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High-dose calcium channel blocker (CCB) monotherapy vs combination therapy of standard-dose CCBs and angiotensin receptor blockers for hypertension: a meta-analysis

Journal of Human Hypertension volume 31, pages 79–88 (2017)Cite this article

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Abstract

In this study, we evaluated the efficacy and safety of high-dose calcium channel blocker (CCB) monotherapy and standard-dose CCBs combined with angiotensin receptor blockers (ARBs) for patients with hypertension. A comprehensive search of PubMed, Embase and the Cochrane Central Register of Controlled Trials was performed in December 2015. Randomized controlled trials designed to identify the above goal were included. Thirteen trials including 2371 patients were identified. The standard-dose CCB/ARB combination resulted in a greater reduction of systolic blood pressure (WMD −2.52, 95% confidence interval (CI): −3.76 to −1.28) and diastolic blood pressure (weighted mean difference (WMD) −2.07, 95% CI: −3.73 to −0.42) compared to high-dose CCB monotherapy. The overall hypertension control rate for the CCB/ARB combination was higher than that for CCB monotherapy (relative risk (RR): 1.17, 95% CI: 1.08–1.26). Furthermore, the CCB/ARB combination treatment yielded significantly fewer overall adverse events (RR: 0.84, 95% CI: 0.74–0.95), oedema (RR: 0.31; 95% CI: 0.18–0.52) and rash (RR: 0.27, 95% CI: 0.08–0.96, P=0.04) than did CCB monotherapy. The standard-dose CCB/ARB combination is superior to high-dose CCB monotherapy for lowering blood pressure and reducing adverse events in hypertensive patients. Future research should focus on the cost-effectiveness and long-term effects of these two treatment strategies for patients with hypertension.

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References

  1. Schiffrin EL . Hypertension: treatments, diabetes, and developing regions. Lancet 2012; 380: 539–541.

    Article  Google Scholar 

  2. Ibrahim MM, Damasceno A . Hypertension in developing countries. Lancet 2012; 380: 611–619.

    Article  Google Scholar 

  3. Hu DY, Liu LS, Yu JM, Yao CH . National survey of blood pressure control rate in Chinese hypertensive outpatients-China STATUS. Zhonghua Xin Xue Guan Bing Za Zhi 2010; 38: 230–238.

    PubMed  Google Scholar 

  4. Brown MJ, Palmer CR, Castaigne A, de Leeuw PW, Mancia G, Rosenthal T et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: intervention as a Goal in Hypertension Treatment (INSIGHT). Lancet 2000; 356: 366–372.

    Article  CAS  Google Scholar 

  5. National Intervention Cooperative Study in Elderly Hypertensives Study Group. Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. Hypertension 1999; 34: 1129–1133.

    Article  Google Scholar 

  6. Tocci G, Battistoni A, Passerini J, Musumeci MB, Francia P, Ferrucci A et al. Calcium channel blockers and hypertension. J Cardiovasc Pharmacol Ther 2015; 20: 121–130.

    Article  CAS  Google Scholar 

  7. Zhu DL, Gao PJ, Holtbruegge W, Huang CL . A randomized, double-blind study to evaluate the efficacy and safety of a single-pill combination of telmisartan 80 mg/amlodipine 5 mg versus amlodipine 5 mg in hypertensive Asian patients. J Int Med Res 2014; 42: 52–66.

    Article  Google Scholar 

  8. Matsui Y, O'Rourke MF, Hoshide S, Ishikawa J, Shimada K, Kario K . Combined effect of angiotensin II receptor blocker and either a calcium channel blocker or diuretic on day-by-day variability of home blood pressure: the Japan Combined Treatment With Olmesartan and a Calcium-Channel Blocker Versus Olmesartan and Diuretics Randomized Efficacy Study. Hypertension 2012; 59: 1132–1138.

    Article  CAS  Google Scholar 

  9. Lu Z, Chen Y, Li L, Wang G, Xue H, Tang W . Combination therapy of renin-angiotensin system inhibitors plus calcium channel blockers versus other two-drug combinations for hypertension: a systematic review and meta-analysis. J Hum Hypertens, (e-pub ahead of print 7 January 2016; doi:10.1038/jhh.2015.125).

