease and that this increased risk probably is independent of tHcy levels Thus commonly applied tHcy lowering regimens combining folic acid and vitamin B6 can not be applied to test the homocysteine theory of atherosclerosis
HOMOCYSTEINE AND VITAMIN MEASUREMENTS Determination of tHcy and associated amino acids and B vitamins will be performed at the Department of Pharmacology of the University of Bergen These analyses will be done on all patients at randomization and at follow-up after 1 month and 1 year and will both serve as monitoring of compliance and also give the possibility to relate clinical events to for example the amount of reduction in plasma tHcy
STEERING COMITTEE
Professor Jan Erik Nordrehaug Chief of the Department of Heart Disease Haukeland University Hospital
Professors Helga Refsum Per Magne Ueland and Stein Emil Vollset at Locus of Homocysteine and Related B vitamins University of Bergen
Professor Ottar Nygård Department of Heart Disease Haukeland University Hospital and Locus of Homocysteine and Related B vitamins
Professor Dennis W Nilsen Section of Heart Disease Stavanger University Hospital
DATA OWNERSHIP AND PUBLICATION OF RESULTS All data collected specifically for the study are owned by WENBIT Data that are already recorded according to routine procedures at the participating centers are owned by the center or department delivering the data and by WENBIT The WENBIT Steering Committee has the disposal of all data registered in the WENBIT database and any use of these data including the preparation and publication of scientific reports must be approved by The Steering Committee Scientific articles will be published by WENBIT or by authors mentioned by name The author sequence should be approved by the Steering Committee and based upon contribution Incentives to involve articles as part of doctoral thesis should be encouraged All collaborators of the study will be mentioned by name in an Appendix section of the main article from the study The results will be published in peer-reviewed scientific journals and in magazines for the general public
LITERATURE
Boushey CJ Beresford SAA Omenn GS Motulsky AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease Probable benefits of increasing folic acid intakes JAMA 19952741049-1057
NORVIT Protocol September 1998 Institute of Community Medicine University of Tromsø Norway
Nygård O Nordrehaug JE Refsum H Farstad M Ueland PM Vollset SE Plasma homocysteine levels and mortality in patients with coronary artery disease N Engl J Med 1997337230-236
Nygård O Vollset SE Refsum H Stensvold I Tverdal A Nordrehaug JE et al Total plasma homocysteine and cardiovascular risk profile The Hordaland Homocysteine Study JAMA 19952741526-1533
Ueland PM Refsum H Brattström L Plasma homocysteine and cardiovascular disease In Francis RBJ ed Atherosclerotic Cardiovascular Disease Hemostasis and Endothelial Function New York Marcel Dekker inc 1992183-236
HOMOCYSTEINE Homocysteine Hcy is an amino acid and total homocysteine tHcy is the sum of several different forms of Hcy that is present in blood usually measured in serum or plasma A population-based study of plasma tHcy in 18043 individuals in Hordaland Norway demonstrated that plasma tHcy usually is between 5 and 15 micromolL is higher in men than in women and increases with age Nygård et al 1995
FOLIC ACID The most common cause of elevated tHcy is low intake of folic acid a B vitamin that occurs in many fruits vegetables liver products milk and bread Vitamin supplements that are sold without prescription commonly contain folic acid 01 or 02 mg in Norway 04 or 08 mg in other countries In the United States and United Kingdom many food products are fortified with folic acid The Food and Drug administration in the United States has made fortification with folic acid mandatory for some products from 1998 The rationale for this policy is to reduce the occurrence of neural tube defects a class of serious congenital malformations Several studies have also shown a direct relation between serum folic acid and coronary heart disease
MODERATELY ELEVATED tHcy AND CARDIOVASCULAR DISEASE More than twenty retrospective and three prospective studies including two Norwegian Nygård et al 1997 over the past twenty years have demonstrated a relation between tHcy measured in serum or plasma and coronary heart disease peripheral artery disease or stroke Boushey et al 1995 Ueland et al 1992 The meta-analysis performed by Boushey et al Boushey et al 1995 estimated that a 5 micromolL difference in tHcy increase the risk of coronary artery disease with 60 Common causes of moderately elevated tHcy include nutritional deficiency of folic acid vitamin B6 and B12 genetic variation in genes coding key enzymes of the Hcy metabolism eg thermolabile MTHFR and as demonstrated in the Hordaland Homocysteine Study Nygård et al 1995 life-style factors as smoking coffee drinking and exercise
