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

Abstract

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.

AT1 antagonism and renin inhibition in mice: pivotal role of targeting angiotensin II in chronic kidney disease

“…After withdrawal, aliskiren plasma levels dropped within 24 h to nondetectable, whereas a delayed decline over several days was found in the heart and kidney. Interestingly, this contrasts with plasma half-life of aliskiren in humans (ϳ30 -40 h after multiple dosing) (15), which was used to explain sustained reduced blood pressure after a missed dose and may counteract adverse effects due to imperfect adherence (5,31). Interspecies variation of the pharmacokinetic entities of aliskiren thus need further evaluation.…”

“…Emerging evidence indicates sustained effects of aliskiren beyond withdrawal (31,35). Besides its long plasma half-life in humans, speculations about any putative renal accumulation of aliskiren were held to explain this phenomenon (10).…”

Aliskiren Monotherapy Does Not Cause Paradoxical Blood Pressure Rises

“…Of 27 aliskiren clinical trials that have assessed BP changes in patients with hypertension as a primary end point, 8 met the study inclusion criteria and were evaluated in the meta-analysis. [11][12][13][14][15][16][17][18] Study details are shown in Table 1. PRA was measured in only a subset of patients in studies 3 to 8.…”

Combined aliskiren-amlodipine treatment for hypertension in African Americans: clinical science and management issues

“…Although relatively poorly absorbed from the gastrointestinal tract, aliskiren is quite potent and its pharmacodynamic half-life markedly exceeds 24 hours [Palatini et al 2010]. This might carry with it potential importance in individuals more likely to miss drug doses, a characteristic that is more frequent in minorities.…”