American Journal of Cardiovascular Drugs

, Volume 9, Issue 5, pp 309–330 | Cite as

Amlodipine/Valsartan Single-Pill Combination

A Review of its Use in the Management of Hypertension
Adis Drug Evaluation

Summary

Abstract

Single-pill combinations of the dihydropyridine calcium channel blocker (CCB) amlodipine and the angiotensin II receptor blocker valsartan (amlodipine/valsartan) [Exforge®] are available in the US for the treatment of patients with hypertension. Prescribing information for amlodipine/valsartan states that it may be used in patients whose BP is not adequately controlled on either component monotherapy, and as initial therapy in patients who are likely to need multiple drugs to achieve their BP goals.

The antihypertensive efficacy of combinations of once-daily oral amlodipine and valsartan (administered as separate agents or as amlodipine/valsartan) has been demonstrated in several large, randomized, double-blind clinical trials of 8–16 weeks’ duration; BP reductions were maintained for ≈1 year in open-label extensions of some of these studies. Combination therapy was more effective than amlodipine or valsartan monotherapy in reducing BP in patients with mild to moderate hypertension, and more effective than amlodipine monotherapy in reducing BP in patients with moderate to severe (stage 2) hypertension. In addition, switching to amlodipine plus valsartan was more effective than continuation of monotherapy in reducing BP in patients with hypertension uncontrolled on amlodipine or valsartan monotherapy. The BP-lowering effect of amlodipine plus valsartan was not significantly different from that of other combinations of antihypertensive drugs, including amlodipine plus atenolol, lisinopril plus hydrochlorothiazide (HCTZ), and irbesartan plus HCTZ. Combination therapy with amlodipine and valsartan was generally well tolerated. Based on these results, amlodipine/valsartan offers a rational and convenient treatment option for the management of patients with hypertension, the majority of whom will require at least two drugs to reach target BP levels recommended in US (and international) guidelines.

Pharmacologic Properties

Amlodipine/valsartan comprises two effective antihypertensive agents with complementary mechanisms of action. The CCB amlodipine inhibits calcium influx into vascular smooth muscle to cause a reduction in peripheral vascular resistance, while valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively inhibiting the binding of angiotensin II to angiotensin II type 1 receptors in tissues such as vascular smooth muscle and the adrenal gland.

The absorption pharmacokinetics of amlodipine and valsartan after administration of amlodipine/ valsartan are similar to those following administration of each of drug individually. Bioequivalence between the amlodipine/valsartan tablet formulation and components administered in free combination has also been demonstrated. Amlodipine achieves peak plasma concentrations (Cmax) 6–8 hours after oral administration of amlodipine/valsartan, has an apparent volume of distribution (Vd) of 21 L/kg, is highly bound to plasma proteins (93.0–97.5%), and has a terminal elimination half-life (t1/2γ) of 30–50 hours. Amlodipine is extensively (≈90%) metabolized in the liver to inactive metabolites. Valsartan reaches Cmax 3 hours after oral administration of amlodipine/valsartan, has a Vd of 17 L/kg, is 94–97% bound to plasma proteins, and has a t1/2γ of ≈9 hours. Valsartan is primarily eliminated in the feces (≈83% of a dose) and urine (≈13% of a dose), mainly as unchanged drug.

Therapeutic Efficacy

The antihypertensive efficacy of combinations of once-daily oral amlodipine and valsartan (administered as separate agents or as amlodipine/valsartan) has been demonstrated in numerous well designed studies in patients with all grades/stages of hypertension and those with hypertension inadequately controlled by prior monotherapy (including that with amlodipine or valsartan).

Short-term (8 weeks’) treatment with dosages of amlodipine plus valsartan equivalent to those available in US-approved amlodipine/valsartan formulations was more effective than placebo and the respective individual monotherapies in reducing BP in two large, randomized, double-blind trials in patients with mild to moderate hypertension (studies 1 and 2). For each regimen, the reduction in mean sitting DBP (MSDBP) from baseline to study end (primary endpoint) was significantly greater than that with placebo, or amlodipine or valsartan alone; similar results were seen for the corresponding reductions in mean sitting SBP (MSSBP). The antihypertensive effect of amlodipine plus valsartan appeared to increase with increasing dose over the approved range (5–10 mg and 160–320 mg once daily, respectively).

