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Long-Term Anti-Hypertensive Therapy and Stroke Prevention: A Meta-Analysis

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Abstract

Background

Stroke causes approximately 6.7 million deaths worldwide per year and is the second leading cause of death. Pharmacotherapy for hypertension, an independent risk factor for stroke, significantly reduces the incidence of stroke. Although prior meta-analyses demonstrate various antihypertensive classes are superior to placebo in reducing stroke risk, which class is most effective is unclear.

Methods

We conducted a systematic MEDLINE search including only randomized controlled trials (RCT) of antihypertensive medications published between 1999 and 2014 in adults with stroke as a primary or secondary outcome. Five classes compared against all others were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-adrenoceptor antagonists (β-blockers), calcium channel blockers (CCBs), and thiazide or thiazide-like diuretics (T-TLDs). Among 17 RCTs with 31 comparative arms, risk ratio was used to assess effect size, and a fixed- and random-effect model was used to calculate summary effect size, utilizing comprehensive meta-analysis statistical software version 2.0.

Results

The 251,853 subjects (46 ± 11.4 % female; mean age 67.2 ± 6.8 years), were grouped as follows: ACEI 52,887; ARB 7278; ACEI/ARB 60,165; β-blocker 24,099; CCB 98,950; and T-TLD 68,639. The mean follow-up was 42.9 ± 15 months. A random-effect model was used to assess for summary effect size in ACEI, ACEI/ARB, ARB, and T-TLD groups. The summary risk ratio for stroke occurrence in the different antihypertensive drug classes were as follows: ACEIs 1.01 (95 % confidence interval [CI] 0.81–1.27; p = 0.92); ACEIs/ARBs 0.94 (95 % CI 0.78–1.13; p = 0.51); T-TLDs 0.90 (95 % CI 0.75–1.08; p = 0.25); ARBs 0.83 (95 % CI 0.59–1.18; p = 0.30); β-blockers 1.42 (95 % CI 1.26–1.61; p < 0.01); and CCBs 0.83 (95 % CI 0.79–0.89; p < 0.01).

Conclusion

Among the antihypertensive classes, CCBs were most effective in reducing the long-term incidence of stroke, whereas β-blockers were associated with significantly increased risk.

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References

  1. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42(6):1206–52.

    Article  CAS  PubMed  Google Scholar 

  2. Ovbiagele B, Goldstein LB, Higashida RT, et al. Forecasting the future of stroke in the United States: a policy statement from the American Heart Association and American Stroke Association. Stroke. 2013;44(8):2361–75.

    Article  PubMed  Google Scholar 

  3. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033–41.

    Article  Google Scholar 

  4. Neal B, MacMahon S, Chapman N, et al. Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists’ Collaboration. Lancet. 2000;356(9246):1955–64.

    Article  CAS  PubMed  Google Scholar 

  5. Turnbull F. Blood Pressure Lowering Treatment Trialists Collaborative. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet. 2003;362(9395):1527–35.

    Article  CAS  PubMed  Google Scholar 

  6. Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Borenstein M. Introduction to meta-analysis. Chichester: Wiley; 2009.

    Book  Google Scholar 

  8. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58.

    Article  PubMed  Google Scholar 

  9. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    Article  CAS  PubMed  Google Scholar 

  10. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22(4):719–48.

    CAS  PubMed  Google Scholar 

  11. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

    Article  CAS  PubMed  Google Scholar 

  12. Orwin RG, Boruch RF. RRT meets RDD: statistical strategies for assuring response privacy in telephone surveys. Public Opin Q. 1983;46(4):560–71 Winter.

    Article  CAS  PubMed  Google Scholar 

  13. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417–28.

    Article  CAS  PubMed  Google Scholar 

  14. ALLHAT Officers and Coordinators for the ALLHAT Collaborative. Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. 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;288(23):2981–97.

    Article  Google Scholar 

  15. Rothwell PM, Howard SC, Dolan E, et al. Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9(5):469–80.

    Article  CAS  PubMed  Google Scholar 

  16. Matsuzaki M, Ogihara T, Umemoto S, et al. Prevention of cardiovascular events with calcium channel blocker-based combination therapies in patients with hypertension: a randomized controlled trial. J Hypertens. 2011;29(8):1649–59.

    Article  CAS  PubMed  Google Scholar 

  17. Liu L, Zhang Y, Liu G, et al. The Felodipine Event Reduction (FEVER) Study: a randomized long-term placebo-controlled trial in Chinese hypertensive patients. J Hypertens. 2005;23(12):2157–72.

    Article  CAS  PubMed  Google Scholar 

  18. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887–98.

    Article  CAS  PubMed  Google Scholar 

  19. Bangalore S, Messerli FH, Cohen JD, et al. Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovascular events in patients with prior myocardial infarction: an INternational VErapamil SR-Trandolapril (INVEST) substudy. Am Heart J. 2008;156(2):241–7.

    Article  CAS  PubMed  Google Scholar 

  20. Kjeldsen SE, Lyle PA, Kizer JR, et al. The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study. J Clin Hypertens. 2005;7(3):152–8.

    Article  Google Scholar 

  21. Yamashita K, Kondo T, Muramatsu T, et al. Effects of valsartan versus amlodipine in diabetic hypertensive patients with or without previous cardiovascular disease. Am J Cardiol. 2013;112(11):1750–6.

    Article  CAS  PubMed  Google Scholar 

  22. Muramatsu T, Matsushita K, Yamashita K, et al. Comparison between valsartan and amlodipine regarding cardiovascular morbidity and mortality in hypertensive patients with glucose intolerance: NAGOYA HEART Study. Hypertension. 2012;59(3):580–6.

