Direct renin inhibitors in hypertension – Approaching the moment of truth

The renin–angiotensin–aldosterone system (RAAS) is central to blood pressure (BP) control, and chronic activation of the system, as occurs in some hypertensive patients, leads to damage of target organs (e.g. the heart and kidneys) and perpetuates BP elevation (1,2). The well-explored pharmacological inhibitors of the RAAS, including angiotensin II receptor blockers (ARB), angiotensin-converting enzymes (ACE) inhibitors (ACEI) and aldosterone antagonists (AA), have contributed significantly to the success of cardiovascular pharmacotherapy during the past decades (3). While ACEI, ARB and AA therapies are well explored and accepted interventions in cardiovascular medicine, direct renin inhibitors (RI) were slower to develop. Early attempts to develop clinically useful and tolerable RIs were hampered by problems of high cost of synthesis, poor oral bioavailability, short plasma half-lives and lack of expected clinical efficacy (2). Despite these difficulties, attempts to develop clinically effective RIs continued because of the perceived advantage of inhibiting the RAAS at its point of activation, thus totally abolishing downstream events (4). An additional expectation was that RIs should be associated with a low risk of adverse events, since renin has high specificity for angiotensinogen, its only naturally occurring substrate (5).

Aliskiren, which was developed as the first orally effective RI for the treatment of hypertension (2,6,7), is a highly specific inhibitor of human renin. Aliskiren has been shown to have good BP lowering efficacy in a broad spectrum of hypertensive patients (2). Beyond BP lowering, the ASPIRE HIGHER clinical assessment programme was designed to assess the extent to which aliskiren prevents or reverses target organ damage in hypertensive patients with diabetic nephropathy or obesity. This programme originally comprised three outcome studies assessing the effect of direct RI with aliskiren in patients with pre-hypertension (AVIATOR), type 2 diabetes patients with hypertension (ALTITUDE) and post-MI patients with renal dysfunction (ASPIRE) (2). Later a large outcome trial in elderly hypertensive persons (APOLLO) was organized.

ALTITUDE was designed as a 4-year multinational randomized, double-blind, placebo-controlled study to evaluate the potential benefits of aliskiren in reducing the risk of fatal and non-fatal cardiovascular and renal outcomes in high risk patients with type 2 diabetes. Most patients enrolled in the study had BPs that were controlled at baseline. To these patients, aliskiren 300 mg or corresponding placebo was given in addition to standard of care, which included an ACE inhibitor or ARB. The primary endpoint of ALTITUDE was the first occurrence of one of the following events: cardiovascular death, resuscitated sudden death, non-fatal myocardial infarction, non-fatal stroke, unplanned hospitalization for heart failure, doubling of baseline serum creatinine concentration to above the upper limit of normal (sustained for at least 1 month) and onset of end-stage renal disease or renal death.

Based on interim results from ALTITUDE announced in January 2012 (8), Novartis, the manufacturer of Aliskiren (9), issued a black box warning advising physicians not to prescribe aliskiren or aliskiren-containing fixed combination products together with ACE inhibitors or ARBs to patients with diabetes. Physicians were further advised to stop aliskiren-containing treatment in patients who were diabetic and also taking an ACE inhibitor or an ARB.

On 26 August 2012, at the ESC conference in Munich, the final results of ALTITUDE were presented. Based on the January 2012 letter from the sponsor, a more detailed explanation of why the study was stopped for safety reasons was anticipated. However, statistical futility of finding significant benefit from aliskiren treatment was presented as the main cause of stopping ALTITUDE. The final cohort included 8561 patients, half of whom were allocated to aliskiren and half to the corresponding placebo. The composite primary endpoint occurred in 767 patients in the aliskiren group (17.9%) and in 721 patients (16.8%) in the placebo group (HR 1.08, 95% CIs 0.98–1.20, p0.14). Stroke occurred in 146 patients in the aliskiren group (3.4%) and 118 patients in the placebo group (2.7%) (HR 1.25, 95% CIs 0.98–1.60, p0.07). Renal endpoints were not significantly different between groups, but albuminuria decreased significantly (14%) in aliskiren-treated patients. However, there were significantly greater increases in serum potassium (8.8 vs 5.6%) and more patients suffered from hypotension (12.1 vs 8.0%) in the aliskiren group compared with the control group.

An important message from ALTITUDE is that using aliskiren with ACE inhibitors or ARBs in high-risk patients cannot be recommended and may even be harmful. Although the results of ALTITUDE may be chance findings, many would argue that the harmful outcomes seen in the aliskiren arm could be direct effects of aliskiren itself. One argument in support of a direct aliskerin effect rather than an effect related to dual RAAS inhibition is that the potential negative effects on stroke incidence were not seen in ONTARGET with the combination of the ACE inhibitor ramipril and the ARB telmisartan compared with each drug given as monotherapy.

Other studies in the ASPIRE HIGHER clinical assessment programme have also failed to provide evidence of outcome benefits of aliskiren treatment. ASPIRE was presented at the American College of Cardiology meeting in Atlanta in 2010 and showed that aliskiren vs placebo did not improve left ventricular function in patients with recent myocardial infarction (n820) when given on top of ACEI or ARB. AVIATOR was stopped before randomization began for reasons that were never fully explained. APOLLO was aborted in the aftermath of AVIATOR and combination of aliskiren with other RAAS blockers is now discouraged (see above).

Much further discussion in the medical community, as well as further analyses of the effects of aliskiren on cardiovascular and renal outcomes in various patient populations, are expected to inform and modify the extent to which the disappointing results from ALTITUDE will change the way aliskerin is used in clinical practice.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.