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Objective: The effect of two different strategies for renin–angiotensin–aldosterone system (RAAS) blockade; direct renin inhibition (DRI) versus angiotensin receptor blockade (ARB) on blood pressure (BP) and plasma renin activity (PRA) was compared during exercise. Methods: Hypertensive adults were randomised to aliskiren (300 mg once daily, n =33) or valsartan (320 mg once daily, n =35). BP and PRA were measured during treadmill exercise (Bruce protocol), at baseline, end of treatment (eight weeks), and after treatment withdrawal (48 hours after last dose). Results: After eight weeks treatment, Aliskiren inhibited PRA (>80%) at rest and during exercise, with inhibition remaining undiminished 48 hours after treatment withdrawal. In contrast, valsartan increased PRA at rest, and more-so during exercise (>400%). Angiotensin receptor blockade, as indicated by PRA increase, was reduced, 48 hours after valsartan treatment withdrawal, suggesting more sustained RAAS blockade with aliskiren. Despite divergent effects on PRA, similar exercise-induced changes in BP were seen. The primary outcome, the rise in systolic BP from rest to peak exercise (baseline to after treatment withdrawal) did not differ between treatments ( p =0.25). Conclusion: Measurement of PRA is a more sensitive index of RAAS blockade than the BP response during exercise. Furthermore, after treatment withdrawal, aliskiren provides more sustained RAAS inhibition than valsartan at rest and during exercise.

Introduction. Aliskiren is the first in a new class of direct renin inhibitors to be approved for the treatment of hypertension. Patients and methods. In this double-blind, multicentre trial, 694 patients with hypertension (mean sitting diastolic blood pressure [BP] ≥ 95 and < 110 mmHg) were randomised to once-daily aliskiren 150 mg (n=231), atenolol 50 mg (n=231) or the combination (150/50 mg; n=232) for six weeks, followed by a further six weeks on double the initial doses of aliskiren and atenolol. Efficacy (reduction from baseline in mean sitting systolic and diastolic BP) and tolerability of study treatments were assessed; plasma renin activity (PRA) was measured in a subset of patients. Results. At Week 12 endpoint, aliskiren, atenolol and aliskiren/atenolol lowered systolic and diastolic BP from baseline by 14.3/11.3, 14.3/13.7 and 17.3/14.1 mmHg, respectively. Systolic BP reductions with aliskiren/atenolol were significantly greater than those with aliskiren (p=0.039) or atenolol (p=0.034) alone, and diastolic BP reductions were greater than with aliskiren alone (p 10 bpm) observed with atenolol. Aliskiren, atenolol and aliskiren/atenolol reduced geometric mean PRA from baseline by 65%, 52% and 61%, respectively. In patients with moderate or high baseline PRA (≥ 0.65 ng/ml/hour), PRA was reduced to low levels (< 0.65 ng/ml/hour) at Week 12 endpoint in a greater proportion of patients receiving aliskiren (11/15 patients, 73.3%) or aliskiren/atenolol (18/23, 78.3%) than with atenolol (10/21, 47.6%). Aliskiren treatment was associated with numerically lower rates of adverse events and discontinuations due to adverse events compared with atenolol or combination treatment, and unlike atenolol was not associated with bradycardia. Conclusions. Direct renin inhibition with aliskiren may be an appropriate substitute for beta-blocker treatment in patients with uncomplicated hypertension. Aliskiren also represents an attractive option for dual therapy with atenolol to improve systolic BP/pulse pressure reductions and BP control with maintained tolerability compared with atenolol alone.