Aliskiren, an Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Sustained 24-Hour Blood Pressure Control in Patients With Hypertension

Oh, Byung Hee; Mitchell, Jerry R.; Herron, James R.; Chung, Jenny; Khan, Mahmudul; Keefe, Deborah L.

doi:10.1016/j.jacc.2006.11.032

Cited by 254 publications

(193 citation statements)

References 26 publications

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“…In a randomized, double-blind, dose-finding study, 608 patients who completed 8 weeks of treatment with aliskiren monotherapy entered a 2-week withdrawal period. 8 Office BP reduction from baseline with aliskiren 300 mg was 14.7/11.1 mm Hg at week 8. BP increased only gradually after stopping aliskiren treatment, and remained 11.6/9.5 mm Hg below baseline at 4 days after stopping treatment (that is, 80% of the BP-lowering effect was maintained); a 64.7% reduction from baseline in PRA also persisted 2 weeks after the last dose.…”

Section: Discussionmentioning

confidence: 89%

“…BP increased only gradually after stopping aliskiren treatment, and remained 11.6/9.5 mm Hg below baseline at 4 days after stopping treatment (that is, 80% of the BP-lowering effect was maintained); a 64.7% reduction from baseline in PRA also persisted 2 weeks after the last dose. 8 Similarly, in a 4-week, placebo-controlled withdrawal period initiated by 675 patients who had completed a 6-month, double-blind comparator study of aliskiren-and ramipril-based therapy, office BP increased more rapidly after stopping ramipril-than aliskirenbased therapy. Median BP exceeded 140/90 mm Hg 1 week after stopping ramipril, but 4 weeks after stopping aliskiren.…”

Section: Discussionmentioning

confidence: 99%

“…5 Aliskiren exhibits a long terminal elimination half-life of approximately 40 h, 6,7 and has shown effective 24-h BP control in ambulatory BP-monitoring substudies. 8 Moreover, clinical studies in patients with hypertension have shown that the effect of aliskiren to lower BP and reduce plasma renin activity (PRA) persists for up to 2 weeks after stopping treatment. 8,9 We report the results of an ambulatory BP-monitoring study designed to assess the antihypertensive efficacy of aliskiren following simulated non-adherence (missed doses) of treatment compared with that of the angiotensin receptor blocker (ARB), irbesartan, and the angiotensin-converting enzyme (ACE) inhibitor, ramipril.…”

Section: Introductionmentioning

confidence: 99%

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Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

et al. 2009

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Most patients inadvertently miss an occasional dose of antihypertensive therapy, and hence drugs that provide sustained blood-pressure (BP) reduction beyond the 24-h dosing interval are desirable. The primary objective of this study was to compare the 24-h mean ambulatory BP reductions from baseline after a simulated missed dose of the direct renin inhibitor aliskiren, irbesartan or ramipril. In this double-blind study, 654 hypertensive patients (24-h mean ambulatory diastolic BP (MADBP) X85 mm Hg) were randomized 1:1:1 to once-daily aliskiren 150 mg, irbesartan 150 mg or ramipril 5 mg. Doses were doubled after 2 weeks. At day 42, patients were again randomized equally within each group to receive 1 day of placebo ('missed dose') on either day 42 or day 49. Patients with a successful 24-h ambulatory BP measurement at baseline and on day 42/49 were included in the analyses. The 24-h mean ambulatory systolic BP (MASBP)/MADBP reductions from baseline after a missed dose of aliskiren 300 mg (9.3/7.0 mm Hg) were similar to irbesartan 300 mg (9.5/7.3 mm Hg) and significantly larger than ramipril 10 mg (7.1/5.0 mm Hg, Pp0.008). Loss of BP-lowering effect with aliskiren in the 24 h after a missed dose (1.0/0.7 mm Hg for 24-48-h vs 0-24-h MASBP/MADBP) was significantly lower than with irbesartan (3.6/2.2 mm Hg, Po0.01) or ramipril (4.0/2.6, Po0.0001). This equates to maintenance of 91/91% of the MASBP/MADBP-lowering effect with aliskiren, greater than irbesartan (73/77%) or ramipril (64/65%). The incidence of adverse events was similar across treatments (32.9-36.0%), although ramipril treatment was associated with an increased incidence of cough (ramipril, 6.1%; aliskiren, 0.5%; irbesartan, 1.8%). Aliskiren 300 mg provided a sustained BP-lowering effect beyond the 24-h dosing interval, with a significantly smaller loss of BP-lowering effect in the 24-48 h period after dose than irbesartan 300 mg or ramipril 10 mg.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

