Allikmets Similar ﬁndings were obtained In 3 open-label studies in which BP was assessed with ambulatory measurement (O’Brien et al 2007). Aliskiren was administered to patients with mild-to-moderate hypertension in combination with hydrochlorothiazide (n = 23), ramipril (n = 21), or irbesartan (n = 23). Aliskiren (150 mg) alone signiﬁcantly inhibited plasma renin activity by 65% (p 0.0001) while ramipril and irbesartan monotherapy caused 90% and 175% increases in plasma renin activity, respectively. By contrast, when aliskiren was co-administered with hydrochlorothiazide, ramipril, or irbesartan, plasma renin activity did not increase but remained similar to baseline levels or was decreased, alon with improved 24-hour blood pressure control (O’Brien et al 2007). Clinical studies with aliskiren in essential hypertensive patients Early phase II trials with aliskiren compared the BP-lowering effects and safety of aliskiren with placebo, with losartan and irbesartan. Aliskiren (at doses 37.5, 75, 150, and 300 mg once daily) and losartan (100 mg once daily) were compared in a 4-week trial in 226 patients with mild-to-moderate essential hyperten- sion. Aliskiren showed dose-dependent reduction in BP, with the changes in patients getting 75–300 mg of aliskiren similar to those receiving 100 mg of losartan (Stanton et al 2003). In a comparative trial with the ARB irbesartan, 652 hyper- tensive subjects were randomized to receive either irbesartan (150 mg) or aliskiren (150, 300 and 600 mg). At a dose of 150 mg, aliskiren was as effective as irbesartan (150 mg) in lowering blood pressure with similar safety and tolerability over the short term (Gradman et al 2005). The BP-lowering effects of aliskiren (75, 150, or 300 mg) alone or in combination with the ARB valsartan (80, 160, or 320 mg) were compared in a multicenter, random- ized, placebo-controlled, 8-week trial in 1123 patients with mild-to-moderate hypertension (Pool et al 2007). In an addi- tional comparator arm, patients were receiving a combination of valsartan/hydrochlorothiazide (160/12.5 mg). The results indicated that co-administration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone, comparable in magnitude to the effect of valsartan/ hydrochlorothiazide, with similar tolerability to the compo- nent monotherapies and to placebo (Pool et al 2007). In subsequent trials, aliskiren has been compared with other antihypertensive drugs. Aliskiren (in doses 75 mg, 150 mg, 300 mg once daily) was compared with HCTZ (in doses 6.25, 12.5, and 25 mg once daily), and with the com- bination of the two agents in an 8-week placebo-controlled, 812 factorial design trial in 2776 hypertensive patients (published so far only as an abstract). This study demonstrated that HCTZ signiﬁcantly potentiates the antihypertensive efﬁcacy of aliskiren. The greatest mean reduction in BP (21.2/14.3 mmHg in systolic and diastolic BP, respectively) was observed with the combination of aliskiren 300 mg and HCTZ 25 mg. The responder rates for aliskiren monotherapy were betweem 51.9% (75 mg) and 63.9% (300 mg), and similar to those observed with HCTZ (Villamil et al 2006). Data for safety and efﬁcacy of aliskiren over long-term use has recently become available. Thus, the efﬁcacy of aliskiren with optional addition of HCTZ was studied in a 12-month open-label study (Sica et al 2006; published so far only as an abstract). Patients with mild-to-moderate essential hypertension were randomized to aliskiren 150 mg (n = 1178) or 300 mg (n = 773) once daily. Dose titration (aliskiren 150 mg titrated to 300 mg) or addition of HCTZ (12.5 mg titrated to 25 mg if required) to aliskiren 300 mg was permit- ted in patients with BP 140/90 mmHg after Month 2. A subgroup of patients remaining on aliskiren monotherapy at Month 11 were randomized to continued aliskiren (n = 132) or placebo (n = 129) during a 4-week double-blind with- drawal phase. In total, 868 patients (45%) required addition of HCTZ, the BP reductions at study end were comparable in these patients (BP reduction of 18.7/12.1 mmHg) and the patients who had responded adequately to aliskiren monotherapy (BP reduction of 17.4/13.3 mmHg). Following treatment withdrawal, BP rose gradually with no evidence of rebound (Sica et al 2006). Rebound hypertension has not emerged as a problem with aliskiren. Theoretically it is conceivable that long-term renin-inhibition therapy could induce pharmacologic toler- ance with renin hypersecretion as well as the phenomenon of rebound hypertension after abrupt cessation of chronic therapy. However, clinical experience with aliskiren does not conﬁrm this, as shown in the long-term study reported recently by Sica et al 2006. In another study in 672 patients with mild-to-moderate essential hypertension, aliskiren with- drawal after 8-week therapy (in doses 150, 300 or 600 mg) was not associated with blood pressure or PRA rebound, despite elevated plasma renin concentration at the time of withdrawal, BP and PRA remained suppressed for 2-weeks after discontinuation of therapy (Herron et al 2006). Recently, Weir et al (2006) have reported a pooled analysis of data from 8 randomized multicenter studies with aliskiren, including 8570 patients with mild to moderate hypertension (published so far only as abstract). Treatment durations ranged from 6 to 52-weeks. The analysis showed Vascular Health and Risk Management 2007:3(6)