Abstract & Commentary
Synopsis: Folic acid supplementation in stable CAD patients on statins, despite reducing homocysteine levels, does not reduce clinical vascular events or death.
Source: Liem A, et al. J Am Coll Cardiol. 2003;41:2105-2113.
Elevated homocysteine levels have been associated with atherosclerosis. Folic acid supplementation is a simple, inexpensive way to reduce homocysteine levels, which has become popular for secondary prevention in patients with coronary artery disease (CAD), despite a paucity of long-term clinical trial data. Thus, Liem and colleagues from the Netherlands studied 593 patients with stable CAD on statins who were randomized to open-label folic acid 0.5 mg/d or standard care, which included aggressive pursuit of lipid goals. The primary end point was a composite of death and major vascular events over 24 months. In folic acid-treated patients, homocysteine levels decreased 18% from 12 to 9 mmol/L but didn’t change in the control group (P < .001). The primary end point was 10% in the folic acid group and the control group (relative risk, 1.05). In a subgroup where it was measured, C-reactive protein levels were unchanged in both groups. Liem et al concluded that over 2 years, folic acid supplementation in stable CAD patients on statins, despite reducing homocysteine levels, does not reduce clinical vascular events or death and that its use should not be encouraged.
Comment by Michael H. Crawford, MD
This study, following on the heals of the recent negative trial in postpercutaneous coronary stenting patients, suggests that we have more to learn about the role of folic acid and homocysteine in CAD. Explanations for the negative results include that in patients on maximum doses of statins at target lipid levels, there may be little to gain with vitamin therapy. Also, some believe that homocysteine is a marker for more diffuse vascular disease and lowering it does little because it is not causative. Support for this latter explanation comes from this study and others, which have noted that homocysteine levels are related to creatinine clearance. Reduced renal function due to vascular disease is a poor prognostic sign and indicates diffuse vascular disease. Thus, homocysteine levels may correlate with the risk of vascular events, but lowering it may not reduce their incidence.
There are several weaknesses of this study that diminish its authority and make us hold off on definitive conclusions until some of the larger, longer trials are completed (NORVIT, VITATOPS, SEARCH). First, based upon previous observational studies in established CAD patients, it was powered for a larger difference in events than has been observed in trials of patients without preexisting vascular disease. Consequently, it may have been underpowered to detect small differences (ie, 15%) in events. Second, the duration of therapy was short (24 months) and the number of patients was relatively small (fewer than 600). Third, about 15% of patients in both groups were already on B vitamin supplementation, which was not discontinued. Finally, the dose of folic acid in this study was low (0.5 mg/d) compared to other studies in which megadoses have been used (5 mg/d). On the other hand, significant reductions in homocysteine levels were observed with this dosage. Interestingly, the Netherlands, where this study was done, does not fortify grain products with folic acid as is done in other industrialized nations. Therefore, lower doses of folic acid may have a more profound effect in this environment. Regardless, Liem et al’s admonition that the routine use of folic acid supplementation should be tempered until more trial outcomes are available seems reasonable given the latest study results.
Dr. Crawford is Professor of Medicine, Associate Chief of Cardiology for Clinical Programs, University of California, San Francisco.
Elevated homocysteine levels have been associated with atherosclerosis. Folic acid supplementation is a simple, inexpensive way to reduce homocysteine levels, which has become popular for secondary prevention in patients with coronary artery disease (CAD), despite a paucity of long-term clinical trial data. Thus, Liem and colleagues studied 593 patients with stable CAD on statins who were randomized to open-label folic acid 0.5 mg/d or standard care, which included aggressive pursuit of lipid goals.
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