By Harold L. Karpman, MD, FACC, FACP
Clinical Professor of Medicine, UCLA School of Medicine
Dr. Karpman reports no financial relationships related to this field of study.
SYNOPSIS: Among adults with hypertension in China without a history of stroke or myocardial infarction, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke.
SOURCE: Huo Y, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China. The CSPPT randomized clinical trial. JAMA 2015;313:1325 – 1335.
Stroke is the leading cause of death in China and the second leading cause of death in the world.1 Since approximately 77% of all strokes are first events,2 primary prevention is particularly important. Some of the many published trials evaluating the beneficial effect of folic acid supplementation for the prevention of cardiovascular disease have suggested a specific reduction in stroke risk.3-5 Polymorphism of the MTHFR gene C677T leads to a reduction in the main regulatory enzyme for folate metabolism, and a large meta-analysis of genetic studies and clinical trials suggested that the effect of gene variants on stroke risk might be modified by folate status. The China Stroke Primary Prevention Trial (CSPPT) was designed to test the efficacy of folic acid therapy in stroke prevention in the context of primary vs secondary prevention and the combined effects of baseline folate levels and MTHFR gene C677T polymorphism.
Yong Huo and his colleagues from the Peking University First Hospital in Beijing, China, designed a study to test whether enalapril–folic acid therapy was more effective in reducing primary stroke incidence then was enalapril alone among adults with hypertension in China.7 A total of 20,702 adults with hypertension and without a history of stroke or myocardial infarction participated in the study. They were randomly assigned to receive a double-blind daily treatment with a single pill combination containing enalapril 10 mg and folic acid 0.8 mg or a tablet containing only enalapril 10 mg. The primary outcome studied was first stroke, and secondary outcomes included first ischemic stroke, first hemorrhagic stroke, myocardial infarction, and the composite of cardiovascular events including cardiovascular death, myocardial infarction, stroke, and, finally, all-cause death. The findings were consistent with benefits from folate use among adults with hypertension and low baseline folate levels, and the authors concluded that among adults with hypertension in China without a history of stroke or myocardial infarction, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke.
The effectiveness of folic acid supplementation in stroke prevention had not previously been well established8,9 until a comprehensive meta-analysis in 2012 found that folic acid supplementation significantly reduced the risk of first stroke.10 The enalapril– folic acid combination in the Huo study also significantly reduced the relative risk of first stroke by 21%, and it should be noted that the result occurred in a population in which there was a very low percentage of concomitant use of lipid-lowering drugs and antiplatelet agents. It was also important to note that since hypertension is a primary risk factor for stroke,8 in the Huo trial, blood pressure was controlled at baseline and throughout follow-up using enalapril and other antihypertensive agents as needed in both the treatment and control groups. It must be remembered that the study focused on primary prevention of stroke in adults with hypertension and that further studies will be needed to determine if the same results can be obtained in secondary stroke prevention and/or in adults without hypertension. The authors speculated that even in countries with folic acid fortification and widespread use of folic acid supplements, such as in the United States and in Canada, there still may be room to further reduce stroke incidence using more targeted folic acid therapy, in particular among those with low or moderate folate levels.
In summary, Huo7 and his colleagues demonstrated that among adults with hypertension in China without a history of stroke or myocardial infarction, the combined use of enalapril and folic acid compared with enalapril alone significantly reduced the risk of first stroke. This finding is consistent with the benefit from folate use observed to occur among adults with hypertension and low baseline folate levels, and in time, folate therapy may also be effective in reducing the incidence of recurrent strokes even in patients who have previously suffered a stroke.
- Lozano R, et al. Global and regional mortality from 235 cases of death for 20 age groups in 1990 and 2010: A systematic analysis of the Global Burden of Disease Study. 2010. Lancet 2012;380:2095-2128.
- Lloyd-Jones ED, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics – 2010 update: A report from the American Heart Association. Circulation 2010;121:e46-e215.
- Lonn E, et al; Heart Outcomes Prevention Evaluation 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-1577.
- Galan P, et al; SU.FOL.OM3 Collaborative Group. Effects of B vitamins and omega-3 fatty acids on cardiovascular diseases: A randomized placebo-controlled trial. BMJ 2010;34:c6273.
- Wang X, et al. Efficacy of folic acid supplementation in stroke prevention: A meta-analysis. Lancet 2007;369:1876-1882.
- Holmes MV, et al. Effect of modification of population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: A meta-analysis of genetic studies and randomized trials. Lancet 2011;378:584-594.
- Huo Y, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China. The CSPPT randomized clinical trial. JAMA 2015;313:1325-1335.
- Meschia JF, et al; American Heart Association Stroke Consul; Consul on Cardiovascular and Stroke Nursing; Consul on Clinical Cardiology: Consul on Functional Genomics and Translational Biology; Consul on Hypertension. Guidelines for the primary prevention of stroke: A statement for health care officials from the American Heart Association/American Stroke Association. Stroke 2014;45:3754-3832.
- Clarke R, et al; B vitamin Treatment Trialists’ Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of eight randomized trials involving 37,485 individuals. Arch Inter Med 2010;170:1622-1631.
- Huo Y, et al. Efficacy of folic acid supplementation in stroke prevention: New insight from a meta-analysis. Int J Clinic Pract 2012;66:544-551.