A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients: a placebo-controlled, forced titration study. Candesartan/Losartan study investigators

The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a longlasting binding to the human AT1-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose intake. After a 4-week placebo lead-in period, 268 patients with sitting diastolic BP 95 to 110 mm Hg and mean awake ambulatory DBP > or =85 mm Hg were randomized to receive either 8 mg of candesartan, 50 mg of losartan, or placebo for a 4-week period. Thereafter, the doses were doubled in all patients for an additional 4-week period. Ambulatory BP monitoring was performed for 36 h after dosing and clinic BP measured 48 h after dosing. Candesartan cilexetil (16 mg) reduced ABP to a significantly greater extent than 100 mg of losartan, particularly for systolic ABP during daytime (P<.05), nighttime (P<.05), and 24-h (P<.01) periods, systolic (P<.01) and diastolic (P<.05) ABP between 0 and 36 h, and both systolic (P<.001) and diastolic (P<0.001) ABP during the day of a missed dose. Clinic BP at 48 h after dosing was significantly reduced exclusively with 16 mg of candesartan. The differences in BP reduction between 8 mg of candesartan and 50 mg of losartan were statistically significant for systolic ABP during daytime (P<.01), nighttime (P<.05), 24-h (P<.01), 0 to 36 h (P<.05) and during the day of missed dose (P<.05). Moreover, although losartan did not significantly reduce ambulatory BP in a dose-related manner, ambulatory systolic and diastolic BP reductions with 16 mg of candesartan were significantly greater (P<.01 and <.001) than those seen with 8 mg of candesartan during every period at the ABP supporting a dose-response relationship. In conclusion, this forced titration study in ambulatory hypertensive patients demonstrates that candesartan cilexetil provides significant dose-dependent reduction in both clinic and ambulatory BP in doses ranging from 8 to 16 mg once daily. Furthermore, candesartan cilexetil is superior to losartan in reducing systolic ABP and in controlling both systolic and diastolic ABP on the day of a missed dose. The differences observed between both agents are most likely attributable to a tighter binding to, and a slower dissociation from, the receptor binding site with candesartan cilexetil.     

Regression of left ventricular hypertrophy by AT1 receptor blockade in renal transplant recipients

AT₁ receptor antagonists control blood pressure (BP) effectively and reduce left ventricular hypertrophy in patients with essential hypertension. Because left ventricular hypertrophy is very common in renal transplant recipients, we examined the cardiovascular effects and the safety profile of the AT₁ receptor antagonist losartan in hypertensive renal transplant recipients. In 20 renal transplant recipients with stable renal graft function 50 mg of losartan was added to the preexisting antihypertensive treatment (no angiotensin-converting enzyme inhibitors) at least 6 months after renal transplantation. Twenty-four–hour ambulatory BP, two-dimensional-guided M-mode echocardiography, and duplex sonography, as well as renal function, red blood cell count, cyclosporine A and FK 506 levels, erythropoetin, and angiotensin II concentration were determined at baseline and after 6 months of therapy. With 24-h ambulatory BP measurement, systolic blood pressure (SBP) was reduced by 7.5 ± 2.4 mm Hg and diastolic blood pressure (DBP) by 4.5 ± 1.8 mm Hg (P < .01 and P < .05, respectively). Posterior, septal, and relative wall thickness decreased by 0.95 ± 0.2 mm, 0.91 ± 0.2 mm and 0.04 ± 0.01 mm, respectively (all P < .001). Left ventricular mass index decreased by 18.1 ± 4.7 g/m² (P < .01). Ejection fraction and midwall fractional fiber shortening as systolic parameters and the relation of passive-to-active diastolic filling of the left ventricle were unaltered. Serum creatinine and cyclosporine A concentration remained stable in all patients. Hemoglobin and hematocrit decreased by 1.0 ± 0.3 g/dL and 3.6% ± 0.9%, respectively (P < .002 and P < .001) without a change in serum erythropoetin level. In renal transplant recipients the AT₁ receptor antagonist losartan reduces left ventricular hypertrophy without altering systolic or diastolic function. It is safe with regard to renal function and immunosuppression, but slightly decreases hemoglobin level.     

