Results of the CARLOS-Study
Objectives: To compare the fixed combinations of candesartan cilexetil and hydrochlorothiazide (HCTZ) and losartan and HCTZ with respect to magnitude and duration of antihypertensive effect and tolerability. Design and Setting: This was a randomised, double-blind, parallel-group study conducted at nine centres in Germany.
Patients: 160 patients with moderate to severe hypertension, untreated or not controlled on previous treatment, completed the study. Interventions: Patients were randomised to 6 weeks of treatment with candesartan cilexetil and HCTZ 16/12.5mg once daily (n = 81) or losartan and HCTZ 50/12.5mg once daily (n = 79). Blood pressure measurements were performed approximately 24 and 48 hours after the last dose.
Results: Both candesartan cilexetil/HCTZ and losartan/HCTZ lowered blood pressure significantly compared with baseline. Mean seated blood pressures were reduced by 32.2/21.1mm Hg (systolic/diastolic) after 6 weeks, 24 hours postdose, in the candesartan cilexetil/HCTZ group. Corresponding reductions in the losartan/HCTZ group were 23.8/14.9mm Hg. The mean differences in antihypertensive effect between treatments were 8.4/6.2mm Hg in favour of candesartan cilexetil (p < 0.001). Blood pressure reductions 48 hours postdose were 25.6/16.4mm Hg for candesartan cilexetil/HCTZ and 9.2/4.2mm Hg for losartan/HCTZ, with differences between treatments being highly significant in favour of candesartan cilexetil/HCTZ (16.5/12.2mm Hg; p < 0.001). The proportions of responders (seated diastolic blood pressure ≤90mm Hg and/or a reduction from baseline ≥10mm Hg) and controlled patients (seated diastolic blood pressure ≤90mm Hg) on candesartan cilexetil/HCTZ were 98 and 58% at 24 hours, and 84 and 37% at 48 hours postdose. Corresponding figures for losartan/HCTZ were 79 and 28%, and 18 and 1.3%, respectively. All differences were significant (p < 0.001) in favour of candesartan cilexetil/HCTZ. Both treatments were well tolerated.
Conclusions: Candesartan cilexetil/HCTZ 16/12.5mg once daily reduced blood pressure more effectively than losartan/HCTZ 50/12.5mg once daily both 24 and 48 hours postdose. The long-lasting effect of candesartan cilexetil/HCTZ provides effective blood pressure control even after a missed dose.
The renin-angiotensin system plays an important role in the pathophysiology of hypertension, and blockade of the angiotensin II type 1 (AT1) receptor with losartan and more recently with newer drugs such as candesartan has been documented to result in considerable blood pressure reductions. Intervening with the effects of angiotensin II by directly blocking the AT1 receptor rather than the angiotensin-converting enzyme (ACE) carries the advantage of an excellent tolerability comparable to that of placebo treatment. Apart from a clear, linear dose response relationship, candesartan differs from losartan through its stronger binding with the AT1 receptor and its slow dissociation from the binding site, leading to greater antihypertensive efficacy, and a prolonged duration of BP reduction.
The combination of an AT1 receptor antagonist such as losartan or candesartan, with a low-dose regimen of hydrochlorothiazide (HCTZ) in patients uncontrolled by monotherapy is a logical step based on pathophysiological considerations. AT1 receptor antagonists are most effective in hypertensive patients with high plasma renin activity. In patients with low plasma renin activity, the addition of a diuretic will stimulate the renin-angiotensin system and hence increase the efficacy of the AT1 receptor antagonist. Fixed combination tablets of losartan and HCTZ and of candesartan and HCTZ have been developed and are potential alternatives for the management of more difficult-to-treat or more advanced hypertension.
Therefore, the aim of this study was to compare the medium-term antihypertensive efficacy and tolerability of the fixed combination of candesartan cilexetil/HCTZ 16/12.5mg with the combination of losartan/HCTZ 50/12.5mg in patients with moderate to severe hypertension.
