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Homocysteine-lowering Treatment in Reduction of Stroke and Coronary Vascular Risk—Do Not Give Up
disease, 1.60 for thrombosis, and 1.59 for stroke. Furthermore, these
Figure 1: Decrease of Relative Stroke Risk within
meta-analyses suggested that a lowering of tHcy concentration by
Treatment Sub-groups
6
3µmol/l might reduce the risk for ischemic heart disease by 16%, for
1.2
thrombosis by 25%, and for stroke by 24%.
8
1.04
1.00
Can Treating Hyperhomocysteinemia
0.89 0.89
0.82*
Provide Protection Against Stroke and
0.8
0.77** 0.75** 0.75
0.71**
Coronary Vascular Disease?
One prospective study that lasted for more than four years observed
a significant reduction of plaque within the carotid artery
9
owing to 0.4
B-vitamin supplementation. Moreover, a significant reduction of the
carotid intima-media thickness in patients at risk for stroke has
recently been reported after treatment with B vitamins lasting for one
0
year.
10
However, several recent treatment studies could not detect
<36 >36
months months
<20% >20% Yes No Yes No
a benefit for B-vitamin supplementation, thus leaving open
Total Treatment period HCY reduction
Folate-enriched
grain
History of stroke
questions about the repeatedly observed association between HHCY
Treatment 373/8,949 224/4,078 149/4,871 179/2,325 172/4,967 179/2,325 194/6,624 152/1,877 221/7,122
and vascular risk in retrospective and prospective studies.
Control 405/7,892 193/3,015 212/4,877 174/2,180 196/4,051 174/2,180 231/5,712 148/1,853 257/6,039
Notably, available trials have inherent errors and are not optimized to Stroke incidents/number of patients
address the role of tHcy lowering on primary or secondary prevention
*p≤0.005; **p≤0.01.
of CVD.
addition to conventional medication for three years. The tHcy level
It is critically important to review the limitations of the available was lowered significantly—by 28% in the group that received folic
studies before reaching a firm conclusion about the protective effect acid and vitamin B
12
. There was no risk reduction regarding the
of the B vitamins against CVD and stroke. Table 1 lists factors to be end-points (heart attack, stroke). This study did not eliminate
considered when planning or interpreting studies on the effect of numerous possible co-variables that may affect the end-points and
Hcy-lowering treatment on the risk for stroke or coronary vascular potentially mask any therapeutic effect (stroke and myocardial
diseases. One serious problem of available studies is that instead infarction). Obviously, looking at the Kaplan-Meier estimates another
of comparing non-treated with treated patients, the results of weak point of this study is that half of the primary end-points
conventional treatment are compared with the results of conventional occurred in the first half-year of treatment. Thus, patients with
treatment to which vitamins are added. Most of these studies coronary events occurring shortly before the beginning of the study
included patients with several medications that interact with tHcy are not to be taken into account for the outcome of the study.
metabolism or levels. Worldwide, more than 50,000 patients are
currently included in intervention studies in order to determine the The VISP study included 3,860 stroke patients who were treated with
possible benefits of vitamin therapy (secondary prevention). First conventional medication over two years and, additionally, in times of
intervention studies, such as the Vitamin Intervention for Stroke fortification with ‘low or high dosages’ of B vitamins (folic acid: low
200µg, high 2,500µg; vitamin B
12
: low 6µg, high 400µg; vitamin
B
6
: low 0.2mg, high 25mg). The tHcy level decreased by only 2µmol/l
Large meta-analyses of retrospective
in the high-dose therapy group. There was no significant effect on the
end-points (stroke, coronary episodes, or death), even though there
and prospective studies stress the
was a significant link between the baseline tHcy level and these
causal correlation between
end-points. Possible reasons for the lack of therapeutic effect are
folate enrichment in grain products in the US during the study, the
hyperhomocysteinemia and
short observation period, and the fact that vitamin B
12
status and
degenerative (vascular) diseases.
kidney function were not taken into consideration.
The HOPE study included 5,222 patients with vascular disease or
Prevention (VISP),
11
Norwegian Vitamin Trial (NORVIT),
12
Heart diabetes who were treated with B vitamins or placebo over a period
Outcomes Prevention Evaluation-2 Study (HOPE 2),
13
Women’s of five years. In this study, the Hcy plasma level was lowered by 26%.
Antioxidant and Folic Acid Cardiovascular Study (WAFACS),
14
and As a result, it was concluded that a treatment combining folic acid,
Western Norway B-vitamin Intervention Trial (WENBIT)
15
studies, have vitamin B
6
, and vitamin B
12
did not result in a reduction in the number
been completed and published. of severe cardiovascular events in patients with vascular diseases.
Moreover, tHcy levels were assessed in only 581 treated patients and
The NORVIT study included 3,749 patients who had suffered a 588 controls in a consecutive manner, limiting the analysis of
myocardial infarction at most seven days before inclusion in the treatment on tHcy to approximately one-fifth of the cohort; therefore,
study. The patients were treated with B vitamins (divided into four any effect of the B vitamins on tHcy was seen only in these patients.
therapeutic groups or placebo in a two-by-two factorial design) in Furthermore, an increased tHcy concentration was not one of the
US CARDIOLOGY 37
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