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. © 2008 Lippincott Williams & Wilkins, Inc.; Indications:420 patients with hypertension. Coexisting diseases were obesity (n=184), metabolic syndrome (n=171), and diabetes mellitus (n=42).; Patients:842 patients. Rasilez group: n=420, 224 males and 196 females, mean age 53.4 years (64 were ≥65 years), 312 Caucasian, 84 black, 14 Asian and 10 other (220 patients received monotherapy only until week 26); 79 dropouts, an unspecified number were due to side effects. Ramipril group: n=422, 256 males and 166 females, mean age 53.1 years (63 were ≥65 years), 326 Caucasian, 67 black, 13 Asian and 16 other (209 patients received monotherapy only until week 26); 71 dropouts, an unspecified number were due to side effects.; TypeofStudy:A randomized, double-blind, multicenter, active and placebo-controlled study comparing the long-term efficacy, safety and tolerability of Rasilez and ramipril alone and in combination with hydrochlorothiazide (HCTZ) in patients with hypertension.; DosageDuration:Initially 150 mg once daily for 6 weeks, then it was increased to 300 mg once daily for 20 weeks. Duration was 26 weeks.; ComparativeDrug:Ramipril was initially given at 5 mg once daily for 6 weeks, then it was increased to 10 mg once daily for 20 weeks. Duration was 26 weeks.; Results:More patients in the ramipril group (n=209, 49.5%) required the addition of HCTZ than in the Rasilez group (n=193, 46.1%) (not significant). At week 26, the mean reductions in msSBP and msDBP were significantly greater with Rasilez (alone or in combination with HCTZ) than with ramipril therapy (from 151.3/98.8 mmHg at baseline to 133.7/85.8 mmHg versus from 151.4/98.9 mmHg to 136.4/87.2 mmHg). The proportion of patients who had their msSBP controlled to <140 mmHg was significantly higher with Rasilez (72.5%; 305/420) than with ramipril (64.1%; 271/422). The proportion of patients achieving BP <140/90 mmHg was also significantly higher with Rasilez (61.4%; 258/420) than with ramipril (53.1%; 224/422). Reductions in mean BP were observed throughout the 26-week active treatment period in both groups, with mean msSBP values decreasing to below 140 mmHg by week 6 in the Rasilez group and week 9 in the ramipril group. Reductions in msDBP were also larger in the Rasilez group. In the subgroup of patients who received only monotherapy for 26 weeks, mean BP reductions were similar to those in the overall population. Rasilez monotherapy also provided greater BP lowering in the subgroup of patients with msSBP ≥160 mmHg at baseline compared with ramipril. For patients switched to placebo, the increases in BP occurred more rapidly after stopping ramipril than Rasilez. Median BP levels reached 140/90 mmHg 1 week after stopping ramipril but did not reach this level until 4 weeks after stopping Rasilez. In the continued active treatment groups, the proportions achieving SBP <140 mmHg (Rasilez, 77.1%; ramipril, 70.6%) and BP <140/90 mmHg (Rasilez, 62.9%; ramipril, 52.8%) were maintained in both groups at week 30. At the end of the 4-week withdrawal period, the systolic control rate and overall BP control rate were higher after stopping Rasilez than ramipril. The majority of AEs reported during the 26-week active treatment period were mild or moderate in intensity and transient, and most events occurred at a similar incidence in the 2 groups. Cough was reported more than twice as frequently by patients receiving ramipril than Rasilez. Cough that was treatment-related was also more frequent with ramipril. Headache was more common with Rasilez than with ramipril, but the rates of treatment-related headache were low and similar in the 2 groups. The most frequent reason for discontinuation was cough, which was more common with ramipril than Rasilez. Only 1 serious AE was considered related to study medication; a case of angioneurotic edema in a patient receiving Rasilez, who recovered completely following discontinuation of study medication. 1 patient died due to mesenteric thrombosis 6 days after discontinuing ramipril plus HCTZ (not related to drug). The incidence of patients with serum potassium levels >5.5 mmol/l was higher in the Rasilez group than in the ramipril group. Few patients in both groups exhibited serum potassium of 6.0 mmol/l or higher. The incidence of AEs during the withdrawal period was similar in both groups. Rates of AEs were higher in patients in the ramipril group, whether they stopped or continued active treatment. AEs in the primary system organ class infections and infestations were more frequent in the ramipril group. Few patients discontinued due to AEs during this phase of the study. 3 patients experienced serious AEs during the withdrawal period (Rasilez group n=1; Rasilez placebo group n=2), but none was considered related to study medication. 1 death occurred during re-randomization from Rasilez to placebo, and the cause of death (massive pulmonary embolism or myocardial infarction) was due to disease progression and not drug-related. Changes in biochemistry and hematology parameters during the withdrawal period were small, with no differences observed between the treatment groups.; AdverseEffects:9 (2.1%) patients had cough, 6 (1.4%) headache leading to withdrawal in 4, 1 angioneurotic edema leading to withdrawal, and an unspecified number of patients had nasopharyngitis, dizziness, fatigue, diarrhea, peripheral edema, back pain, pain in extremity, bronchitis, upper respiratory tract infection, nausea, dyspepsia, sinusitis, influenza, potassium blood level <3.5 mmol/l, >5.5 mmol/l and ≥6 mmol/l, blood urea nitrogen >14.28 mmol/l and creatinine >176.8 mcmol/l.; AuthorsConclusions:In conclusion, aliskiren-based treatment (alone or in combination with HCTZ) provided long-term reductions in BP that were larger than those observed with a regimen based on the ACE [angiotensin converting enzyme] inhibitor ramipril in patients with hypertension. These BP reductions persisted for longer after stopping aliskiren-based therapy than ramipril-based therapy. Aliskiren therapy was well tolerated during long-term treatment, suggesting the potential for good patient compliance with aliskiren treatment. These results suggest that aliskiren will be an important new addition to the existing treatment options for hypertension.; FreeText:Patients entered a single-blind, placebo run-in period of up to 4 weeks to establish baseline blood pressure (BP) measurements. Patients then received once daily treatment with Rasilez 150 mg or ramipril 5 mg. Uptitration to Rasilez 300 mg or ramipril 10 mg, and subsequent addition of HCTZ 12.5 mg and uptitration to HCTZ 25 mg were permitted sequentially for patients not achieving adequate BP control (<140/90 mmHg) at weeks 6, 12, 18 and 21. Patients completing the 26-week active treatment period were re-randomized equally to either their current regimen or placebo for a 4-week, double-blind withdrawal period. The BP-lowering efficacy were compared by testing noninferiority and superiority (if noninferiority was achieved) of both drugs for the changes from baseline in mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP). The primary efficacy measure was the change from baseline in msDBP at the week 26 endpoint. Secondary efficacy measures included change from baseline in msSBP at week 26 endpoint; change in msSBP and msDBP at week 6 and 12 endpoints (comparing Rasilez and ramipril monotherapy); and the proportions of patients achieving BP control at week 6, 12 and 26 endpoints. The impact of stopping treatment on BP was evaluated during the withdrawal period. BP (by a standard sphygmomanometer) and pulse rate were recorded. Adverse events (AEs) were monitored and recorded.
