Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial.

OBJECTIVES: This double-blind study compared long-term efficacy, safety and tolerability of the oral direct renin inhibitor aliskiren and the angiotensin-converting enzyme inhibitor ramipril alone and combined with hydrochlorothiazide in patients with hypertension. METHODS: After a 2-4-week placebo run-in, 842 patients [mean sitting diastolic blood pressure (msDBP) 95-109 mmHg] were randomized to aliskiren 150 mg (n = 420) or ramipril 5 mg (n = 422). Dose titration (to aliskiren 300 mg/ramipril 10 mg) and subsequent hydrochlorothiazide addition (12.5 mg, titrated to 25 mg if required) were permitted at weeks 6, 12, 18 and 21 for inadequate blood pressure control. Patients completing the 26-week active-controlled treatment period were re-randomized to their existing regimen or placebo for a 4-week double-blind withdrawal phase. RESULTS: Six hundred and eighty-seven patients (81.6%) completed the active treatment period. At week 26, aliskiren-based therapy produced greater mean reductions in mean sitting systolic blood pressure (17.9 versus 15.2 mmHg, P = 0.0036) and msDBP (13.2 versus 12.0 mmHg, P = 0.025), and higher rates of systolic blood pressure control (< 140 mmHg; 72.5 versus 64.1%, P = 0.0075) compared with ramipril-based therapy. During withdrawal, blood pressure increased more rapidly after stopping ramipril than aliskiren-based therapy; median blood pressure reached 140/90 mmHg after 1 and 4 weeks, respectively. Blood pressure reductions were maintained with continued active treatment. Aliskiren therapy was well tolerated. Overall adverse event rates were similar with aliskiren (61.3%) and ramipril (60.4%); cough was more frequent with ramipril (9.5%) than aliskiren (4.1%). CONCLUSIONS: Aliskiren-based therapy was well tolerated and produced sustained blood pressure reductions in patients with hypertension over 6 months, greater than those with ramipril-based therapy.

Antihypertensive efficacy of the oral direct renin inhibitor aliskiren as add-on therapy in patients not responding to amlodipine monotherapy.

This study investigated the addition of the direct renin inhibitor aliskiren to amlodipine in patients with mild to moderate hypertension that was inadequately controlled with amlodipine alone. Following once-daily treatment with amlodipine 5 mg for 4 weeks, patients whose hypertension responded inadequately to therapy (mean sitting diastolic blood pressure [DBP] 90-109 mm Hg) (n=545) were randomized to 6 weeks of double-blind treatment with amlodipine 5 mg plus aliskiren 150 mg, amlodipine 5 mg, or amlodipine 10 mg. At the study's end, mean systolic blood pressure and DBP reductions with the combination of aliskiren 150 mg and amlodipine 5 mg (11.0/8.5 mm Hg) were significantly greater (P<.0001) than with amlodipine 5 mg (5.0/4.8 mm Hg)--the comparator group--but similar to amlodipine 10 mg (9.6/8.0 mm Hg). All treatments were well tolerated. Edema occurred more frequently with amlodipine 10 mg (11.2%) than with combination therapy (2.1%) or amlodipine 5 mg (3.4%). In conclusion, aliskiren 150 mg plus amlodipine 5 mg shows similar but not better blood pressure-lowering efficacy when compared with amlodipine 10 mg in patients not completely responsive to amlodipine 5 mg; less edema was noted with combination therapy.

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.

QTc interval prolongation associated with intravenous methadone.

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

Efficacy, safety, and tolerability of aliskiren monotherapy administered with a light meal in elderly hypertensive patients: a randomized, double-blind, placebo-controlled, dose-response evaluation study.

This randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of aliskiren 75, 150, and 300 mg to clarify the dose-response relationship and characterize the optimum aliskiren dose when given with a light meal to elderly hypertensive patients. After washout, 754 patients aged ≥65 years with hypertension (mean sitting systolic blood pressure [msSBP] ≥150 and <180 mm Hg; mean sitting diastolic blood pressure [msDBP] <110 mm Hg) were randomized to aliskiren 75, 150, or 300 mg or placebo for 8 weeks; medication was taken each morning with a light meal. The primary efficacy variable was change in msSBP from baseline to week 8 end point. Change from baseline in msDBP and dose-response curves for aliskiren 75, 150, and 300 mg were also assessed. At week 8 end point, all 3 aliskiren doses provided significantly greater least squares mean reductions in msSBP/msDBP (75 mg, 13/5 mm Hg; 150 mg, 15/6 mm Hg; 300 mg, 14/7 mm Hg) compared with placebo (8/4 mm Hg; P < .05). Aliskiren was generally well tolerated at all doses. There was a significant dose-response relationship for aliskiren, with an estimated minimum effective dose of 81.9 mg. In conclusion, aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal.

Antihypertensive treatment in patients with class 3 obesity.

BACKGROUND: Even though patients with class 3 obesity (body mass index ≥ 40 kg/m(2)) are prone to arterial hypertension and respond less to antihypertensive drugs, they are not considered in hypertension treatment guidelines and data from prospective clinical trials are lacking. METHODS: In a post hoc analysis of a clinical trial, we compared patients with class 3 obesity with patients with class 1/2 obesity. RESULTS AND CONCLUSIONS: Blood pressure control in class 3 obesity was less likely to be achieved with hydrochlorothiazide monotherapy. While addition of amlodipine, irbesartan, or aliskiren to hydrochlorothiazide improved the blood pressure response, amlodipine was less effective and induced peripheral edema in 19% of patients with class 3 obesity.

Comparison of aliskiren/hydrochlorothiazide combination therapy and amlodipine monotherapy in patients with stage 2 systolic hypertension and type 2 diabetes mellitus.

Patients with stage 2 hypertension and diabetes are at high cardiovascular risk and require large blood pressure (BP) reductions to reach treatment goals. This randomized double-blind study compared aliskiren/hydrochlorothiazide (HCTZ) combination therapy with amlodipine monotherapy in 860 patients with mean sitting systolic BP (msSBP) ≥160 mm Hg to <200 mm Hg and type 2 diabetes. Patients received either once-daily aliskiren/HCTZ 150/12.5 mg or amlodipine 5 mg for 1 week then force-titrated to double the doses for 7 weeks. Baseline BP was 167.7/91.4 mm Hg. At week 8 end point, aliskiren/HCTZ provided significantly greater reductions in msSBP than amlodipine (28.8 mm Hg vs 26.2 mm Hg; P<.05). Mean sitting diastolic BP reductions were similar with aliskiren/HCTZ (9.9 mm Hg) and amlodipine (9.0 mm Hg). Achievement of BP control (<130/80 mm Hg) was significantly greater with aliskiren/HCTZ (23.2%) than amlodipine (13.8%; P<.0001). Aliskiren/HCTZ provides substantial msSBP reductions and greater BP control rates than amlodipine, and offers an attractive treatment option for patients with hypertension and diabetes mellitus.

Long-term safety and tolerability of the oral direct renin inhibitor aliskiren with optional add-on hydrochlorothiazide in patients with hypertension: a randomized, open-label, parallel-group, multicentre, dose-escalation study with an extension phase.

