Review Article

Rationale for Combination Therapy in Hypertension Management: Focus on Angiotensin Receptor Blockers and Thiazide Diuretics

Authors: David T. Nash, MD


Despite recognition that hypertension is a major risk factor for cardiovascular events and mortality, blood pressure control rates remain low in the US population. Reflecting clinical trial results, hypertension management guidelines assert the clinical benefit of achieving current blood pressure goals and indicate that most patients will require 2 or more drugs to reach goal. Well-designed drug combinations counter hypertension via complementary mechanisms that increase antihypertensive efficacy, potentially with lower rates of adverse events than higher dose monotherapy regimens. Lower adverse event rates, in turn, may contribute to greater adherence with treatment. The combination of a low-dose diuretic with agents that block the effects of the renin-angiotensin system (RAS), such as angiotensin receptor blockers, has been found in numerous clinical trials to be highly effective for lowering blood pressure in patients with uncomplicated as well as high-risk hypertension, with a comparable favorable side effect profile compared with monotherapy. Moreover, agents that block the RAS are associated with a lower risk of new-onset diabetes mellitus than other antihypertensive classes. Complementary combinations of antihypertensive agents provide an efficient and effective approach to hypertension management.

Key Points

* Results of large-scale clinical trials indicate that most patients, particularly those at high risk for cardiovascular events require 2 or more antihypertensive agents to reach blood pressure goals recommended by current clinical guidelines.

* Because the pathophysiology of hypertension is multifactorial, well-designed combination regimens that target complementary blood pressure-lowering mechanisms provide an effective approach to achieving goals.

* The combination of an angiotensin receptor blocker with a thiazide diuretic provides several advantages for treating essential hypertension as well as patients at high risk for cardiovascular or renal disease events, based on their additive efficacy and lower rate of adverse effects and treatment discontinuations compared with higher dose component monotherapy or other antihypertensive regimens.

* Rates of patient adherence to antihypertensive therapy are higher with angiotensin receptor blockers than other antihypertensive classes in several observational studies.

* Agents that block the renin-angiotensin system also are associated with a lower incidence of new-onset diabetes than other antihypertensive classes or placebo.

This content is limited to qualifying members.

Existing members, please login first.

If you have an existing account please login now to access this article or view your purchase options.

Purchase only this article ($15)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.


