azilsartan and candesartan-cilexetil

We investigated whether 10 mg per day of azilsartan, one-half of the normal dosage, would be non-inferior to 8 mg per day of candesartan cilexetil for controlling blood pressure in Japanese patients with hypertension. In this open-label, randomized, crossover trial, 309 hypertensive Japanese adults treated with 8-mg candesartan cilexetil were randomized into two arms and received either 10-mg azilsartan or 8-mg candesartan cilexetil in a crossover manner. The primary efficacy outcome was systolic blood pressure, and the margin of non-inferiority was set to be 2.5 mm Hg. The participants were 67±11 years old, and 180 (58%) were male. The baseline systolic and diastolic blood pressure levels were 127.1±13.2 and 69.7±11.2 mm Hg, respectively. During the study period, the difference in systolic blood pressure between the treatments with 10-mg azilsartan and 8-mg candesartan cilexetil was -1.7 mm Hg, with the two-sided 95% confidence interval (CI) ranged from -3.2 to -0.2 mm Hg. The upper boundary of the 95% CI was below the margin of 2.5 mm Hg, confirming the non-inferiority of 10-mg azilsartan to 8-mg candesartan cilexetil. The difference also reached significance (P=0.037). The corresponding difference in diastolic blood pressure was -1.4 (95% CI: -2.4 to -0.4) mm Hg (P=0.006). Treatment with 10-mg azilsartan was similar to 8-mg candesartan cilexetil in its association with rare adverse events. In conclusion, 10-mg azilsartan was non-inferior to 8-mg candesartan cilexetil for controlling systolic blood pressure in Japanese hypertensive patients already being treated with 8-mg candesartan cilexetil.

Topics: Aged; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Cross-Over Studies; Female; Humans; Hypertension; Japan; Male; Middle Aged; Oxadiazoles; Tetrazoles; Treatment Outcome

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.

Topics: Aged; Angiotensin Receptor Antagonists; Antihypertensive Agents; Asian People; Benzimidazoles; Biphenyl Compounds; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Oxadiazoles; Severity of Illness Index; Tetrazoles

Topics: Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Female; Humans; Hypertension; Male; Oxadiazoles; Tetrazoles

To clarify the hypotensive mechanism of angiotensin II receptor-blockers (ARBs), drug concentrations in plasma and vascular tissues were measured using matrix-assisted laser desorption ionization time-of-flight mass spectrometry and imaging mass spectrometry. In spontaneously hypertensive rats, systolic blood pressure (SBP) was measured 2 and 24 h after administration of candesartan cilexetil (0.3, 1, or 3 mg/kg) or azilsartan (0.3, 1, or 3 mg/kg). SBP was similarly lowered 2 h after administration of azilsartan or candesartan cilexetil, but it was significantly lower in the azilsartan-treated group than in the candesartan cilexetil-treated group at 24 h. Angiotensin II-induced vascular contractions were similarly attenuated 2 h after administration of these drugs, and the contractions were significantly lower in the azilsartan-treated group at 24 h. Although plasma concentration was significantly lower in the azilsartan-treated group at 24 h, vascular concentration of azilsartan was significantly greater than that of candesartan. Significant correlations between SBP and vascular concentrations were observed both at 2 and 24 h, while no significant correlation was observed between plasma and vascular concentrations. In conclusion, the mechanism of ARB-induced hypotension is likely to depend on vascular concentrations rather than plasma concentrations.

Topics: Administration, Oral; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Vessels; Heart Rate; In Vitro Techniques; Male; Mass Spectrometry; Oxadiazoles; Rats; Rats, Inbred SHR; Tetrazoles; Vasoconstriction