VITAMIN THERAPY A common feature of most individuals with elevated tHcy is responsiveness to folic acid therapy One exception is vitamin B12 deficiency that needs to be corrected with appropriate therapy A recent meta-analysis shows that the mean tHcy lowering effect of folic acid at doses 05-50 mgday is 25 at tHcy levels of 12 micromolL Homocysteine Lowering Trialists Collaboration 1998 1892 The study further shows that the absolute and percentage reduction in tHcy is higher in subjects with higher tHcy levels and particular low folic acid concentrations Moreover additional daily oral therapy with 05 mg B12 seems to have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean dose of 165 mg daily has no effect on basal tHcy levels
RANDOMIZED TRIALS WITH FOLIC ACID There is solid evidence that tHcy is associated with cardiovascular disease We know that tHcy is easily lowered by folic acid in most patients but we cannot know that folic acid will prevent cardiovascular disease or complications of such disease until randomized double-blind trials are carried out The only possible problem with folic acid is that it may correct the anemia but not the neuropathy of vitamin B12 deficiency This necessitates careful screening for B12 deficiency or combining folic acid with B12 in a sufficient oral dose to treat an occasional pernicious anemia
RANDOMIZED TRIALS WITH VITAMIN B6 Data from several studies show that inappropriate vitamin B6 status is a strong risk factor for cardiovascular disease and that this increased risk probably is independent of tHcy levels Thus commonly applied tHcy lowering regimens combining folic acid and vitamin B6 can not be applied to test the homocysteine theory of atherosclerosis
HOMOCYSTEINE AND VITAMIN MEASUREMENTS Determination of tHcy and associated amino acids and B vitamins will be performed at the Department of Pharmacology of the University of Bergen These analyses will be done on all patients at randomization and at follow-up after 1 month and 1 year and will both serve as monitoring of compliance and also give the possibility to relate clinical events to for example the amount of reduction in plasma tHcy
STEERING COMITTEE
Professor Jan Erik Nordrehaug Chief of the Department of Heart Disease Haukeland University Hospital
Professors Helga Refsum Per Magne Ueland and Stein Emil Vollset at Locus of Homocysteine and Related B vitamins University of Bergen
Professor Ottar Nygård Department of Heart Disease Haukeland University Hospital and Locus of Homocysteine and Related B vitamins
Professor Dennis W Nilsen Section of Heart Disease Stavanger University Hospital
DATA OWNERSHIP AND PUBLICATION OF RESULTS All data collected specifically for the study are owned by WENBIT Data that are already recorded according to routine procedures at the participating centers are owned by the center or department delivering the data and by WENBIT The WENBIT Steering Committee has the disposal of all data registered in the WENBIT database and any use of these data including the preparation and publication of scientific reports must be approved by The Steering Committee Scientific articles will be published by WENBIT or by authors mentioned by name The author sequence should be approved by the Steering Committee and based upon contribution Incentives to involve articles as part of doctoral thesis should be encouraged All collaborators of the study will be mentioned by name in an Appendix section of the main article from the study The results will be published in peer-reviewed scientific journals and in magazines for the general public
LITERATURE
Boushey CJ Beresford SAA Omenn GS Motulsky AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease Probable benefits of increasing folic acid intakes JAMA 19952741049-1057
NORVIT Protocol September 1998 Institute of Community Medicine University of Tromsø Norway
Nygård O Nordrehaug JE Refsum H Farstad M Ueland PM Vollset SE Plasma homocysteine levels and mortality in patients with coronary artery disease N Engl J Med 1997337230-236
Nygård O Vollset SE Refsum H Stensvold I Tverdal A Nordrehaug JE et al Total plasma homocysteine and cardiovascular risk profile The Hordaland Homocysteine Study JAMA 19952741526-1533
Ueland PM Refsum H Brattström L Plasma homocysteine and cardiovascular disease In Francis RBJ ed Atherosclerotic Cardiovascular Disease Hemostasis and Endothelial Function New York Marcel Dekker inc 1992183-236
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None