Candesartan cilexetil plus hydrochlorothiazide combination: a review of its use in hypertension

The combination of candesartan cilexetil [an angiotensin II type 1 (AT(1)) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of candesartan cilexetil 4 to 16 mg with hydrochlorothiazide 12.5 or 25 mg induced significant reductions reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension. Data from clinical trials indicated that reductions in BP induced by candesartan cilexetil 4 to 32 mg/hydrochlorothiazide 12.5 mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg or candesartan cilexetil 16 mg induced SBP/DBP reductions of 12.0/7.5 mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given candesartan cilexetil 4 or 8 mg/hydrochlorothiazide 12.5 mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg demonstrated a greater antihypertensive effect than losartan 50 mg/hydrochlorothiazide 12.5 mg in two clinical trials. Candesartan cilexetil 8 mg/hydrochlorothiazide 12.5 mg showed a similar antihypertensive effect compared with that of combined lisinopril 10 mg/hydrochlorothiazide 12.5 mg. Candesartan cilexetil/hydrochlorothiazide combination was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving candesartan cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events. CONCLUSION: The combination of candesartan cilexetil and hydrochlorothiazide (AT(1)-receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of candesartan cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.