Drugs that block a hormonal cascade, known as the renin-angiotensin-aldosterone system (RAAS), help patients with heart failure. Direct renin inhibitors (DRIs) block the RAAS at its first and rate-limiting step. As a result, all downstream products in the RAAS cascade are suppressed and DRIs are specific for the RAAS. Both these properties differentiate DRIs from angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs).
We examined the tolerability and safety of the first clinically available orally acting DRI, aliskiren, in a randomised placebo-controlled trial in heart failure. In the ALiskiren Observation of heart Failure Treatment study (ALOFT) we enrolled 302 patients with New York Heart Association (NYHA) class II-IV heart failure with current or prior hypertension and a plasma B-type natriuretic peptide (BNP) concentration > 100 pg/mL from 73 sites in 9 countries. Patients had to be optimally treated with an ACE-I or ARB and a beta-blocker, unless contraindicated or not tolerated. Patients were studied for 3 months.
Although primarily a safety and tolerability study, a variety of “efficacy” measurements were made. The first three of these were to study the effect of aliskiren, compared to placebo, on N terminal pro BNP, BNP and aldosterone. Compared to placebo, aliskiren reduced plasma NT-pro BNP by 25 (95%CI 6-39)%, p=0.0106; plasma BNP by 25 (5-41)%, p=0.0160 and urinary aldosterone by 21(4-34)%, p=0.0150. There was also a favourable change in a Doppler-echocardiographic measure of left ventricular filling pressure. Aliskiren was well tolerated and there was no significant excess of hypotension or renal dysfunction.
In summary, this first sizeable, placebo-controlled, trial with aliskiren, the lead agent in the new class of orally active DRIs showed favourable neurohumoral and other effects in otherwise optimally treated patients with heart failure. These promising initial findings support further evaluation of aliskiren as a possible future treatment for heart failure.