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

Background: The renin system plays a key role in regulation of blood pressure (BP).  Several classes of drugs manipulate the renin system, including angiotensin converting enzyme (ACE) inhibitors and the new direct renin inhibitor.  With ACE inhibitors, ACE-independent pathways can result in BP increases.  Renin inhibitors should block this system entirely and result in optimal BP control.

Objective: To compare the long-term efficacy, safety and tolerability of aliskiren and ramipril alone and in combination with hydrochlorothiazide (HCTZ) in patients with hypertension.

Methods:  This randomized, double-blind, multicenter, active and placebo-controlled study took place in over 90 study centers in 2007.  It was funded by Novartis Pharmaceuticals, the manufacturers of aliskiren (Tekturna).  Patients over 18 with mean sitting diastolic blood pressure (msDBP) ≥ 90 mmHg and < 110 mmHg were enrolled.  Patients were excluded if they suffered severe hypertension (msDBP ≥ 110 mmHg or msSBP ≥ 180 mmHg), hypertensive retinopathy, diabetes mellitus with HbA1c > 9%, history of cerebrovascular or cardiovascular disease, had any condition that could affect pharmacokinetics, or were pregnant or nursing.
For the 26-week, active-controlled study period, 842 patients were randomized to receive either aliskiren 150mg (n=420) or ramipril 5mg (n=422) once daily.  For those patients not achieving adequate BP control (< 140/90), up titration and HCTZ addition was permitted at weeks 6, 12, 18, and 21.  BP was evaluated at weeks 3, 6, 9, 12, 15, 18, 21, and 26.  During the four-week, double-blind, placebo-controlled withdrawal period, patients were re-randomized to either their current regimen or placebo.  BP was evaluated weekly.  The primary outcome measure was the change from baseline in msDBP at the week 26 endpoint.  Secondary outcome measures included change in msSBP and msDBP at weeks 6 and 12, and the proportion of patients achieving BP control (< 140/90 mmHg) at weeks 6, 12, and 26.

Results:  A total of 687 patients completed the six-month main study period (80% of aliskiren patients and 82% of ramipril patients).  The mean reduction in msDBP at 26 weeks (mean ± SEM) was 13.2 ± 0.7 mmHg for aliskiren and 12.0 ± 0.7 mmHg for ramipril (p = 0.025).  The proportion of patients achieving BP control at week 26 was 61.4% in the aliskiren group vs. 53.1% in the ramipril group (p = 0.205).  The mean reduction in msDBP at 6 and 12 weeks for aliskiren vs. ramipril were 10.5% ± 0.4 mmHg vs. 9.5 ± 0.4 mmHg and 11.3 ± 0.4 mmHg vs. 9.7 ± 0.4 mmHg respectively (p = 0.0689, 0.0056).  The mean reduction in msSBP at 6 and 12 weeks for aliskiren vs. ramipril were 12.9% ± 0.6 mmHg vs. 10.5 ± 0.6 mmHg and 14.0 ± 0.6 mmHg vs. 11.3 ± 0.6 mmHg respectively (p = 0.0041, 0.0027).  All results were statistically significant except for the change in msDBP at 6 weeks.  Authors conclude that aliskiren-based treatment provided larger reductions in BP than ramipril-based treatment, and that aliskiren will be an important new addition to existing treatment options for hypertension.

Strengths:  The study objective was clearly-defined and the method used to study the drug was appropriate (double-blind, active-controlled, prospective experimental trial).  In addition, the study lasted for six months, which is a relatively long duration and should be more than adequate to provide reliable results.

Weaknesses:  More patients in the ramipril group were obese or had metabolic syndrome or diabetes at baseline compared to the aliskiren group.  The study’s power is not reported, nor is any confidence interval, so it is difficult to extrapolate results to a larger patient population.  Authors also use misleading statistics (SEM instead of SD).  In addition, although authors did find a statistically significant difference between the study groups, the actual difference in msDBP decrease was only 1 mmHg.  This difference is very small and not likely to be clinically significant.

Conclusion:    Considering the study’s irresponsible design, misleading data reporting, and the small actual difference in DBP between the two drugs, it is definitely not wise to assume that aliskiren is superior to ramipril in the treatment of hypertension.  Results in diabetes patients are particularly interesting, since many hypertensive patients also suffer diabetes and vice versa.  However, aliskiren does significantly reduce blood pressure in this study, which is of decent size and good duration.  The authors’ conclusion that aliskiren-based-treatment is a good addition to hypertensive treatment options is fair and warranted based on the results of this study.

Andersen K, et al.  Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: a 6-month, randomized, double-blind trial.  Journal of Hypertension 2008; 26(3): 589-98.

Keri Del Signore, Doctor of Pharmacy Candidate