The Antihypertensive Effect and Tolerability of Candesartan Cilexetil, a New Generation Angiotensin II Antagonist, in Comparison with Losartan

This multicentre study compared the antihypertensive effect and tolerability of the novel angiotensin II antagonist candesartan cilexetil with those of losartan and placebo. Men and women aged 20-80 years, with primary hypertension and sitting diastolic blood pressure (DBP) 95-114 mm Hg after a 4-week placebo run-in period, were randomized to once daily double-blind treatment with candesartan cilexetil 8 mg (n = 82), candesartan cilexetil 16 mg (n = 84), losartan 50 mg (n = 83) or placebo (n = 85) for 8 weeks. Blood pressure was measured 6 and 24 h after dose, i.e. at peak and trough. Differences between treatments were analysed by analysis of covariance, and the primary effect variable was reduction in trough sitting DBP. Compared with placebo treatment, trough DBP was significantly reduced by a mean (95% CI) of 8.9 (6.0; 11.8) mm Hg with 8 mg and 10.3 (7.4; 13.2) mm Hg with 16 mg candesartan cilexetil. The 8 mg dose was as effective as losartan 50 mg, while 16 mg candesartan cilexetil was significantly more effective, with a difference between treatments of 3.7 (0.8; 6.7) mm Hg (p = 0.013). The placebo corrected trough/peak ratio was 0.9-1.1 with candesartan cilexetil and 0.7 with losartan. Candesartan cilexetil was similarly well tolerated as placebo. In conclusion, candesartan cilexetil 8 mg or 16 mg once daily is an effective and well tolerated antihypertensive treatment. Candesartan cilexetil 16 mg is significantly more effective than losartan 50 mg once daily.     

A forced titration study of antihypertensive efficacy of candesartan cilexetil in comparison to losartan: CLAIM Study II.

An 8-week, multicentre (72 sites in the US), double-blind, randomised, parallel group, forced titration study compared the antihypertensive efficacy of candesartan cilexetil and losartan. A total of 611 patients with essential hypertension (diastolic blood pressure 95 to 114 mm Hg) were randomised initially to candesartan cilexetil 16 mg once daily or losartan 50 mg once daily. After 2 weeks of randomised treatment, the doses of candesartan cilexetil and losartan were doubled to 32 mg and 100 mg once daily and continued respectively for 6 weeks. At week 8, candesartan cilexetil lowered the blood pressure (BP) at 24 h (trough), 6 h (peak) and 48 h post dose to a significantly greater extent (P < 0.05) than losartan: candesartan cilexetil lowered trough BP by 13.4/10.5 mm Hg, peak BP by 15.5/12.9 mm Hg and 48-h BP by 10.5/9.9 mm Hg compared to a reduction of trough BP by 10.1/9.1 mm Hg, peak BP by 12.0/9.5 mm Hg, and 48-h BP by 5.9/7.0 mm Hg by losartan. The responder and control rates were numerically higher in the candesartan cilexetil group, but the differences did not reach statistical significance; the responder rates were 58.8% for the candesartan cilexetil group and 52.1% for the losartan group and control rates were 49.0% for the candesartan cilexetil group and 44.6% for the losartan group. Overall, both treatment regimens were well tolerated. A total of 15 of the 611 (2.5%) patients withdrew from the study due to an adverse event, including nine (2.9%) in the candesartan cilexetil group and six (2.0%) in the losartan group. In conclusion, this forced titration study confirms that candesartan cilexetil is more effective in lowering BP than losartan when compared at once daily maximum doses.     

A new approach to assessing antihypertensive therapy: effect of treatment on pulse pressure. Candesartan cilexetil in Hypertension Ambulatory Measurement of Blood Pressure (CHAMP) Study Investigators

BACKGROUND: A high pulse pressure is an independent cardiovascular risk factor. It has therefore been suggested that antihypertensive treatment should not only reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP), but should also decrease pulse pressure (SBP minus DBP). In a previous analysis, we showed that two angiotensin II type 1 (AT1)-receptor blockers, candesartan cilexetil and losartan, differed in their effects in reducing SBP and DBP. OBJECTIVE: To compare the efficacy of candesartan cilexetil and losartan according to a new approach--their effect on pulse pressure--and to describe the dose-effect relationship for SBP, DBP and pulse pressure, in a placebo-controlled study. METHODS: After a 4-week placebo run-in period, 268 patients with mild-to-moderate hypertension were allocated randomly to groups to receive placebo, candesartan cilexetil (8 mg once daily) or losartan (50 mg once daily), for 4 weeks. The doses were then doubled to 16 and 100 mg, respectively, for the final 4 weeks of the study. Clinic blood pressure was measured 24 and 48 h after each dose of drug or placebo, and ambulatory blood pressure was monitored from 0 to 36 h after each dose, at baseline and after 4 and 8 weeks of treatment. RESULTS: Candesartan cilexetil decreased ambulatory pulse pressure significantly (P < 0.05) more than did losartan during both daytime and night-time, and over the 24 h period after the previous dose. A different dose-effect relationship on SBP, DBP and pulse pressure was observed. The duration of action of candesartan cilexetil was greater than that of losartan. After a missed dose (i.e. approximately 24-36 h after the previous dose), mean ambulatory pulse pressure values after 4 and 8 weeks of treatment with candesartan cilexetil were lower than those observed with losartan (P < 0.005). Clinic pulse pressure measurements were consistent with these ambulatory measurements. CONCLUSIONS: AT1 -receptor blockers differ both in their ability to reduce pulse pressure and in their duration of effect, candesartan cilexetil having a greater and more sustained effect than losartan. Different dose-effect relationships on SBP, DBP or pulse pressure were observed. Further prospective studies based on pulse pressure are needed to analyse the mechanism of reduction of pulse pressure and to determine its prognostic value.     

