Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The CSPPT Randomized Clinical Trial

Jane Oh, Mercer University College of Pharmacy 2015

According to the National Stroke Association, a stroke is a “brain attack” caused by oxygen deprivation to an area of the brain due to blood flow that is cut off.  The National Stroke Association states that up to 80% of strokes are preventable.1  The American Heart Association and American Stroke Association (AHA/ ASA) guidelines for the primary prevention of stroke state that there is inconsistent data regarding the use of folic acid for the primary prevention of stroke.  The AHA/ ASA guideline states that the use of the B complex vitamins, cobalamin (B12), pyridoxine (B6), and folic acid might be considered for the prevention of ischemic stroke for patients with hyperhomocysteinemia, but the effectiveness is not well established.2

The main regulatory enzyme for folate metabolism is methylenetetrahydrofolate reductase (MTHFR).  Genetic polymorphism of the MTHFR gene C677T leads to reduced enzyme activity, leading to decreased folate levels.  A meta-analysis of 237 genetic study datasets suggests that the gene variants of MTHFR on stroke risk may be modified by folate status.3

Title: Efficacy of Folic Acid Therapy in Primary Prevention of Stroke Among Adults With Hypertension in China: The China Stroke Primary Prevention Trial (CSPPT) Randomized Clinical Trial4
Design Randomized, double-blind clinical trial; N= 20,702
Objective

(Primary)

To test the primary hypothesis that therapy with enalapril and folic acid is more effective in reducing first stroke than enalapril alone among Chinese adults with hypertension
Study Groups Thirty-two communities in Jiangsu and Anhui provinces in China with hypertension without a history of stroke or myocardial infarction (MI) were randomized to either enalapril and folic acid or enalapril alone.
Methods Run-in treatment: All eligible patients received enalapril 10mg orally daily for three weeks (n= 28,202).  Participants with good adherence and tolerance entered the next stage.

Treatment: Participants were stratified by MTHFR C677T genotypes (CC, CT, and TT), then assigned to either a single-pill combination containing enalapril 10 mg and folic acid 0.8 mg (n= 10,348) or a single tablet containing enalapril 10 mg (n= 10,354).

Duration May 19, 2008 to August 24, 2013
Primary outcome measure First stroke
Baseline Characteristics Enalapril-folic acid group: 41.0% male, mean age 60.0, mean body mass index 25.0, MTHFR C677T polymorphisms: 27.3% CC, 49.2% CT, 23.5% TT, 68.8% never smoker, 69.2% never drank alcohol, mean total cholesterol 213.6, mean triglycerides 147.4, mean HDL-C 52.0, mean fasting glucose 104.5, median homocysteine 12.5, median vitamin B12 379.6, 45.6% taking antihypertensive drugs, 10.0% taking calcium channel blockers, 9.1% taking angiotensin-converting enzyme inhibitors

Enalapril group: 41.1% male, mean age 60.0, mean body mass index 24.9, MTHFR C677T polymorphisms: 27.3% CC, 49.1% CT, 23.6% TT, 68.9% never smoker, 68.7% never drank alcohol, mean total cholesterol 213.2, mean triglycerides 146.9, mean HDL-C 51.8, mean fasting glucose 104.5, median homocysteine 12.5, median vitamin B12 379.6, 46.5% taking antihypertensive drugs, 9.2% taking calcium channel blockers, 9.2% taking angiotensin-converting enzyme inhibitors

Results First stroke: 282 in the enalapril-folic acid group versus 355 in the enalapril alone group; 95% confidence interval, 0.68-0.93; p= .003
Adverse Events Common Adverse Effects: enalapril versus (vs.) enalapril-folic acid – 19.9% vs. 19.8% cough, 0.6% vs. 0.4% headache, 0.2% vs. 0.2% abdominal discomfort
Serious Adverse Events: None reported
Percentage that Discontinued due to Adverse Events: None reported
Study Author Conclusions Among adults with hypertension in China without a history of stroke or MI, the combined use of enalapril and folic acid, compared with enalapril alone, significantly reduced the risk of first stroke.  These findings are consistent with benefits from folate use among adults with hypertension and low baseline folate levels.

The effectiveness of folic acid supplementation in primary stroke prevention was evaluated.  The study reported the occurrence of first stroke in 282 participants (2.7%) in the enalapril-folic acid group compared with 355 participants (3.4%) in the enalapril group.  Upon further analysis, the study suggests that an important determinant of folic acid therapy efficacy in stroke prevention is baseline folate levels because the beneficial effect appeared more pronounced when folate levels were lower.  Folic acid fortification in countries is a factor that may play a role in the effectiveness of folic acid supplementation for primary stroke prevention, in addition to genotype, concomitant diseases and concomitant medications.  The results are promising in favor of folic acid for primary stroke prevention, but it is important to consider that the population had relatively lower percentages of concomitant use of lipid-lowering drugs and antiplatelet agents than average, and that the study was not adequately powered to make conclusions regarding MTHFR C677T polymorphisms and baseline folate levels.

References:

  1. What is stroke? National Stroke Association. http://www.stroke.org/understand-stroke/what-stroke. Accessed April 13, 2015.
  2. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke. Journal of the American Heart Association. December 2014. DOI: 10.1161/STR.0000000000000046.
  3. Holmes MV, Newcombe P, Hubacek JA, et al. Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomized trials. 2011; 378(979): 584-594. DOI:10.1016/S0140-6736(11)60872-6
  4. Huo Y, Li J, Qin X, 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(13): 1325-1335. DOI: 10.1001/jama.2015.2274.
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