  10. Chi C, Tai C, Bai B, Yu S, Karamanou M, Wang J et al. Angiotensin system blockade combined with calcium channel blockers is superior to other combinations in cardiovascular protection with similar blood pressure reduction: a meta-analysis in 20451 hypertensive patients. J Clin Hypertens (Greenwich), (e-pub ahead of print 17 January 2016; doi:10.1111/jch.12771).

  11. Ma J, Wang XY, Hu ZD, Zhou ZR, Schoenhagen P, Wang H . Meta-analysis of the efficacy and safety of adding an angiotensin receptor blocker (ARB) to a calcium channel blocker (CCB) following ineffective CCB monotherapy. J Thorac Dis 2015; 7: 2243–2252.

    PubMed  PubMed Central  Google Scholar 

  12. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF . Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. QUOROM Group. Br J Surg 2000; 87: 1448–1454.

    Article  CAS  Google Scholar 

  13. Higgins JPT, Green S (eds). Cochrane Handbook for Systematic Reviews of Interventions: cochrane Book Series. John Wiley & Sons: Chichester, UK, 2008.

    Book  Google Scholar 

  14. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008; 336: 924–926.

    Article  Google Scholar 

  15. Andreadis EA, Tsourous GI, Marakomichelakis GE, Katsanou PM, Fotia ME, Vassilopoulos CV et al. High-dose monotherapy vs low-dose combination therapy of calcium channel blockers and angiotensin receptor blockers in mild to moderate hypertension. J Hum Hypertens 2005; 19: 491–496.

    Article  CAS  Google Scholar 

  16. Andreadis EA, Sfakianakis ME, Tsourous GI, Georgiopoulos DX, Fragouli EG, Katsanou PM et al. Differential impact of angiotensin receptor blockers and calcium channel blockers on arterial stiffness. Int Angiol 2010; 29: 266–272.

    CAS  PubMed  Google Scholar 

  17. Chrysant SG, Melino M, Karki S, Lee J, Heyrman R . The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther 2008; 30: 587–604.

    Article  CAS  Google Scholar 

  18. Derosa G, Cicero AF, Carbone A, Querci F, Fogari E, D'Angelo A et al. Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies. Expert Opin Drug Saf 2013; 12: 621–629.

    Article  CAS  Google Scholar 

  19. Goyal J, Khan ZY, Upadhyaya P, Goyal B, Jain S . Comparative study of high dose mono-therapy of amlodipine or telmisartan, and their low dose combination in mild to moderate hypertension. J Clin Diagn Res 2014; 8: HC08–HC11.

    PubMed  PubMed Central  Google Scholar 

  20. Kang SM, Youn JC, Chae SC, Park CG, Yang JY, Kim MH et al. Comparative efficacy and safety profile of amlodipine 5 mg/losartan 50 mg fixed-dose combination and amlodipine 10 mg monotherapy in hypertensive patients who respond poorly to amlodipine 5 mg monotherapy: an 8-week, multicenter, randomized, double-blind phase III noninferiority study. Clin Ther 2011; 33: 1953–1963.

    Article  CAS  Google Scholar 

  21. Lee H-Y, Kim Y-J, Ahn T, Youn H-J, Chull Chae S, Seog Seo H et al. A randomized, multicenter, double-blind, placebo-controlled, 3 × 3 factorial design, phase II study to evaluate the efficacy and safety of the combination of fimasartan/amlodipine in patients with essential hypertension. Clin Ther 2015; 37: 2581–2596.e2583.

    Article  CAS  Google Scholar 

  22. Lin TH, Tsai CD, Pan JP, Hou CJY, Hsia CH, Tsai JP et al. Efficacy and tolerability between an olmesartan/amlodipine fixed-dose combination and an amlodipine double dose in mild to moderate hypertension. Kaohsiung J Med Sci 2013; 29: 265–270.

    Article  CAS  Google Scholar 

  23. Littlejohn TW III, Majul CR, Olvera R, Seeber M, Kobe M, Guthrie R et al. Original research: telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 x 4 factorial study. Postgrad Med 2009; 121: 5–14.

    Article  Google Scholar 

  24. Neldam S, Lang M, Jones R . Telmisartan and amlodipine single-pill combinations vs amlodipine monotherapy for superior blood pressure lowering and improved tolerability in patients with uncontrolled hypertension: results of the TEAMSTA-5 study. J Clin Hypertens (Greenwich) 2011; 13: 459–466.