    Article  CAS  PubMed  Google Scholar 

  23. Hansson L, Hedner T, Lund-Johansen P, 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. 2000;356(9227):359–65.

    Article  CAS  PubMed  Google Scholar 

  24. Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia. 2011;54(12):2978–86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Sandset EC, Bath PM, Boysen G, et al. The angiotensin-receptor blocker candesartan for treatment of acute stroke (SCAST): a randomised, placebo-controlled, double-blind trial. Lancet. 2011;377(9767):741–50.

    Article  CAS  PubMed  Google Scholar 

  26. Papademetriou V, Farsang C, Elmfeldt D, et al. Stroke prevention with the angiotensin II type 1-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J Am Coll Cardiol. 2004;44(6):1175–80.

    CAS  PubMed  Google Scholar 

  27. Perry HM Jr, Davis BR, Price TR, et al. Effect of treating isolated systolic hypertension on the risk of developing various types and subtypes of stroke: the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 2000;284(4):465–71.

    Article  PubMed  Google Scholar 

  28. Hansson L, Lindholm LH, Ekbom T, et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet. 1999;354(9192):1751–6.

    Article  CAS  PubMed  Google Scholar 

  29. Narumi H, Takano H, Shindo S, et al. Effects of valsartan and amlodipine on cardiorenal protection in Japanese hypertensive patients: the Valsartan Amlodipine Randomized Trial. Hypertens Res. 2011;34(1):62–9.

    Article  CAS  PubMed  Google Scholar 

  30. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754–832.

    Article  PubMed  Google Scholar 

  31. Sipahi I, Swaminathan A, Natesan V, et al. Effect of antihypertensive therapy on incident stroke in cohorts with prehypertensive blood pressure levels: a meta-analysis of randomized controlled trials. Stroke. 2012;43(2):432–40.

    Article  CAS  PubMed  Google Scholar 

  32. Psaty BM, Lumley T, Furberg CD, et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA. 2003;289(19):2534–44.

    Article  CAS  PubMed  Google Scholar 

  33. Thompson AM, Hu T, Eshelbrenner CL, et al. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA. 2011;305(9):913–22.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Group SPSS, Benavente OR, Coffey CS, et al. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507–15.

    Article  Google Scholar 

  35. Verdecchia P, Reboldi G, Angeli F, et al. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension. 2005;46(2):386–92.

    Article  CAS  PubMed  Google Scholar 

  36. Hornslien AG, Sandset EC, Bath PM, et al. Effects of candesartan in acute stroke on cognitive function and quality of life: results from the Scandinavian Candesartan Acute Stroke Trial. Stroke. 2013;44(7):2022–4.

    Article  CAS  PubMed  Google Scholar 

  37. Bangalore S, Bhatt DL, Steg PG, et al. β-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial. Circ Cardiovasc Qual Outcomes. 2014;7(6):872–81.

    Article  PubMed  Google Scholar 

  38. Bangalore S, Steg G, Deedwania P, et al. Beta-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA. 2012;308(13):1340–9.

    Article  CAS  PubMed  Google Scholar 

  39. Bangalore S, Parkar S, Grossman E, et al. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol. 2007;100(8):1254–62.

    Article  CAS  PubMed  Google Scholar 

  40. Deedwania P. Hypertension, dyslipidemia, and insulin resistance in patients with diabetes mellitus or the cardiometabolic syndrome: benefits of vasodilating beta-blockers. J Clin Hypertens. 2011;13(1):52–9.

    Article  CAS  Google Scholar 

  41. Mukete BN, Rosendorff C. Effects of low-dose thiazide diuretics on fasting plasma glucose and serum potassium-a meta-analysis. J Am Soc Hypertens. 2013;7(6):454–66.

    Article  CAS  PubMed  Google Scholar 

  42. Dahlof B, Sever PS, Poulter NR, 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-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895–906.

    Article  PubMed  Google Scholar 

  43. Kizer JR, Dahlof B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study. Hypertension. 2005;45(1):46–52.

    Article  CAS  PubMed  Google Scholar 

  44. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213–25.

    Article  CAS  PubMed  Google Scholar 

  45. Burke TA, Sturkenboom MC, Ohman-Strickland PA, et al. The effect of antihypertensive drugs and drug combinations on the incidence of new-onset type-2 diabetes mellitus. Pharmacoepidemiol Drug Saf. 2007;16(9):979–87.

    Article  CAS  PubMed  Google Scholar 

  46. Thornley-Brown D, Wang X, Wright JT Jr, et al. Differing effects of antihypertensive drugs on the incidence of diabetes mellitus among patients with hypertensive kidney disease. Arch Int Med. 2006;166(7):797–805.

    Article  CAS  Google Scholar 

  47. Blackburn DF, Wilson TW. Antihypertensive medications and blood sugar: theories and implications. Can J Cardiol. 2006;22(3):229–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24(1):3–10.

    Article  CAS  PubMed  Google Scholar 

  49. Grimm C, Koberlein J, Wiosna W, et al. New-onset diabetes and antihypertensive treatment. GMS Health Technol Assess. 2010;6:Doc03.

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Acknowledgments

No sources of funding were used to conduct this study or prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this article. KC Ferdinand has previously received consulting fees or honorarium from AstraZeneca, Boehringer Ingelheim, Amgen, and Sanofi.

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  1. Tulane University School of Medicine, New Orleans, LA, 70112, USA

    Bertrand N. Mukete, Mark Cassidy, Keith C. Ferdinand & Thierry H. Le Jemtel

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Correspondence to Thierry H. Le Jemtel.

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Mukete, B.N., Cassidy, M., Ferdinand, K.C. et al. Long-Term Anti-Hypertensive Therapy and Stroke Prevention: A Meta-Analysis. Am J Cardiovasc Drugs 15, 243–257 (2015). https://doi.org/10.1007/s40256-015-0129-0

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