et al. 2009

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“…As this mechanism should operate independently of plasma drug levels, 101 it may help to explain the prolonged BP benefits observed in rats discussed earlier, and in patients in whom aliskiren treatment has been stopped. 104 Aliskiren, prorenin and the (pro)renin receptor The recent discovery of a receptor for renin and prorenin, the (P)RR, 105 has added an important new dimension to the tissue RAAS. [106][107][108] In the kidney, gene and/or protein expression of the (P)RR has been reported in the glomerular mesangium, 109 vascular wall 87,109 and tubular cells.…”

Section: Aliskiren Localizes In the Kidneymentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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“…14,15,[17][18][19][20][21][22] Data were analysed for aliskiren 150 mg and 300 mg (the US Food and Drug Administration and European Union approved doses for the treatment of hypertension) and placebo after 8 or 12 weeks of treatment for the subgroups of women and men. All of the trials were 8 weeks in duration, except for the aliskiren vs ramipril (6 months) and aliskiren vs HCT (12 months) studies.…”

Section: Methodsmentioning

confidence: 99%

Efficacy, safety and tolerability of aliskiren, a direct renin inhibitor, in women with hypertension: a pooled analysis of eight studies

et al. 2010

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Hypertension is a major risk factor for cardiovascular disease, which is the leading cause of mortality in women in developed countries. This pooled analysis assessed the antihypertensive efficacy, safety and tolerability of monotherapy with the direct renin inhibitor aliskiren (150 mg and 300 mg) over 8-12 weeks in women with mild-to-moderate hypertension (mean sitting diastolic blood pressure (msDBP)X95 and o110 mm Hg) across eight randomized and double-blind trials. Safety and tolerability were assessed in the five placebo-controlled trials in the analysis. In the 1527 women enrolled in these studies, aliskiren 150 mg and 300 mg produced significantly greater blood pressure (BP) reductions (14.1/11.0 and 16.1/12.3 mm Hg, respectively) compared with placebo (7.2/7.6 mm Hg; Po0.0001). BP reductions with aliskiren monotherapy in women were similar to those observed in men, and consistent across subgroups of age, metabolic syndrome and obesity. The overall incidence of adverse events in women was similar with aliskiren treatment (150 mg, 42.3%; 300 mg, 46.0%) and placebo (39.0%); adverse events with aliskiren were more frequent in women than in men, consistent with previous studies of gender differences in drug tolerability. In conclusion, aliskiren monotherapy at 150 mg and 300 mg doses provided effective, dose-dependent BP-lowering in women with mild-to-moderate hypertension, and it was well tolerated.

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Aliskiren, an Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Sustained 24-Hour Blood Pressure Control in Patients With Hypertension

Abstract: Aliskiren provides significant antihypertensive efficacy in patients with hypertension, with no rebound effects on blood pressure after treatment withdrawal.

Cited by 254 publications

References 26 publications

Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

Maintenance of blood-pressure-lowering effect following a missed dose of aliskiren, irbesartan or ramipril: results of a randomized, double-blind study

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Efficacy, safety and tolerability of aliskiren, a direct renin inhibitor, in women with hypertension: a pooled analysis of eight studies

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