Combination therapy with amlodipine 2.5–5 mg plus valsartan 80–320 mg once daily, with or without the optional addition of HCTZ 12.5 mg once daily, also achieved clinically significant and persistent reductions in MSSBP/MSDBP over a period of 52 or 54 weeks in open-label extensions to studies 1 and 2. Subgroup analyses of studies 1 and 2 and their respective extensions suggested that amlodipine plus valsartan combination therapy was effective, regardless of hypertension severity (stage 1 or 2), age (≥65 or <65 years) or race (Black or White patients).

In randomized, open-label (blinded endpoint) trials, longer-term (24–48 weeks’) treatment with amlodipine 2.5–10 mg plus valsartan 160 mg once daily produced reductions in BP that did not differ significantly from those with a combination of amlodipine 2.5–10 mg plus atenolol 100 mg once daily in patients with mild hypertension, well controlled type 2 diabetes mellitus, and a recent history of atrial fibrillation, and those with a combination of irbesartan 300 mg plus HCTZ 12.5–25 mg once daily in very elderly patients with moderate hypertension. Ambulatory BP monitoring indicated that amlodipine plus valsartan provided a persistent and smooth antihypertensive effect throughout the 24-hour dosing interval.

BP was reduced more rapidly, and to a greater extent, during short-term (4–8 weeks’) treatment with amlodipine 5–10 mg plus valsartan 160–320 mg once daily than with amlodipine 5–10 mg once daily in two randomized, double-blind studies in patients with moderate to severe (stage 2) hypertension. Reductions in MSSBP/MSDBP, as well as BP control rates, significantly favored amlodipine plus valsartan over amlodipine alone both before and after the optional addition of HCTZ 12.5 mg once daily in these trials. The short-term (6-week) BP-lowering efficacy of amlodipine 5–10 mg plus valsartan 160 mg once daily was not significantly different from that of lisinopril 10–20 mg plus HCTZ 12.5 mg in a third randomized, double-blind study in patients with severe (stage 2) hypertension.

In other randomized, double-blind studies, short-term (8–12 weeks’) treatment with amlodipine 5–10 mg plus valsartan 160 mg once daily provided significant additional BP-lowering effects compared with continuing on the same dose of amlodipine or valsartan in patients with mild to moderate hypertension not adequately controlled on amlodipine 10 mg once daily or valsartan 160 mg once daily, and compared with doubling the dose of amlodipine in patients with hypertension not adequately controlled on amlodipine 5 mg once daily. In one of these trials, responder and BP control rates significantly favored combination therapy over amlodipine monotherapy before, but not 4 weeks after, all monotherapy recipients switched to combination therapy.

Switching directly to either amlodipine/valsartan 5 mg/160 mg once daily or amlodipine/valsartan 5 mg/160 mg once daily plus amlodipine 5 mg once daily, with the optional addition of HCTZ 12.5–25 mg once daily, was effective in establishing BP control in around three-quarters of patients with hypertension not controlled with previous monotherapy (various antihypertensive agents). BP control rates were generally similar before and after the optional addition of HCTZ in this randomized, double-blind study; subgroup analyses suggested that the additional antihypertensive efficacy of amlodipine/valsartan (with or without HCTZ) was maintained irrespective of the prior monotherapy, hypertension severity, diabetic status, body mass index, and age.

Tolerability

Combination therapy with amlodipine and valsartan (administered as separate agents or as amlodipine/ valsartan) was generally well tolerated in patients with all grades/stages of hypertension, including those with hypertension not adequately controlled on previous monotherapy. Most adverse events were mild or moderate in severity and transient in nature. The incidences of peripheral edema, headache, and dizziness — the most common suspected drug-related adverse events with amlodipine plus valsartan — did not differ significantly from those with placebo in studies 1 and 2. In contrast, peripheral edema and headache occurred less frequently with combination therapy than with amlodipine alone, whereas peripheral edema occurred more frequently with combination therapy than with valsartan alone. Adverse events leading to drug discontinuation occurred in 2.1% of amlodipine plus valsartan recipients compared with 1.8% of placebo recipients.

