Folic Acid for Secondary Prevention: Effects on Clinical Outcomes - Folic Acid for Secondary Prevention: Effects on Clinical Outcomes


The goal of the trial was to compare the effect of folic acid with placebo on clinical outcomes in patients with stable coronary artery disease (CAD) on statin therapy.


Folic acid, which previously has been shown to have favorable effects on vascular endothelium and plasma homocysteine levels, will reduce the rate of clinical events in patients with stable CAD.

Study Design

Study Design:

Patients Enrolled: 593
Mean Follow Up: Mean 24 months
Mean Patient Age: Mean age 65 years
Female: 78%

Patient Populations:

Presence of one of the following: MI, significant coronary artery lesions >60 on coronary angiography, PCI, and/or CABG; stable, with no invasive vascular procedures scheduled; and statin therapy for ≥3 months


Use of any form of vitamin B-containing medication; age below 18 years; history of low vitamin B12 level; treatment for hyperhomocysteinemia, severe renal failure, or any other treatment for renal disease; known hepatic disease; signs and symptoms of severe heart failure (New York Heart Association functional class IV); or any other serious illness that would exclude follow-up time of at least three years

Primary Endpoints:

Composite of vascular events, defined as death, recurrent MI, invasive coronary procedures (PCI, CABG), CVA, TIA, or any other vascular surgery

Drug/Procedures Used:

Patients were randomized open label to folic acid 0.5 mg/day (n=300) or placebo (n=293).

Concomitant Medications:

Patients had been on statin therapy for a mean of 3.2 years at baseline.

Principal Findings:

At three-month follow-up, plasma homocysteine levels decreased in patients in the folic acid group (12.0 ± 4.8 to 9.4 ± 3.5 µmol/l), but levels did not change in the control group (12.2 ± 3.8 µmol/l at both time points, p<0.001 between groups). Similar results were seen at six months. Serum folate levels also increased in the folic acid arm, from 17 ± 7 to 33 ± 6 nmol/l, p<0.001).

There was no difference in the primary composite endpoint of all-cause mortality or vascular events at a mean two-year follow-up (10.3% in the folic acid group and 9.6% in the control group, relative risk (RR) 1.05, 95% confidence interval [CI] 0.63-1.75, p=0.85). Similar results were observed in an analysis restricted to patients in the highest quartile of plasma homocysteine (>13.7 µmol/l; log-rank test, p=0.86).

There was also no difference in any component of the composite endpoint: all-cause mortality (n=12 vs. n=14); myocardial infarction (MI; n=3 vs. n=4); percutaneous coronary intervention (PCI; n=6 vs. n=3); coronary artery bypass graft surgery (CABG; n=4 vs. n=3); cerebrovascular accident/transient ischemic attack (CVA/TIA; n=4 vs. n=3); and vascular surgery (n=9 vs. n=6) for the folic acid group versus control, respectively.


Among patients with stable CAD on statin therapy, treatment with folic acid was not associated with a reduction in the primary composite endpoint of all-cause mortality or vascular event at a mean two-year follow-up. Despite the lack of benefit in clinical events, treatment with folic acid was associated with a reduction in plasma homocysteine levels, findings which have been observed in other trials.

The authors speculate that lack of benefit may be due to the fact that patients were also on statin therapy for a mean of 3.2 years prior to the trial. However, they also note that other randomized trials to date have not shown a reduction in clinical events with folic acid therapy, with the only exception being a trial by Schnyder G, et al. (Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. New Engl J Med 2001;345:1593–600) of folic acid with vitamin B12 and pyridoxine given after PCI, which showed a reduction in the rate of restenosis and revascularization. However, this trial also showed no reduction in cardiac death or nonfatal MI. Several other large-scale trials of folic acid therapy are ongoing, including NORVIT, VITATOPS, and SEARCH.


Liem A, Reynierse-Buitenwerf GH, Zwinderman AH, Jukema JW, van Veldhuisen DJ. Secondary prevention with folic acid: effects on clinical outcomes. J Am Coll Cardiol 2003;41:2105–13.

Clinical Topics: Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Stable Ischemic Heart Disease, Aortic Surgery, Cardiac Surgery and SIHD, Statins, Interventions and Imaging, Angiography, Nuclear Imaging, Chronic Angina

Keywords: Myocardial Infarction, Stroke, Ischemic Attack, Transient, Coronary Restenosis, Coronary Angiography, Folic Acid, Endothelium, Vascular, Pyridoxine, Vitamin B 12, Coronary Artery Bypass, Percutaneous Coronary Intervention

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