Efficacy of sacubitril/valsartan versus olmesartan in Japanese patients with essential hypertension: a randomized, double-blind, multicenter study.

This phase III study assessed the efficacy and safety of sacubitril/valsartan compared with those of olmesartan in Japanese patients with essential hypertension. Patients (n = 1161, aged ≥20 years) with mild to moderate hypertension (mean sitting systolic blood pressure [msSBP] ≥150 to <180 mmHg) were randomized to receive sacubitril/valsartan 200 mg (n = 387), sacubitril/valsartan 400 mg (n = 385), or olmesartan 20 mg (n = 389) once daily for 8 weeks. The primary assessment was a reduction in msSBP from baseline with sacubitril/valsartan 200 mg vs. olmesartan 20 mg at Week 8. Secondary assessments included msSBP reduction with sacubitril/valsartan 400 mg vs. olmesartan at Week 8 and reductions in mean sitting diastolic blood pressure (msDBP), mean sitting pulse pressure (msPP), and overall blood pressure (BP) control rate for all treatment groups at Week 8. Sacubitril/valsartan 200 mg provided a significantly greater reduction in msSBP from baseline than olmesartan at Week 8 (between-treatment difference: -5.01 mmHg [95% confidence interval: -6.95 to -3.06 mmHg, P < 0.001 for noninferiority and superiority]). Greater reductions in msSBP with sacubitril/valsartan 400 mg vs. olmesartan, as well as in msDBP and msPP with both doses of sacubitril/valsartan vs. olmesartan (P < 0.05 for all), were also observed. Patients treated with sacubitril/valsartan achieved an overall higher BP control rate. The safety and tolerability profiles of sacubitril/valsartan were generally comparable to those of olmesartan. The adverse event rate with sacubitril/valsartan was not dose-dependent. Treatment with sacubitril/valsartan was effective and provided superior BP reduction, with a higher proportion of patients achieving target BP goals than treatment with olmesartan in Japanese patients with mild to moderate essential hypertension.

LCZ696, a First-in-Class Angiotensin Receptor-Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension.

The safety of LCZ696, a novel angiotensin receptor-neprilysin inhibitor, was evaluated for the first time in patients with severe hypertension in this 8-week, multicenter, open-label study. Thirty-five Japanese patients with either office systolic blood pressure (SBP) ≥180 mm Hg or diastolic blood pressure (DBP) ≥110 mm Hg received LCZ696 200 mg. If blood pressure was uncontrolled, the LCZ696 dose was increased to 400 mg after 2 weeks (if there were no safety concerns; n=32), followed by an optional addition of another antihypertensive drug (except angiotensin receptor blocker and angiotensin-converting enzyme inhibitor) after 4 weeks (n=21). Reductions in office SBP/DBP (baseline, 173.4 mm Hg/112.4 mm Hg) and pulse pressure (baseline, 61.0 mm Hg) at week 8 were 35.3/22.1 mm Hg and 13.2 mm Hg, respectively. The overall incidence of adverse events was 48.6% with no reports of dizziness, hypotension, or angioedema. The LCZ696-based regimen was generally well-tolerated and could present a treatment option for severe hypertension in Asian patients especially in reducing SBP and pulse pressure.

Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction.

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

Efficacy and safety of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study.

LCZ696 (Japanese adopted name: sucabitril valsartan sodium hydrate), a first-in-class angiotensin receptor neprilysin inhibitor, concomitantly inhibits neprilysin and blocks angiotensin type 1 receptor. This randomized, double-blind, placebo-controlled study, the first in Asia for this drug, evaluated the dose-related efficacy and safety of LCZ696 in patients with hypertension using 24-hour ambulatory blood pressure (BP) monitoring. Asian patients aged ≥18 years (n=389) with hypertension were randomized to receive LCZ696 100 mg (n=100), 200 mg (n=101), 400 mg (n=96), or placebo (n=92) for 8 weeks. The primary end point was mean difference across the 3 single-dose pairwise comparisons of LCZ696 versus placebo in clinic diastolic BP after 8-week treatment. Key secondary efficacy variables included changes in clinic systolic BP and pulse pressure and changes in 24-hour, daytime, and nighttime ambulatory BPs and pulse pressure. Safety assessments included recording all adverse events and serious adverse events. A total of 362 patients completed the study. Reductions in clinic systolic BP, diastolic BP (P<0.0001), and pulse pressure (P<0.001) were significantly greater with all doses of LCZ696 than with placebo. There were also significant reductions in 24-hour, daytime, and nighttime ambulatory systolic BP, diastolic BP, and pulse pressure for all doses of LCZ696 compared with placebo (P<0.0001). LCZ696 was well tolerated, and no cases of angioedema were reported. In conclusion, LCZ696 is effective for the treatment of hypertension in Asian population and, in general, is safe and well tolerated. Clinical Trial Information- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01193101.

Long-term safety, tolerability, and antihypertensive efficacy of aliskiren, an oral direct renin inhibitor, in Japanese patients with hypertension.

Inhibition of renin, the first rate-limiting enzyme in the renin-angiotensin system, has long been a therapeutic goal for treatment of hypertension. Aliskiren, the first in a new class of oral direct renin inhibitors, has been shown to reduce blood pressure (BP) in several short-term studies. In this 52-week, open-label, multicenter, parallel-group study, the long-term safety, tolerability, and efficacy of aliskiren-based therapy were assessed in Japanese patients (N=345) with mild-to-moderate essential hypertension. The study had two periods: (i) an 8-week, dose-titration period and (ii) a 44-week, fixed-dose period with an optional addition of a diuretic or a calcium channel blocker (CCB). Safety was assessed by monitoring all adverse events (AEs), serious AEs (SAEs), vital signs, laboratory parameters, ECGs, and physical examinations. Efficacy was assessed by trough mean sitting BP and responder rate. Aliskiren alone or in combination with a diuretic or a CCB was well tolerated. No deaths were reported during this study. Nine SAEs were reported, and for three of these, a possible relation to the study drug could not be excluded. The overall incidence of AEs was 85.2%, and most of these were mild-to-moderate events such as nasopharyngitis. The incidence of suspected study drug-related AEs was 25.3%. A clinically meaningful reduction of 17.6/12.8 mm Hg from baseline was achieved in the mean sitting BP at the end point with aliskiren, irrespective of the dose and additional treatments. The overall responder rate was 73.3% at the end point. In conclusion, this first long-term study in Japanese patients showed the safety and efficacy of aliskiren-based therapy in mild-to-moderate essential hypertension.

Aliskiren, a novel oral renin inhibitor, provides dose-dependent efficacy and placebo-like tolerability in Japanese patients with hypertension.

Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95-110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks' treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by > or =10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53-55%) being similar to that in the placebo group (50%). This study, which is the first to assess the antihypertensive efficacy and safety of aliskiren in Japanese patients with hypertension, demonstrates that the once-daily oral renin inhibitor aliskiren provides significant, dose-dependent reductions in blood pressure with placebo-like tolerability.