, Volume 67, Issue 9, pp 1309–1327

Dihydropyridine Calcium Channel Antagonists in the Management of Hypertension

  • Benjamin J. Epstein
  • Katherine Vogel
  • Biff F. Palmer
Review Article


Dihydropyridine calcium channel antagonists have been maligned in recent years because of concerns regarding their cardiovascular and overall safety profile. Specifically, it was widely publicised in the mid-1990s that these agents might increase the risk of myocardial infarction, gastrointestinal bleeding and cancer. Data linking these agents with increased cardiovascular risk were based on nonrandomised studies and implicated short-acting, immediate-release agents. These results were inappropriately extrapolated to longer-acting compounds, extended-release products, and to the non-dihydropyridine class. Fortunately, recent studies have vindicated the class from safety allegations. These studies are reviewed herein.

Compared with both diuretics and contemporary agents, amlodipine decreases cardiovascular events to a similar or greater extent without evidence for increased coronary heart disease, gastrointestinal bleeding or cancer. Despite these data, initial concerns have had lasting repercussions, as the use of dihydropyridine calcium channel antagonists appears to lag behind what emerging data would support. Dihydropyridine calcium channel antagonists have several noteworthy attributes that merit consideration in the management of hypertension. The blood pressure response to this class of drugs is less contingent on patient factors such as age and race compared with other antihypertensive agents (e.g. ACE inhibitors). Dihydropyridine calcium channel antagonists may exert effects that protect against stroke that are independent of their blood pressure-lowering mechanism. Unlike diuretics and β-adrenoceptor anatagonists (β-blockers), dihydropyridine calcium channel antagonists are lipid neutral and do not disturb glucose homeostasis. Dihydropyridine calcium channel antagonists demonstrate a highly desirable profile when administered as part of combination therapy. Combinations of dihydropyridine calcium channel antagonists and ACE inhibitors or angiotensin receptor antagonists display additive efficacy and an enviable adverse-effect profile. Collectively, the cardiovascular benefit, metabolic neutrality and homogeneous blood pressure response illuminated in recent studies, and reviewed here, represent a reaffirmation of the benefit of long-acting dihydropyridine calcium channel antagonists and should serve to help reinforce the critical importance of these agents in the therapeutic armamentarium against cardiovascular disease.


  1. 1.
    Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937–52PubMedCrossRefGoogle Scholar
  2. 2.
    UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317: 703–13CrossRefGoogle Scholar
  3. 3.
    Weber MA, Julius S, Kjeldsen SE, et al. Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial. Lancet 2004; 363: 2049–51PubMedCrossRefGoogle Scholar
  4. 4.
    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: 1903–13PubMedCrossRefGoogle Scholar
  5. 5.
    Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022–31PubMedCrossRefGoogle Scholar
  6. 6.
    Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–72PubMedCrossRefGoogle Scholar
  7. 7.
    Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 2003; 290: 199–206PubMedCrossRefGoogle Scholar
  8. 8.
    Fournier A, Messerli FH, Achard JM, et al. Cerebroprotection mediated by angiotensin II: a hypothesis supported by recent randomized clinical trials. J Am Coll Cardiol 2004; 43:1343–7PubMedCrossRefGoogle Scholar
  9. 9.
    Epstein BJ, Gums JG. Angiotensin receptor blockers versus ACE inhibitors: prevention of death and myocardial infarction in high-risk populations. Ann Pharmacother 2005; 39: 470–80PubMedCrossRefGoogle Scholar
  10. 10.
    Sever PS, Poulter NR, Elliott WJ, et al. Blood pressure reduction is not the only determinant of outcome. Circulation 2006; 113: 2754–72PubMedCrossRefGoogle Scholar
  11. 11.
    Choi KL, Elliott WJ. Antihypertensive, antiproteinuric therapy and myocardial infarction and stroke prevention. Curr Hypertens Rep 2005; 7: 367–73PubMedCrossRefGoogle Scholar
  12. 12.
    Lindholm LH, Carlberg B, Samuelsson O. Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 2005; 366: 1545–53PubMedCrossRefGoogle Scholar
  13. 13.
    Izuhara Y, Nangaku M, Inagi R, et al. Renoprotective properties of angiotensin receptor blockers beyond blood pressure lowering. J Am Soc Nephrol 2005; 16: 3631–41PubMedCrossRefGoogle Scholar
  14. 14.
    Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. The Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J Med 1993; 328: 914–21PubMedCrossRefGoogle Scholar
  15. 15.
    Mason RP, Marche P, Hintze TH. Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine. Arterioscler Thromb Vasc 2003 Dec; 23 (12): 2155–63CrossRefGoogle Scholar
  16. 16.
    Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet 2007; 369: 201–7PubMedCrossRefGoogle Scholar
  17. 17.
    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 ben-droflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906PubMedCrossRefGoogle Scholar
  18. 18.
    Julius S, Kjeldsin SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022–31PubMedCrossRefGoogle Scholar
  19. 19.
    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: 2981–97Google Scholar
  20. 20.
    Messerli FH, Stassen JA. Amlodipine better than lisinopril? How one randomized clinical trial ended fallacies from observational studies [published erratum in Hypertension 2006 Oct; 48 (4): e24]. Hypertension 2006 Sep; 48 (3): 359–61PubMedCrossRefGoogle Scholar
  21. 21.
    Psaty BM, Manolio TA, Smith NL, et al. Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. Arch Intern Med 2002; 162: 2325–32PubMedCrossRefGoogle Scholar
  22. 22.
    Ma J, Lee KV, Stafford RS. Changes in antihypertensive prescribing during us outpatient visits for uncomplicated hypertension between 1993 and 2004. Hypertension 2006 Sep 18. EpubGoogle Scholar
  23. 23.
    Ohbayashi Y, Tsutamoto T, Sakaguchi T, et al. Effect of an angiotensin II type 1 receptor blocker, valsartan, on neurohu-moral factors in patients with hypertension: comparison with a long-acting calcium channel antagonist, amlodipine. J Cardiovasc Pharmacol 2003; 42 Suppl. 1: S71–4PubMedCrossRefGoogle Scholar
  24. 24.
    Psaty BM, Heckbert SR, Koepsell TD, et al. The risk of myocar-dial infarction associated with antihypertensive drug therapies. JAMA 1995; 274: 620–5PubMedCrossRefGoogle Scholar
  25. 25.
    Psaty BM. On record, US Food and Drug Administration hearing. Bethesda (MD), 1996 Jan 25Google Scholar
  26. 26.
    Messerli FH. Safety of calcium antagonists: dissecting the evidence. Am J Cardiol 1996; 78: 19–23PubMedCrossRefGoogle Scholar
  27. 27.
    Opie LH, Yusuf S, Kubler W. Current status of safety and efficacy of calcium channel blockers in cardiovascular diseases: a critical analysis based on 100 studies. Prog Cardiovasc Dis 2000; 43: 171–96PubMedCrossRefGoogle Scholar
  28. 28.
    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: 2805–16PubMedCrossRefGoogle Scholar
  29. 29.
    Kloner RA, Vetrovec G, Materson BJ, et al. Safety of long-acting dihydropyridine calcium channel blockers in hypertensive patients. Am J Cardiol 1998; 81 (2): 163–9PubMedCrossRefGoogle Scholar
  30. 30.
    Bakris GL, Williams M, Dworkin L. 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 Sep; 36 (3): 646–61PubMedCrossRefGoogle Scholar
  31. 31.
    Abbott KC, Bakris GL. What have we learned from the current trials? Med Clin North Am 2004; 88: 189–207PubMedCrossRefGoogle Scholar
  32. 32.
    Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001 Sep 20; 345 (12): 870–8PubMedCrossRefGoogle Scholar
  33. 33.
    Brenner BM, Cooper ME, de Zeeuw D. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001 Sep 20; 345 (12): 861–9PubMedCrossRefGoogle Scholar
  34. 34.
    Palmer BF. Disturbances in renal autoregulation and the susceptibility to hypertension-induced chronic kidney disease. Am J Medical Sci 2004; 328: 330–43Google Scholar
  35. 35.
    Bakris GL, Copley JB, Vicknair N, et al. Calcium channel blockers versus other antihypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996; 50: 1641–50PubMedCrossRefGoogle Scholar
  36. 36.
    Agodoa LY, Appel L, Bakris GL, et al. Effect of ramipril vs amlodipine on renal outcomes in hypertensive nephrosclerosis: a randomized controlled trial. JAMA 2001; 285: 2719–28PubMedCrossRefGoogle Scholar
  37. 37.
    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. 2002 Nov 20; 288 (19): 2421–31Google Scholar
  38. 38.
