Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients with Hypertension

Department of Cardiology, Nihon University Surugadai Hospital, Tokyo, Japan.
Hypertension Research (Impact Factor: 2.66). 01/2007; 29(12):997-1005. DOI: 10.1291/hypres.29.997
Source: PubMed


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.

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    ABSTRACT: Background: Visit-to-visit blood pressure (BP) variability limits the ability to detect therapeutic effects in hypertension trials. Methods: To enable future renal denervation trials to detect smaller effect sizes and reliably identify technical improvements, we examined within-patient visit-to-visit BP variability, quantified as SD of change from baseline to final BP (SDΔ), in renal denervation (RDN) trials, trials of BP-lowering tablets, and the VOLTAGE study including 4151 patients. Results: The control arms of RDN trials had more visit-to-visit BP variability than tablet trials (SDΔ 23.6 versus 13.5 mmHg; P < 0.001). This might be explained by more prescribed antihypertensive patients in the RDN trials (5.19 ± 0.13 versus 0.11 ± 0.11; P < 0.001). In the VOLTAGE study, as the number of medications prescribed rose from 0 to 4, SDΔ rose: 11.9, 11.2, 12.9, 14.4 and 18.0 mmHg (P < 0.001 for trend). Neither baseline BP, nor demographics, nor diabetes independently affected variability. The sample size required for a trial rises proportionally to the square of the number of medications prescribed (rather than just linearly). The relationship between the number of background medications prescribed in a cohort and the excess test-retest variance closely fitted this quadratic formula (R = 0.98, P = 0.001). Conclusion: Visit-to-visit variability in BP is dramatically larger in patients with more background medications prescribed. If this is due to variable adherence, then future RDN trials, needing to detect smaller effect sizes, would benefit from measures to guarantee adherence. Conceivable measures include enrolling patients on no background medication, preceding each BP measurement with a period off medication, or directly supervising medication intake.
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    • "Although the incidence of diarrhea reported with aliskiren up to 300 mg daily did not differ significantly from placebo, when aliskiren 600 mg daily was administered in one study, the incidence of diarrhea was significantly higher than that of placebo (11.4% vs 0.2%; P < 0.001).[35] Aliskiren use was associated with a slight increase in cough in placebo-controlled studies (1.1% for any aliskiren use vs 0.6% for placebo).[353639] In studies comparing aliskiren and ACE inhibitors, the rates of cough for aliskiren were about one-third to one-half the rates of ACE inhibitors. "
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    ABSTRACT: Renin inhibitors are antihypertensive drugs that block the first step in the renin-angiotensin system. Their mechanism of action differs from that of the angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists, but like these drugs, renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion. The renin-angiotensin-aldosterone system (RAAS) has long been recognized to play a significant role in hypertension pathophysiology. Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes. Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug. Aliskiren is the first of a new class of antihypertensive agents. Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. In short-term studies, it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide, and had a low incidence of serious adverse effects. It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives. Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin-receptor blocker. The most common adverse effects reported in clinical trials were headache, fatigue, dizziness, diarrhea, and nasopharyngitis. Aliskiren has not been studied in patients with moderate renal dysfunction; as an RAAS-acting drug, it should be prescribed for such patients only with caution.
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    • "In a placebo-controlled study of 455 Japanese patients with hypertension and a mean sitting diastolic blood pressure of 95–110 mmHg, aliskiren in doses of 75, 150, and 300 mg lowered blood pressure in a dose-dependent manner. Interestingly, after correcting for placebo, the reduction in systolic and diastolic blood pressure was 5.7/4 mmHg, 5.9/4.5 mmHg, and 11.2/7.5 mmHg, respectively, indicating a rather small effect.37 "
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    ABSTRACT: Arterial hypertension is one of the major diseases in the Western world. It is an independent cardiovascular risk factor and is associated with increased morbidity and mortality. Several drug classes have been shown to be effective in the treatment of hypertension. Aliskiren is a direct renin inhibitor and belongs to the class of renin-angiotensin-aldosterone system inhibitors. Several large studies have shown that aliskiren is effective in lowering blood pressure, and equivalent in this respect to the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor-1 blockers (ARBs). Furthermore, aliskiren has a safety and tolerability profile comparable with that of the ARBs and slightly better than that of the ACE inhibitors. From a pathophysiologic perspective, it can be combined with hydrochlorothiazide successfully, because it can block the diuretic-induced increase in plasma renin activity. Its combination with hydrochlorothiazide in a single pill has been investigated and shown to be superior to monotherapy with respect to blood pressure control and improvement in patient compliance with therapy. Further studies are needed to show whether aliskiren and its combination with hydrochlorothiazide is effective in preventing cardiovascular events and mortality when end organ damage is present.
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