Aliskiren

Aliskiren (Tekturna®) is an orally active, nonpeptidic inhibitor of renin, the enzyme involved in the initial and rate-limiting step of the renin-angiotensin system (RAS). In the US, aliskiren is approved for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents.

Monotherapy with aliskiren 150–300mg once daily was effective in lowering blood pressure (BP) and providing 24-hour BP control; it was generally well tolerated when administered for up to 1 year to patients with mild to moderate hypertension. In the short term (1–3 months), the BP-lowering effect of aliskiren 150–300mg once daily was significantly greater than that of hydrochlorothiazide (HCTZ) 12.5–25mg once daily and noninferior to, or significantly greater than, that of ramipril 5–10mg once daily. It was similar to that of valsartan 160–320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren provided significant additional BP-lowering effects when combined with HCTZ 12.5–25 mg/day, ramipril 5–10 mg/day, amlodipine 5mg once daily or valsartan 160–320 mg/day; combination therapy was well tolerated. Long-term administration of aliskiren-based therapy was superior to HCTZ- and ramipril-based therapies in lowering BP after 6 months, and was similarly well tolerated.

The ultimate role of aliskiren will be determined by the results of target organ protection studies, which are ongoing, and a cardiovascular outcome trial, which is planned. Nonetheless, by offering a new approach to the blockade of the RAS, aliskiren provides a useful addition to the therapeutic options available to treat patients with mild to moderate hypertension.

Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin, the enzyme involved in the initial and rate-limiting step in the RAS cascade that results in angiotensin II production. Aliskiren reduces plasma renin activity (PRA), despite stimulating dose-dependent increases in plasma renin levels. In comparison, ACE inhibitors and angiotensin II receptor antagonists increase both PRA and renin levels; however, the clinical implications of the differences in effect on PRA are not known. Aliskiren continues to reduce PRA when combined with other antihypertensive agents that (as monotherapy) increase PRA and renin levels.

Aliskiren demonstrated dose-linear pharmacokinetics over the dose range 75–600mg in healthy volunteers. It has a low absolute bioavailability (≈2.5%); plasma concentrations of the drug are substantially reduced when aliskiren is administered with a high fat meal. Following oral administration, aliskiren undergoes minimal metabolism and is mainly eliminated as unchanged (mostly unabsorbed) compound in the faeces. The mean elimination half-life of aliskiren (≈40 hours) permits once-daily administration.

Aliskiren has a low potential for drug interactions; coadministration of aliskiren with many other commonly used antihypertensive and cardiovascular medications (e.g. amlodipine, HCTZ, ramipril, valsartan, atenolol, lovastatin and digoxin) did not result in clinically relevant drug interactions.

Short-term (8 weeks) monotherapy with recommended dosages of aliskiren 150 and 300mg once daily was consistently and, almost without exception, superior to placebo in lowering trough mean sitting diastolic blood pressure (primary efficacy variable) and trough mean sitting systolic blood pressure in patients with mild to moderate hypertension. The BP-lowering effect of aliskiren was evident after 2 weeks and near maximal after 4 weeks of treatment; it was sustained and consistent throughout the 24-hour dosing interval. Responder and BP control rates were mostly higher (relative to placebo) with aliskiren 150 mg/day and consistently higher with aliskiren 300 mg/day. There was no evidence of rebound hypertension after discontinuation of aliskiren.

Aliskiren 150–300mg once daily provided a short-term (1–3 months) BP-lowering effect that was significantly greater than that of HCTZ 12.5–25mg once daily and noninferior to, or significantly greater than, that of ramipril 5–10mg once daily. It was similar to that of valsartan 160–320mg once daily and losartan 100mg once daily, and similar to, or significantly greater than, that of irbesartan 150mg once daily. Aliskiren 150–300 mg/day provided significant additional BP-lowering effects when combined with HCTZ 12.5–25 mg/day, ramipril 5–10 mg/day, amlodipine 5 mg/day or valsartan 160–320 mg/day.

Aliskiren 150–300 mg/day was effective in the treatment of mild to moderate hypertension for up to 1 year; there was no evidence of rebound hypertension following aliskiren withdrawal. Aliskiren-based therapy (i.e. aliskiren as monotherapy or in combination with another antihypertensive agent) was superior to HCTZ-and ramipril-based therapies in lowering BP after 6 months.

Short-term monotherapy with aliskiren 150–300 mg/day was generally well tolerated, with an adverse event profile similar to that of placebo. Adverse events commonly associated with aliskiren monotherapy included headache, nasopharyngitis and diarrhoea. Although data indicate that diarrhoea may be more frequent with aliskiren at dosages ≥300 mg/day than with placebo, this and other gastrointestinal symptoms (which include abdominal pain, dyspepsia and gastrointestinal reflux) are typically mild and rarely result in discontinuation of treatment.

Short-term (1–3 months) monotherapy with aliskiren 150 and 300 mg/day was at least as well tolerated as that with other antihypertensive agents (HCTZ 6.25–25mg, losartan 100mg, irbesartan 150mg, valsartan 160–320mg and ramipril 5–10mg; all administered once daily). Moreover, short-term combination therapy with aliskiren 150–300 mg/day plus ramipril 5–10 mg/day resulted in a numerically lower incidence of cough and headache compared with ramipril monotherapy at the same dosages, while aliskiren 150–300 mg/day combined with amlodipine 5 mg/day resulted in a significantly lower incidence of peripheral oedema compared with amlodipine monotherapy at double the dosage.

Long-term administration of aliskiren-based therapy was well tolerated for up to 1 year. Combining aliskiren with HCTZ was as well tolerated as ramipril combined with HCTZ, while aliskiren combined with amlodipine was as well tolerated as HCTZ combined with amlodipine, in terms of the frequency of adverse events after 6 months.