I read with interest the comments by Wald et al (1) in the November
issue of the eBMJ regarding folic acid and cardiovascular prevention.
Although many studies showed that folic acid reduces homocysteine levels
in all populations (2), can improve artery stiffness (3), endothelial
function (4) and even reduce atherosclerosis (5), no randomized placebo
controlled study ever proved that folic acid reduces hard endpoint
occurrence such as cardiovascular events (6,7). Interestingly, this non-
significant effect was observed despite a significant reduction of
homocysteine levels. In view of this data, and despite the association
between homocysteine and cardiovascular risk, I think that regarding
homocysteine a cardiovascular “risk factor”, somewhat premature. The term
“risk factor” (instead of “risk marker” for instance) denotes that
intervention aimed at reducing the levels of homocysteine (i.e. folic
acid) reduces cardiovascular risk, a speculation still to be proven. It is
indeed highly likely that this relationship between homocysteine and
cardiovascular risk is not random. However, the beneficial effects of
folic acid treatments are still to be proven.
I also find the beginning of the section somewhat misleading, since the
Meta-analyses of cohort studies did not show that a 3-µmol/l decrease in
serum homocysteine reduces the incidence of myocardial infarction and
stroke, but rather the opposite. I would prefer interpreting the data as:
increased risk of myocardial infarction by 15% and stroke by 24%, with an
increase of 3 µmol/l increase in serum homocysteine levels.
The authors failed to provide unequivocal evidence to show that reducing
homocysteine levels reduce cardiovascular risk. The authors tend to rely
on genetic and population based surveys that suggest the possibility that
this treatment might work. To my knowledge, no data is available even
among “high-risk” patients that have a better chance of risk reduction
with folic acid, such as individuals with high homocysteine levels and/or
MTHFR gene mutations.
From a clinical standpoint, patients’ compliance is lacking, even with
medications proven repeatedly to have a marked beneficial effect on
cardiovascular disease incidence, such as statins and blood pressure
reducing medications. I think that adding a debatable treatment,
especially one with a moderate effect at best, such as folic acid to the
regime will not help, and might even hinder the patients’ compliance.
Given the once presumed beneficial hormonal replacement therapy
“experience”, I consider recommending folic acid to all cardiovascular
patients premature. It is therefore my opinion that caution should be used
when recommending the addition of a new drug to the preventive drug
regime.
Sincerely
Dr. Eyal Leibovitz
1.Wald DS, et al. Folic acid, homocysteine, and cardiovascular
disease: judging causality in the face of inconclusive trial evidence. BMJ
2006;333:1114-1117
2. Ho GY, et al. Methylenetetrahydrofolate reductase polymorphisms
and homocysteine-lowering effect of vitamin therapy in Singaporean stroke
patients. Stroke. 2006;37:456-60
3. Williams C, et al. Folic acid supplementation for 3 wk reduces
pulse pressure and large artery stiffness independent of MTHFR genotype.
Am J Clin Nutr. 2005;82:26-31.
4. Assanelli D, et al. Folic acid and vitamin E supplementation
effects on homocysteinemia, endothelial function and plasma antioxidant
capacity in young myocardial-infarction patients. Pharmacol Res.
2004;49:79-84
5. Marcucci R, et al. Vitamin supplementation reduces the progression
of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.
Transplantation. 2003;75:1551-5
6. Bonaa KH, et al; NORVIT Trial Investigators. Homocysteine lowering
and cardiovascular events after acute myocardial infarction. N Engl J Med.
2006;354(15):1578-88
7. Lonn E, et al (HOPE) 2 Investigators. Homocysteine lowering with
folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr
13;354
Competing interests:
None declared
Competing interests:
No competing interests
11 December 2006
Eyal Leibovitz
Post doctoral research fellow
Lady davis Institute at the Jewish General hospital, Montreal, Canada
Rapid Response:
We should use caution
To the editor
I read with interest the comments by Wald et al (1) in the November
issue of the eBMJ regarding folic acid and cardiovascular prevention.
Although many studies showed that folic acid reduces homocysteine levels
in all populations (2), can improve artery stiffness (3), endothelial
function (4) and even reduce atherosclerosis (5), no randomized placebo
controlled study ever proved that folic acid reduces hard endpoint
occurrence such as cardiovascular events (6,7). Interestingly, this non-
significant effect was observed despite a significant reduction of
homocysteine levels. In view of this data, and despite the association
between homocysteine and cardiovascular risk, I think that regarding
homocysteine a cardiovascular “risk factor”, somewhat premature. The term
“risk factor” (instead of “risk marker” for instance) denotes that
intervention aimed at reducing the levels of homocysteine (i.e. folic
acid) reduces cardiovascular risk, a speculation still to be proven. It is
indeed highly likely that this relationship between homocysteine and
cardiovascular risk is not random. However, the beneficial effects of
folic acid treatments are still to be proven.
I also find the beginning of the section somewhat misleading, since the
Meta-analyses of cohort studies did not show that a 3-µmol/l decrease in
serum homocysteine reduces the incidence of myocardial infarction and
stroke, but rather the opposite. I would prefer interpreting the data as:
increased risk of myocardial infarction by 15% and stroke by 24%, with an
increase of 3 µmol/l increase in serum homocysteine levels.
The authors failed to provide unequivocal evidence to show that reducing
homocysteine levels reduce cardiovascular risk. The authors tend to rely
on genetic and population based surveys that suggest the possibility that
this treatment might work. To my knowledge, no data is available even
among “high-risk” patients that have a better chance of risk reduction
with folic acid, such as individuals with high homocysteine levels and/or
MTHFR gene mutations.
From a clinical standpoint, patients’ compliance is lacking, even with
medications proven repeatedly to have a marked beneficial effect on
cardiovascular disease incidence, such as statins and blood pressure
reducing medications. I think that adding a debatable treatment,
especially one with a moderate effect at best, such as folic acid to the
regime will not help, and might even hinder the patients’ compliance.
Given the once presumed beneficial hormonal replacement therapy
“experience”, I consider recommending folic acid to all cardiovascular
patients premature. It is therefore my opinion that caution should be used
when recommending the addition of a new drug to the preventive drug
regime.
Sincerely
Dr. Eyal Leibovitz
1.Wald DS, et al. Folic acid, homocysteine, and cardiovascular
disease: judging causality in the face of inconclusive trial evidence. BMJ
2006;333:1114-1117
2. Ho GY, et al. Methylenetetrahydrofolate reductase polymorphisms
and homocysteine-lowering effect of vitamin therapy in Singaporean stroke
patients. Stroke. 2006;37:456-60
3. Williams C, et al. Folic acid supplementation for 3 wk reduces
pulse pressure and large artery stiffness independent of MTHFR genotype.
Am J Clin Nutr. 2005;82:26-31.
4. Assanelli D, et al. Folic acid and vitamin E supplementation
effects on homocysteinemia, endothelial function and plasma antioxidant
capacity in young myocardial-infarction patients. Pharmacol Res.
2004;49:79-84
5. Marcucci R, et al. Vitamin supplementation reduces the progression
of atherosclerosis in hyperhomocysteinemic renal-transplant recipients.
Transplantation. 2003;75:1551-5
6. Bonaa KH, et al; NORVIT Trial Investigators. Homocysteine lowering
and cardiovascular events after acute myocardial infarction. N Engl J Med.
2006;354(15):1578-88
7. Lonn E, et al (HOPE) 2 Investigators. Homocysteine lowering with
folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr
13;354
Competing interests:
None declared
Competing interests: No competing interests