Donald G. Vidt, MD
Aliskiren and Blood Pressure Control in Patients with Hypertension
Oh BH, Mitchell J, Herron JR, et al.: Aliskiren, an oral renin inhibitor, provides dose-dependent efficacy and sustained 24-hour blood pressure control in patients with hypertension. J Am Coll Cardiol 2007, 49:1157–1163.
Rating: •• Of major importance.
Introduction: Aliskiren is the first agent in a new class of orally effective renin inhibitors and is a potent inhibitor of human renin. Renin inhibitors, however, constitute the fourth class of drugs to lower blood pressure by blocking the renin-angiotensin system. In this dose-ranging study the authors evaluated the antihypertensive efficacy of aliski-ren at doses of 150 to 600 mg daily in patients with mild to moderate essential hypertension. Aliskiren does have a long half-life of approximately 40 hours, which makes it suitable for once-daily administration. In addition to office blood pressure (BP) measurements, a subgroup of patients underwent 24-hour ambulatory blood pressure monitor-ing (ABPM) before randomization and after the last dose of study medication in the double-blind treatment. Safety and tolerability assessments were also undertaken and both plasma renin activity (PRA) by radioimmunoassay and renin concentrations (RC) by direct renin assay were also obtained periodically throughout the study. Consistent with its mech-anism of action, aliskiren has been shown to reduce plasma renin activity from baseline, both in hypertensive patients and in healthy volunteers.
Aims: The primary objective of the study was to evaluate reductions in mean sitting diastolic blood pressure (msDBP) with aliskiren 150, 300, or 600 mg daily compared with placebo. Secondary objectives were to assess reductions in msDBP and dose-response relationship, 24-hour ABPM profiles, and trough-to-peak ratios as well as a propor-tion of patients achieving a successful treatment response. Treatment response was defined as msDBP less than 90 mm Hg and/or 10 mm Hg or greater reduction from baseline or blood pressure control less than 140/90 mm Hg. The effects of aliskiren on PRA and RC; the safety and tolerability of aliskiren 150 to 600 mg; and the effective treatment with-drawal on BP, PRA, and RC were also assessed.
Methods: Male and female adults with msDBP 95 mm Hg or greater and less than 110 mm Hg were recruited at 68 centers in this international trial. The patients were random-ized to aliskiren 150, 300, or 600 mg or placebo once daily
for 8 weeks following a 2-week washout period of prior antihypertensive therapy. Patients completing this treatment phase entered a 2-week treatment-free withdrawal period. Follow-up visits were conducted at weeks 2, 4, 6, and 8, and at 4 days and again at 2 weeks after drug withdrawal. A sub-group of patients underwent ambulatory BP monitoring.
Results: A total of 672 patients were randomized to a treat-ment period. After 8 weeks, aliskiren 150, 300, and 600 mg significantly reduced mean sitting BP by 13/10.3, 14.7/11.1, and 15.8/12.5 mm Hg, respectively, versus 3.8/4.9 mm Hg with placebo (P < 0.0001 for all treatment arms). The BP-lowering effect of aliskiren persisted for up to 2 weeks after treatment withdrawal. Aliskiren also significantly reduced mean 24-hour ambulatory BP with all doses (P < 0.0001 vs placebo). Trough-to-peak ratios for aliskiren 150, 300, and 600 mg were 0.64, 0.98, and 0.86, respectively.
Aliskiren 150, 300, and 600 mg reduced PRA from baseline (geometric mean change) by 79.5%, 81.1%, and 75%, respectively, whereas PRA increased by 19.5% from baseline in the placebo group. The 8 weeks of aliskiren treatment also resulted in dose-dependent increases from baseline in RC (51.5%, 101.6%, and 228.5%) for 150, 300, and 600 mg, respectively. RC was essentially unchanged in the placebo group. The proportion of patients experiencing adverse effects with aliskiren 150, 300, and 600 mg was 40.1%, 46.7%, and 52.4%, respec-tively, compared with 43% in the placebo group.
Discussion: The current study demonstrated that the antihy-pertensive efficacy of once-daily aliskiren 150 to 600 mg in patients with mild-to-moderate hypertension and the main-tenance of BP reductions over the 24-hour dosing period is consistent with the long duration of action for this agent. Approximately 60% to 70% of study participants achieved a successful treatment response across the dose range, with treatment response defined as a reduction of msDBP from baseline to less than 90 mm Hg or by 10 mm Hg or greater.