BACKGROUND: Most patients with hypertension will require combination therapy with at least two agents from different antihypertensive classes to achieve blood pressure (BP) control. Thiazide diuretics, such as hydrochlorothiazide (HCTZ), are widely used in combination therapy. The volume reduction with these agents stimulates the renin-angiotensin system (RAS), making RAS inhibitors such as the direct renin inhibitor aliskiren a logical choice for combination therapy with HCTZ. OBJECTIVE: The aim of this study was to investigate the long-term safety, tolerability and efficacy of the direct renin inhibitor aliskiren, with or without addition of the diuretic HCTZ. METHODS: In the 12-month core study, patients with hypertension (mean sitting diastolic BP ≥90 mmHg and <110 mmHg) were randomized in a 3 : 2 ratio to once-daily aliskiren 150 mg or 300 mg. At months 2, 3, 4, 6 and 9, treatment was adjusted in patients not achieving a BP goal of <140/90 mmHg. Patients not at goal on aliskiren 150 mg once daily were up-titrated to aliskiren 300 mg once daily. Patients not at goal with aliskiren 300 mg once daily received add-on HCTZ 12.5 mg once daily, which was up-titrated to 25 mg once daily if BP remained inadequately controlled. At month 12, patients who received aliskiren/HCTZ 300 mg/25 mg once daily for at least 8 months in the core study were eligible to enter a 4-month extension study. RESULTS: Overall, 1625/1955 patients completed the core study, and 870/1955 patients received add-on HCTZ; 189/198 patients completed the 4-month extension. Aliskiren, with or without add-on HCTZ, was generally well tolerated; the incidence of adverse events (AEs) during the core study was similar among the four final treatment groups. The most frequently reported AEs in the core and extension studies were mild and transient cases of nasopharyngitis, headache and dizziness. Few patients exhibited laboratory abnormalities. Overall, aliskiren, with or without add-on HCTZ, reduced mean BP by 18.0/12.7 mmHg at core study endpoint, and 61.2% of patients achieved BP control. BP reductions with aliskiren/HCTZ 300 mg/25 mg combination therapy at the core study endpoint were maintained during the extension study. CONCLUSION: In patients with hypertension, long-term treatment with aliskiren, with or without add-on HCTZ, is well tolerated and provides effective BP lowering that is sustained over 12 months.

Safety and tolerability of the direct renin inhibitor aliskiren in combination with angiotensin receptor blockers and thiazide diuretics: a pooled analysis of clinical experience of 12,942 patients.

Combinations of the direct renin inhibitor aliskiren with angiotensin receptor blockers (ARBs) or diuretics are effective therapeutic regimens for the treatment of hypertension. A large database of safety information has become available during the past several years with aliskiren in combination trials. Data were pooled from 9 short-term (8-week) and 4 longer-term (26- to 52-week) randomized controlled trials of aliskiren in patients with hypertension. Adverse event (AE) rates were assessed for aliskiren combination therapy compared with component monotherapies. In short-term studies, overall AE rates were similar for patients receiving aliskiren/valsartan or aliskiren/diuretic combinations (32.2%-39.8%) and those receiving the component monotherapies (30.0%-39.6%). In longer-term studies, AE rates with aliskiren/losartan (55.5%) and aliskiren/diuretic (45.0%) combination therapy were similar to those with losartan (53.9%) and diuretic (48.9%) alone. Angioedema and hyperkalemia occurred in similar proportions of patients taking combination therapies vs monotherapy. The safety and tolerability profile of aliskiren in combination with the ARBs valsartan or losartan, or diuretic, is similar to aliskiren, ARBs, or diuretics alone.

Influence of body weight and gender on the pharmacokinetics, pharmacodynamics, and antihypertensive efficacy of aliskiren.

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Comparative efficacy of aliskiren monotherapy and ramipril monotherapy in patients with stage 2 systolic hypertension: subgroup analysis of a double-blind, active comparator trial.

Aliskiren is the first direct renin inhibitor approved for the treatment of hypertension. Blood pressure (BP) control in stage 2 hypertension with aliskiren monotherapy has not been reported. This was a post hoc analysis of the subgroup of patients with stage 2 systolic hypertension (baseline mean sitting systolic BP [msSBP]≥160 mmHg) who completed the 12-week monotherapy phase of a 6-month, double-blind, randomized study. A total of 175 patients were randomized to aliskiren 150 mg (n = 88) or ramipril 5 mg (n = 87) with optional up-titration to aliskiren 300 mg or ramipril 10 mg, respectively, at weeks 6 and 12. In the subgroup of patients with stage 2 systolic hypertension, aliskiren lowered msSBP and mean sitting diastolic BP (msDBP) by 22.3/12.7 mmHg from baseline to week 12; compared with a reduction of 18.1/10.2 mmHg with ramipril. The maximum BP reductions achieved with aliskiren were 60.0/34.0 mmHg (from a baseline of 172.7/107.3 mmHg). Aliskiren was noninferior (P < 0.0001) to ramipril for SBP reduction with nonsignificant superiority (P = 0.052), and superior (P = 0.043) to ramipril for DBP reduction. The proportion of patients who achieved BP control (<140/90 mmHg) after 12 weeks of monotherapy was larger with aliskiren (34/88, 38.6%) than with ramipril (22/87, 25.3%; P = 0.038). In this post hoc analysis, 12 weeks of monotherapy with aliskiren 150-300 mg provided effective mean BP reductions (22/13 mmHg) and was superior to ramipril 5-10 mg in controlling BP in patients with stage 2 systolic hypertension.