Objectives: To compare the fixed combinations of candesartan cilexetil and hydrochlorothiazide (HCTZ) and losartan and HCTZ with respect to magnitude and duration of antihypertensive effect and tolerability. Design and Setting: This was a randomised, double-blind, parallel-group study conducted at nine centres in Germany.
Patients: 160 patients with moderate to severe hypertension, untreated or not controlled on previous treatment, completed the study. Interventions: Patients were randomised to 6 weeks of treatment with candesartan cilexetil and HCTZ 16/12.5mg once daily (n = 81) or losartan and HCTZ 50/12.5mg once daily (n = 79). Blood pressure measurements were performed approximately 24 and 48 hours after the last dose.
Results: Both candesartan cilexetil/HCTZ and losartan/HCTZ lowered blood pressure significantly compared with baseline. Mean seated blood pressures were reduced by 32.2/21.1mm Hg (systolic/diastolic) after 6 weeks, 24 hours postdose, in the candesartan cilexetil/HCTZ group. Corresponding reductions in the losartan/HCTZ group were 23.8/14.9mm Hg. The mean differences in antihypertensive effect between treatments were 8.4/6.2mm Hg in favour of candesartan cilexetil (p < 0.001). Blood pressure reductions 48 hours postdose were 25.6/16.4mm Hg for candesartan cilexetil/HCTZ and 9.2/4.2mm Hg for losartan/HCTZ, with differences between treatments being highly significant in favour of candesartan cilexetil/HCTZ (16.5/12.2mm Hg; p < 0.001). The proportions of responders (seated diastolic blood pressure ≤90mm Hg and/or a reduction from baseline ≥10mm Hg) and controlled patients (seated diastolic blood pressure ≤90mm Hg) on candesartan cilexetil/HCTZ were 98 and 58% at 24 hours, and 84 and 37% at 48 hours postdose. Corresponding figures for losartan/HCTZ were 79 and 28%, and 18 and 1.3%, respectively. All differences were significant (p < 0.001) in favour of candesartan cilexetil/HCTZ. Both treatments were well tolerated.
Conclusions: Candesartan cilexetil/HCTZ 16/12.5mg once daily reduced blood pressure more effectively than losartan/HCTZ 50/12.5mg once daily both 24 and 48 hours postdose. The long-lasting effect of candesartan cilexetil/HCTZ provides effective blood pressure control even after a missed dose.
The renin-angiotensin system plays an important role in the pathophysiology of hypertension, and blockade of the angiotensin II type 1 (AT1) receptor with losartan and more recently with newer drugs such as candesartan has been documented to result in considerable blood pressure reductions. Intervening with the effects of angiotensin II by directly blocking the AT1 receptor rather than the angiotensin-converting enzyme (ACE) carries the advantage of an excellent tolerability comparable to that of placebo treatment. Apart from a clear, linear dose response relationship, candesartan differs from losartan through its stronger binding with the AT1 receptor and its slow dissociation from the binding site, leading to greater antihypertensive efficacy, and a prolonged duration of BP reduction.
The combination of an AT1 receptor antagonist such as losartan or candesartan, with a low-dose regimen of hydrochlorothiazide (HCTZ) in patients uncontrolled by monotherapy is a logical step based on pathophysiological considerations. AT1 receptor antagonists are most effective in hypertensive patients with high plasma renin activity. In patients with low plasma renin activity, the addition of a diuretic will stimulate the renin-angiotensin system and hence increase the efficacy of the AT1 receptor antagonist. Fixed combination tablets of losartan and HCTZ and of candesartan and HCTZ have been developed and are potential alternatives for the management of more difficult-to-treat or more advanced hypertension.
Therefore, the aim of this study was to compare the medium-term antihypertensive efficacy and tolerability of the fixed combination of candesartan cilexetil/HCTZ 16/12.5mg with the combination of losartan/HCTZ 50/12.5mg in patients with moderate to severe hypertension.
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