Antihypertensive Efficacy of Candesartan in Comparison to Losartan: The CLAIM Study

An 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study was conducted to evaluate the antihypertensive efficacy of candesartan vs. losartan in 654 hypertensive patients with a diastolic blood pressure between 95 and 114 mm Hg from 72 sites throughout the U.S. Eligible patients were randomized to candesartan cilexetil 16 mg once daily, or losartan 50 mg once daily. Two weeks following randomization, patients doubled the respective doses of their angiotensin receptor blockers for an additional 6 weeks. At week 8, candesartan cilexetil lowered trough systolic/diastolic blood pressure by a significantly greater amount than did losartan (13.3/10.9 mm Hg with candesartan cilexetil vs. 9.8/8.7 mm Hg with losartan; p < 0.001). At the same period, candesartan cilexetil also lowered peak blood pressure by a significantly greater amount than did losartan (15.2 to 11.6 mm Hg with candesartan cilexetil vs. 12.6 to 10.1 mm Hg with losartan; p < 0.05). There were statistically significantly ( p < 0.05) higher proportions of responders and controlled patients in the candesartan cilexetil group (62.4% and 56.0%, respectively) than in the losartan group (54.0% and 46.9%, respectively). Both treatment regimens were well tolerated; 1.8% in the candesartan cilexetil group and 1.6% in the losartan group withdrew because of adverse events. In conclusion, this forced-titration study confirms that candesartan cilexetil is more effective than losartan in lowering blood pressure when both are administered once daily at maximum doses. Both drugs were well tolerated.     

Does the antihypertensive response to angiotensin converting enzyme inhibition predict the antihypertensive response to angiotensin receptor antagonism?

To test the hypothesis that the antihypertensive response to angiotensin converting enzyme (ACE) inhibition can predict the response to angiotensin II type I receptor (AT₁R) antagonism, 33 hypertensive patients were randomized to receive lisinopril (20 mg) or losartan (50 mg) for 5 weeks. Patients were then crossed-over to the alternative treatment for a second 5-week period. Twenty-four-hour ambulatory BP (ABP) was measured before randomization and on the final day of each period. The agreement in ABP response between the two drugs was assessed using the following approaches: Subjects were classified as responders and nonresponders using as a threshold an arbitrary level of response (ABP fall ≥ 10 mm Hg systolic or ≥ 5 mm Hg diastolic) or the median ABP response achieved by each of the drugs. Disagreement between the two drugs in the responders-nonresponders classification was expressed as the proportion of subjects whose ABP responded to one of the drugs only. Lisinopril was more effective than losartan in reducing ABP (mean difference 4.7 ± 8.1/3.3 ± 5.7 mm Hg, systolic/diastolic, P < .05). Disagreement in the antihypertensive response between the two drugs was found in 39%/33% of subjects for systolic/diastolic ABP using the arbitrary response criterion (33%/39% using the median response criterion). Significant correlations were found between the responses to lisinopril and losartan (r = 0.47/0.59, systolic/diastolic, P < .01). We conclude that in more than one third of hypertensive subjects, the BP response to ACE inhibition fails to predict the response to AT₁ R antagonism and vice versa. These data suggest that there are differences between these two drug classes that are not only of theoretical but also of practical significance.     

Effects of candesartan cilexetil in patients with severe systemic hypertension. Candesartan Cilexetil Study Investigators.

