Comparative Efficacy of Antihypertensive Drugs for Primary Stroke Prevention–A Network Meta-Analysis of Randomized Controlled Trials
DOI:
https://doi.org/10.19166/lijn.v1i2.10286Keywords:
antihypertensive drugs, stroke, primary preventionAbstract
Introduction: Hypertension is a major modifiable risk factor for stroke, making antihypertensive therapy essential for primary stroke prevention. However, the comparative efficacy of different antihypertensive drug classes remains uncertain. This study aims to evaluate the comparative efficacy of various antihypertensive drug classes in reducing the risk of stroke in patients with hypertension through a network meta-analysis of randomized controlled trials (RCTs).
Methods: A search was conducted using various online databases, including PubMed, Google Scholar, Scopus, and ScienceDirect, to identify RCTs which were written in English and published before January 2025. A network meta-analysis was performed to compare the effectiveness of different drug classes, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs), beta-blockers, and diuretics in stroke primary prevention. Independently, two reviewers (D.N. and L.D.P.), extracted the data and assess the quality of studies using Cochrane RoB 2.0.
Results: This analysis included 43 RCTs involving 255299 participants with hypertension. Among the evaluated drug classes, non-dihydropyridine CCB demonstrated the highest efficacy in stroke prevention (RR 0.61; 95%CI 0.48 – 0.77), followed by dihydropyridine CCB (RR 0.62; 95%CI 0.54 – 0.72). Most of the studies had decent quality assessment with moderate heterogeneity across them with I2 = 39%. Egger’s test showed nonsignificant results (p= 0.16), suggesting the absence of publication bias in the included trials.
Conclusion: This meta-analysis showed that calcium channel blocker emerges as the most effective option for reducing stroke risk, but considerations of adverse effects and individual patient profiles remain critical in treatment selection.
References
1. Chalmers J, Todd A, Chapman N, Beilin L, Davis S, Donnan G, et al. International Society of Hypertension (ISH): statement on blood pressure lowering and stroke prevention. J Hypertens. 2003 Apr;21(4):651–63. https://doi.org/10.1097/01.hjh.0000052490.18130.95
2. Mancia G, Ambrosioni E, Rosei EA, Leonetti G, Trimarco B, Volpe M. Blood pressure control and risk of stroke in untreated and treated hypertensive patients screened from clinical practice: results of the ForLife study. J Hypertens. 2005 Aug;23(8):1575–81. https://doi.org/10.1097/01.hjh.0000175932.78774.32
3. McEvoy JW, McCarthy CP, Bruno RM, Brouwers S, Canavan MD, Ceconi C, et al. 2024 ESC Guidelines for the management of elevated blood pressure and hypertension. Eur Heart J. 2024 Oct;45(38):3912–4018. https://doi.org/10.1093/eurheartj/ehae178
4. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Coun. Stroke. 2006 Jun;37(6):1583–633. https://doi.org/10.1161/01.str.0000223048.70103.f1
5. Mancia G, Grassi G. Secondary prevention of stroke: old and new evidence. Aging Clin Exp Res. 2002 Jun;14(3):216–20. https://doi.org/10.1007/BF03324440
6. Jussil H, Chaimani A, Carlberg B, Brunström M. Comparative efficacy and acceptability of different antihypertensive drug classes for cardiovascular disease prevention: protocol for a systematic review and network meta-analysis. BMJ Open. 2021 Mar;11(3):e044302. https://doi.org/10.1136/bmjopen-2020-044302
7. Gronewold J, Kropp R, Lehmann N, Stang A, Mahabadi AA, Weimar C, et al. Population impact of different hypertension management guidelines based on the prospective population-based Heinz Nixdorf Recall study. BMJ Open [Internet]. 2021 Feb;11(2):e039597. Available from: https://doi.org/10.1136/bmjopen-2020-039597
8. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar;372:n71. https://doi.org/10.1136/bmj.n71
9. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019 Aug;366:l4898. https://doi.org/10.1136/bmj.l4898
10. Lv X, Zhang Y, Niu Y, Song Q, Zhao Q. Comparison of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on cardiovascular outcomes in hypertensive patients with type 2 diabetes mellitus: A PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2018 Apr;97(15):e0256. https://doi.org/10.1097/md.0000000000010256
11. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981–97. https://doi.org/10.1001/jama.288.23.2981
12. Baba S. Nifedipine and enalapril equally reduce the progression of nephropathy in hypertensive type 2 diabetics. Diabetes Res Clin Pract. 2001 Dec;54(3):191–201. https://doi.org/10.1016/s0168-8227(01)00288-1
13. Beckett N, Peters R, Leonetti G, Duggan J, Fagard R, Thijs L, et al. Subgroup and per-protocol analyses from the Hypertension in the Very Elderly Trial. J Hypertens. 2014 Jul;32(7):1478–87; discussion 1487. https://doi.org/10.1097/hjh.0000000000000195
14. Black HR, Elliott WJ, Grandits G, Grambsch P, Lucente T, White WB, et al. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA. 2003 Apr;289(16):2073–82. https://doi.org/10.1001/jama.289.16.2073
15. Borhani NO, Mercuri M, Borhani PA, Buckalew VM, Canossa-Terris M, Carr AA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA. 1996 Sep;276(10):785–91. https://doi.org/10.1001/jama.1996.03540100029024
16. Alonso P, Menchón JM, Segalàs C, Jaurrieta N, Jiménez-Murcia S, Cardoner N, et al. Clinical implications of insight assessment in obsessive-compulsive disorder. Compr Psychiatry. 2008;49(3):305–12. https://doi.org/10.1016/j.comppsych.2007.09.005
17. Dahlöf B, Lindholm LH, Hansson L, Scherstén B, Ekbom T, Wester PO. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet (London, England). 1991 Nov;338(8778):1281–5. https://doi.org/10.1016/0140-6736(91)92589-t
18. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet (London, England). 2002 Mar;359(9311):995–1003. https://doi.org/10.1016/s0140-6736(02)08089-3
19. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-. Lancet (London, England). 2005 Sep;366(9489):895–906. https://doi.org/10.1016/S0140-6736(05)67185-1
20. Estacio RO, Schrier RW. Antihypertensive therapy in type 2 diabetes: implications of the appropriate blood pressure control in diabetes (ABCD) trial. Am J Cardiol. 1998 Nov;82(9B):9R-14R. https://doi.org/10.1016/s0002-9149(98)00750-4
21. Dahlöf B, Hansson L, Lindholm LH, Scherstén B, Wester PO, Ekbom T, et al. STOP-Hypertension 2: a prospective intervention trial of “newer” versus “older” treatment alternatives in old patients with hypertension. Swedish Trial in Old Patients with Hypertension. Blood Press. 1993 Jun;2(2):136–41. https://doi.org/10.3109/08037059309077541
22. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet (London, England). 1999 Feb;353(9153):611–6. https://doi.org/10.1016/s0140-6736(98)05012-0
23. Hansson L, Hedner T, Lund-Johansen P, Kjeldsen SE, Lindholm LH, Syvertsen JO, et al. Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet (London, England). 2000 Jul;356(9227):359–65. https://doi.org/10.1016/s0140-6736(00)02526-5
24. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet (London, England). 2004 Jun;363(9426):2022–31. https://doi.org/10.1016/S0140-6736(04)16451-9
25. Kaplan NM, Vidt DG. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. Curr Hypertens Rep. 2003 Oct;5(5):362–3. https://pubmed.ncbi.nlm.nih.gov/12948426/
26. Kasanuki H, Hagiwara N, Hosoda S, Sumiyoshi T, Honda T, Haze K, et al. Angiotensin II receptor blocker-based vs. non-angiotensin II receptor blocker-based therapy in patients with angiographically documented coronary artery disease and hypertension: the Heart Institute of Japan Candesartan Randomized Trial for Evaluation in. Eur Heart J. 2009 May;30(10):1203–12. https://doi.org/10.1093/eurheartj/ehp101
27. Kjeldsen SE, Jamerson KA, Bakris GL, Pitt B, Dahlöf B, Velazquez EJ, et al. Predictors of blood pressure response to intensified and fixed combination treatment of hypertension: the ACCOMPLISH study. Blood Press. 2008;17(1):7–17. https://doi.org/10.1080/08037050801972857
28. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003 May;21(5):875–86. https://doi.org/10.1097/00004872-200305000-00011
29. Liu L, Wang JG, Gong L, Liu G, Staessen JA. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Systolic Hypertension in China (Syst-China) Collaborative Group. J Hypertens. 1998 Dec;16(12 Pt 1):1823–9. https://doi.org/10.1097/00004872-199816120-00016
