The recently approved medication, aliskiren (Tekturna), is the first antihypertensive that directly inhibits the renin?angiotensin system (RAS), by targeting the renin enzyme as its main mechanism.

Until now, 2 antihypertensive classes offered RAS inhibition—angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs)—although indirectly. In targeting the renin enzyme directly, aliskiren offers an improved mechanism of RAS inhibition, which may offer other benefits for blood pressure (BP) control.

The Evidence

Evidence from clinical trials shows sustained BP control with aliskiren. In one trial of 672 patients with hypertension, 8 weeks of once-daily aliskiren monotherapy provided sustained 24-hour BP control, with mean BP reductions of about 7/10 mm Hg with 150 mg/day and 6/9 mm Hg with 300 mg/day, compared with a 1.6/1.75-mm Hg rise in BP with placebo. Such around-the-clock BP control may help reduce the early-morning BP surges that are associated with increased cardiovascular events.

In another 8-week trial involving 2776 patients, BP reduction with aliskiren monotherapy was similar to that seen with 25 mg of hydrochlorothiazide, and the combination of both agents resulted in significantly greater BP reductions than either agent alone (Figure).

Figure. Mean BP reduction from baseline: aliskiren and HCTZ, by week 8

Yet another 8-week trial of 837 patients showed BP reductions of 14.7/11.3 mm Hg with aliskiren compared with 12.0/10.7 mm Hg with the ACE inhibitor ramipril (Altace). The combination of both agents resulted in reduction of about 16/13 mm Hg.

Aliskiren has also been shown to be comparable with the effects of the ARB valsartan (Diovan), and BP reductions were significantly greater when the 2 agents were combined.

The BP reductions of aliskiren appear to persist for a few weeks after discontinuation of therapy. In one 8-week randomized, placebo-controlled study of 608 hypertensive patients, those who had been taking aliskiren remained below BP baseline levels for up to 1 month after discontinuing therapy.

Prescribing Aliskiren

Aliskiren is indicated for the treatment of elevated BP in patients of all ages. Evidence suggests that its benefits are greater when combined with another antihypertensive, especially an ACE inhibitor or an ARB.

Aliskiren offers a new once-daily option, with a long half-life. Clinical benefits are usually seen within 2 weeks. The recommended starting dose is 150 mg/day, which can be titrated up to 300 mg/day. The drug is not approved at doses higher than 300 mg. Doses greater than 300 mg/day have been shown to increase the risk for diarrhea and have not shown added efficacy.

Initial doses should not be titrated up in the elderly or in patients with renal or hepatic impairment. Patients with bilateral renal artery stenosis are not good candidates for aliskiren.

Additional caution should be used in patients with severely impaired renal function, for whom safety data are not yet available. Aliskiren should be discontinued in any woman who becomes pregnant.

Aliskiren is metabolized by the cytochrome P3A4 enzyme. When coadministered with furosemide (Lasix), serum concentrations of furosemide are significantly reduced.

Adverse Effects

In clinical trials, gastrointestinal side effects appeared to be dose-related; 2.3% of patients taking the 300-mg dose reported diarrhea (compared with 1.2% of those taking placebo). Women and the elderly appear to be more susceptible to diarrhea at the 150-mg dose. About 1.1% of study participants had treatment-related cough (versus 0.6% with placebo).

Rates of discontinuation because of adverse events, including uncontrolled hypertension, were 2.2% with aliskiren and 3.5% with placebo. Rare serious adverse events include 2 cases of angioedema and 2 cases of periorbital edema.

The Aliskiren Advantage

The following advantages may make aliskiren an attractive option for the treatment of elevated BP:

• Unique mechanism of action, which would also apply to combining aliskiren with another BP-lowering drug, particularly other RAS blockers
• Combining aliskiren with an ARB provides the added benefit of preventing the ARB-associated rise in angiotensin II. This is also true when combined with an ACE inhibitor
• Adding aliskiren to an ACE inhibitor resulted in a reduction in the incidence of ACE inhibitor?induced cough in one study
• The effects of aliskiren appear to linger for some time after patients stop taking it.