The efficacy, tolerability, and safety of the potent angiotensin II receptor blocker candesartan cilexetil were evaluated in 217 adult patients (68% men, 41% black) with severe systemic hypertension on background therapy with hydrochlorothiazide (HCTZ) in a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Patients with sitting diastolic blood pressure (BP) > or =110 mm Hg during the placebo run-in received HCTZ 12.5 mg once daily for 1 week. Those with sitting diastolic BP >95 mm Hg after the HCTZ run-in were randomized (2:1) to receive candesartan cilexetil 8 mg once daily (n = 141) or placebo (n = 76), plus HCTZ 12.5 mg. After 1 week of double-blind treatment, patients with sitting diastolic BP > or =90 mm Hg were uptitrated to candesartan cilexetil 16 mg once daily or matching placebo, plus HCTZ 12.5 mg; 84% required uptitration. Primary efficacy measurement was a change in trough (24+/-3 hours after treatment) sitting diastolic BP from the end of the HCTZ run-in to double-blind week 4. Mean changes in systolic and diastolic BP were significantly greater with candesartan cilexetil than with placebo, -11.3/-9.1 mm Hg versus -4.1/-3.1 mm Hg, p <0.001/p <0.001, respectively. Patients with higher sitting diastolic BP at the end of the HCTZ run-in tended to have greater decreases in BP (p <0.05). Most patients (53%) receiving candesartan cilexetil were responders (diastolic BP <90 mm Hg or > or =10 mm Hg decrease) and 32% were controlled (diastolic BP <90 mm Hg). Tolerability and safety profiles were similar in the candesartan and placebo groups. In conclusion, candesartan cilexetil 8 to 16 mg once daily was an effective and well-tolerated therapy for lowering BP when added to HCTZ 12.5 mg in a diverse population of patients with severe systemic hypertension in the United States.     

Comparative effects of candesartan cilexetil and amlodipine in patients with mild systemic hypertension. Comparison of Candesartan and Amlodipine for Safety, Tolerability and Efficacy (CASTLE) Study Investigators

The comparative antihypertensive efficacy and tolerability of the angiotensin II receptor blocker candesartan cilexetil and the calcium channel blocker amlodipine were evaluated in an 8-week, multicenter, double-blind, randomized, parallel-group, forced-titration study in 251 adult patients (45% women, 16% black) with mild hypertension (stage 1). Following a 4- to 5-week placebo run-in period, patients with sitting diastolic blood pressure (BP) of 90 to 99 mm Hg received candesartan cilexetil 16 mg (n = 123) or amlodipine 5 mg (n = 128) once daily. After 4 weeks of double-blind treatment, patients were uptitrated to candesartan cilexetil 32 mg or amlodipine 10 mg once daily. There were no significant differences between the candesartan cilexetil and amlodipine regimens for reducing BP; mean systolic BP/diastolic BP reductions were -15.2/-10.2 mm Hg versus -15.4/-11.3 mm Hg, respectively (p = 0.88/0.25). Overall, 79% of patients on candesartan cilexetil and 87% of those on amlodipine were controlled (diastolic BP <90 mm Hg). A total of 3.3% of patients on candesartan cilexetil discontinued treatment, compared with 9.4% of patients on amlodipine, including 2.4% versus 4.7% for adverse events and 0% versus 1.6% for peripheral edema, respectively. Peripheral edema, the prespecified primary tolerability end point, occurred with significantly greater frequency in patients on amlodipine (22.1%; mild 8.7%, moderate 11.8%, severe 1.6%) versus patients on candesartan cilexetil (8.9%; mild 8.1%, moderate 0.8%) (p = 0.005). Candesartan cilexetil and amlodipine are both highly effective in controlling BP in patients with mild hypertension. Candesartan cilexetil offers a significant tolerability advantage with respect to less risk of developing peripheral edema.     

Accuracy of a new wrist cuff oscillometric blood pressure device: Comparisons with intraarterial and mercury manometer measurements

Accurate measurement of arterial blood pressure is of great importance for the diagnosis and treatment of hypertension. Because of the chronic nature of antihypertensive drug therapy, the involvement of the patient in blood pressure control is desirable. Such an involvement, however, is only feasible if simple, user-friendly, and precise blood pressure measurement devices are available.

In this study we tested a new wrist cuff oscillometric blood pressure measurement device in 100 consecutive patients undergoing cardiac catheterization. Blood pressures were simultaneously taken intraarterially (axillary artery) and with a mercury manometer and stethoscope or noninvasive measurement device (OMRON R3). Intraarterial measurements were directly compared with two measurements taken in random order with either an arm cuff mercury manometer or the wrist cuff device.

Systolic and diastolic blood pressure as assessed with the mercury manometer was higher, especially when compared with the intraarterial and the wrist cuff values, which were comparable. Correlations of blood pressure values with intraarterial measurement were 0.86 systolic and 0.75 diastolic (P < .01) for the wrist cuff and 0.84 systolic (P < .01) and 0.59 diastolic (P < .05) for the mercury manometer measurements. Reproducibility of both measurements was good for the wrist cuff device ([systolic/diastolic]: r = 0.94/0.92; P < .01) and the mercury manometer (r = 0.97/0.88; P < .01). Both methods overestimated high diastolic values, whereas only the wrist cuff underestimated high systolic values.

