Safety Study With Aliskiren
Further data on the long-term efficacy, safety, and tolerability of aliskiren, the first orally available direct renin inhibitor, were reported in 2 posters presented at the 2007 American Society of Hypertension annual conference in Chicago. Aliskiren was developed by Novartis (Basel, Switzerland) in collaboration with Speedel (Basel, Switzerland). A regulatory submission for use of aliskiren in Europe was made in September 2006 and Novartis has said it expects a decision by the end of 2007. The drug was approved for use in the United States in March 2007, alone or in combination with other antihypertensive agents. The usual recommended starting dose of aliskiren is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be doubled, to 300 mg.
Alan H Gradman, MD (The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania) and colleagues in the United States and Germany reported on the safety of long-term use of aliskiren 300 mg coadministered with the diuretic, hydrochlorothiazide (HCTZ) 25 mg. These are the highest doses likely to be prescribed for hypertension, Dr. Gradman noted. The data were derived from a 4-month extension phase of a 12-month, open-label study of aliskiren 150 mg or 300 mg, with or without concomitant HCTZ 12.5-25 mg, in 1955 patients with uncomplicated mild-to-moderate hypertension.
Initial Open-label Study
The first results of this study, which were reported during the 2006 World Congress of Cardiology (see Related Links), showed that aliskiren, as monotherapy or with HCTZ, reduced blood pressure effectively and maintained its blood pressure-lowering effect over 12 months. Twenty-four-hour ambulatory blood pressure monitoring showed a clear separation between aliskiren and placebo at most hourly time points, demonstrating that reductions in blood pressure with aliskiren were sustained throughout the 24-hour dosing period.
Patients who entered the initial 12-month study had a mean sitting diastolic blood pressure (msDBP) of 95-109 mm Hg. A total of 1178 patients were randomized to once-daily treatment with aliskiren 150 mg and 773 patients to once-daily aliskiren 300 mg. In patients whose blood pressure was ≥ 140/90 mm Hg after 2 months, aliskiren was sequentially titrated from 150 mg to 300 mg, followed by addition of HCTZ 12.5 mg titrated to 25 mg.
A total of 1625 patients completed the initial open-label study. At this point, reductions in DBP and systolic blood pressure (SBP) were similar in the aliskiren monotherapy and aliskiren + HCTZ groups ( Table 1 ). Combination therapy produced substantial blood pressure reductions in the patients who did not show an adequate response to aliskiren monotherapy, Dr. Gradman and his colleagues reported.
Open-label Extension Phase
Patients who completed the initial study and had received aliskiren 300 mg + HCTZ 25 mg for ≥ 8 months were eligible for a 4-month open-label extension phase. Of a total of 198 eligible patients, 189 (95.5%) completed this part of the study, with a mean exposure of 375 days to aliskiren 300 mg + HCTZ 25 mg. Mean blood pressure reductions from baseline in the initial 12-month study were maintained during the extension phase in these patients ( Table 2 ). At the end of the 4-month extension, 65.2% of patients had achieved msDBP < 90 mm Hg and/or ≥ 10 mm Hg decreased in msDBP and 33.3% had their blood pressure controlled (< 140/90 mm Hg).
The regimen of aliskiren 300 mg + HCTZ 25 mg was well tolerated during the extension, consistent with the results reported during the initial treatment period, Dr. Gradman reported. The majority of adverse events were not considered related to study medication, and only 2 patients discontinued treatment due to adverse events ( Table 3 ). The most frequently reported adverse events were bronchitis, nasopharyngitis, and headache (3.5%). Two serious adverse events (cerebrovascular accident, umbilical hernia) were not considered related to study medication. Over the total 16-month study period, serum potassium < 3.5 mmol/L was reported in 12 patients on this regimen, and 5 patients experienced serum potassium > 5.5 mmol/L.
Regulatory Approval
Based on these data and from 6 other clinical trials, involving a total of > 6200 patients, Novartis has submitted a single-tablet combination of aliskiren and HCTZ for US regulatory approval. The company announced that submissions were made for 4 different single-tablet formulations of aliskiren/HCTZ: 150/12.5, 150/25, 300/12.5, and 300/25 mg aliskiren/HCTZ.
This represents the first regulatory submission for a single-tablet combination therapy involving aliskiren. Dr. Gradman observed that "a tablet combining the first direct renin inhibitor and a diuretic would give doctors an important new treatment option to help patients reach their treatment goals." Novartis said that it has not yet determined when the combination of aliskiren with HCTZ will be submitted for approval in Europe.