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Prof. Guido Grassi
Current guidelines recommend combination treatment as a means to allow hypertensives to achieve hypertension levels closer to ones of untreated individuals, provided the five main requirements regarding mechanisms of action, effect, protectibililty, side effects and adverse effects are followed. Although fixed combinations help with patient compliance and treatment costs, extemporaneous combinations are flexible and increase physician awareness. Combination treatment is needed to control blood pressure in the majority of patients; It is almost mandatory in diabetic, renal and high risk hypertensive patients and may allow blood pressure targets to be reduced earlier than with monotherapy.
The New European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines on hypertension, issued in 2007, offer an in-depth examination into the problem of blood pressure control during treatment, emphasising the need in current clinical practice for combination drug treatment. Guidelines address in this regard a number of clinically relevant questions, such as:
On these questions (and on the related answers) is focused the present article
Combination treatment allows hypertensives to achieve hypertension levels closer to ones of untreated individuals.
A large number of controlled studies have conclusively shown that treatment of hypertension is beneficial. In virtually all hypertensive conditions, drugs that lower diastolic and/or systolic blood pressure reduce cardiovascular morbidity and mortality (1, 2). However, this is counterbalanced by the evidence that current management of hypertension is unable to bring the cardiovascular risk of the treated hypertensive patients back to the level of the normotensive individuals (3). Although several factors are believed to be responsible for this finding, a likely candidate is poor blood pressure control, i.e. the fact that blood pressure levels of treated hypertensives remain, almost invariably, higher than those of normotensive controls. This limitation can be overcome by a therapeutic strategy based on a combination of two or more antihypertensive drugs, which allows to achieve a better blood pressure control (and thus greater cardiovascular protection) in a much larger fraction of hypertensive patients (4). This is one of the reason for which this therapeutic approach has been recommended by the 2007 European Society of Hypertension/European Society of Cardiology Hypertension Guidelines (5).
Combination therapy is successive overall and has five main requirements
Whereas initial monotherapy effectively lowers blood pressure in only a limited fraction of the hypertensive population, combined administration of two or three drugs achieves a successful antihypertensive response in about 80% and 90% of cases, respectively. Combination therapy plays a fundamental role in the overall treatment of hypertension that is not limited to clinical practice (and thus to the possible incorrect use of single-drug regimens) ; combination treatment with two and three drugs has also been commonly employed to achieve optimal blood pressure in controlled studies. Optimal two-drug combinations are characterised by five main requirements.
Extemporaneous combinations are flexible and increase physician awareness
Fixed combinations have advantages, but also disadvantages, over the separate administration of the same drugs. Extemporaneous combinations :
Except for the flexibility of dosing, these advantages, however, are not in principle incompatible with fixed-dose combinations, provided that doctors receive proper information.
Fixed combinations help with patient compliance and reduce the cost of treatment.
However, fixed combinations have specific advantages. It should be remembered that fixed combinations allow blood pressure control to be achieved with a reduced number of daily tablets compared with extemporaneous combinations, thus simplifying the therapeutic approach.
ESH/ESC 2007 Guidelines (5) make a clear statement on the use of monotherapy and combination drug therapy strategies (Figure). They first emphasise that combination treatment “is needed to control blood pressure in the majority of patients”, making the issue related to the drug of first therapeutic choice less relevant.
They also recognise that combination treatment is almost mandatory in diabetic, renal and high risk hypertensive patients because in all these clinical conditions blood pressure goal is set at 130/80 mmHg or even lower and thus a large blood pressure reduction is oftentimes needed, making the use of single monotherapy not recommended. Guidelines make a further point in favour of combination therapy, underling the concept that starting treatment with a two-drug combination may allow blood pressure targets to be reduced earlier than with monotherapy. This is of particular importance in high-risk patients, in the light of the evidence provided by the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study that a lack of a prompt blood pressure control may be associated in these individuals with a higher events rate (10)
In practical terms the choice of the preferable combination of drugs regimen should be based on a number of factors, including the patient’s age, metabolic and cardiovascular risk profile, the presence of target organ damage, tolerability and side effects of the combinations used. A final recommendation given by the ESH/ESC 2007 Guidelines refers to the use of low-dose combinations. These should be preferred to high dose combinations because they
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
1. MacMahon S, Rodgers A. The effects of antihypertensive treatment on vascular disease: reappraisal of evidence in 1994. J Vasc Med Biol 1993;4:265-271. 2. Struijker-Boudier HA, Ambrosioni E, Holzgreve H, et al. The need for combination antihypertensive therapy to reach target blood pressures: what has been learned from clinical practice and morbidity-mortality trials? Int J Clin Pract 2007;61:1592-1602. 3. Isles CG, Walker LM, Beevers GD, et al. Mortality in patients of the Glasgow Blood Pressure Clinic.J Hypertens 1986;4:141-156. 4. Mancia G. Blood pressure reduction and cardiovascular outcomes: past, present, and future. Am J Cardiol 2007;100:3J-9J. 5. Mancia G, De Backer G, Dominiczak A, et al.; Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology. 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. 6. Nesbitt SD. Antihypertensive combination therapy: optimizing blood pressure control and cardiovascular risk reduction. J Clin Hypertens 2007;9:26-32. 7. Burt VL, Cutler JA, Higgins M, e coll. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension 1995;26:60-69. 8. Chobanian AV, Bakris GL, Black HR, et al. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206–1252 9. Swales JD. Current clinical practice in hypertension: the EISBERG (Evaluation and Interventions for Systolic Blood pressure Elevation-Regional and Global) project. Am Heart J 1999;138:231-237. 10. Julius S, Kjeldsen SE, Weber M, et al.; 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.
Prof. Guido Grassi Past Chairman ESC Working Group Hypertension and the Heart Clinica Medica, Università di Milano-Bicocca, Milan, Italy.