Thus, the new oscillometric wrist cuff blood pressure measurement device measures arterial blood pressure with great accuracy and reproducibility. As compared with intraarterial values, the wrist cuff device overestimated high diastolic and underestimated high systolic blood pressure values. Blood pressure values as measured by the mercury manometer were higher than intraarterial values and those of the wrist cuff. Both noninvasive devices overestimated high diastolic values.     

Effect of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics

BACKGROUND: Hyperuricemia may counter benefits of blood pressure (BP) reduction, although this is controversial. METHODS: We examined the effects of candesartan and losartan on uric acid, creatinine, and fibrinogen. Patients with hypertension and serum uric acid > or = 0.42 mmol/L (7 mg/dL) associated with diuretics were randomized to receive losartan 50 to 100 mg or candesartan 8 to 16 mg for 24 weeks. At randomization and after 24 weeks, systolic and diastolic BP, serum uric acid, creatinine, and fibrinogen were measured. RESULTS: A total of 59 patients were entered into the study (30 in the losartan and 29 in the candesartan group). Mean systolic and diastolic BP were reduced in the candesartan group, from 156 mm Hg at baseline to 132 mm Hg at 24 weeks, and from 90.9 to 80.8 mm Hg respectively, P < .0001), and in the losartan group from 150.3 to 132 mm Hg and from 89.6 to 77.6 respectively, P < 0001). Overall mean values of fibrinogen levels were again reduced from 4.39 g/L at baseline to 4.01 g/L at 24 weeks (P < .02). Mean values of serum uric acid in the losartan and candesartan groups were similar at baseline (0.44 and 0.46 mmol/L, respectively), but they were lower in the losartan group after 24 weeks (0.39 and 0.48 mmol/L, P = .01). Twelve patients (44%) in the candesartan group had a 10% increase in serum creatinine compared with four patients (14.2%) in the losartan group (P < .02). CONCLUSIONS: Candesartan and losartan lowered BP, but only losartan reduced uric acid. The lowering of fibrinogen in both groups may explain the reduction in stroke with angiotensin receptor blockers. The effect of persistent hyperuricemia on renal function requires further study.     

Effect of angiotensin ii receptor blockade on arterial stiffness: beyond blood pressure reduction

We compared the effect of losartan (50 mg/day) to hydrochlorthiazide (12.5 mg/day) on blood pressure (BP) and arterial stiffness in 11 untreated hypertensive patients aged 47 to 69 years in a 4-week single blind randomized crossover study with an intervening 4-week washout period. Both drugs produced a significant (P < .001) and similar decrease in brachial BP. Only losartan induced a significant decrease in arterial wave reflection (P < .0001), with a preferential reduction in aortic (P < .001) compared to brachial pulse pressure. Losartan also significantly increased pulse pressure amplification and reduced pulse wave velocity. These results suggest that an AT₁ receptor antagonist induces a BP independent decrease in aortic stiffness and arterial wave reflection.     

Risk variables of insulin resistance syndrome in African-American and Caucasian young adults with microalbuminuria: the Bogalusa heart study

Microalbuminuria is a strong predictor of cardiovascular disease. Previous studies are inconsistent regarding the relationship between microalbuminuria and insulin resistance syndrome. Therefore, we examined this relationship in 1031 young adults (61% Caucasian, 39% African-American) aged 19 to 32 years. Individuals with either urinary albumin to creatinine ratio at or above the 90th percentile (age, race, and gender specific) or urinary albumin level at or above 30 mg/L were considered as having slightly elevated albumin excretion (microalbuminuria). The multiple risk variables of insulin resistant syndrome measured include body mass index, waist circumference, blood pressure (BP), triglycerides, high-density lipoprotein (HDL) cholesterol, glucose, insulin, insulin resistance index (calculated from a homeostasis model assessment equation), and uric acid. After controlling for age and gender, African-Americans with microalbuminuria by either measure had higher mean systolic (P < .001) and diastolic (P < .05) BP, prevalence of hypertension (P < .05), and, contrary to expectations, HDL cholesterol (P < .05) than those without this condition. On the other hand, Caucasians showed no such associations. In African-Americans, the above differences in BP levels persisted when hypertensive subjects were excluded. None of the other risk variables displayed any relation to microalbuminuria in both races. These results suggest that microalbuminuria is not necessarily an intrinsic component of the insulin resistance syndrome, at least in the young adult age. Furthermore, the observed association between hypertension and microalbuminuria among young African-Americans may reflect early evidence of renal dysfunction due to the burden of elevated BP in this group.     