Safety and tolerability of the direct renin inhibitor aliskiren: a pooled analysis of clinical experience in more than 12,000 patients with hypertension.

While the safety of renin-angiotensin system (RAS)-blocking drugs such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers is well known, less is known about the new direct renin inhibitor aliskiren. The authors pooled data from 12 randomized controlled trials of aliskiren in patients with hypertension and analyzed the incidence and types of adverse events (AEs) and laboratory abnormalities. Studies were characterized as short-term (≤2 months) placebo-controlled or long-term (>2 months) active-controlled. Relative risks for AEs of particular interest for RAS blockers were calculated. In short-term studies, AEs occurred in similar proportions of aliskiren 150 mg and 300 mg (33.6% and 31.6%, respectively) and placebo treatment groups (36.8%). In long-term studies, a lower proportion of patients treated with aliskiren 150 mg and 300 mg had AEs (33.7% and 43.2%, respectively) than those treated with ACE inhibitors (60.1%), angiotensin receptor blockers (53.9%), and thiazide diuretics (48.9%). Events of special interest, including angioedema, hyperkalemia, and diarrhea occurred in similar proportions of patients taking aliskiren, placebo, and comparator agents. In studies of up to 36 weeks, patients treated with aliskiren were significantly less likely to develop cough than those treated with ACE inhibitors. At the registered doses of 150 mg and 300 mg daily, aliskiren has safety and tolerability profiles similar to placebo, other RAS blockers, and diuretics. Cough rates are lower with aliskiren compared with ACE inhibitors.

Aliskiren-based therapy lowers blood pressure more effectively than hydrochlorothiazide-based therapy in obese patients with hypertension: sub-analysis of a 52-week, randomized, double-blind trial.

OBJECTIVES: To compare the long-term efficacy, safety and tolerability of the direct renin inhibitor aliskiren against the diuretic hydrochlorothiazide (HCTZ) in obese patients with hypertension. METHODS: A post hoc analysis of 396 obese patients (body mass index > or = 30 kg/m2) in a 52-week study in 1124 patients with hypertension was performed. Patients were randomized to receive aliskiren 150 mg or HCTZ 12.5 mg for 3 weeks, or placebo for 6 weeks. At week 3, active treatment doses were doubled. Patients receiving placebo were randomized to aliskiren 300 mg or HCTZ 25 mg at week 6. Add-on amlodipine 5-10 mg was permitted from week 12 to achieve blood pressure (BP) control (<140/90 mmHg). RESULTS: In the subgroup of obese patients, aliskiren monotherapy provided significantly greater BP reductions than HCTZ at week 12 endpoint (-16.7/-12.3 vs. -12.2/-9.1 mmHg, P < or = 0.001). Reductions were also greater with aliskiren-based therapy than HCTZ-based therapy at week 52 endpoint (-19.9/-15.5 vs. -17.5/-13.3 mmHg; P = 0.138 for systolic BP and P = 0.007 for diastolic BP). Mean BP reductions from baseline with aliskiren-based therapy were similar in obese and nonobese patients. By contrast, HCTZ-based therapy provided significantly smaller mean reductions in BP from baseline in obese patients vs. nonobese patients (P < 0.05). Aliskiren-based therapy was generally well tolerated in obese patients, and was associated with a significantly lower incidence of hypokalemia (1.0 vs. 14.0%, P < 0.0001) than HCTZ-based therapy. CONCLUSION: Aliskiren-based therapy provided superior BP reductions to HCTZ-based therapy with good tolerability in obese patients with hypertension.

