A Randomised Double Blind Study of the Effects of Homocysteine Lowering Therapy on Mortality and Cardiac Events in Patients Undergoing ... View Homepage


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Clinical Trial Info

YEARS

1999-2008

ABSTRACT

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. 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 18,043 individuals in Hordaland, Norway demonstrated that plasma tHcy usually is between 5 and 15 micromol/L, 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 (0.1 or 0.2 mg in Norway, 0.4 or 0.8 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 micromol/L 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 (e.g., 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 0.5-5.0 mg/day is 25% at tHcy levels of 12 micromol/L [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 0,5 mg B12 seems to have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean dose of 16,5 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 1995;274:1049-1057. - 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 1997;337:230-236. - 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 1995;274:1526-1533. - 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.; 1992:183-236. More... »

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https://clinicaltrials.gov/show/NCT00354081

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    "description": "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. 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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.\n\nDetailed Description\nBACKGROUND 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 18,043 individuals in Hordaland, Norway demonstrated that plasma tHcy usually is between 5 and 15 micromol/L, is higher in men than in women and increases with age [Nyg\u00e5rd, et al., 1995]. 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MODERATELY ELEVATED tHcy AND CARDIOVASCULAR DISEASE More than twenty retrospective and three prospective studies, including two Norwegian [Nyg\u00e5rd, 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 micromol/L 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 (e.g., thermolabile MTHFR) and, as demonstrated in the Hordaland Homocysteine Study [Nyg\u00e5rd, 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 0.5-5.0 mg/day is 25% at tHcy levels of 12 micromol/L [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 0,5 mg B12 seems to have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean dose of 16,5 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 Nyg\u00e5rd, 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 1995;274:1049-1057. - NORVIT Protocol September 1998, Institute of Community Medicine, University of Troms\u00f8, Norway - Nyg\u00e5rd O, Nordrehaug JE, Refsum H, Farstad M, Ueland PM, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. 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3 schema:description 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. 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 18,043 individuals in Hordaland, Norway demonstrated that plasma tHcy usually is between 5 and 15 micromol/L, 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 (0.1 or 0.2 mg in Norway, 0.4 or 0.8 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 micromol/L 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 (e.g., 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 0.5-5.0 mg/day is 25% at tHcy levels of 12 micromol/L [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 0,5 mg B12 seems to have a small but significant additional tHcy lowering effect whereas vitamin B6 at a mean dose of 16,5 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 1995;274:1049-1057. - 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 1997;337:230-236. - 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 1995;274:1526-1533. - 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.; 1992:183-236.
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