Evaluation of the Antihypertensive Effect of Barnidipine, a Dihydropyridine Calcium Entry Blocker, as Determined by the Ambulatory Blood Pressure Level Averaged for 24 h, Daytime, and Nighttime

We evaluated the effect of barnidipine, a dihydropyridine calcium antagonist, administered once daily in the morning in a dose of 5, 10, or 15 mg on ambulatory blood pressure (BP) in 34 patients (51.3 ± 9.6 years). Hypertension was diagnosed based on the clinic BP. The patients were classified into groups according to the ambulatory BP: group 1, dippers with true hypertension; group 2, nondippers with true hypertension; group 3, dippers with false hypertension; and Group 4, nondippers with false hypertension. Barnidipine reduced the clinic systolic BP (SBP) and diastolic BP (DBP) in all groups and significantly reduced the average 24 h ambulatory BP (133.0 ± 16.5/90.7 ± 12.3 mm Hg v 119.7 ± 13.7/81.8 ± 10.3 mm Hg, P < .0001 for both SBP and DBP). Barnidipine significantly reduced the daytime ambulatory SBP in groups 1, 2, and 3, but not in group 4, and significantly reduced daytime ambulatory DBP in group 1 but not in groups 2, 3, and 4. Barnidipine significantly reduced the nighttime ambulatory SBP only in group 2 and the nighttime ambulatory DBP in groups 2 and 4. Once-a-day administration of barnidipine influenced 24 h BP on true hypertensives (the ratio of the trough to peak effect > 50%), but had minimal effect on low BP such as the nocturnal BP in dippers and the ambulatory BP in false hypertensives. These findings suggest that barnidipine can be used safely in patients with isolated clinic (“white coat”) hypertension and in those with dipping patterns of circadian BP variation whose nocturnal BP is low before treatment.     

The effect duration of candesartan cilexetil once daily, in comparison with enalapril once daily, in patients with mild to moderate hypertension

OBJECTIVE: To determine the antihypertensive efficacy, effect duration and safety of the angiotensin II type 1 receptor blocker candesartan cilexetil and the angiotensin converting enzyme inhibitor enalapril once daily in patients with mild to moderate hypertension. METHODS: A multicenter, randomised, double-blind parallel group study was performed in Finland, France, the Netherlands, Spain and Sweden. Three-hundred-and-ninety-five men and women in the age range 20-80 years with primary hypertension were randomised to an 8-week double-blind treatment period with either candesartan cilexetil 8-16 mg or enalapril 10-20 mg once daily, with forced dose titration after 4 weeks. Non-invasive ambulatory blood pressure was measured for 36 h at baseline and after 8 weeks. The primary efficacy variable was the change in mean diastolic and systolic ambulatory blood pressure 22-24 h post-dose. RESULTS: There was a significant difference in the adjusted mean difference for the change from baseline to week 8 between candesartan cilexetil and enalapril 22-24 h post-dose by -3.5 mmHg (95% confidence interval, CI: -6.8 to -0.3 mmHg; p < 0.032) in ambulatory systolic blood pressure and -3.0 mmHg (95% CI: -5.1 to -0.8 mmHg; p < 0.008) in ambulatory diastolic blood pressure. There was a significant difference in adjusted mean daytime ambulatory blood pressure 24-36 h post-dose by -4.2 mmHg (95% CI: -6.8 to -1.6 mmHg; p < 0.002)/-3.5 mmHg (95% CI: -5.1 to -1.8 mmHg; p < 0.001). Both drugs were generally well tolerated. CONCLUSION: The results of the present study suggest that advantages may be attributed to the use of candesartan cilexetil, as compared to enalapril in the treatment of patients with essential hypertension. In comparison with enalapril 20 mg, candesartan cilexetil 16 mg more effectively lowered blood pressure at trough and in particular on the day following the day after the last dose.     