Evaluation of the dose--response relationship of aliskiren, a direct renin inhibitor, in an 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study in adult patients with stage 1 or 2 essential hypertension.

BACKGROUND: Aliskiren is approved for the treatment of hypertension at once-daily doses of 150 or 300 mg by the US Food and Drug Administration and the European Commission. It is generally well tolerated and provides 24-hour, dose-dependent blood pressure (BP) reduction; however, the effect of the 75-mg dose has been inconsistent in previous trials. OBJECTIVES: This study was designed to assess the efficacy and tolerability of once-daily administration of aliskiren 75 mg and to evaluate the dose-response relationship across all 3 doses of aliskiren (75, 150, and 300 mg). METHODS: In this 8-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled study, patients aged > or =18 years with stage 1 or 2 essential hypertension entered a 3- to 4-week, single-blind, placebo run-in period. Eligible patients were randomized (1:1:1:1) to receive oral, once-daily doses of aliskiren 75, 150, or 300 mg or placebo. The primary efficacy variable was the change from baseline in mean sitting diastolic BP (msDBP) at the week-8 end point. Tolerability was assessed by monitoring and recording all adverse events (AEs). RESULTS: A total of 642 patients (mean [SD] age, 52.0 [10.73] years; 60.0% male; 80.8% white; mean body weight, 89.2 [18.4] kg [range, 50-160 kg]) were included in the study. Overall, 576 patients (89.7%) completed the double-blind treatment period. The most frequent reasons for discontinuation were unsatisfactory therapeutic effect (27/642 randomized patients [4.2%]) and AEs (17/642 [2.6%]). At end point, aliskiren 150 and 300 mg significantly reduced msDBP (both, P < 0.001) and mean sitting systolic CONCLUSIONS: This study found a positive linear dose-response relationship in BP reduction with aliskiren 75, 150, and 300 mg dosed once daily, but only aliskiren 150 and 300 mg provided statistically significant reductions from baseline compared with placebo. All 3 doses of aliskiren were generally well tolerated.

Comparative effects of aliskiren-based and ramipril-based therapy on the renin system during long-term (6 months) treatment and withdrawal in patients with hypertension.

INTRODUCTION: This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed. METHODS: After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95-109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase. RESULTS: BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren- than ramipril-based therapy at Week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, p<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, p<0.05; n=103), while ramipril-based therapy increased PRA (+143%, p<0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both p<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy. CONCLUSIONS: Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug.

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.

Effects of the direct renin inhibitor aliskiren and atenolol alone or in combination in patients with hypertension.

INTRODUCTION: Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension. PATIENTS AND METHODS: In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] > or = 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma renin activity (PRA) was measured in a subset of patients. RESULTS: At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, and diastolic BP reductions were greater than with aliskiren alone (p<0.001). Diastolic BP changes were larger with atenolol than with aliskiren (p=0.003, correlating with the large reductions in pulse rate (> 10 bpm) observed with atenolol. Aliskiren, atenolol and aliskiren/atenolol reduced geometric mean PRA from baseline by 65%, 52% and 61%, respectively. In patients with moderate or high baseline PRA (> or = 0.65 ng/ml/hour), PRA was reduced to low levels (< 0.65 ng/ml/hour) at Week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events compared with atenolol or combination treatment, and unlike atenolol was not associated with bradycardia. CONCLUSIONS: Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone.

Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure.

