Aliskiren was the first oral direct renin inhibitor and was approved for the treatment of hypertension at once-daily doses of 150 mg and 300 mg in 2007. By inhibiting the enzyme renin, aliskiren reduces plasma renin activity (PRA) and prevents the conversion of angiotensinogen to angiotensin (Ang) I, which, in turn, reduces levels of Ang II and aldosterone.1 Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) act at later steps in the pathway and stimulate a reactive increase in PRA. ACE inhibitors also increase levels of Ang I, while ARBs increase both Ang I and Ang II.1 With long-term ACE inhibition, Ang I can be converted to Ang II via ACE-independent mechanisms.1 A theoretic difference for renin inhibitors is that they may provide more comprehensive inhibition of the renin-angiotensin system (RAS) compared with ACE inhibitors and ARBs and may have a different safety profile than these agents.
Clinical trials have shown that aliskiren reduces blood pressure (BP) in patients with hypertension when given alone or in combination with other antihypertensive therapies.2–11 Moreover, aliskiren has been shown to induce reductions in albuminuria in diabetic nephropathy,2 B-type natriuretic peptide levels in heart failure,3 and left ventricular mass in hypertensive patients with left ventricular hypertrophy.4 In preregistration clinical trials, the safety profile of aliskiren was similar to that of placebo.2–11 However, because RAS blockers have been associated with cough,12,13 angioedema,12 and hyperkalemia,14,15 post-approval monitoring of these events has been required for aliskiren.
In 2006, a global safety oversight committee was formed to analyze and review all safety data related to the administration of aliskiren in patients with hypertension and related comorbid populations. The safety data were pooled from all short-term placebo-controlled and long-term active-controlled aliskiren clinical trials. We report our findings from these data on more than 12,000 patients.