Review Article
Rationale for Fixed-Dose Combination Therapy to Reach Lower Blood Pressure Goals
Abstract
Expert committees in the United States and Europe formulated their currently recommended target blood pressures of <140/90 mm Hg or <130/80 mm Hg in persons with diabetes, chronic kidney disease, or coronary artery disease based on the totality of clinical data available at the time. However, accumulating evidence indicates that increased risk for cardiovascular and renal complications of hypertension may begin at a threshold of 115/75 mm Hg, suggesting that benefit from treatment may occur when blood pressure targets are lower than those currently recommended. Combination therapy with two or more agents having complementary mechanisms of action is the most effective method for achieving strict blood pressure goals in high-risk patients. Several clinical trials are under way to further determine the risks and benefits of lowering blood pressure beyond the currently recommended threshold.
Key Points
* Lowering blood pressure to levels below currently recommended goals may improve cardiovascular outcomes, especially in high-risk patients.
* The aggressive blood pressure goals needed to reduce risk in high-risk patients may be difficult to achieve.
* Most high-risk patients will require more than one antihypertensive agent to achieve their goal.
* Fixed-dose combination therapy offers a number of potential advantages over two drugs given separately.
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References
1. 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.
2. American Heart Association. Heart Disease and Stroke Statistics—2007 Update. Dallas, TX, American Heart Association, 2007.
3. Ong KL, Cheung BM, Man YB, et al. Prevalence, awareness, treatment, and control of hypertension among United States adults, 1999–2004. Hypertension 2007;49:69–75.
4. Giles T, Aranda JM Jr, Suh DC, et al. Ethnic/racial variations in blood pressure awareness, treatment, and control. J Clin Hypertens (Greenwich) 2007;9:345–354.
5. 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.
6. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the european society of hypertension (ESH) and of the european society of cardiology (ESC). J Hypertens 2007;25:1105–1187.
7. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hypertension in the prevention and management of ischemic heart disease: a scientific statement from the American heart association council for high blood pressure research and the councils on clinical cardiology and epidemiology and prevention. Circulation 2007;115:2761–2788.
8. Vasan RS, Larson MG, Leip EP, et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N Engl J Med 2001;345:1291–1297.
9. Giles TD, Berk BC, Black HR, et al. Expanding the definition and classification of hypertension. J Clin Hypertens (Greenwich) 2005;7:505–512.
10. Kshirsagar AV, Carpenter M, Bang H, et al. Blood pressure usually considered normal is associated with an elevated risk of cardiovascular disease. Am J Med 2006;119:133–141.
11. 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 one million adults in 61 prospective studies. Lancet 2002;360:1903–1913.
12. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703–713.
13. Sipahi I, Tuzcu EM, Schoenhagen P, et al. Effects of normal, pre-hypertensive, and hypertensive blood pressure levels on progression of coronary atherosclerosis. J Am Coll Cardiol 2006;48:833–838.
14. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National kidney foundation hypertension and diabetes executive committees working group Am J Kidney Dis 2000;36:646–661.
15. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American heart association councils on kidney in cardiovascular disease, high blood pressure research, clinical cardiology, and epidemiology and prevention. Circulation 2003;108:2154–2169.
16. Arauz-Pacheco C, Parrott MA, Raskin P, et al. Hypertension management in adults with diabetes. Diabetes Care 2004;27(suppl 1):S65–S67.
17. Ferdinand KC, Saunders E. Hypertension-related morbidity and mortality in African Americans: why we need to do better. J Clin Hypertens (Greenwich) 2006;8(1 suppl 1):21–30.
18. Weycker D, Nichols GA, O'Keeffe-Rosetti M, et al. Risk-factor clustering and cardiovascular disease risk in hypertensive patients. Am J Hypertens 2007;20:599–607.
19. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351:1755–1762.
20. Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383–393.
21. Cushman WC, Grimm RH Jr, Cutler JA, et al. Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Am J Cardiol 2007;99(12A):44i–55i.
22. Kundhal K, Lok CE. Clinical epidemiology of cardiovascular disease in chronic kidney disease. Nephron Clin Pract 2005;101:c47–c52.
23. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002;288:2421–2431.
24. Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med 2005;142:342–351.
25. Appel LJ, Middleton J, Miller ER III, et al. The rationale and design of the AASK cohort study. J Am Soc Nephrol 2003;14(7 Suppl 2):S166–S172.
26. Pepine CJ, Handberg EM, Cooper-DeHoff RM, 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;290:2805–2816.
27. Pepine CJ. What is the optimal blood pressure and drug therapy for patients with coronary artery disease? JAMA 2004;292:2271–2273.
28. Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217–2225.