1. Messerli FH. This day 50 years ago. N Engl J Med 1995;332:1038–1039.
2. Hachinski V. Stalin’s last years: delusions or dementia? Eur J Neurol 1999;6:129–132.
3. Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension 2004;44:398–404.
4. Cheung BM, Ong KL, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension: United States National Health and Nutrition Examination Survey 2001-2002. J Clin Hypertens (Greenwich) 2006;8:93–98.
5. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. N Engl J Med 2001;345:479–486.
6. 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;42:1206–1252.
7. Franklin SS, Jacobs MJ, Wong ND, et al. Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 2001;37:869–874.
8. Turnbull F, Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362:1527–1535.
9. Staessen JA, Wang JG, Thijs L. Cardiovascular prevention and blood pressure reduction: a quantitative overview updated until 1 March 2003. J Hypertens 2003;21:1055–1076.
10. Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs 2002;62:443–462.
11. Giles TD. Assessment of global risk: a foundation for a new, better definition of hypertension. J Clin Hypertens (Greenwich). 2006;8(8 Suppl 2):5–14.
12. Conlin PR, Gerth WC, Fox JB, et al. Four-year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other antihypertensive drug classes.Clin Ther 2001;23:1999–2010.
13. Caro JJ, Speckman JL, Salas M, et al. Effect of initial drug choice on persistence with antihypertensive therapy: the importance of actual practice data. CMAJ 1999;160:41–46.
14. Law MR, Wald NJ, Morris JK, et al. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427–1431.
15. Burnier M. Angiotensin II type 1 receptor blockers. Circulation 2001;103:904–912.
16. Dickstein K, Kjekshus J, and the OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial.Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002;360: 752–760.
17. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial: the Losartan Heart Failure Survival Study ELITE II. Lancet 2000;355:1582–1587.
18. Pfeffer MA, McMurray JJ, Velazquez EJ, et al, for the Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893–1906.
19. Julius S, Kjeldsen SE, Weber M, et al, for the VALUE Trial Group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022–2031.
20. Viberti G, Wheeldon NM, MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation 2002;106:672–678.
21. Dahlöf B, Devereux RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.
22. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–1675.
23. Granger CB, McMurray JJ, Yusuf S, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003;362:772–776.
24. McMurray JJ, Ostergren J, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–771.
25. Bakris GL, Williams M, Dworkin L, et al, for the National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis 2000;36:646–661.
26. Cushman WC, Ford CE, Cutler JA, et al. Success and predictors of blood pressure control in diverse North American settings: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin Hypertens (Greenwich) 2002;4:393–404.
27. Arauz-Pacheco C, Parrott MA, Raskin P, et al, American Diabetes Association. Hypertension management in adults with diabetes. Diabetes Care 2004;27 (Suppl 1):S65–S67.
28. Hertz RP, Unger AN, Cornell JA, et al. Racial disparities in hypertension prevalence, awareness, and management. Arch Intern Med 2005;165:2098–2104.
29. American Heart Association. Heart Disease and Stroke Statistics: 2004 Update. Dallas: American Heart Association; 2004.
30. Douglas JG, Bakris GL, Epstein M, et al. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med 2003;163:525–541.
31. Waeber B. Very-low-dose combination: a first-line choice for the treatment of hypertension? J Hypertens Suppl 2003;21(Suppl 3):S3–S10.
32. Waeber B. Combination therapy with ACE inhibitors/angiotensin II receptor antagonists and diuretics in hypertension. Expert Rev Cardiovasc Ther 2003;1:43–50.
33. Elliott WJ. Therapeutic trials comparing angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Curr Hypertens Rep 2000;2:402–411.
34. Salerno CM, Demopoulos L, Mukherjee R, et al. Combination angiotensin receptor blocker/hydrochlorothiazide as initial therapy in the treatment of patients with severe hypertension. J Clin Hypertens (Greenwich) 2004;6:614–620.
35. Lacourcière Y, Poirier L, Hebert D, et al. Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: an 8-week, randomized, double-blind, parallel-group trial. Clin Ther 2005;27:1013–1021.
36. Mallion JM, Carretta R, Trenkwalder P, et al. Valsartan/hydrochlorothiazide is effective in hypertensive patients inadequately controlled by valsartan monotherapy. Blood Press Suppl 2003;1:36–43.
37. Sachse A, Verboom CN, Jäger B. Efficacy of eprosartan in combination with HCTZ in patients with essential hypertension. J Hum Hypertens 2002;16:169–176.
38. Chrysant SG, Weber MA, Wang AC, et al. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Am J Hypertens 2004;17:252–259.
39. Lacourcière Y, Poirier L. Antihypertensive effects of two fixed-dose combinations of losartan and hydrochlorothiazide versus hydrochlorothiazide monotherapy in subjects with ambulatory systolic hypertension. Am J Hypertens 2003;16:1036–1042.
40. Weir MR, Ferdinand KC, Flack JM, et al. A noninferiority comparison of valsartan/hydrochlorothiazide combination versus amlodipine in black hypertensives. Hypertension 2005;46:508–513.
41. Neldam S, Edwards C, ATHOS Study Group. Telmisartan plus HCTZ vs amlodipine plus HCTZ in older patients with systolic hypertension: results from a large ambulatory blood pressure monitoring study. Am J Geriatr Cardiol 2006;15:151–160.
42. Franco RJ, Goldflus S, McQuitty M, et al. Efficacy and tolerability of the combination valsartan/hydrochlorothiazide compared with amlodipine in a mild-to-moderately hypertensive Brazilian population. Blood Press Suppl 2003;2:41–47.
43. Ruilope LM, Malacco E, Khder Y, et al. Efficacy and tolerability of combination therapy with valsartan plus hydrochlorothiazide compared with amlodipine monotherapy in hypertensive patients with other cardiovascular risk factors: the VAST study. Clin Ther 2005;27:578–587.
44. Ruilope LM, Heintz D, Brandão AA, et al. Twenty-four-hour ambulatory blood-pressure effects of valsartan and hydrochlorothiazide combinations compared with amlodipine in hypertensive patients at increased cardiovascular risk: a VAST sub-study. Blood Press Monit 2005;10: 85–91.
45. de Pablos-Velasco PL, Pazos Toral F, Esmatjes JE, et al. Losartan titration versus diuretic combination in type 2 diabetic patients. J Hypertens 2002;20:715–719.
46. Pool J Glazer R, Weinberger M, et al. Treatment with valsartan and hydrochlorothiazide alone and in combination at doses up to 320/25 mg provides effective blood pressure control in hypertensive patients. Presented at the 21st annual meeting of the American Society of Hypertension; New York; May 16–20, 2006.
47. Weir MR. Angiotensin II receptor blockers: the importance of dose in cardiovascular and renal risk reduction. J Clin Hypertens (Greenwich) 2004;6:315–323.
48. Parving HH, Lehnert H, Brochner-Mortensen J, et al, for the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345:870–878.
49. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861–869.
50. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345:851–860.
51. Abuissa H, Jones PG, Marso SP, et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 2005;46:821–826.
52. 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;288:2981–2997.
53. Lindholm L, Ibsen H, Dahlöf B, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:1004–1010.
54. Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol 2004;44:509–512.
55. Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004;43:963–969.
56. Aguilar D, Solomon SD, Køber L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the Valsartan in Acute Myocardial Infarction (VALIANT) Trial. Circulation 2004;110:1572–1578.
57. Degli Esposti E, Sturani A, Di Martino M, et al. Long-term persistence with antihypertensive drugs in new patients. J Hum Hypertens 2002;16:439–444.
58. Bloom BS. Continuation of initial antihypertensive medication after 1 year of therapy. Clin Ther 1998;20:671–681.
59. Marentette MA, Gerth WC, Billings DK, et al. Antihypertensive persistence and drug class. Can J Cardiol 2002;18:649–656.
60. Hasford J, Mimran A, Simons WR. A population-based European cohort study of persistence in newly diagnosed hypertensive patients. J Hum Hypertens 2002;16:569–575.
61. Wogen J, Kreilick CA, Livornese RC, et al. Patient adherence with amlodipine, lisinopril, or valsartan therapy in a usual-care setting. J Manag Care Pharm 2003;9:424–429.
62. Degli Esposti L, Di Martino M, Saragoni S, et al. Pharmacoeconomics of antihypertensive drug treatment: an analysis of how long patients remain on various antihypertensive therapies. J Clin Hypertens (Greenwich) 2004;6:76–84.
63. Neutel JM, Smith DH. Improving patient compliance: a major goal in the management of hypertension. J Clin Hypertens (Greenwich) 2003;5:127–132.
64. Lewington S, Clarke R, Qizilbash N, et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for 1 million adults in 61 prospective studies. Lancet 2002;360:1903–1913.