We reviewed homocysteine-lowering interventions for preventing cardiovascular events.
Cardiovascular disease is the number one cause of death worldwide. The most common causes of cardiovascular disease leading to both morbidity and mortality are ischaemic heart disease, stroke and congestive heart failure. Many people with cardiovascular diseases may be asymptomatic, but may have a high risk of developing myocardial infarction, angina pectoris or stroke (ischaemic, haemorrhagic or both). 'Emergent' or new risk factors for cardiovascular disease have recently been added to the established risk factors (which are diabetes mellitus, high blood pressure, active smoking and an adverse blood lipid profile). One of these risk factors is elevated circulating total homocysteine levels. Homocysteine is an amino acid and its levels in the blood are influenced by blood levels of B-complex vitamins: cyanocobalamin (B12), folic acid (B9) and pyridoxine (B6). High plasma total homocysteine levels are associated with an increased risk of atherosclerotic diseases (where there is a build-up of plaque in the arteries).
In this second update, we included 12 studies involving 47,429 participants living in countries with or without mandatory fortification of foods. These studies compared different regimens of B-complex vitamins (cyanocobalamin (B12), folic acid (B9) and pyridoxine (B6)) with a control or any other comparison. The studies were published between 2002 and 2010.
We found no evidence that homocysteine-lowering interventions, in the form of supplements of vitamins B6, B9 or B12 given alone or in combination, at any dosage compared with placebo or standard care, prevent myocardial infarction or stroke, or reduce total mortality in participants at risk of or with established cardiovascular disease. Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer).
Quality of evidence
Our confidence in the results of this review is high because the included trials we synthesised were of high quality and conducted with a large number of participants.
This second update of this Cochrane Review found no evidence to suggest that homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination should be used for preventing cardiovascular events. Furthermore, there is no evidence to suggest that homocysteine-lowering interventions are associated with an increased risk of cancer.
Cardiovascular disease, which includes coronary artery disease, stroke and congestive heart failure, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor is an elevated circulating total homocysteine level, which is associated with cardiovascular events. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events. This is an update of a review previously published in 2009 and 2013.
To determine whether homocysteine-lowering interventions, provided in patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as all-cause mortality and evaluate their safety.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 1), MEDLINE (1950 to January week 5 2014), EMBASE (1980 to 2014 week 6) and LILACS (1986 to February 2014). We also searched Web of Science (1970 to 7 February 2014). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search.
We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease.
We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I2 statistic. We used a random-effects model.
In this second updated Cochrane Review, we identified no new randomised controlled trials. Therefore, this new version includes 12 randomised controlled trials involving 47,429 participants. In general terms, 75% (9/12) trials had a low risk of bias. Homocysteine-lowering interventions compared with placebo did not significantly affect non-fatal or fatal myocardial infarction (1743/23,590 (7.38%) versus 1247/20,190 (6.17%); RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, high quality evidence), stroke (968/22,348 (4.33%) versus 974/18,957 (5.13%); RR 0.91, 95% CI 0.82 to 1.0, I2 = 11%, high quality evidence) or death from any cause (2784/22,648 (12.29%) versus 2502/19,250 (10.64%); RR 1.01, 95% CI 0.96 to 1.07, I2 = 6%, high quality evidence). Homocysteine-lowering interventions compared with placebo did not significantly affect serious adverse events (cancer) (1558/18,130 (8.59%) versus 1334/14,739 (9.05%); RR 1.06, 95% CI 0.98 to 1.13; I2 = 0%, high quality evidence).