29. Stewart D, Johnson W, Saunders E. Hypertension in black Americans as a special population: why so special? Curr Cardiol Rep 2006;8:405–410.
30. Hertz RP, Unger AN, Cornell JA, et al. Racial disparities in hypertension prevalence, awareness, and management. Arch Intern Med 2005;165:2098–2104.
31. Levine RS, Foster JE, Fullilove RE, et al. Black-white inequalities in mortality and life expectancy, 1933–1999: implications for healthy people 2010. Pub Health Rep 2001;116:474–483.
32. 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.
33. Pickering TG. Hypertension in Hispanics. J Clin Hypertens (Greenwich) 2004;6:279–282.
34. Centers for Disease Control and Prevention. Hypertension-related mortality among Hispanic subpopulations: United States – 1995–2002. MMWR Morb Mort Wkly Rep 2006;55:177–180.
35. Hunt KJ, Resendez RG, Williams K, et al. All-cause and cardiovascular mortality among Mexican-American and non-Hispanic white older participants in the San Antonio Heart Study: evidence against the “Hispanic paradox.” Am J Epidemiol 2003;158:1048–1057.
36. Gale K. Hispanic women develop cardiac risk factors early. Reuters Health Information. March 2, 2007. Available at: http://www.reutershealth.com/archive/2007/03/02/eline/links/20070302elin028.html. Accessed April 2, 2007
37. American Heart Association. Celebrate Hispanic heritage—protect your heart. September 15, 2005. Available at: http://www.americanheart.org/presenter.jhtml?identifier=3034056. Accessed March 12, 2007.
38. Kjeldsen SE, Aksnes TA, de la Sierra A, et al. Amlodipine and valsartan: calcium channel blockers/angiotensin II receptor blockers combination for hypertension. Therapy 2007;4:31–40.
39. Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care 2000;9(9 suppl):2–6.
40. The 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;288:2981–2997.
41. Five-year findings of the Hypertension Detection, Follow-up Program I. reduction in mortality of persons with high blood pressure, including mild hypertension. Hypertension Detection and Follow-up Program Cooperative Group. JAMA 1979;242:2562–2571.
42. Mortality rates after 10.5 years for hypertensive participants in the Multiple Risk Factor Intervention Trial. Circulation 1990;82:1616–1628.
43. Prevention of stroke by antihypertensive treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991;265:3255–3264.
44. Ernst ME, Carter BL, Goerdt CJ, et al. Comparative antihypertensive effects of hydrochlorothiazide and chlorthalidone on ambulatory and office blood pressure. Hypertension 2006;47:352–358.
45. Philipp T, Smith TR, Glazer R, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007;29:563–580.
46. Mason RP. Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research. Cerebrovasc Dis 2003;16(suppl 3):11–17.
47. Arishiro K, Hoshiga M, Negoro N, et al. Angiotensin receptor-1 blocker inhibits atherosclerotic changes and endothelial disruption of the aortic valve in hypercholesterolemic rabbits. J Am Coll Cardiol 2007;49:1482–1489.
48. Suzuki J, Iwai M, Li Z, et al. Effect of combination of calcium antagonist, azelnidipine, and AT1 receptor blocker, olmesartan, on atherosclerosis in apolipoprotein E-deficient mice. J Hypertens 2005;23:1383–1389.
49. Bakris G, Molitch M, Hewkin A, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care 2006;29:2592–2597.
50. Wright JT Jr, Harris-Haywood S, Pressel S, et al. Clinical outcomes by race in hypertensive patients with and without the metabolic syndrome: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2008;168:207–217.
51. Black HR, Davis B, Barzilay J, et al. Metabolic and clinical outcomes in nondiabetic individuals with the metabolic syndrome assigned to chlorthalidone, amlodipine, or lisinopril as initial treatment for hypertension: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Diabetes Care 2008;31:353–360.
52. Weber MA, Bakris GL, Dahlöf B, et al. Baseline characteristics in the Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: a hypertensive population at high cardiovascular risk. Blood Press 2007;16:13–19.
53. Jamerson K, Bakris GL, Dahlöf B, et al. Exceptional early blood pressure control rates: the ACCOMPLISH trial. Blood Press 2007;16:80–86.
54. O'Riordan M. ACCOMPLISH at 18 months: better blood-pressure control with single-tablet combination therapy. Available at: http://www.medscape.com/viewarticle/557061. Accessed August 1, 2007.
55. Russell M, Fleg JL, Galloway WJ, et al. Examination of lower targets for low-density lipoprotein cholesterol and blood pressure in diabetes: the Stop Atherosclerosis in Native Diabetics Study (SANDS). Am Heart J 2006;152:867–875.