Adverse events associated with low BP occurred infrequently (<1%), or not at all, in amlodipine plus valsartan-treated patients. Combination therapy was not associated with clinically significant changes in laboratory parameters. Long-term (52 or 54 weeks’) treatment with amlodipine 2.5–5 mg plus valsartan 80–320 mg once daily, with or without the optional addition of HCTZ 12.5 mg once daily, was well tolerated in the open-label extensions to studies 1 and 2; no signficant new adverse events were reported compared with those observed in the short-term (8-week) core trial.

Amlodipine plus valsartan and other combinations of antihypertensive agents (irbesartan plus HCTZ or lisinopril plus HCTZ) were generally well tolerated in comparative studies. Compared with irbesartan plus HCTZ, amlodipine plus valsartan was associated with less pronounced BP orthostatic changes and a lack of metabolic adverse effects in very elderly patients with moderate hypertension.

References

  1. 1.
    He J, Whelton PK. Epidemiology and prevention of hypertension. Med Clin North Am 1997 Sep; 81(5): 1077–97.PubMedCrossRefGoogle Scholar
  2. 2.
    Ong KL, Cheung BMY, Man YB. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999–2004. Hypertension 2007; 49: 69–75.PubMedCrossRefGoogle Scholar
  3. 3.
    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 Dec; 42(6): 1206–52.PubMedCrossRefGoogle Scholar
  4. 4.
    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 May 29; 115(21): 2761–88.PubMedCrossRefGoogle Scholar
  5. 5.
    Chrysant SG. Using fixed-dose combination therapies to achieve blood pressure goals. Clin Drug Invest 2008; 28(11): 713–34.CrossRefGoogle Scholar
  6. 6.
    Neutel JM. Prescribing patterns in hypertension: the emerging role of fixed-dose combinations for attaining BP goals in hypertensive patients. Curr Med Res Opin 2008 Aug; 24(8): 2389–401.PubMedCrossRefGoogle Scholar
  7. 7.
    Calhoun DA. Use of single-pill combination therapy in evolving paradigm of hypertension management. Expert Opin Pharmacother 2009 Aug; 10(12): 1869–74.PubMedCrossRefGoogle Scholar
  8. 8.
    Waeber B, Ruilope LM. Amlodipine and valsartan as components of a rational and effective fixed-dose combination. Vasc Health Risk Manag 2009; 5(1): 165–74.PubMedCrossRefGoogle Scholar
  9. 9.
    Ram CVS. Antihypertensive efficacy of olmesartan medoxomil or valsartan in combination with amlodipine: a review of factorial design studies. Curr Med Res Opin 2009; 25(1): 177–85.PubMedCrossRefGoogle Scholar
  10. 10.
    Bakris GL. Combined therapy with a calcium channel blocker and an angiotensin II type 1 receptor blocker. J Clin Hypertens (Greenwich) 2008 Jan; 10 (1 Suppl. 1): 27–32.CrossRefGoogle Scholar
  11. 11.
    Gojanovic B, Feihl F, Liaudet L, et al. Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension. J Renin Angiotensin Aldosterone Syst 2008 Mar; 9(1): 1–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Ferri C, Croce G, Desideri G. Role of combination therapy in the treatment of hypertension: focus on valsartan plus amlodipine. Adv Ther 2008 Apr; 25(4): 300–20.PubMedCrossRefGoogle Scholar
  13. 13.
    de la Sierra A. Mitigation of calcium channel blocker-related oedema in hypertension by antagonists of the renin-angiotensin system. J Hum Hypertens 2009 Aug; 23(8): 503–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Exforge® (amlodipine and valsartan) tablets: US prescribing information. East Hanover (NJ): Novartis Pharmaceuticals Corp., 2008 Jul.Google Scholar
  15. 15.
    Azor® (amlodipine and olmesartan medoxomil) tablets. US prescribing information. Parsippany (NJ): Daiichi Sankyo Inc., 2007.Google Scholar
