ASHP 08: New antihypertensive drugs' place in therapy not yet known

The niches that aliskiren and nebivolol, two newly approvedtherapies for hypertension, will occupy in the therapeuticarmamentarium for hypertension remain unknown until more outcomesdata are obtained with these agents, said Stuart T. Haines,PharmD, BCPS, FASHP, professor, University of Maryland School ofPharmacy, Baltimore, in his discussion of new and emergingtherapies for hypertension.

Aliskiren is a direct renin inhibitor that results in a reductionin plasma renin activity. As monotherapy, aliskiren reduces bloodpressure in a dose-dependent manner, to a maximum of 15.8 mmHgsystolic blood pressure (SBP) and 12.9 mmHg diastolic bloodpressure (DBP). The effect is similar to that ofangiotensin-converting enzyme (ACE) inhibitors, angiotensinreceptor blockers (ARBs), and thiazide diuretics.

Expect a blood pressure reduction at about 2 weeks and a maximaleffect at 4 weeks with aliskiren, said Dr. Haines. Therefore,"don't measure blood pressure right away" after starting therapy,he advised.

"Aliskiren will probably be used as combination therapy inpractice, not as first-line therapy," he said. The drug does havea modest effect when added to other antihypertensive agents;healthcare professionals can expect an additional reduction of 6to 8 mmHg in SBP, he said. Aliskiren will blunt the compensatoryincrease in plasma renin activity observed with many otherantihypertensive drugs.

In a trial that evaluated aliskiren in combination with losartancompared with losartan alone, the combination was associated withan 18% reduction in the albumin/creatinine ratio, adjusted forblood pressure change, compared with losartan monotherapy.

Aliskiren is extremely tolerable, with rates of adverse eventslower than the rates associated with placebo. Diarrhea is a sideeffect at higher dosages, Dr. Haines said.

Nebivolol is a third-generation beta-blocker with vasodilatingproperties that are modulated by release of nitric oxide. Asmonotherapy, it is as potent as other beta-blockers at loweringblood pressure but without the quality of life side effects seenwith traditional beta-blockers, said Dr. Haines.

Nebivolol has been tested in a placebo-controlled trial of olderpatients with stable heart failure who were taking other standardtreatments for heart failure. The mean age of patients was 76years, and they had baseline blood pressures of approximately140/80 mmHg.

In the study, nebivolol was associated with a 14% relativereduction in the risk of all-cause death or hospital admissionfor a cardiovascular reason (p = .039). The number neededto treat to prevent one such event was 30. The discontinuationrate was the same as the rate observed with placebo in thistrial.

Darusentan is an investigational endothelin type A receptorantagonist. Unlike bosentan, a related drug, darusentan is highlyselective for the endothelin type A receptor; whether or not this propertymakes it more specific in lowering arterial hypertension is notknown, said Dr. Haines.

In a phase 2 trial in patients with stage 2 hypertension,darusentan lowered blood pressure by approximately 11/8 mmHgversus placebo, and 56% of darusentan-treated patients achievedgoal blood pressure, "which is significant in a group withstage 2 hypertension," Dr. Haines said. This agent is also potentas add-on therapy, producing an additional blood pressurereduction of 11.5/6.3 mmHg.

Headache, flushing, and edema may prevent darusentan from beingused as a first-line agent, however, said Dr. Haines.

A conjugate vaccine that induces high titers of specificantibodies directed against angiotensin II has been tested in aphase 2b trial of 72 patients, who were given three injections ofthe vaccine or placebo.

Blood pressure, as measured by 24-hour monitoring, was reducedonly modestly in the active vaccine group, and only during theday. Dr. Haines said he doubts the vaccine's bloodpressure-lowering effect, stating that the difference in bloodpressure between the vaccine and placebo groups was amplified byan unusual increase in blood pressure in the placebo group, not areduction in blood pressure in the vaccine group. The vaccine didgenerate antibodies to angiotensin II after the secondinjection.

The long-term effects of generating antibodies to angiotensin IIare unknown, he said.