Expedited blood pressure control with initial angiotensin II antagonist/diuretic therapy compared with stepped-care therapy in patients with ambulatory systolic hypertension

OBJECTIVES: The present study investigated whether initiating therapy with a combination of losartan (L) and hydrochlorothiazide (HCTZ) allows for faster blood pressure (BP) control and fewer medications than the usual stepped-care approach in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension. METHODS: Patients with a mean daytime systolic ambulatory BP (ABP) of 135 mmHg or higher were randomly assigned to receive L 50 mg plus HCTZ 12.5 mg titrated to L 100 mg plus HCTZ 25 mg versus HCTZ 12.5 mg plus atenolol 50 mg. Amlodipine 5 mg was then added, if needed, to achieve a BP goal of less than 130 mmHg. Treatment titration was based on ABP. RESULTS: Significantly more patients randomly assigned to L/HCTZ (63.5%) than stepped-care (37.5%; P=0.008) achieved the primary end point (daytime systolic BP of less than 130 mmHg). Initial L/HCTZ induced significantly greater decreases in ABP during each 24 h period after six weeks of therapy. Although reductions in systolic and diastolic ABP were not statistically different at the end of the study, ABP reduction was significantly greater (P<0.001) with the L/HCTZ-based regimen. Twice as many patients in the L/HCTZ group achieved the goal ABP with no more than two drugs (30.0% versus 14.7%; P=0.03). Moreover, tolerability was significantly better (P=0.006) in the L/HCTZ group, with a 40.0% incidence of adverse events, versus 65.6% in the stepped-care group. CONCLUSION: Initiating antihypertensive therapy with the combination of L/HCTZ in patients with stage 2 or 3 hypertension and ambulatory systolic hypertension reaches a target BP faster in a higher proportion of patients, with fewer adverse events and less need for a third drug regimen than the conventional stepped-care approach.     

Comparison of the efficacy and safety of azilsartan with that of candesartan cilexetil in Japanese patients with grade I-II essential hypertension: a randomized, double-blind clinical study

Azilsartan is a novel angiotensin receptor blocker being developed for hypertension treatment. This 16-week, multicenter, randomized, double-blind study compared the efficacy and safety of azilsartan (20-40 mg once daily by forced titration) and its ability to provide 24-h blood pressure (BP) control, with that of candesartan cilexetil (candesartan; 8-12 mg once daily by forced titration) in 622 Japanese patients with grade I-II essential hypertension. Efficacy was evaluated by clinic-measured sitting BP, and by ambulatory BP monitoring (ABPM) at week 14. Participants (mean age: 57 years, 61% males) had a mean baseline sitting BP of 159.8/100.4 mm Hg. The mean change from baseline in sitting diastolic BP at week 16 (primary endpoint) was -12.4 mm Hg in the azilsartan group and -9.8 mm Hg in the candesartan group, demonstrating a statistically significant greater reduction with azilsartan vs. candesartan (difference: -2.6 mm Hg, 95% confidence interval (CI): -4.08 to -1.22 mm Hg, P=0.0003). The week 16 (secondary endpoint) mean change from baseline in sitting systolic BP was -21.8 mm Hg and -17.5 mm Hg, respectively, a significant decrease with azilsartan vs. candesartan (difference: -4.4 mm Hg, 95% CI: -6.53 to -2.20 mm Hg, P<0.0001). On ABPM, the week 14 mean changes from baseline in diastolic and systolic BP were also significantly greater with azilsartan over a 24-h period, and during the daytime, night-time and early morning. Safety and tolerability were similar among the two groups. These data demonstrate that once-daily azilsartan provides a more potent 24-h sustained antihypertensive effect than that of candesartan but with equivalent safety.     

Efficacy and tolerability of a combination tablet of candesartan cilexetil and hydrochlorothiazide in insufficiently controlled primary hypertension--comparison with a combination of losartan and hydrochlorothiazide

This randomized, double-blind study compared the antihypertensive effect, safety and tolerability of a candesartan cilexetil/hydrochlorothiazide (candesartan/HCT; 16/12.5 mg) combination tablet with that of a losartan/HCT (50/12.5 mg) combination tablet in patients with mild-to-moderate primary hypertension insufficiently controlled on previous monotherapy. Men and women, aged 20-80 years, with a sitting diastolic blood pressure (DBP) > or = 90 and < or = 110 mmHg and sitting systolic blood pressure (SBP) < or = 200 mmHg during treatment with any kind of antihypertensive monotherapy for at least 4 weeks were randomized to candesartan/HCT or losartan/HCT once daily for 12 weeks. All BP measurements were performed 24 h after previous dose. Mean values and standard deviations (SD) or confidence intervals (CI) are given. A total of 340 patients were enrolled, of whom 299 (144 women and 155 men, mean age 59.5 [10.5] years) were randomized to candesartan/HCT (n = 151) or losartan/HCT (n = 148). BPs at randomization were 159.5 (15.4)/98.4 (5.8)mmHg and 160.5 (16.1)/98.5 (5.4)mmHg, respectively. There was a greater reduction in BP with candesartan/HCT than with losartan/HCT: DBP -10.4 (-11.8; -8.9) vs -7.8 (-9.3; -6.3) mmHg, difference between treatments -2.6 (-4.7; -0.5) mmHg (p = 0.016); SBP -19.4 (-22.1; -16.7) vs - 13.7 (-16.5; - 10.9) mmHg, difference between treatments -5.7 (-9.6; -1.8) mmHg (p = 0.004). The proportion of patients achieving a DBP < or = 90 mmHg was greater in the candesartan/HCT group: 60.9 (53.1; 68.7) vs 49.3 (41.3; 57.4)% (p = 0.044). There were 12 withdrawals in the candesartan/HCT group, of which 8 were due to adverse events, and 17 and 12, respectively in the losartan/HCT group. We conclude that the combination of candesartan and HCT reduces BP effectively and is well tolerated. BP was normalized in 61% of these patients who had insufficient response to previous monotherapy. The reduction in BP and the proportion of patients with normalized BP were greater with the candesartan/HCT 16/12.5 mg combination than with the losartan/ HCT 50/12.5 mg combination.     

