From Medscape Medical News—a professional news service of WebMD

Barcelona, Spain - A pooled data analysis of antihypertensive treatment with the still-investigational oral renin inhibitor aliskiren (Rasilez, Novartis) in more than 8000 patients suggest that the drug reduces blood pressure (BP) effectively regardless of age or gender, is well tolerated, and appears to be additive to most other antihypertensive agents, with the exception of angiotensin receptor blockers [1].

Dr Matthew R Weir (University of Maryland School of Medicine, Baltimore) presented the pooled analysis of results to date with this new antihypertensive agent.

"Obviously, the hope is that the mechanism of action will provide an incremental opportunity in a sense to tame the renin angiotensin system and better facilitate risk reduction with regard to cardiovascular and kidney disease progression," he concluded.

Findings from these studies were presented here at the World Congress of Cardiology 2006.

Durable effects

Aliskiren is the first in a new class of orally available direct renin inhibitors that block the action of renin at the top of renin-angiotensin system (RAS) cascade, the authors said. Previous studies, presented at the American Society of Hypertension meeting in May 2006 and reported by heartwire at that time, suggested that its long half-life provides more continuous BP control through the morning surge of BP that is associated with increased cardiovascular events and may have effects additive to hydrochlorothiazide (HCTZ), and to a much lesser extent, the angiotensin receptor blocker valsartan.

At the European Society of Hypertension in June, researchers presented further data suggesting aliskiren provided similar BP reductions to ramipril, and the combination appeared not only to be somewhat additive but to reduce cough associated with the ACE inhibitor.

At the meeting here, Weir presented a pooled analysis of data from 8 randomized multicenter studies, including 8570 patients with mild to moderate hypertension. Treatment durations ranged from six to 52 weeks.

"Aliskiren as monotherapy effectively reduces blood pressure in a dose-dependent fashion between 75 and 600 mg, its effect was quite similar regardless of age or gender, and it is quite well tolerated," Weir said.

In placebo-controlled studies, treatment-emergent adverse events (TEAEs) were similar between groups, as was the incidence of discontinuation due to adverse events.

Pooled analysis: adverse events with aliskiren vs placebo

End point	Placebo (%)	Aliskiren (%)
Treatment-emergent adverse events	40.2	39.8
Discontinuation due to adverse events	3.5	1.9

The most common TEAEs, occurring in 2% or more of patients, were headache, nasopharyngitis, and diarrhea.

Added to other antihypertensive agents, including HCTZ, aliskiren provided incremental BP lowering, "with the exception of angiotensin receptor blockers, which need to be studied in greater detail," Weir noted.

"Even when added to other therapies, it does not provide any problems with regard to tolerability, and I would add too that there are very few identified drug-drug interactions that will require concern or adjustment of dose," he concluded in his presentation.

Weir was asked during the discussion period what the incremental benefit of this drug would be over an angiotensin receptor blocker. He pointed out that interruption of the RAS cascade has been of great interest, with current research looking at higher doses of angiotensin receptor blockers as well as combinations of ACE inhibitors and angiotensin receptor blockers.

"The interest is that aliskiren intercepts the system at the point of activation, where we see a reduction in plasma renin activity, angiotensin-1 and angiotensin-2, while the others tend to increase it," he responded. "The question is, what is the relevance for vascular biology long-term with that type of approach? Is it a benefit or a decrement? I suspect it may prove to be beneficial," he said.

Other aliskiren results were presented in four additional posters. Among these were:

Dr James L Pool (Baylor College of Medicine, Houston, TX) and colleagues report effects of withdrawal of open-label treatment with aliskiren alone or with the addition of HCTZ after 11 months [2]. BP and plasma renin activity reductions seen during treatment persisted until 12 months after acute withdrawal of treatment at the 11-month mark, despite increased renin concentration elevation, the authors note, "suggesting continued renin inhibition far beyond the drug's plasma half-life."

Dr Mark A Munger (University of Utah, Salt Lake City) and colleagues carried out a six-week randomized parallel group study in patients with mild to moderate hypertension [3]. Patients were treated with 5 mg of amlodipine (Norvasc, Pfizer) for four weeks, and those still at >90 mm Hg diastolic were randomized to continue on 5-mg amlodipine, double the dose to 10 mg, or the addition of 150 mg of aliskiren.

Aliskerin provided significant incremental BP lowering over amlodipine 5 mg and higher control rates, and the combination was at least numerically but not significantly higher than amlodipine 10 mg on these measures. However, the combination was associated with lower rates of edema than seen with amlodipine 10 mg.

BP reductions and edema with amlodipine 5 mg, amlodipine 10 mg, and amlodipine 5 mg plus aliskiren 150 mg

End point	Amlodipine 5 mg	Amlodipine 10 mg	Amlodipine 5 mg/aliskiren 150 mg
MSDBP (mean change mm Hg)	-4.84	-8.04	-8.46
MSSBP (mean change mm Hg)	-4.96	-9.63	-10.98
Control rate (%)	22.6	37.9	42.8
Edema (%)	3.4	11.2	2.1

"Aspire higher"

Dr Ameet Nathwani, global head of cardiovascular and metabolic research for Novartis, said the company has a broad program of further clinical trials looking at the effects of aliskiren.

Surrogate marker trials include:

• Aliskiren Observation of Heart Failure Treatment (ALOFT) will compare placebo with 150-mg aliskiren for 12 weeks in patients with hypertension and stable congestive heart failure. The primary end point will be the reduction in brain natriuretic peptide (BNP).
• Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) will compare the effects of 300-mg aliskiren with placebo over six months in patients with type 2 diabetes with proteinuria, already treated with an angiotensin receptor blocker. The primary end point is the percent reduction in urinary albumin/creatinine ratio.
• Aliskiren in Left Ventricular Hypertrophy (ALLAY) compares aliskiren 300 mg with losartan (Cozaar, Merck) and the combination of both agents over 9 months in patients with left ventricular hypertrophy (LVH). The end point is LV mass by MRI.

All are expected to report in the latter half of 2007, he noted.

Nathwani added that several clinical-end-point trials are now planned in what the company is calling the "Aspire Higher" program, studies of primary and secondary prevention in more than 40,000 subjects with both cardiovascular and renal risk. These studies, including trials called AVIATOR and ALTITUDE, should report in the next five to seven years, he said.

All of these studies were sponsored by Novartis and list Novartis employees as coauthors. Weir reports he is a consultant for Novartis Pharmaceuticals Corp, Merck Sharp & Dohme Ltd, and on the speaker's bureau for Boehringer Ingelheim Pharmaceuticals, Inc; Bristol-Myers Squibb Co./Sanofi-Synthelabo, Inc; Merck Sharp & Dohme Ltd; and Novartis Pharmaceuticals Corp.

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