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Homocysteine Lowering Therapy in Vascular Disease - No Reduction in Recurrent Events

Tera D. Moore, Pharm.D., BCPS*
May, 2006

The relationship between plasma total homocysteine level as a graded and independent risk factor for coronary heart disease (CHD) and stroke, and the benefit from homocysteine-lowering therapy has been supported by epidemiological and prospective observational studies.1 The Homocysteine Studies Collaboration concluded that a 25% reduction in the homocysteine level (about 3┬Ámol/L [0.4mg/L]) was associated with an 11% reduction in the risk of CHD and a 19% reduction in the risk of stroke.

The Heart Outcomes Prevention Evaluation (HOPE) 2 study evaluated whether prolonged administration of folic acid combined with vitamins B6 and B12 reduces the risk of major vascular events in a high-risk population.2 The 5522 patients consisted of men and women (~71% vs. ~29%) 55 years of age or older with a history of vascular disease (coronary, cerebrovascular, or peripheral vascular) or diabetes. Patients were randomly assigned to receive a combination pill containing 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12 or matching placebo. Average follow-up was five years and 72.1% were from countries with folate fortification, while 27.9% were from countries without folate fortification. Although the mean plasma homocysteine level was substantially reduced in the active group versus placebo, there was no significant difference in the composite primary outcome (death from CV causes, MI, or stroke) or any of the secondary outcomes. There was a significant reduction in stroke, but the authors note that the number of strokes was much lower then the number of coronary events.

The results of HOPE 2 are consistent with the other two trials that prospectively evaluated the effects of homocysteine-lowering therapy on recurrent CV events.3,4 The Norwegion Vitamin (NORVIT) study evaluated 3749 men and women from Norway with an acute myocardial infarction within the previous 7 days. Patients were randomized to one of four daily treatments: folic acid, vitamin B6, vitamin B12; folic acid and vitamin B12; vitamin B6 or placebo. Treatment did not reduce the primary outcome (composite of new nonfatal and fatal MI, nonfatal and fatal stroke, and sudden death attributed to CHD) or secondary outcomes. Similarly, there was no treatment benefit with different daily doses of folic acid, vitamin B6, and vitamin B12 in the Vitamin Intervention for Stroke Prevention (VISP) study that evaluated 3680 patients with a history of stroke.

The outcomes are consistent among these three prospective studies and conclude that the reduction in plasma homocysteine levels does not translate to a significant reduction in recurrent events in patients with established vascular disease. In an accompanying editorial,5 Loscalzo identifies two questions that must be considered based on the results of the recent studies. Does the failure of homocysteine-lowering therapy to reduce the rates of cardiovascular events suggest that the homocysteine hypothesis is incorrect and if homocysteine is an atherogenic determinant, do the results of these trials suggest that vitamin therapy has other, potentially adverse effects that offset its homocysteine-lowering benefit? To answer these questions, further exploration of the relations among the intermediates in the metabolic pathway and their association with atherothrombotic mediators will be needed and we should consider alternative approaches to reducing homocysteine concentrations.5


  1. The Homocysteine Studies Collaboration: Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002;288:2015-22.

  2. The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1567-77.

  3. Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering for the prevention of cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.

  4. Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.

  5. Loscalzo J. Homocysteine trials - clear outcomes for complex reasons. N Engl J Med 2006;354:1629-32.

*Dr. Moore is a guest editor for ClotCare. Dr. Moore is a primary care clinical specialist with the South Texas Veterans Health Care System in San Antonio, TX.

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