Comparison of Two- and Three-Drug Combination Therapy With Candesartan in Patients With Severe Hypertension

Heinrich Holzgreve; Reinhard Gotzen; Gerhard Kiel


Br J Cardiol. 2005;12(4):291-297. 

In This Article

Abstract and Introduction

The efficacy and tolerability of two candesartan treatment regimens were evaluated in 578 severely hypertensive patients already receiving a diuretic plus an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker (CCB) or a beta blocker. Existing treatments were standardised during a two-week run-in period. Patients with uncontrolled blood pressure (diastolic blood pressure [DBP] ≥ 90 mmHg) were randomly switched to a regimen comprising candesartan 16 mg plus hydrochlorothiazide (HCT) 12.5 mg once daily for four weeks (switch regimen, n=291), or had candesartan 8 mg once daily added to their existing treatment (add-on regimen, n=287). After four weeks' treatment, mean sitting DBP was reduced from baseline by 11.2 mmHg (SD 11.2) and 13.9 mmHg (SD 11.5) in the switch and add-on treatment groups, respectively. Mean sitting SBP was decreased by 15.3 mmHg (SD 18.7) and 20.7 mmHg (SD 20.3), respectively. During an additional four weeks' treatment, 'switch' non-responders had their doses of study medications doubled, resulting in a further reduction of 5.4 mmHg (SD 9.8) DBP and 5.9 mmHg (SD 14.9) SBP. Both treatment regimens were well tolerated. Thus, in patients with severe hypertension, adding candesartan to a standard-dose two-drug combination, or switching from a pre-existing two-drug, standard-dose combination to high-dose candesartan plus HCT enables enhanced BP control, with superiority of the three- over the two-drug combination.

Hypertension remains poorly controlled in the majority of patients, despite the fact that it is strongly associated with poor cardiovascular outcomes, and guidelines throughout the world continue to demand tighter blood pressure (BP) control.[1,2,3,4]

A key need in addressing this problem is the greater use of combination therapy in everyday practice.[2,3,4,5,6,7] Recognising this, the British Hypertension Society Guidelines explicitly state that "most people with hypertension will require at least two BPlowering drugs to achieve the recommended BP goals."[2] Similarly, the European guidelines from the European Society of Hypertension (ESH)/International Society of Hypertension (ISH), and the US guidelines from the Joint National Committee, both recommend three-drug combinations after an insufficient response to a two-drug combination.[3,4] What is less clear at a practical level, however, is how such two- and three-drug combinations should be dosed: whether, for instance, each drug should be titrated to its maximum before adding another, or whether low-dose multiple combinations offer the best balance of efficacy and side-effects.

Candesartan cilexetil is a potent angiotensin II receptor blocker that has been shown in clinical studies to combine dose-dependent antihypertensive efficacy with placebo-like tolerability.[8,9,10,11,12,13,14,15,16] Candesartan is suitable for use both as monotherapy and in combination with other drugs. In this large study, conducted in patients with severe hypertension, we set out to investigate the effects of adding candesartan to a two-drug combination given at standard dose, versus switching from a pre-existing two-drug, standard-dose combination to a high-dose candesartan plus hydrochlorothiazide (HCT) combination.