Efficacy and safety of sacubitril/valsartan in patients with essential hypertension uncontrolled by olmesartan: A randomized,double‐blind, 8‐week study

A majority of patients with hypertension fail to achieve blood pressure (BP) control despite treatment with commonly prescribed drugs. This randomized, double‐blind phase III trial assessed the superiority of sacubitril/valsartan 200 mg (97/103 mg) to continued olmesartan 20 mg in reducing ambulatory systolic BP after 8‐week treatment in patients with mild to moderate essential hypertension uncontrolled with olmesartan 20 mg alone. A total of 376 patients were randomized to receive either sacubitril/valsartan (n = 188) or olmesartan (n = 188). Superior reductions in 24‐hour mean ambulatory systolic BP were observed in the sacubitril/valsartan group vs the olmesartan group (−4.3 mm Hg vs −1.1 mm Hg, P < .001). Reductions in 24‐hour mean ambulatory diastolic BP and pulse pressure and office systolic BP and diastolic BP were significantly greater with sacubitril/valsartan vs olmesartan (P < .014). A greater proportion of patients achieved BP control with sacubitril/valsartan vs olmesartan. The overall incidence of adverse events was comparable between the groups. Compared with continued olmesartan, sacubitril/valsartan was more effective and generally safe in patients with hypertension uncontrolled with olmesartan 20 mg.     

Pharmacokinetic-pharmacodynamic interactions of candesartan cilexetil and losartan.

BACKGROUND: The variability of the blood pressure response to blockade of the angiotensin II type 1 receptor is influenced by renin status and pharmacokinetics and pharmacokinetic-pharmacodynamic interactions. OBJECTIVE: To compare the pharmacokinetic-pharmacodynamic interactions of two doses of an ester prodrug of a noncompetitive angiotensin II type 1 receptor antagonist, candesartan cilexetil, at 8 and 16 mg, with those of the reference angiotenisn II type 1 receptor blocker, losartan, at the standard dose (50 mg), in a human model that controls renin status. DESIGN AND METHODS: In a double-blind placebo-controlled crossover study, we compared the effects on renin and mean blood pressure over 24 h of single oral doses of candesartan cilexetil at 8 and 16 mg and losartan at 50 mg in 16 sodium-depleted normotensive subjects. RESULTS: The area under the curve (0-24 h) for plasma active renin did not differ significantly between 8 mg candesartan cilexetil and 50 mg losartan, but was significantly higher for 16 than for 8 mg candesartan cilexetil or for 50 mg losartan. The area under the curve (0-24 h) for the fall in mean blood pressure with 16 mg candesartan cilexetil (-197 +/- 96 mmHg/h) was significantly greater than that for placebo (-112 +/- 81 mmHg/h; P< 0.05) but the difference was not statistically significant compared with either 8 mg candesartan cilexetil (-158 +/- 95 mmHg/h) or 50 mg losartan (-144 +/- 66 mmHg/h). The area under the curve (0-24 h) for the fall in mean blood pressure did not significantly differ between 8 mg candesartan cilexetil, 50 mg losartan and placebo. The area under the curve (0-24 h) for plasma active renin was significantly correlated to that for plasma levels of the active metabolite of losartan, EXP 3174 (r = 0.65, n = 16, P< 0.01). No such correlation was detected for each single dose of candesartan cilexetil but a dose-response relationship was present when both doses were combined. CONCLUSIONS: The pharmacodynamic effects of a single oral dose of 16 mg candesartan cilexetil are greater than those of 50 mg losartan and 8 mg candesartan cilexetil. The variability in the pharmacokinetic-pharmacodynamic interaction is less pronounced for candesartan than for EXP 3174, which could result in reduced variability of the blood pressure effects in patients.