Although the 600-mg dose of aliskiren induced larger BP reductions compared with the 300-mg dose, the differences were not statistically significant, sug-gesting that aliskiren 600 mg, at least as monotherapy, does not offer a significantly greater BP-lowering effect than aliskiren 300 mg in patients with mild-to-moderate hypertension. It was also observed that a smaller subset of black patients demonstrated a smaller magnitude of BP reduction than the Caucasian patients, although the
352 Antihypertensive Therapy: Patient Selection and Special Problems
direction in response patterns was similar in the two racial groups.
Aliskiren provided effective and smooth 24-hour BP control with trough-to-peak ratios for mean ambulatory DBP of 64% for the 150-mg dose and in the range of 90% for higher doses. These trough-to-peak ratios actu-ally surpassed those observed with some other commonly used antihypertensive drugs.
Aliskiren treatment was well tolerated with placebolike tolerability at doses up to and including 300 mg. The higher incidence of adverse effects at the 600-mg dose was largely related to diarrhea. The mechanism by which diarrhea was induced is not clear and was not observed with aliskiren 150 and 300 mg. The diarrhea was not severe enough to affect persistence on study treatment; in fact, few patients discontinued treatment due to any adverse effect.
Editor’s commentsAliskiren is the prototype of a new class of orally effective renin inhibitors and has been shown to effectively lower BP as well as decrease PRA when used as monotherapy. In con-trast to angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) therapy, both of which increase PRA by disrupting the normal feedback inhibition of renin release, aliskiren has been shown to provide dose-dependent decreases in PRA and angiotensin II formation in doses up to 300 mg daily.
Even in patients with mild-to-moderate hyperten-sion, long-term control of blood pressure often requires using two or more antihypertensive agents. O’Brien et al. [1] recently reported the results of three small open-label clinical trials in which aliskiren was combined with a diuretic (hydrochlorothiazide), an ACE inhibi-tor (ramipril), and an ARB (irbesartan). The rationale for these studies was that combination therapy with aliskiren would offer incremental BP reduction and blunt the reactive PRA increase seen with the three other antihypertensive medications. Indeed, when used in combination with a thiazide diuretic, ACE inhibi-tor, or ARB, aliskiren induced further reductions in 24-hour ambulatory BP, and blunted the compensatory rise in PRA, and the combinations were well tolerated.
When aliskiren was used in combination with 25 mg of hydrochlorothiazide, 5 mg of ramipril, or 150 mg of irbesartan, PRA did not increase and either remained similar to baseline levels or decreased. Unfortunately, these results must be tempered by the small sample size of 18 to 24 subjects in each trial, the short follow-up periods, and failure to use the maximal clinical doses of the other agents included. Nevertheless, aliskiren did blunt the reactive increase in PRA seen with hydrochlo-rothiazide, ramipril, or irbesartan.
Another recent publication is pertinent to this dis-cussion. Sealey and Laragh [2] reviewed six clinical trials of aliskiren involving more than 5000 patients with mild-to-moderate hypertension. They concluded that aliskiren is no more effective than ACE inhibi-tors, ARBs, or diuretics for lowering blood pressure. They also note that the 600-mg dose of aliskiren is no more effective than the 300-mg dose. They point to the much greater rises in plasma renin concentration than seen with other antihypertensive classes because aliski-ren, like other agents that block the renin-angiotensin system, only blocks 90% to 95% of plasma renin. The pressor consequences of its greater reactive increases in plasma renin concentration may offset its ability to lower blood pressure, especially with higher doses.
Further carefully controlled clinical trials are needed to eliminate the risk of inducing increases in blood pres-sure with aliskiren in patients with highly reactive renin levels, such as renovascular hypertension or severe-to-malignant hypertension. It is hoped that further trials also will clarify the value of this newest class of anti-hypertensive agents as monotherapy or in combination with other classes of agents across the spectrum of the hypertensive population.
References1. O’Brien EO, Barton J, Nussberger J, et al.: Aliskiren reduces
blood pressure and suppresses plasma renin activity in combination with a thiazide diuretic, an angiotensin convert-ing enzyme inhibitor, or an angiotensin receptor blocker. Hypertension 2007, 49:276–284.
2. Sealey JE, Laragh JH: Aliskiren, the first renin inhibitor for treating hypertension: reactive renin secretion may limit its effectiveness. Am J Hypertens 2007, 5:587–597.
