, Volume 66, Issue 8, pp 1107–1115 | Cite as

Zofenopril plus Hydrochlorothiazide

Combination Therapy for the Treatment of Mild to Moderate Hypertension
  • Alberto Zanchetti
  • Gianfranco Parati
  • Ettore Malacco
Review Article


Achieving target blood pressure (BP) levels in clinical practice is one of the main challenges for physicians in the management of patients with hypertension. It is now recognised that the majority of patients will require at least two antihypertensive drugs to achieve optimal BP control; the use of combination therapy as first-line treatment is also increasing as BP goals of antihypertensive therapy become more ambitious.

The fixed combination of zofenopril/hydrochlorothiazide (HCTZ) 30/12.5 mg/day is approved in Italy, France, Switzerland and Greece for the management of mild to moderate hypertension. In clinical trials comparing zofenopril/HCTZ with each agent administered as monotherapy, combination therapy was more effective in normalising BP. This effect was particularly evident in one trial in which patients who were nonresponsive to zofenopril monotherapy were studied. In addition, in clinical trials to date, combination therapy provided sustained and consistent BP control over the entire 24-hour dose interval.

Despite the greater efficacy of zofenopril/HCTZ 30/12.5 mg/day, when directly compared with each agent administered as monotherapy, there were no significant differences in the nature, severity or incidence of treatment-related adverse events; headache, dizziness, cough and polyuria were most frequently reported. Notably, in one study, fewer patients discontinued treatment with combination therapy than with zofenopril monotherapy due to adverse events.

In conclusion, zofenopril/HCTZ 30/12.5 mg/day provides more optimal BP control in a larger proportion of patients than would be achievable with monotherapy, while maintaining the tolerability profile observed with each individual agent, and thereby potentially enhancing patient compliance. The efficacy and safety profiles of this combination shown in clinical trials to date indicate that it will be a useful addition to currently available therapy for patients who have mild to moderate hypertension that is not adequately controlled by monotherapy, as well as for patients who require more rapid, intensive BP control.


HCTZ Blood Pressure Goal Zofenopril Achieve Target Blood Pressure Enhance Patient Compliance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Professor Zanchetti has served as an occasional consultant for and received lecturing honoraria from Menarini, and provided expert testimony for the registration of zofenopril/HCTZ. Drs Parati and Malacco have served as occasional consultants for Menarini. This article was written with financial assistance from Menarini.