    Article  CAS  Google Scholar 

  25. Park CG, Youn HJ, Chae SC, Yang JY, Kim MH, Hong TJ et al. Evaluation of the dose-response relationship of amlodipine and losartan combination in patients with essential hypertension: an 8-week, randomized, double-blind, factorial, phase II, multicenter study. Am J Cardiovasc Drugs 2012; 12: 35–47.

    Article  CAS  Google Scholar 

  26. Schrader J, Salvetti A, Calvo C, Akpinar E, Keeling L, Weisskopf M et al. The combination of amlodipine/valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg. Int J Clin Pract 2009; 63: 217–225.

    Article  CAS  Google Scholar 

  27. Park JB, Ha JW, Jung HO, Rhee MY . Randomized trial comparing the effects of a low-dose combination of nifedipine GITS and valsartan versus high-dose monotherapy on central hemodynamics in patients with inadequately controlled hypertension: FOCUS study. Blood Press Monit 2014; 19: 294–301.

    Article  Google Scholar 

  28. Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ . Combination therapy versus monotherapy in reducing blood pressure: meta-analysis on 11000 participants from 42 trials. Am J Med 2009; 122: 290–300.

    Article  Google Scholar 

  29. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–520.

    Article  CAS  Google Scholar 

  30. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M et al. 2013 ESH/ESC guidelines for the management of arterial hypertension. Blood Press 2013; 22: 193–278.

    Article  Google Scholar 

  31. Caballero-Gonzalez FJ . Calcium channel blockers in the management of hypertension in the elderly. Cardiovasc Hematol Agents Med Chem 2015; 12: 160–165.

    Article  Google Scholar 

  32. Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM . Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel-group trial. Lancet 2011; 377: 312–320.

    Article  CAS  Google Scholar 

  33. Lv Y, Zou Z, Chen GM, Jia HX, Zhong J, Fang WW . Amlodipine and angiotensin-converting enzyme inhibitor combination versus amlodipine monotherapy in hypertension: a meta-analysis of randomized controlled trials. Blood Press Monit 2010; 15: 195–204.

    Article  Google Scholar 

  34. Ke Y, Zhu D, Hong H, Zhu J, Wang R, Cardenas P et al. Efficacy and safety of a single-pill combination of amlodipine/valsartan in Asian hypertensive patients inadequately controlled with amlodipine monotherapy. Curr Med Res Opin 2010; 26: 1705–1713.

    Article  CAS  Google Scholar 

  35. Xu R, Sun S, Huo Y, Yun L, Huang S, Li G et al. Effects of ACEIs versus ARBs on Proteinuria or albuminuria in primary hypertension: a meta-analysis of randomized trials. Medicine (Baltimore) 2015; 94: e1560.

    Article  CAS  Google Scholar 

  36. Murthy MB, Murthy B . Amlodipine-induced petechial rash. J Postgrad Med 2011; 57: 341–342.

    Article  CAS  Google Scholar 

  37. Tuchinda P, Kulthanan K, Khankham S, Jongjarearnprasert K, Dhana N . Cutaneous adverse reactions to calcium channel blockers. Asian Pac J Allergy Immunol 2014; 32: 246–250.

    CAS  PubMed  Google Scholar 

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Acknowledgements

The study was supported by the National Natural Science Foundation of China (no. 81273594), the National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ (no. 2012ZX0903014001), the National Key Technology R&D Program (no. 2012BAI37B05), the Fundamental Research Funds of Central South University (no. 2015zzts122) and the Fundamental Research Funds for the Central Universities of Central South University (no. 2016zzts565).

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Author notes

  1. T He and X Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China

    T He, X Liu, X Y Liu, Q Y Wu & H Yuan

  2. Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China

    Y Li & H Yuan

  3. Department of Gerontology, The First Hospital of Beijing University, Beijing, People’s Republic of China

    M L Liu

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Correspondence to H Yuan.

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He, T., Liu, X., Li, Y. et al. High-dose calcium channel blocker (CCB) monotherapy vs combination therapy of standard-dose CCBs and angiotensin receptor blockers for hypertension: a meta-analysis. J Hum Hypertens 31, 79–88 (2017). https://doi.org/10.1038/jhh.2016.46

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