Efficacy of folic acid in stroke primary prevention among patients with H-Type hypertension: a meta-analysis_Chinese Journal of Evidence-Based Medicine

Authors：

LUO Jinwen ¹ , DUAN Wenhui ² , TAN Yu ² , QU Hua ² ,  SHI Dazhuo ²

1. Beijing University of Chinese Medicine, Beijing 100029, P.R.China;
2. National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, China Academy of Traditional Chinese Medicine, Beijing 100091, P.R.China;

Corresponding author：

SHI Dazhuo, Email: shidazhuo@126.com

Keywords：

Folic acid; H-Type hypertension; Stroke; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.202005174

Video：

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Objectives To systematically review the efficacy of folic acid supplementation in the primary prevention of stroke among patients with H-Type hypertension.Methods PubMed, EMbase, The Cochrane Library, WanFang Data, CNKI, VIP and Sinomed databases were electronically searched to collect randomized controlled trials (RCTs) of folic acid supplementation in the primary prevention of stroke among patients with H-Type hypertension from inception to April, 2020. Two reviewers independently screened literature, extracted data and assessed the risk of bias of included studies, then, meta-analysis was performed by using RevMan 5.3 software and Stata 12.0 software.Results A total of 12 RCTs involving 18 170 participants were included. The results of meta-analysis showed that H-Type hypertensive patients who received folic acid and antihypertensive had a significant low risk of stroke (RR=0.34, 95%CI 0.21 to 0.55, P<0.000 1) compared with patients who received antihypertensive alone. In the stratified analyses, folic acid >2 mg/d (RR=0.27, 95%CI 0.14 to 0.51, P<0.000 1) and ≤2 mg/d (RR=0.36, 95%CI 0.20 to 0.65, P=0.000 8) both could reduce the risk of stroke. Enalapril folic acid tablets (RR=0.35, 95%CI 0.16 to 0.77, P=0.009) and free combinations of folic acid and antihypertensive drugs (RR=0.29, 95%CI 0.18 to 0.47, P<0.000 01) could lower the incidence of stroke.Conclusions Current evidence shows that the folic acid supplementation significantly reduce the risk of stroke among patients with H-Type hypertension. Enalapril folic acid tablets and free combinations of folic acid with antihypertensive drugs both play an important role in stroke prevention. There is no significant dose-response relationship between dosage of folic acid and prevention of stroke. Due to limited quality and quantity of the included studies, more high-quality studies are required to verify above conclusions.

Citation： LUO Jinwen, DUAN Wenhui, TAN Yu, QU Hua, SHI Dazhuo. Efficacy of folic acid in stroke primary prevention among patients with H-Type hypertension: a meta-analysis. Chinese Journal of Evidence-Based Medicine, 2020, 20(10): 1173-1179. doi: 10.7507/1672-2531.202005174 Copy

