Aliskiren: First Direct Renin Inhibitor Improves BP Control

Internal Medicine World ReportMay 2007
Volume 0
Issue 0

The recent approval of aliskiren (Tekturna; Novartis)?the first drug in a new class of antihypertensives that inhibits the renin-angiotensin system (RAS) by directly targeting the renin enzyme?is also the first approval of a new class of antihypertensives in more than a decade.

"The development of aliskiren has truly been a breakthrough," says Alan Gradman, MD, chief of the Division of Cardiovascular Diseases, Western Pennsylvania Hospital, Pittsburgh, and professor of medicine, Temple University, Philadelphia.

"Everybody has been looking for a renin inhibitor for more than 25 years," says Dr Gradman. Early efforts were stymied when the first generation of oral agents could not be absorbed well enough into the bloodstream to be effective. "Aliskiren is not only effective, it's also a good, solid, once-a-day drug with a long half-life," he adds.

RAS Inhibition

The potential benefits of inhibiting the RAS, a contributing factor to cardiovascular (CV) and renal diseases, have been known for more than 3 decades. Until now, angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) were the 2 classes that offered RAS inhibition, but they do so indirectly. Aliskiren's direct renin inhibition offers an improved mechanism for controlling elevated blood pressure (BP).

"The way an ACE inhibitor works is to inhibit the conversion of angiotensin I to angiotensin II, and by increasing the availability of the vasoactive peptide, bradykinin," says Dr Gradman. "The way ARBs work is to directly block the main receptor that angiotensin II binds to in order to produce its effects."

In contrast, the new class of direct renin inhibitors blocks the RAS cascade "proximal to that point. By blocking the system at its point of activation, you also block everything else downstream," he says. "The concept behind direct renin inhibition is that by blocking the system at the point of activation, you will not get these reactive or compensatory effects that you get with other blockers of the RAS," such as ACE inhibitors or ARBs, he adds.

Safety and Efficacy

The safety and efficacy of aliskiren were investigated for aliskiren monotherapy as well as in combination with other antihypertensives.

One trial of 672 patients with hypertension showed that 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 will also reduce the early-morning BP surges that are associated with increases in CV events. ?

In another trial, BP reductions with aliskiren monotherapy were similar to reductions seen with 25 mg of hydrochlorothiazide (HCTZ) (Figure 1). Yet another trial demonstrated 14.7 mm Hg systolic and 11.3 mm Hg diastolic BP reductions with aliskiren compared with 12 mm Hg systolic and 10.7 mm Hg with ramipril (Altace). And in another trial, aliskiren had effects similar to valsartan (Diovan). In all these trials, combining aliskiren with the comparator resulted in a significantly greater BP reduction than with either agent alone.


Dr Gradman was lead investigator of one randomized controlled study (. 2005;111:1012-1018) that included 652 patients with hypertension. Aliskiren, 150 mg, was as effective as the 150-mg dose of the ARB irbesartan (Avapro), but higher doses of aliskiren (300 or 600 mg/d) resulted in significantly greater BP control than with irbesartan.

Also, aliskiren at up to 300 mg/day was as safe as irbesartan or placebo.

The Aliskiren Advantage

"So the question that everybody is asking is, ?Why would you choose aliskiren over anything else?'" Dr Gradman says. He suggests several reasons:

? Aliskiren's unique mechanism of action, which would also apply to combining aliskiren with another BP-lowering drug, particularly another RAS blocker.?

? Combining aliskiren with an ARB would provide additional BP control, and prevent the ARB-associated rise in angiotensin II. This is also true when combined with an ACE inhibitor.

? Adding aliskiren to an ACE inhibitor reduced the incidence of ACE inhibitor?induced cough in one study.

? The effects of aliskiren appear to linger after patients stop taking it.

J Clin Hypertens

In one 8-week randomized, placebo-controlled study of 608 hypertensive patients (. 2006; 8 [suppl A]:A93), those who had been taking aliskiren remained below BP baseline levels for up to 1 month after discontinuing aliskiren therapy.

"It's very interesting," Dr Gradman says, "that if you take people off of aliskiren, there is a continued effect. It's not as potent as while they're taking the drug, but there's a continued BP reduction for a couple of weeks." This could be a boon to physicians whose carefully thought-out treatment plans are often undermined by noncompliant patients.

Dr Gradman notes that the real advantages of aliskiren are its "comparable efficacy, good safety profile, the theoretical mechanistic advantages, it combines pretty well with other drugs, and it can be used across the board. They've looked at women versus men, older versus younger, and you get the same effect in all of those subgroups. The only group I would be a little hesitant about is blacks, in whom it probably has a little bit less of an effect."

Prescribing Aliskiren

Aliskiren is indicated for the treatment of hypertension, alone or in combination with other antihypertensives. BP reductions with this drug usually occur within 2 weeks.

The idea of combining aliskiren with other drugs that block the RAS is particularly attractive from a mechanistic perspective. "When you want to get some additional BP reduction, aliskiren works well when combined with a diuretic, just like all the other RAS-blocking drugs," Dr Gradman says.

Aliskiren would not always be the first choice for combination therapy in patients receiving ARBs or ACE inhibitors. "Usually you'd go with diuretics or calcium channel blockers. But there is an additional BP reduction with aliskiren, and at least a theoretical value in terms of suppression of the RAS."

The recommended starting dose of aliskiren is 150 mg/day, taken in 1 tablet; it can be titrated up to 300 mg/day. Higher doses increase the risk for diarrhea and have not shown added efficacy.

Do not adjust the initial doses in the elderly or in patients with renal or hepatic impairment.

As first-line monotherapy, aliskiren can be used in the majority of patients; thus, any patient who is a candidate for RAS inhibition with an ACE inhibitor or an ARB can take aliskiren.

Contraindications, Mild Side Effects

Those with bilateral renal artery stenosis should not use aliskiren.

Aliskiren is metabolized by the cytochrome P450-3A4 enzyme. When coadministered with furosemide (Lasix), serum concentrations of furosemide are significantly reduced.?

Use extra caution in patients with severely impaired renal function, for whom safety data are not yet available.

Aliskiren is in pregnancy category C for the first trimester and category D for the second and third trimesters. Discontinue use of aliskiren in any woman who becomes pregnant.

Gastrointestinal side effects appear to be dose-related. Among patients taking the 300-mg dose, 2.3% reported diarrhea (vs 1.2% taking placebo). Women and the elderly appear to be more susceptible to diarrhea at the 150-mg dose.

In clinical trials, the incidence of cough was 1.1% with aliskiren and 0.6% with placebo.

Reported rates of drug discontinuation because of adverse events, including uncontrolled hypertension, were 2.2% with aliskiren and 3.5% with placebo. Serious adverse events were rare but included 2 cases of angioedema and 2 cases of periorbital edema.

The FDA approval was primarily based on short-duration trials, but data are available for more than 1000 patients who have been treated for at least 1 year. "None of the RAS drugs has ever shown any long-term side effects that were unexpected and not related to their mechanism of action," says Dr Gradman.

"Aliskiren is?very specific for this 1 enzyme, and renin itself is very, very specific for this 1 reaction?.I'd be very surprised if there's any big-time side effect that pops up," he emphasizes.


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