  16. 16.
    Haria M, Wagstaff AJ. Amlodipine: a reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs 1995; 50(3): 560–86.PubMedCrossRefGoogle Scholar
  17. 17.
    Plosker GL, Robinson DM. Amlodipine/valsartan: fixed-dose combination in hypertension. Drugs 2008; 68(3): 373–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Markham A, Goa KL. Valsartan: a review of its pharmacology and therapeutic use in essential hypertension. Drugs 1997 Aug; 54(2): 299–311.PubMedCrossRefGoogle Scholar
  19. 19.
    Norvasc (amlodipine besylate) tablets. US prescribing information. New York: Pfizer Inc., 2006 Aug.Google Scholar
  20. 20.
    Diovan (valsartan) tablets. US prescribing information. East Hanover (NJ): Novartis Pharmaceuticals Corp., 2008 Dec.Google Scholar
  21. 21.
    Top C, Cingözbay BY, Terekeci H, et al. The effects of valsartan on insulin sensitivity in patients with primary hypertension. J Int Med Res 2002; 30(1): 15–20.PubMedGoogle Scholar
  22. 22.
    Ram CVS, Ames RP, Applegate WB, et al. Double-blind comparison of amlodipine and hydrochlorothiazide in patients with mild to moderate hypertension. Clin Cardiol 1994; 17: 251–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Scheen AJ. Prevention of type 2 diabetes mellitus through inhibition of the renin-angiotensin system. Drugs 2004; 64(22): 2537–65.PubMedCrossRefGoogle Scholar
  24. 24.
    Fogari R, Derosa G, Lazzari P, et al. Effect of valsartan-amlodipine combination on inflammation markers, oxidative stress and on assymetric dimethylarginine in type 2 diabetic hypertensive patients [abstract no. PS12/MON/05]. J Hypertens 2008; 26 Suppl. 1: 188.Google Scholar
  25. 25.
    Fogari R, Zoppi A, Mugellini A, et al. Comparative evaluation of effect of valsartan/amlodipine and atenolol/amlodipine combinations on atrial fibrillation recurrence in hypertensive patients with type 2 diabetes mellitus. J Cardiovasc Pharmacol 2008 Mar; 51(3): 217–22.PubMedCrossRefGoogle Scholar
  26. 26.
    Fogari R, Preti P, Zoppi A, et al. Effect of valsartan addition to amlodipine on insulin sensitivity in overweight-obese hypertensive patients. Intern Med 2008; 47(21): 1851–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Fogari R, Derosa G, Lazzari P, et al. Effect of valsartan-amlodipine combination on cognitive function in elderly hypertensive patients [abstract no. PS26/WED/06]. J Hypertens 2008; 26 Suppl. 1: 372.Google Scholar
  28. 28.
    Fogari R, Zoppi A, Derosa G, et al. Effect of valsartan addition to amlodipine on ankle oedema and subcutaneous tissue pressure in hypertensive patients. J Hum Hypertens 2007 Mar; 21(3): 220–4.PubMedGoogle Scholar
  29. 29.
    de Champlain J, Karas M, Assouline L, et al. Effects of valsartan or amlodipine alone or in combination on plasma catecholamine levels at rest and during standing in hypertensive patients. J Clin Hypertens 2007 Mar; 9(3): 168–78.CrossRefGoogle Scholar
  30. 30.
    Exforge 5 mg/80 mg, 5 mg/160 mg, 10 mg/160 mg film coated tablets: summary of product characteristics. Camberley, UK: Novartis Pharmaceuticals UK Ltd, 2008 Jun 10.Google Scholar
  31. 31.
    European Medicines Agency. Exforge European public assessment report: scientific discussion [online]. Available from URL: http://www.emea.europa.eu/humandocs/PDFs/EPAR/exforge/H-716-en6.pdf [Accessed 2009 Mar 25].
  32. 32.
    Co-Diovan® valsartan and hydrochlorothiazide: Australian prescribing information. North Ryde (NSW): Novartis Pharmaceuticals Australia Pty Ltd, 2009 Feb 13.Google Scholar
  33. 33.