1.	Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation, 2015, 131(4): e29-322.
2.	Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J, 2015, 14: 6.
3.	Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ, 2002, 325(7374): 1202.
4.	胡大一, 徐希平. 有效控制“H型”高血压-预防卒中的新思路. 中华内科杂志, 2008, 47(12): 976-977.
5.	Qin X, Huo Y. H-Type hypertension, stroke and diabetes in China: Opportunities for primary prevention. J Diabetes, 2016, 8(1): 38-40.
6.	Towfighi A, Markovic D, Ovbiagele B. Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: a nationwide study. J Neurol Sci, 2010, 298(1-2): 153-157.
7.	Ciaccio M, Bivona G, Bellia C. Therapeutical approach to plasma homocysteine and cardiovascular risk reduction. Ther Clin Risk Manag, 2008, 4(1): 219-224.
8.	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.
9.	Wang WW, Wang XS, Zhang ZR, et al. A meta-analysis of folic acid in combination with anti-hypertension a hyperhomocysteinemia. Front Pharmacol, 2017, 8: 585.
10.	Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
11.	Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
12.	Yanping Li, Tianyi Huang, Yan Zheng, et al. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAHA, 2016, 5(8): e003768.
13.	Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109): 629-634.
14.	李毅, 郭勇, 苟华, 等. 同型半胱氨酸与H型高血压左室肥厚的相关性及马来酸依那普利叶酸片的干预效果. 现代生物医学进展, 2019, 19(18): 3554-3558.
15.	井元辉. 叶酸联合降压药物治疗H型高血压效果. 中国民康医学, 2019, 31(11): 12-14.
16.	孙慧萍, 张美荣. 马来酸依那普利叶酸片对H型高血压患者脑卒中的预防效果. 中国卫生标准管理, 2018, 9(13): 105-107.
17.	赵宝华, 张硕锐, 李长明, 等. 叶酸辅助治疗对H型高血压患者同型半胱氨酸水平及脑卒中发病率的影响. 中国药业, 2018, 27(5): 39-41.
18.	冯立春. 叶酸联合降压药物治疗H型高血压效果分析. 新乡医学院学报, 2018, 35(3): 196-200.
19.	周仕涛. 马来酸依那普利叶酸片对H型高血压脑卒中的预防作用. 临床合理用药杂志, 2017, 10(28): 80-82.
20.	李哲, 孙凌瑜, 谭琦, 等. 马来酸依那普利叶酸片对H型高血压脑卒中的预防性应用价值分析. 中国医药科学, 2016, 6(13): 72-75.
21.	田井强, 曾恋. 叶酸对H型高血压患者Hcy水平及心血管意外发生的影响研究. 当代医学, 2016, 22(13): 36-37.
22.	翟德林, 李慧. 叶酸干预治疗对 H 型高血压患者血浆同型半胱氨酸血压水平及主要心脑血管事件的影响. 山西医药杂志, 2015, (14): 1672-1674.
23.	谢锋, 李菁, 杨惠敏, 等. H型高血压流行病学调查及低剂量叶酸的干预性研究. 中国民族民间医药, 2013, 22(12): 54-55.
24.	赵明枝. 叶酸对同型半胱氨酸升高型高血压的疗效观察. 中国实用神经疾病杂志, 2012, 15(7): 63-64.
25.	Wang Y, Jin Y, Wang Y, et al. The effect of folic acid in patients with cardiovascular disease: a systematic review and meta-analysis. Medicine, 2019, 98(37): e17095.
26.	Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr, 2005, 82(4): 806-812.
27.	郭珊池. 不同剂量叶酸联合依那普利治疗H型高血压的疗效观察. 长沙: 中南大学, 2014.
28.	石晓辉, 马小川. 不同剂量叶酸组合依那普利片治疗H型高血压的疗效分析. 延安大学学报(医学科学版), 2013, 11(1): 1-2, 5.
29.	Han L, Wu Q, Wang C, et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke, 2015, 46(7): 1777-1786.
30.	Lee M, Hong KS, Chang SC, et al. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke, 2010, 41(6): 1205-1212.
31.	Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet, 2007, 369(9576): 1876-1882.
32.	孙宁玲, 秦献辉, 李建平, 等. 依那普利叶酸片固定复方与依那普利和叶酸自由联合在H型高血压人群中降低同型半胱氨酸的疗效比较. 中国新药杂志, 2009, 18(17): 1635-1640.

1. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation, 2015, 131(4): e29-322.
2. Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J, 2015, 14: 6.
3. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ, 2002, 325(7374): 1202.
4. 胡大一, 徐希平. 有效控制“H型”高血压-预防卒中的新思路. 中华内科杂志, 2008, 47(12): 976-977.
5. Qin X, Huo Y. H-Type hypertension, stroke and diabetes in China: Opportunities for primary prevention. J Diabetes, 2016, 8(1): 38-40.
6. Towfighi A, Markovic D, Ovbiagele B. Pronounced association of elevated serum homocysteine with stroke in subgroups of individuals: a nationwide study. J Neurol Sci, 2010, 298(1-2): 153-157.
7. Ciaccio M, Bivona G, Bellia C. Therapeutical approach to plasma homocysteine and cardiovascular risk reduction. Ther Clin Risk Manag, 2008, 4(1): 219-224.
8. 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.
9. Wang WW, Wang XS, Zhang ZR, et al. A meta-analysis of folic acid in combination with anti-hypertension a hyperhomocysteinemia. Front Pharmacol, 2017, 8: 585.
10. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ, 2011, 343: d5928.
11. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med, 2002, 21(11): 1539-1558.
12. Yanping Li, Tianyi Huang, Yan Zheng, et al. Folic acid supplementation and the risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAHA, 2016, 5(8): e003768.
13. Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ, 1997, 315(7109): 629-634.
14. 李毅, 郭勇, 苟华, 等. 同型半胱氨酸与H型高血压左室肥厚的相关性及马来酸依那普利叶酸片的干预效果. 现代生物医学进展, 2019, 19(18): 3554-3558.
15. 井元辉. 叶酸联合降压药物治疗H型高血压效果. 中国民康医学, 2019, 31(11): 12-14.
16. 孙慧萍, 张美荣. 马来酸依那普利叶酸片对H型高血压患者脑卒中的预防效果. 中国卫生标准管理, 2018, 9(13): 105-107.
17. 赵宝华, 张硕锐, 李长明, 等. 叶酸辅助治疗对H型高血压患者同型半胱氨酸水平及脑卒中发病率的影响. 中国药业, 2018, 27(5): 39-41.
18. 冯立春. 叶酸联合降压药物治疗H型高血压效果分析. 新乡医学院学报, 2018, 35(3): 196-200.
19. 周仕涛. 马来酸依那普利叶酸片对H型高血压脑卒中的预防作用. 临床合理用药杂志, 2017, 10(28): 80-82.
20. 李哲, 孙凌瑜, 谭琦, 等. 马来酸依那普利叶酸片对H型高血压脑卒中的预防性应用价值分析. 中国医药科学, 2016, 6(13): 72-75.
21. 田井强, 曾恋. 叶酸对H型高血压患者Hcy水平及心血管意外发生的影响研究. 当代医学, 2016, 22(13): 36-37.
22. 翟德林, 李慧. 叶酸干预治疗对 H 型高血压患者血浆同型半胱氨酸血压水平及主要心脑血管事件的影响. 山西医药杂志, 2015, (14): 1672-1674.
23. 谢锋, 李菁, 杨惠敏, 等. H型高血压流行病学调查及低剂量叶酸的干预性研究. 中国民族民间医药, 2013, 22(12): 54-55.
24. 赵明枝. 叶酸对同型半胱氨酸升高型高血压的疗效观察. 中国实用神经疾病杂志, 2012, 15(7): 63-64.
25. Wang Y, Jin Y, Wang Y, et al. The effect of folic acid in patients with cardiovascular disease: a systematic review and meta-analysis. Medicine, 2019, 98(37): e17095.
26. Homocysteine Lowering Trialists' Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr, 2005, 82(4): 806-812.
27. 郭珊池. 不同剂量叶酸联合依那普利治疗H型高血压的疗效观察. 长沙: 中南大学, 2014.
28. 石晓辉, 马小川. 不同剂量叶酸组合依那普利片治疗H型高血压的疗效分析. 延安大学学报(医学科学版), 2013, 11(1): 1-2, 5.
29. Han L, Wu Q, Wang C, et al. Homocysteine, ischemic stroke, and coronary heart disease in hypertensive patients: a population-based, prospective cohort study. Stroke, 2015, 46(7): 1777-1786.
30. Lee M, Hong KS, Chang SC, et al. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke, 2010, 41(6): 1205-1212.
31. Wang X, Qin X, Demirtas H, et al. Efficacy of folic acid supplementation in stroke prevention: a meta-analysis. Lancet, 2007, 369(9576): 1876-1882.
32. 孙宁玲, 秦献辉, 李建平, 等. 依那普利叶酸片固定复方与依那普利和叶酸自由联合在H型高血压人群中降低同型半胱氨酸的疗效比较. 中国新药杂志, 2009, 18(17): 1635-1640.

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Efficacy of folic acid in stroke primary prevention among patients with H-Type hypertension: a meta-analysis

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