Effects of combination olmesartan medoxomil plus azelnidipine versus monotherapy with either agent on 24-hour ambulatory blood pressure and pulse rate in Japanese patients with essential hypertension: additional results from the REZALT study.

BACKGROUND: In a previously reported randomized, double-blind, parallel-group study of the efficacy and tolerability of olmesartan medoxomil (OLM) and azelnidipine (AZL) combination therapy compared with monotherapy with each agent in Japanese patients with essential hypertension (the REZALT study), the use of a combination of OLM, an angiotensin II receptor blocker, plus AZL, a dihydropyridine calcium channel blocker, was associated with significantly greater reductions in office sitting blood pressure (BP) and 24-hour ambulatory BP compared with monotherapy with either agent, and was well tolerated. OBJECTIVE: This article reports the results from an a priori planned analysis and post hoc analyses of the diurnal BP and pulse rate (PR) profiles of OLM/AZL versus monotherapy with either agent from the REZALT study. METHODS: Male and female Japanese outpatients with essential hypertension were eligible if they met the following inclusion criteria: age > or = 20 years; systolic BP (SBP) > or = 140 to <180 mm Hg and diastolic BP (DBP) > or = 90 to <110 mm Hg; and 24-hour ambulatory SBP/DBP > or = 135/> or = 80 mm Hg. Patients were randomly assigned to receive OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM 20 mg, or AZL 16 mg, once daily for 12 weeks. The effectiveness of the treatments was assessed using 24-hour ambulatory BP monitoring (ABPM) and PR, analyzed by time period (BP and PR, 24 hours, daytime [7 AM-<10 PM], nighttime [10 PM-<7 AM], and early morning [6 AM-<9 AM]; PR, morning [6 AM -<11 AM]) and dipping status at baseline (dippers [(Daytime BP - Nighttime BP)/Daytime BP > or = 10%] or nondippers [(Daytime BP - Nighttime BP)/Daytime BP <10%]). RESULTS: A total of 867 patients were enrolled, and 862 randomized patients were included in the full analysis set (590 men, 272 women; mean age, 56.6 years). A total of 839 patients had assessable ABPM data (213, 211, 206, and 209 patients in the OLM/AZL 10/8 mg, OLM/AZL 20/16 mg, OLM, and AZL groups, respectively). No clinically significant between-group differences were observed in baseline demographic and clinical characteristics. Combination therapy was associated with significantly greater antihypertensive effects on 24-hour ABPM compared with either monotherapy in all of the time periods, as follows: SBP/DBP reductions with OLM/AZL 20/16 mg in the daytime, nighttime, and early morning were -22.6/-14.1, -21.2/-12.5, and -20.6/-11.9 mm Hg, respectively (all, P < 0.05 vs the other 3 treatment groups). The SBP/DBP reductions with OLM/AZL 10/8 mg (daytime, -18.2/-11.0 mm Hg; nighttime, -18.1/-10.0 mm Hg; and early morning, -15.6/-9.3 mm Hg) were also significantly greater than with OLM 20 mg (-11.8/-6.7, -12.8/-7.2, and -11.0/ -6.9 mm Hg, respectively; all, P < 0.01) and AZL 16 mg (-13.1/-7.8, -10.2/-5.5, and -9.9/-6.1 mm Hg; all, P < 0.001) in all of the time periods. The antihypertensive effects associated with OLM/AZL 10/8 mg or 20/16 mg were significantly greater than those with monotherapies regardless of dipping pattern at baseline (all, P < 0.05) in all of the time periods, with the exception of nighttime reduction with OLM/AZL 10/8 mg versus OLM in dippers. The numbers of patients who had any increase in BP were 12/213 (5.6%) with OLM/AZL 10/8 mg, 13/211 (6.2%) with OLM/AZL 20/16 mg, 35/206 (17.0%) with OLM, and 36/209 (17.2%) with AZL. The AZL-containing regimens were associated with reduced morning PR (mean [95% CI] changes from baseline to week 12: -1.5 beats/min [-2.5 to -0.4] with OLM/AZL 10/8 mg, -2.1 beats/min [-3.0 to -1.1] with OLM/AZL 20/16 mg, 0.4 beat/min [-0.5 to 1.3] with OLM, and -1.9 beats/min [-2.8 to -1.0] with AZL). CONCLUSION: In this study in Japanese patients with essential hypertension, the reductions in daytime, nighttime, and early-morning BP assessed using 24-hour ABPM were significantly greater with combination OLM/AZL than with either monotherapy, regardless of dipping pattern at baseline. Japan Pharmaceutical Information Center registration number: JapicCTI-060286.

A randomized, double-blind, four-arm parallel-group study of the efficacy and safety of azelnidipine and olmesartan medoxomil combination therapy compared with each monotherapy in Japanese patients with essential hypertension: the REZALT study.