BACKGROUND: Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme (ACE) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone (RAAS) cascade. This may overcome ACE inhibition but should be blocked by a direct renin inhibitor. We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure. METHODS AND RESULTS: Patients with New York Heart Association class II to IV heart failure, current or past history of hypertension, and plasma brain natriuretic peptide (BNP) concentration >100 pg/mL who had been treated with an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker were randomized to 3 months of treatment with placebo (n=146) or aliskiren 150 mg/d (n=156). The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP (NT-proBNP). Patients' mean age was 68 years, mean ejection fraction was 31%, and mean+/-SD systolic blood pressure was 129+/-17.4 mm Hg. Sixty-two percent of the patients were in New York Heart Association functional class II, and 33% were taking an aldosterone antagonist. Plasma NT-proBNP rose by 762+/-6123 pg/mL with placebo and fell by 244+/-2025 pg/mL with aliskiren (P=0.0106). BNP and urinary (but not plasma) aldosterone were also reduced by aliskiren. Clinically important differences in blood pressure and biochemistry were not seen between aliskiren and placebo. CONCLUSIONS: Addition of aliskiren to an ACE inhibitor (or angiotensin receptor blocker) and beta-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated.

Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension.

OBJECTIVES: This dose-ranging study evaluated the antihypertensive efficacy and tolerability of aliskiren in patients with mild-to-moderate hypertension. BACKGROUND: Low blood pressure (BP) control rates among patients with hypertension indicate a need for improved treatment options. This study investigates aliskiren, the first in a new antihypertensive class called renin inhibitors. METHODS: Patients with mean sitting diastolic BP 95 to 109 mm Hg were randomized to aliskiren 150, 300, or 600 mg or placebo once daily for 8 weeks. Patients completing this treatment phase entered a 2-week treatment-free withdrawal period. Office BP was recorded at baseline, weeks 2, 4, 6, and 8 of treatment, and 4 days and 2 weeks after cessation of treatment. A subgroup of patients underwent ambulatory BP monitoring. RESULTS: In total, 672 patients were randomized to treatment. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean sitting BP (systolic/diastolic) by 13.0/10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (all p < 0.0001 for systolic and diastolic BP). The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren significantly reduced mean 24-h ambulatory BP (p < 0.0001 vs. placebo with all doses) exhibiting smooth, sustained effects and high trough-to-peak ratios. Aliskiren was well tolerated; overall adverse event rates were 40.1%, 46.7%, and 52.4% with aliskiren 150, 300, and 600 mg, respectively, and 43.0% with placebo. Few patients discontinued treatment due to adverse events. CONCLUSIONS: Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on blood pressure after treatment withdrawal.

Direct Renin inhibition with aliskiren in obese patients with arterial hypertension.

Current guidelines from the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure recommend first-line treatment with a thiazide diuretic but do not provide specific guidance for obese patients. The renin system is activated in obesity-associated arterial hypertension. Therefore, we tested the hypothesis that the oral direct renin inhibitor aliskiren could provide additive blood pressure lowering in obese patients with hypertension (body mass index >or=30 kg/m(2); mean sitting diastolic blood pressure: 95 to 109 mm Hg) who had not responded to 4 weeks of treatment with hydrochlorothiazide (HCTZ) 25 mg. After a 2- to 4-week washout, 560 patients received single-blind HCTZ (25 mg) for 4 weeks; 489 nonresponders were randomly assigned to double-blind aliskiren (150 mg), irbesartan (150 mg), amlodipine (5 mg), or placebo for 4 weeks added to HCTZ (25 mg), followed by 8 weeks on double the initial doses of aliskiren, irbesartan, or amlodipine. After 8 weeks of double-blind treatment (4 weeks on the higher dose), aliskiren/HCTZ lowered blood pressure by 15.8/11.9 mm Hg, significantly more (P<0.0001) than placebo/HCTZ (8.6/7.9 mm Hg). Aliskiren/HCTZ provided blood pressure reductions similar to those with irbesartan/HCTZ and amlodipine/HCTZ (15.4/11.3 and 13.6/10.3 mm Hg, respectively), with similar tolerability to placebo/HCTZ. Adverse event rates were highest with amlodipine/HCTZ because of a higher incidence of peripheral edema (11.1% versus 0.8% to 1.6% in other groups). In conclusion, combination treatment with aliskiren is a highly effective and well-tolerated therapeutic option for obese patients with hypertension who fail to achieve blood pressure control with first-line thiazide diuretic treatment.