    US Food and Drug Administration Center for Drug Evaluation and Research. Application number: 21–990 Exforge; amlodipine besylate & valsartan. Clinical Pharmacology and Biopharmaceutics Review [online]. Available from URL: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021990s00_ClinPharmR.pdf [Accessed 2009 Jul 16].
  34. 34.
    US Food and Drug Administration Center for Drug Evaluation and Research. Application number: 21–990 Exforge; amlodipine besylate & valsartan. Medical Review [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2007/021990s000_MedR.pdf [Accessed 2009 Mar 3].
  35. 35.
    Allemann Y, Fraile B, Lambert M, et al. Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study. J Clin Hypertens (Greenwich) 2008 Mar; 10(3): 185–94.CrossRefGoogle Scholar
  36. 36.
    Data on file, Novartis Pharmaceuticals Corp., 2009.Google Scholar
  37. 37.
    Schrader J, Salvetti A, Calvo C, 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(2): 217–25.PubMedCrossRefGoogle Scholar
  38. 38.
    Flack JM, Calhoun DA, Satlin L, et al. Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study. J Hum Hypertens 2009 Jul; 23(7): 479–89.PubMedCrossRefGoogle Scholar
  39. 39.
    Destro M, Luckow A, Samson M, et al. Efficacy and safety of amlodipine/ valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS Study. J Am Soc Hypertens 2008; 2(4): 294–302.PubMedCrossRefGoogle Scholar
  40. 40.
    Sinkiewicz W, Glazer RD, Kavoliuniene A, et al. Efficacy and tolerability of amlodipine/valsartan combination therapy in hypertensive patients not adequately controlled on valsartan monotherapy. Curr Med Res Opin 2009 Feb;25(2): 315–24.PubMedCrossRefGoogle Scholar
  41. 41.
    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 Apr; 29(4): 563–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Poldermans D, Glazer R, Karagianniss S, et al. Tolerability and blood pressure-lowering efficacy of the combination of amlodipine plus valsartan compared with lisinopril plus hydrochlorothiazide in adult patients with stage 2 hypertension. Clin Ther 2007 Feb; 29(2): 279–89.PubMedCrossRefGoogle Scholar
  43. 43.
    Fogari R, Zoppi A, Mugellini A, et al. Efficacy and safety of two treatment combinations of hypertension in very elderly patients. Arch Gerontol Geriatr 2008 May; 48(3): 401–5.PubMedCrossRefGoogle Scholar
  44. 44.
    Smith TR, Philipp T, Vaisse B, et al. Amlodipine and valsartan combined and as monotherapy in stage 2, elderly, and black hypertensive patients: subgroup analyses of 2 randomized, placebo-controlled studies. J Clin Hypertens 2007 May; 9(5): 355–64.CrossRefGoogle Scholar
  45. 45.
    Brachmann J, Ansari A, Mahla G, et al. Effective and safe reduction of blood pressure with the combination of amlodipine 5 mg and valsartan 160 mg in hypertensive patients not controlled by calcium channel blocker monotherapy. Adv Ther 2008 Sep; 25(5): 399–411.PubMedCrossRefGoogle Scholar
  46. 46.
    Philipp T, Glazer RD, Zhao Y, et al. Long-term tolerability and efficacy of the combination of amlodipine/valsartan in hypertensive patients: a 54-week, open-label extension study. Curr Med Res Opin 2009; 25(1): 187–93.PubMedCrossRefGoogle Scholar
  47. 47.
    Smith TR, Glazer R, Koren MJ, et al. Long-term safety and efficacy of combination therapy with amlodipine and valsartan in hypertensive patients [abstract P-70]. J Clin Hypertens 2008 May; 10 (5 Suppl. A): 35.Google Scholar
  48. 48.
    Gu Q, Paulose-Ram R, Dillon C, et al. Antihypertensive medication use among US adults with hypertension. Circulation 2006; 113: 213–21.PubMedCrossRefGoogle Scholar