A 12-week randomized, double-blind, four-arm parallel-group, comparative study was conducted in patients with essential hypertension to evaluate the antihypertensive effect and safety of combination therapy with olmesartan medoxomil (OLM, an angiotensin-receptor blocker) 20 mg plus azelnidipine (AZL, a long-acting dihydropyridine calcium channel blocker) 16 mg, (O/A (20/16)), or OLM 10 mg/AZL 8 mg (O/A (10/8)) compared with those of monotherapy with OLM 20 mg (OLM (20)) or AZL 16 mg (AZL (16)). The change from baseline to week 12 in seated blood pressure (SeBP) was -23.6/-14.2 mm Hg (systolic/diastolic BP) in the O/A (20/16) group, and -20.3/-13.0 mm Hg in the O/A (10/8) group, which was a significantly greater reduction in SeBP than in the monotherapy groups (-15.7/-9.9 mm Hg in OLM (20); -15.0/-9.4 mm Hg in AZL (16)). The change from baseline in 24-h ambulatory BP was also significantly greater in the O/A (20/16) and O/A (10/8) combination groups (-22.1/-13.5 and -18.2/-10.6 mm Hg, respectively) than in the OLM (20) and AZL (16) monotherapy groups (-12.1/-6.9 and -12.0/-6.9 mm Hg). The proportion of patients achieving the SeBP goal (<130/85 mm Hg for normal BP or <140/90 mm Hg for high-normal BP) was significantly higher in the O/A (20/16) combination group than in the monotherapy groups. The incidence of adverse events was similar in the O/A combination groups and the monotherapy groups. These results showed that combination therapy with O/A was well tolerated and exerted a stronger antihypertensive effect compared with monotherapy with OLM or AZL in patients with essential hypertension.

Comparative pharmacodynamics of olmesartan and azelnidipine in patients with hypertension: a population pharmacokinetic/pharmacodynamic analysis.

SUMMARY: The objectives of this study were to identify the factors influencing antihypertensive response to the angiotensin receptor blocker, olmesartan medoxomil, or the calcium channel blocker, azelnidipine, and to discuss the possibility of utilizing them as predictors for drug selection prior to therapy. A two-way crossover study of olmesartan medoxomil and azelnidipine was conducted in 29 patients with mild to moderate essential hypertension. The 24-hour ambulatory blood pressure measurements (ABPM) and plasma drug concentrations were obtained on the first and at the end of each treatment period, and were analyzed using population pharmacokinetic/pharmacodynamic (PK/PD) modeling approach. The population PK/PD models considering circadian variations in baseline blood pressure well described the observed plasma drug concentrations and 24-hour ABPM profiles. Pre-treatment plasma renin activity (PRA) was identified as a significant covariate on the maximum drug effect (E(max)) of olmesartan, whereas azelnidpine E(max) was independent of patient background characteristics investigated. No patient was found to have a high E(max) to one agent who also had a high E(max) to the other. In conclusion, the effects of olmesartan medoxomil and azelnidipine were modestly correlated with pharmacokinetic profiles, and the pre-treatment PRA level could be a useful determinant of responsiveness in selecting olmesartan medoxomil and azelnidipine.

In half of hypertensive diabetics, co-administration of a calcium channel blocker and an angiotensin-converting enzyme inhibitor achieved a target blood pressure of <130/80 mmHg: the azelnidipine and temocapril in hypertensive patients with type 2 diabetes (ATTEST) study.

We conducted a multicenter, randomized, open-label, ascending dose study to investigate the efficacy and safety of combination therapy using the calcium channel blocker azelnidipine and angiotensin-converting enzyme (ACE) inhibitor temocapril in hypertensive diabetics. Patients received monotherapy with 8 mg azelnidipine (group A, n=112) or 2 mg temocapril (group T, n=111) for 4 weeks. If the target blood pressure (<130/80 mmHg) was not achieved, doses were doubled. If it was still not achieved, both drugs were coadministered at week 8, and, if needed, another antihypertensive drug was added after week 16. The treatment period was 52 weeks. Blood pressure was decreased significantly beginning at week 8 (p<0.0001 in both groups), and the systolic and diastolic blood pressure at the end of the treatment period was 128.2+/-11.1/76.4+/-8.1 mmHg. Overall, 53.8% (113/210) of patients achieved the target blood pressure by the end of the study. The effect during the monotherapy period (through week 8) was greater in group A than in group T (systolic, p=0.0475; diastolic, p=0.0001). Laboratory tests showed significant decreases in the urine albumin:creatinine ratio (p=0.0006), high-sensitivity C-reactive protein concentration (p=0.0073), and urine 8-isoprostane concentration (p=0.0215) at the end of the treatment period, as compared with baseline values. No adverse events caused safety problems. In conclusion, combination therapy using azelnidipine and temocapril is an effective treatment for hypertensive diabetics.

Azelnidipine and amlodipine: a comparison of their pharmacokinetics and effects on ambulatory blood pressure.

We objected: 1) To compare the effects of azelnidipine and amlodipine on 24-h blood pressure; 2) To monitor the plasma concentration vs. the time profile in order to assess the association between pharmacokinetics and hypotensive activity after administration of either drug for 6 weeks. Blood pressure and pulse rate were measured by 24-h monitoring with a portable automatic monitor in a randomized double-blind study of 46 patients with essential hypertension. Azelnidipine 16 mg (23 patients) or amlodipine 5 mg (23 patients) was administered once daily for 6 weeks. Pharmacokinetics were analyzed after the last dose was taken. Both drugs showed similar effects on the office blood pressure and pulse rate. During 24-h monitoring, both drugs caused a decrease in systolic blood pressure of 13 mmHg and had a similar hypotensive profile during the daytime period (07:00-21:30). The pulse rate decreased by 2 beats/min in the azelnidipine group, whereas it significantly increased by 4 beats/min in the amlodipine group. Similar trends in the blood pressure and pulse rate were observed during the nighttime (22:00-6:30) and over 24 h. Excessive blood pressure reduction during the nighttime was not seen in either group. The pharmacokinetic results indicated that the plasma half-life (t1/2) of amlodipine was 38.5 +/- 19.8 h and that of azelnidipine was 8.68 +/- 1.33 h. Despite this difference in pharmacokinetics, the hypotensive effects of amlodipine and azelnidipine were similar throughout the 24-h administration period.