30. Liu L, Zhang Y, Liu G, Li W, Zhang X, Zanchetti A. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005 Dec;23(12):2157–72. https://doi.org/10.1097/01.hjh.0000194120.42722.ac
31. Malacco E, Mancia G, Rappelli A, Menotti A, Zuccaro MS, Coppini A. Treatment of isolated systolic hypertension: the SHELL study results. Blood Press. 2003;12(3):160–7. https://doi.org/10.1080/08037050310009545
32. Matsuoka H. A 12-Month Comparison of ACE Inhibitor and Ca Antagonist Therapy in Mild to Moderate Essential Hypertension. The GLANT Study. Vol. 18, Miscellaneous. 1995. p. 235. https://pubmed.ncbi.nlm.nih.gov/7584934/
33. Matsuzaki M, Hori M, Izumi T, Fukunami M. Efficacy and safety of tolvaptan in heart failure patients with volume overload despite the standard treatment with conventional diuretics: a phase III, randomized, double-blind, placebo-controlled study (QUEST study). Cardiovasc drugs Ther. 2011 Dec;25 Suppl 1:S33-45. https://doi.org/10.1007/s10557-011-6304-x
34. A Medical Research Council (MRC) randomised trial of palliative radiotherapy with two fractions or a single fraction in patients with inoperable non-small-cell lung cancer (NSCLC) and poor performance status. Medical Research Council Lung Cancer Working. Br J Cancer. 1992 Jun;65(6):934–41. https://doi.org/10.1038/bjc.1992.196
35. Muramatsu T, Matsushita K, Yamashita K, Kondo T, Maeda K, Shintani S, et al. Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study. Hypertens (Dallas, Tex 1979). 2012 Mar;59(3):580–6. https://doi.org/10.1161/HYPERTENSIONAHA.111.184226
36. Takano H, Hasegawa H, Narumi H, Shindo S, Mizuma H, Kuwabara Y, et al. Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: A subanalysis of the VART. J Hum Hypertens. 2011;26:656–63. https://doi.org/10.1038/jhh.2011.91
37. National Intervention Cooperative Study in Elderly Hypertensives Study Group. Randomized Double-Blind Comparison of a Calcium Antagonist and a Diuretic in Elderly Hypertensives. Hypertension [Internet]. 1999;34(5):1129–33. https://doi.org/10.1161/01.HYP.34.5.1129
38. Ogawa H, Kim-Mitsuyama S, Matsui K, Jinnouchi T, Jinnouchi H, Arakawa K. Angiotensin II receptor blocker-based therapy in Japanese elderly, high-risk, hypertensive patients. Am J Med. 2012 Oct;125(10):981–90. https://doi.org/10.1016/j.amjmed.2011.12.010
39. Ogihara T, Matsuoka H, Rakugi H. Practitioner’s trial on the efficacy of antihypertensive treatment in elderly patients with hypertension II (PATE-hypertension II study) in Japan. Geriatr Gerontol Int. 2011 Oct;11(4):414–21. https://doi.org/10.1111/j.1447-0594.2011.00690.x
40. Ogihara T, Saruta T, Rakugi H, Saito I, Shimamoto K, Matsuoka H, et al. Combinations of olmesartan and a calcium channel blocker or a diuretic in elderly hypertensive patients: a randomized, controlled trial: 1. J Hypertens [Internet]. 2014;32(10). Available from: https://doi.org/10.1097/hjh.0000000000000281
41. Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, et al. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003 Dec;290(21):2805–16. https://doi.org/10.1001/jama.290.21.2805
42. Rosei EA, Dal Palù C, Leonetti G, Magnani B, Pessina A, Zanchetti A. Clinical results of the Verapamil inHypertension and Atherosclerosis Study. VHAS Investigators. J Hypertens. 1997 Nov;15(11):1337–44. https://doi.org/10.1097/00004872-199715110-00019
43. Ruggenenti P, Fassi A, Ilieva AP, Iliev IP, Chiurchiu C, Rubis N, et al. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens. 2011 Feb;29(2):207–16. https://doi.org/10.1097/hjh.0b013e32834069bd
44. Schrader J, Lüders S, Kulschewski A, Hammersen F, Plate K, Berger J, et al. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005 Jun;36(6):1218–26. https://doi.org/10.1161/01.STR.0000166048.35740.a9
45. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991 Jun 26;265(24):3255–64. https://doi.org/10.1097/00008483-199205000-00014
46. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhäger WH, et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet (London, England). 1997 Sep;350(9080):757–64. https://doi.org/10.1016/s0140-6736(97)05381-6