    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: 851–60PubMedCrossRefGoogle Scholar
  39. 39.
    Pahor M, Guralnik JM, Furberg CD, et al. Risk of gastrointestinal haemorrhage with calcium antagonists in hypertensive persons over 67 years old. Lancet 1996; 347: 1061–5PubMedCrossRefGoogle Scholar
  40. 40.
    Rodriguez LC, Cattaruzzi C, Tronçon MG, et al. Risk of hospi-talization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists and other antihypertensive drugs. Arch Intern Med 1998; 158: 33–9CrossRefGoogle Scholar
  41. 41.
    Kaplan RC, Heckbert SR, Koepsell TD, et al. Use of calcium channel blockers and risk of hospitalized gastrointestinal bleeding. Arch Intern Med 2000; 160: 1849–55PubMedCrossRefGoogle Scholar
  42. 42.
    Pahor M, Guralnik JM, Salive ME, et al. Do calcium-channel blockers increase the risk of cancer? Am J Hypertens 1996; 9: 695–9PubMedCrossRefGoogle Scholar
  43. 43.
    Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet 1996; 348: 493–7PubMedCrossRefGoogle Scholar
  44. 44.
    Hardell L, Fredrikson M, Axelson O. Case-control study in colon cancer regarding previous diseases and drug intake. Int J Oncol 1995; 8: 439–45Google Scholar
  45. 45.
    Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol 1999 Dec; 34 (7): 1857–66PubMedCrossRefGoogle Scholar
  46. 46.
    Kizer JR, Kimmel SE. Epidemiologic review of the calcium channel blocker drugs: an up-to-date perspective on the proposed hazards. Arch Intern Med 2001 14; 161: 1145–58PubMedCrossRefGoogle Scholar
  47. 47.
    Gore JM, Sloan M, Price TR, et al. Intracerebral hemorrhage, cerebral infarction, and subdural hematoma after acute myocardial infarction and thrombolytic therapy in the Thrombolysis in Myocardial Infarction Study: thrombolysis in myocardial infarction, phase II, pilot and clinical trial. Circulation 1991; 83: 448–59PubMedCrossRefGoogle Scholar
  48. 48.
    Fallowfield JM, Blenkinsopp J, Raza A, et al. Post-marketing surveillance of lisinopril in general practice in the UK. Br J Clin Pract 1993; 47: 296–304PubMedGoogle Scholar
  49. 49.
    Poole-Wilson PA, Lubsen J, Kirwan BA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004; 364: 849–57PubMedCrossRefGoogle Scholar
  50. 50.
    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: 2217–25PubMedCrossRefGoogle Scholar
  51. 51.
    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. FEVER Study Group. J Hypertens 2005; 23: 2157–72PubMedCrossRefGoogle Scholar
  52. 52.
    Brown MJ, Palmer CR, Castaigne A, 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: 366–72PubMedCrossRefGoogle Scholar
  53. 53.
    ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. JAMA 2000; 283: 1967–75CrossRefGoogle Scholar
  54. 54.
    Leenen FH, Nwachuku CE, Black HR, et al. Clinical events in high-risk hypertensive patients randomly assigned to calcium channel blocker versus angiotensin-converting enzyme inhibitor in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Hypertension 2006, 846Google Scholar
  55. 55.
    Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165: 1401–9PubMedCrossRefGoogle Scholar
  56. 56.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study investigators. N Engl J Med 2000; 342: 145–53PubMedCrossRefGoogle Scholar
  57. 57.
    Fox KM, on behalf of EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003; 362: 782–8PubMedCrossRefGoogle Scholar
  58. 58.
    Kjeldsen SE, Julius S, Mancia G, et al. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens 2006; 24: 1405–12PubMedCrossRefGoogle Scholar
  59. 59.
    McCall KL, Craddock D, Edwards K. Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis. Pharmacotherapy 2006; 26: 1297–306PubMedCrossRefGoogle Scholar
  60. 60.
    Weber MA, Julius S, Kjeldsen SE, et al. The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial: outcomes in patients receiving monotherapy. Hypertension 2006; 48: 385–91PubMedCrossRefGoogle Scholar
  61. 61.
    Braunwald E, Domanski MJ, Fowler SE, et al. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. PEACE Trial Investigators. N Engl J Med 2004; 351: 2058–68PubMedCrossRefGoogle Scholar
  62. 62.
    Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. REVERSAL Investigators. JAMA 2004; 291: 1071–80PubMedCrossRefGoogle Scholar
  63. 63.
    Zanchetti A, Bond MG, Hennig M, et al. Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, long-term trial. European Lacidipine Study on Atherosclerosis investigators. Circulation 2002; 106: 2422–7PubMedCrossRefGoogle Scholar
  64. 64.
    Zanchetti A, Rosei EA, Dal Palu C, et al. The Verapamil in Hypertension and Atherosclerosis Study (VHAS): results of long-term randomized treatment with either verapamil or chlorthalidone on carotid intima-media thickness. J Hypertens 1998; 16: 1667–76PubMedCrossRefGoogle Scholar
  65. 65.
    Poulter NR, Wedel H, Dahlof B, et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). ASCOT Investigators. Lancet 2005; 366: 907–13PubMedCrossRefGoogle Scholar
  66. 66.
    Modeliard SS, Serot JM, Mansour J, et al. FEVER study: a trial further supporting the concept of a blood pressure-independent stroke protective effect by dihydropyridines. J Hypertens 2006; 24: 1213–5PubMedCrossRefGoogle Scholar
  67. 67.
    Turnbull F, for Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospec-tively-designed overviews of randomised trials. Lancet 2003; 362: 1527–35PubMedCrossRefGoogle Scholar
  68. 68.
    Epstein BJ, Gums JG. Can the renin-angiotensin system protect against stroke? A focus on angiotensin II receptor blockers. Pharmacotherapy 2005; 25: 531–9PubMedCrossRefGoogle Scholar
  69. 69.
    Fournier A, Messerli FH, Achard JM, et al. Cerebroprotection mediated by angiotensin II: a hypothesis supported by recent randomized clinical trials. J Am Coll Cardiol 2004; 43: 1343–7PubMedCrossRefGoogle Scholar
  70. 70.
    Psaty BM, Smith NL, Siscovick DS, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA 1997 Mar 5; 277 (9): 739–45PubMedCrossRefGoogle Scholar
  71. 71.
    Furberg CD, Psaty BM, Meyer JV. Nifedipine: dose-related increase in mortality in patients with coronary heart disease. Circulation 1995 Sep 1; 92 (5): 1326–31PubMedCrossRefGoogle Scholar
  72. 72.
    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: 2534–44PubMedCrossRefGoogle Scholar
  73. 73.
    Kannel WB. Fifty years of Framingham study contributions to understanding hypertension. J Hum Hypertens 2000; 14:83–90PubMedCrossRefGoogle Scholar
  74. 74.
    Bakris GL, Sowers JR. When does new onset diabetes resulting from antihypertensive therapy increase cardiovascular risk? Hypertension 2004; 43: 941–2PubMedCrossRefGoogle Scholar
  75. 75.
    Verdecchia P, Reboldi GP, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension 2004; 43: 963–9PubMedCrossRefGoogle Scholar
  76. 76.
    Kostis JB, Wilson AC, Freudenberger RS, et al. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. SHEP Collaborative Research Group. Am J Cardiol 2005; 95: 29–35PubMedCrossRefGoogle Scholar
  77. 77.
    Zillich AJ, Garg J, Basu S, et al. Thiazide diuretics, potassium, and the development of diabetes: a quantitative review. Hypertension 2006; 48: 219–24PubMedCrossRefGoogle Scholar
  78. 78.
    American Heart Association. Heart disease and stroke statistics: 2005 update. Dallas (TX): American Heart Association, 2005Google Scholar
  79. 79.
    Cooper R, Rotimi C. Hypertension in blacks. Am J Hypertens 1997; 10: 804–12PubMedCrossRefGoogle Scholar
  80. 80.
    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: 525–41PubMedCrossRefGoogle Scholar
  81. 81.
    Saunders E, Weir MR, Kong BW, et al. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Arch Intern Med. 1990; 150: 1707–13PubMedCrossRefGoogle Scholar
  82. 82.
    Cushman WC, Reda DJ, Perry HM, et al. Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Arch Intern Med 2000; 160: 825–31PubMedCrossRefGoogle Scholar
  83. 83.
    Materson BJ, Reda DJ, Cushman WC, et al. Single-drug therapy for hypertension in men: a comparison of six antihypertensive agents with placebo. N Engl J Med 1993; 328: 914–21PubMedCrossRefGoogle Scholar
  84. 84.
    Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165: 1401–9PubMedCrossRefGoogle Scholar
  85. 85.
    Trenkwalder P. Combination therapy with AT(l)-receptor blockers. J Hum Hypertens 2002; 16 Suppl. 3: S17–25PubMedCrossRefGoogle Scholar
  86. 86.
    Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure? J Renin Angiotensin Aldosterone Syst 2004; 5: 155–60PubMedCrossRefGoogle Scholar
  87. 87.
    Malacco E, Vari N, Capuano V, et al. A randomized, double-blind, active-controlled, parallel-group comparison of val-sartan and amlodipine in the treatment of isolated systolic hypertension in elderly patients: the Val-Syst study. Clin Ther 2003; 25: 2765–80PubMedCrossRefGoogle Scholar
  88. 88.
    Whitworth JA, for World Health Organization. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 1983–92Google Scholar
  89. 89.
    Cifkova R, Erdine S, Fagard R, et al. Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertens 2003; 21: 1779–86PubMedCrossRefGoogle Scholar
  90. 90.
    Management of hypertension in adults in primary care: partial update. The National Institute for Health and Clinical Excellence [online]. Available from URL: http://www.nice.org.uk/guidance/CG34. [Accessed 2007 Feb 21]
  91. 91.
    Sica DA. Rationale for fixed-dose combinations in the treatment of hypertension: the cycle repeats. Drugs 2002; 62: 443–62PubMedCrossRefGoogle Scholar
  92. 92.
    Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 2005; 45: 880–6PubMedCrossRefGoogle Scholar
  93. 93.
    MacKinnon M, Shurraw S, Akbari A, et al. Combination therapy with an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systematic review of the efficacy and safety data. Am J Kidney Dis 2006; 48: 8–20PubMedCrossRefGoogle Scholar
  94. 94.
    Cohn JN, Tognoni G, for Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345 (23): 1667–75PubMedCrossRefGoogle Scholar
  95. 95.
    McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. CHARM Investigators and Committees. Lancet 2003; 362: 767–71PubMedCrossRefGoogle Scholar
  96. 96.
    Gums JG, Lopez LM, Quay GP, et al. Comparative evaluation of enalapril and hydrochlorothiazide in elderly patients with mild to moderate hypertension. Drug Intell Clin Pharm 1988; 22: 680–4PubMedGoogle Scholar
  97. 97.
    Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure? J Renin Angiotensin Aldosterone Syst 2004; 5: 155–60PubMedCrossRefGoogle Scholar
  98. 98.
    Mimran A, Weir MR. Angiotensin-receptor blockers and diuretics: advantages of combination. Blood Press 2005; 14: 6–11PubMedCrossRefGoogle Scholar
  99. 99.
    Poldermans D, Gamboa R, Fomina I, et al. Comparative safety and blood pressure-lowering efficacy of a combination of amlodipine/valsartan and lisinopril/HCTZ in patients with stage 2 hypertension [abstract P-217]. Presented at American Society of Hypertension; New York (NY); 2006 May 17Google Scholar
  100. 100.
    Stergiou GS, Makris T, Papavasiliou M, et al. Comparison of antihypertensive effects of an angiotensin-converting enzyme inhibitor, a calcium antagonist and a diuretic in patients with hypertension not controlled by angiotensin receptor blocker monotherapy. J Hypertens 2005; 23: 883–9PubMedCrossRefGoogle Scholar
  101. 101.
    Messerli FH, Weir MR, Neutel JM. Combination therapy of amlodipine/benazepril versus monotherapy of amlodipine in a practice-based setting. Am J Hypertens 2002 Jun; 15 (6): 550–6PubMedCrossRefGoogle Scholar
  102. 102.
    Messerli FH. Vasodilatory edema: a common side effect of antihypertensive therapy. Curr Cardiol Rep 2002; 4: 479-82PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Benjamin J. Epstein
    • 1
  • Katherine Vogel
    • 2
  • Biff F. Palmer
    • 3
  1. 1.Department of Pharmacy Practice and Division of Internal Medicine, Colleges of Pharmacy and MedicineUniversity of FloridaGainesvilleUSA
  2. 2.North Florida/South Georgia Veterans Health System, and College of PharmacyUniversity of FloridaGainesvilleUSA
  3. 3.Department of Medicine, Division of NephrologyUniversity of Texas Southwestern Medical SchoolDallasUSA

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