  1. 1.
    Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: 212–23Google Scholar
  2. 2.
    Kearney PM, Whelton M, Reynolds K, et al. Worldwide prevalence of hypertension: a systematic review. J Hypertens 2004; 22: 11–9PubMedCrossRefGoogle Scholar
  3. 3.
    Wang TJ, Vasan RS. Epidemiology of uncontrolled hypertension in the United States. Circulation 2005; 112: 1651–62PubMedCrossRefGoogle Scholar
  4. 4.
    Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and global and regional burden of disease. Lancet 2002; 360: 1347–60PubMedCrossRefGoogle Scholar
  5. 5.
    Franklin S, Larson MG, Khan SA, et al. Does the relation of blood pressure to coronary heart disease risk change with aging? The Framingham Heart Study. Circulation 2001; 103: 1245–9PubMedCrossRefGoogle Scholar
  6. 6.
    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(18): 1291–7PubMedCrossRefGoogle Scholar
  7. 7.
    Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med Bull 1994; 50: 272–98PubMedGoogle Scholar
  8. 8.
    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) randomized trial. Lancet 1998; 351: 1755–62PubMedCrossRefGoogle Scholar
  9. 9.
    Guidelines Committee. 2003 European Society of Hypertension-European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21: 1011–53CrossRefGoogle Scholar
  10. 10.
    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: 1527–35CrossRefGoogle Scholar
  11. 11.
    National Heart, Lung and Blood Institute. The seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. NIH Publication No. 03-5233, 2003 MayGoogle Scholar
  12. 12.
    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: 1983–92CrossRefGoogle Scholar
  13. 13.
    Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 2003; 290(2): 199–206PubMedCrossRefGoogle Scholar
  14. 14.
    Hansson L, Zanchetti A, for the HOT Study Group. The Hypertension Optimal Treatment (HOT) study: 24-month data on blood pressure and tolerability. Blood Pressure 1997; 6: 313–7PubMedCrossRefGoogle Scholar
  15. 15.
    Wetzels GEC, Nelemans P, Schouten JS, et al. Facts and fiction of poor compliance as a cause of inadequate blood pressure: a systematic review. J Hypertens 2004; 22: 1849–55PubMedCrossRefGoogle Scholar
  16. 16.
    Moser M. Rationale for combination therapy in the management of hypertension. J Clin Hypertens 2003; 5 (6 Suppl. 4): 17–25CrossRefGoogle Scholar
  17. 17.
    Zanchetti A. Contribution of fixed low-dose combinations to initial therapy in hypertension. Eur Heart J Suppl 1999; 1 Suppl. L: L5–9Google Scholar
  18. 18.
    Mancia G, Grassi G. Rationale for the use of a fixed dose combination in the treatment of hypertension. Eur Heart J Suppl 1999; 1 Suppl. L: L14–19Google Scholar
  19. 19.
    Mancia G, Zanchetti A, Agabiti-Rosei E, et al. Ambulatory blood pressure is superior to clinic blood pressure in predicting treatment-induced regression of left ventricular hypertrophy. Circulation 1997; 95: 1464–70PubMedCrossRefGoogle Scholar
  20. 20.
    Lewis EJ, Hunsicker LG, Bain RP, et al. The effect of angiotensin-converting-enzyme therapy on diabetic nephropathy. N Engl J Med 1993; 329: 1456–62PubMedCrossRefGoogle Scholar
  21. 21.
    Giatras I, Lau J, Levey AS, et al. Effect of angiotensin-con-verting-enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Ann Intern Med 1997; 127(5): 337–45PubMedGoogle Scholar
  22. 22.
    Zanchetti A, Ruilope LM. Antihypertensive treatment in patients with type-2 diabetes mellitus: what guidance from well controlled randomized trials? J Hypertens 2002; 20: 2095–110CrossRefGoogle Scholar
  23. 23.
    Borghi C, Ambrosioni E. Zofenopril: a review of the evidence of its benefits in hypertension and acute myocardial infarction. Clin Drug Invest 2000; 20(5): 371–84CrossRefGoogle Scholar
  24. 24.
    Parati G, Omboni S, Malacco E, et al. Antihypertensive efficacy of zofenopril and hydrochlorothiazide combination on ambulatory blood pressure. Blood Pressure 2006; 15 Suppl. 1: 7–17CrossRefGoogle Scholar
  25. 25.
    Malacco E, Omboni S. Antihypertensive efficacy of zofenopril plus hydrochlorothiazide fixed combination is superior to that of single components [abstract]. Eur Heart J 2005; 26: 401Google Scholar
  26. 26.
    Zozide prescribing information. Menarini International Operations Luxembourg S.A., 2005 MarGoogle Scholar
  27. 27.
    Toto RD, Rinner S, Ram CVS. ACE inhibitors and target organ protection: an expanded role for these antihypertensive agents? Postgrad Med 2004; 116(2): 11–6PubMedCrossRefGoogle Scholar
  28. 28.
    Dzau V. The cardiovascular continuum and renin-angiotensinaldosterone system blockade. J Hypertens 2005; 23 Suppl. 1: S9-17Google Scholar
  29. 29.
    Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensinconverting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. N Engl J Med 2000; 342(3): 145–53Google Scholar
  30. 30.
    The 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: 782–8CrossRefGoogle Scholar
  31. 31.
    Ambrosioni E, Borghi C, Magnani B, et al. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995; 333: 80–5CrossRefGoogle Scholar
  32. 32.
    Pfeffer MA, Braunwald E, Moye LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival And Ventricular Enlargement trial. N Engl J Med 1992; 324: 669–77Google Scholar
  33. 33.
    SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685–91CrossRefGoogle Scholar
  34. 34.
    Ferrari R, for the PREAMI Investigators. Effects of angiotensinconverting enzyme inhibition with perindopril on left ventricular remodeling and clinical outcome: results of the randomized Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) study. Arch Intern Med 2006; 166: 659–66PubMedCrossRefGoogle Scholar
  35. 35.
    Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355: 253–9CrossRefGoogle Scholar
  36. 36.
    García-Estan J, Ortiz C, O’Valle F, et al. Effects of angiotensin converting enzyme inhibitors in combination with diuretics on blood pressure and renal injury in nitric oxide deficiency induced hypertension in rats. Clin Sci 2006; 110: 227–33PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Alberto Zanchetti
    • 1
  • Gianfranco Parati
    • 2
  • Ettore Malacco
    • 3
  1. 1.Centro di Fisiologia Clinica e Ipertensione, Istituto Auxologico Italiano, Ospedale Maggiore di MilanoUniversity of MilanMilanItaly
  2. 2.Cardiology II, S. Luca Hospital, Istituto Auxologico ItalianoUniversity of Milano-BicoccaMilanItaly
  3. 3.Internal Medicine IIIL. Sacco HospitalMilanItaly

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