  49. 49.
    Wang RY, Alexander GC, Stafford RS. Outpatient hypertension treatment, treatment intensification, and control in Western Europe and the United States. Arch Intern Med 2007; 167: 141–7.PubMedCrossRefGoogle Scholar
  50. 50.
    Whitworth JA. World Health Organization, International Society of Hypertension Writing Group. 2003 World Health Organization (WHO)/International Society of Hypertension (ISH) statement on management of hypertension. J Hypertens 2003; 21: 1983–92.PubMedCrossRefGoogle Scholar
  51. 51.
    ESH-ESC Task Force on the Management of Arterial Hypertension. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension. J Hypertens 2007; 25: 1751–62.CrossRefGoogle Scholar
  52. 52.
    Cooper R, Rotimi C. Hypertension in blacks. Am J Hypertens 1997 Jul; 10 (7 Pt 1): 804–12.PubMedCrossRefGoogle Scholar
  53. 53.
    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 Mar 10; 163(5): 525–41.PubMedCrossRefGoogle Scholar
  54. 54.
    Kohlmann Jr O, Oigman W, Mion D, et al. The “LOTHAR” study: evaluation of efficacy and tolerability of the fixed combination of amlodipine and lo sartan in the treatment of essential hypertension. Arq Bras Cardiol 2006 Jan; 86(1): 39–51.PubMedCrossRefGoogle Scholar
  55. 55.
    Sharma A, Bagchi A, Kinagi SB, et al. Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension. Clin Ther 2007 Dec; 29(12): 2667–76.PubMedCrossRefGoogle Scholar
  56. 56.
    Leenen FHH, 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. Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Collaborative Research Group. Hypertension 2006; 48: 374–84.PubMedCrossRefGoogle Scholar
  57. 57.
    Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes. CAFE Investigators. Circulation 2006; 113: 1213–25.PubMedCrossRefGoogle Scholar
  58. 58.
    Pitt B, Byington RP, Furberg CD, et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000; 102: 1503–10.PubMedCrossRefGoogle Scholar
  59. 59.
    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 Nov 10; 292(18): 2217–26.PubMedCrossRefGoogle Scholar
  60. 60.
    Dahlöf 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 multientre randomised controlled trial. Lancet 2005 Sep 10; 366(9489): 895–906.PubMedCrossRefGoogle Scholar
  61. 61.
    Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. Valsartan Heart Failure Trial (Val-HeFT) Investigators. N Engl J Med 2001 Dec 6; 345(23): 1667–75.PubMedCrossRefGoogle Scholar
  62. 62.
    Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the valsartan heart failure trial (Val-HeFT). Am Heart J 2005; 149: 548–57.PubMedCrossRefGoogle Scholar
  63. 63.
    Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. Valsartan in Acute Myocardial Infarction (VALIANT) Trial Investigators. N Engl J Med 2003 Nov 13; 349(20): 1893–906.PubMedCrossRefGoogle Scholar
  64. 64.
    Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet 2007 Apr 28; 369: 1431–9.PubMedCrossRefGoogle Scholar
  65. 65.
    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 Jun 19; 363: 2022–31.PubMedCrossRefGoogle Scholar
  66. 66.
    ICH Steering Committee. Guidance document: principles for evaluation of new antihypertensive drugs [online]. Available from URL: http://www.ich.org/LOB/media/MEDIA488.pdf [Accessed 2009 Apr 29].
  67. 67.
    White WB. Relevance of blood pressure variation in the circadian onset of cardiovascular events. J Hypertens 2003; 21 Suppl. 6: S9–15.Google Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Adis, a Wolters Kluwer BusinessMairangi Bay, North Shore 0754, AucklandNew Zealand

Personalised recommendations