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Effect of homocysteine lowering by B vitamins on cardiovascular risk

Despite the significant association between HHCY and cardiovascular risk an important piece of the causality chain remains to be answered, whether the reduction of cardiovascular risk after B vitamin supplementation is effective. Worldwide more than 50,000 cardiovascular patients have been included in in secondary prevention trial with B vitamins supplementation in order to clarify whether B vitamins supplementation is accompanied by lowering of disease risk. However secondary prevention trials have in relation to their clinical validity important limitations, which are based on the fact that these patients have a basic medication, which is necessary to treat their diseases. Therefore is hard to show an additional effect of homocysteine lowering by B vitamins supplementation on the patient’s cardiovascular outcome. A sufficient clinical power is, therefore, only reached in large meta-analysis, including a high number of clinical studies with a large number of patients. Most of these studies had been finished and are already published (1-3).

The meta-analysis by Wald et al. (4) includes data from 75 clinical studies (22,068 patients and 23,618 controls) investigating the relation between tHcy plasma concentration and cardiovascular risk as well as 14 therapeutic studies with cardiovascular patients where B vitamins were administered in order to lower homocysteine. At the end it has been shown an independent and significant association between plasma tHcy and the risk for ischemic heart and circulatory diseases. Subjects who were carriers of the so-called MTHFR-TT genotype had compared the MTHFR-CC genotype (wild type) a significant higher plasma tHcy and a 16% increased cardiovascular risk whereby the difference in plasma tHcy between TT and CC genotype yielded in average 1.9 μmol/L. Furthermore, the meta-analysis by Zhang et al. (3) which included 57,953 subjects from 12 primary and 12 secondary prevention trials reported that B vitamins supplementation does not lead to a risk reduction in cardiac events, total mortality, sudden heart death, myocardial infarction or stroke. In the meta-analysis by Wald including 14 therapeutic studies, despite a tHcy lowering by B vitamins by 3.3 μmol/L, over all studies no effect on cardiovascular risk was observed (4). In most of the studies the daily B vitamins supplementation ranged between 0.8 - 2.5 mg FA, 0.4 - 1.0 mg vitamin B12 and 25 – 50 mg vitamin B6 and the intervention was between two and five years. However, a subgroup analysis found that the tHcy lowering in patients with low dose aspirin intake (platelet aggregation inhibitor) was associated with lowering in cardiovascular risk by 7%. This was not the case in patients taking high dose aspirin. Therefore, it has been concluded that B vitamins supplementation in primary prevention, where no regular aspirin use takes place, contributes to the lowering of cardiovascular risk. Contrary, in secondary prevention where aspirin is routinely prescribed, no risk reduction can be expected (4).

B vitamins, homocysteine, and stroke risk

HHCY is often seen in stroke patients. Silent brain infarction and brain atrophy are also associated with high tHcy and low B vitamin status (5;6). The incidence of silent brain infarction increases significantly with age and studies on elderly subjects with such lesions reported compared with subjects without silent brain infarction a higher plasma tHcy level (6). Data from the Rotterdam study show that per 1 μmol/L increase in tHcy concentration the stroke risk increases by 6 to 7% (7) . In the “Physicians Health Study” the stroke in subjects having tHcy >12.7 μmol/L was compared with subjects having lower plasma tHcy moderately elevated (1.4 fold) (8). Similar results were obtained from the “Northern Manhattan Study” where the adjusted Hazard Ratio for ischemic stroke at a plasma tHcy level >15 μmol/L compared with <10 μmol/L was double as high (9). The “Third National Health and Nutrition Examination Survey” reported that subjects within the fourth tHcy quartile had compared with the lower quartiles an adjusted Odds ratio (OR) for stroke of 2.3 (95% CI = 1.2 – 2.6) (10). Another publication of the Rotterdam study described a significant and independent association between plasma tHcy concentration and brain white matter lesions proven by MRI (11). These lesions represent usually intracranial diseases of small vessels causing small area of ischemic demyelination.

A meta-analysis of retro- as well as prospective studies found out that a lowering of tHcy plasma level by 3 µmol/L would be associated with a lowering of stroke risk by 24% (12). Another meta-analysis of eight randomized secondary prevention studies with 16,841 patients did investigate whether B vitamin supplementation (FA, vitamin B6 and / or vitamin B12) influence the stroke risk (13). FA supplementation lowered the stroke risk by 18% and the effect was even stronger when the period of supplementation exceeded 3 years (risk reduction 29%), when plasma tHcy was lowered more than 20% (risk reduction 23% or when patients came from countries without mandatory FA fortification of basic food (risk reduction 25%). It is concluded that FA fortification may lower the stroke risk. A further meta-analysis dealing with the efficiency of tHcy lowering in relation to stroke risk included 39,005 patients from 13 randomized and controlled clinical trials. Altogether mild stroke prevention had been observed. Additionally those studies with non-secondary prevention showed an significant stroke risk reduction by 11% (RR 0.89; CI 0.79 – 0.99; p = 0.03). By means of stratified analysis was figured out that the utility was higher in those studies that administered a combination of FA with vitamin B6 and vitamin B12 (RR 0.83; 95% CI = 0.71 – 0.91; p = 0.02) and also in studies that had included an over-proportional rate of males, reduction of stroke risk by 16%. The authors of this meta-analysis concluded that FA has a mild effect in relation to stroke prevention and that the supplementation is more effective when male subjects are supplemented with a combination of FA with vitamin B6 and vitamin B12. However Zhang et al. (3) could not observe in his meta-analysis, which included 57,953 patients from 12 primary and 12 secondary prevention trials that B vitamin supplementation lowers the stroke risk.

A recent large Chinese study investigated the efficacy of folic therapy in primary prevention of stroke among adults with hypertension (14). The study with duration of 4.5 years was divided into two arms; in one arm 10,348 hypertensive patients were daily treated with Enalapril plus 0.8 mg FA, in the control arm 10.354 patients were treated with Enalapril only. The FA group showed compared with controls after a follow up period of 4.5 years a significantly decreased stroke risk by 20%. Furthermore, the HOPE-2 study reported in patients with vascular diseases or diabetes mellitus that daily supplements containing FA (2.5 mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) over a period of 5 years reduced the stroke risk by 25% (15). The efficacy of the vitamin supplements was even larger in subjects with certain risk profiles or medications. A significant risk reduction was seen only when the treatment period exceeded three years. However patients under therapy with platelet aggregation inhibitors or with cholesterol lowering drugs or patients coming from regions where FA fortification of basic food has been introduced did profit from B vitamins supplements. Investigations utilizing MRI showed that the reduction of plasma tHcy by B vitamin supplements was associated with moderate improvements of cerebrovascular and cerebral indices (16).

Since the FA fortification of grain products introduced nationwide in the US and Canada in 1998 the stroke incidence declined significantly (17). Since then the US have annually about 13,000 less people dying from stroke which corresponds to a 10% lowering of stroke mortality. The decline in stroke mortality correlates with the decrease of plasma tHcy and is seen as causal association.


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