The ASPIRE-HIGHER program was introduced as the largest outcomes program in the CV field, with more than 35,000 patients in 14 clinical trials. This section summarizes the concluded trials of the ASPIRE-HIGHER program.
The AVOID (Aliskiren in the Evaluation of Proteinuria in Diabetes) study was designed to investigate the renoprotective effects of dual RAAS blockade with aliskiren and losartan combination treatment. The results of this study have shown that the addition of 300 mg aliskiren to optimal antihypertensive therapy (including 100 mg losartan) significantly reduced the mean urinary albumin–creatinine ratio by 20% compared with the addition of placebo (95% CI 9–30; p
< 0.001). Furthermore, there were similar BP reductions between the groups (SBP: 2 mmHg lower, p
= 0.07; DBP: 1 mmHg lower, p
= 0.08 in the aliskiren group) [Parving et al. 2008
]. The results show that the renoprotective effect of aliskiren is independent of BP.
The ALOFT (the Aliskiren Observations of Heart Failure Treatment) study addressed the change in brain natriuretic peptide (BNP) and its precursor N-terminal (NT)-BNP in patients with heart failure (HF). When aliskiren was added to standard therapy in patients with HF and hypertension, it resulted in a significant reduction in BNP, NT-prohormone of BNP (NT-proBNP) and urine aldosterone levels compared with those of placebo. However, discontinuations related to the primary endpoint (renal dysfunction, symptomatic hypotension or hyperkalemia) and worsening HF did not differ in both groups (two patients with hypotension, one with hyperkalemia and one with worsening HF in those on aliskiren and three with worsening HF in patients receiving placebo). The most common adverse effects seen in the aliskiren arm were nasopharyngitis (3.8%), asthenia (3.2%), diarrhea (3.2%), hyperuricemia (3.2%), nausea (3.2%) and hypotension (3.2%) [McMurray et al. 2008
]. Consequently, the results of the ALOFT study have shown that addition of aliskiren to standard therapy has favorable neurohumoral effects with good tolerability and thus could be beneficial in reducing CV mortality and morbidity in patients with HF. However, the ALOFT study results were in contradiction to the results of a recent study, the AVANT-GARDE study, although this study was performed in a different population and this fact should be taken into account.
The AVANT-GARDE (Aliskiren and Valsartan Versus
Placebo in Lowering NT-proBNP in Patients Stabilized Following an Acute Coronary Syndrome) study was designed to evaluate the effects of direct renin inhibition in 1101 patients stabilized after acute coronary syndrome (ACS) without clinical evidence of HF or left-ventricular function up to 40%. The change in NT-proBNP, from baseline to week 8, was assessed as the primary endpoint. The reduction of NT-proBNP levels was similar: 42%, 44%, 39% and 36% for the placebo, aliskiren, valsartan and combination arm respectively. Moreover there were more serious adverse events reported in all three active treatment arms compared with placebo (overall 9.4% for placebo versus
14.4% for all active therapy groups combined, p
= 0.03). The two most common adverse events leading to study drug discontinuation with no significant difference in all study groups were hyperkalemia and hypotension [Scirica et al. 2010
The ALLAY (Aliskiren in Left Ventricular Hypertrophy) study was designed to evaluate the effect of aliskiren on left-ventricular hypertrophy (LVH) in patients with hypertension compared with losartan or their combination therapy. The results suggested that aliskiren was as effective as losartan in reducing LVH (p
< 0.0001 for noninferiority). However, all three groups provided similar reductions in LVH from baseline (5.4%, 4.7% and 6.4% reductions in the aliskiren, losartan and combination arms respectively). The reduction in LVH in the combination group was not significantly different from that with losartan alone (p
= 0.52) [Solomon et al. 2009
The ASPIRE study compared the addition of aliskiren to standard optimal therapy against standard optimal therapy alone in 820 patients after myocardial infarction (MI) with the left-ventricular ejection fraction (LVEF) less than 45%. The primary endpoint was change in left-ventricular end-systolic volume from baseline to 36 weeks. There was no significant reduction in left-ventricular end-systolic volume with the addition of aliskiren (4.4 ± 16.8 ml reduction with aliskiren versus
3.5 ± 16.3 ml with placebo, p
= 0.44). Also there were no differences in rates of any efficacy variables, including composite of CV death, hospitalization for HF with LVEF reduction of more than 6 units, or with stroke, recurrent MI and resuscitated sudden death (p
= 0.85 and 0.98 respectively). The rates of all-cause mortality were also similar in both treatment arms (2% in placebo, 4% in aliskiren arm, p
= 0.22). Although similar serious adverse effects were reported in both treatment arms, more adverse effects like renal dysfunction (2.4% versus
= 0.09), hypotension (8.8% versus
= 0.02) and hyperkalemia (5.2% versus
= 0.001) were reported with the addition of aliskiren than with placebo [Solomon et al. 2011
The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-renal Disease Endpoints) trial studied the effects of aliskiren in addition to ACEI or ARB therapy in patients with diabetes and renal disease (glomerular filtration rate < 60 ml/min per 1.73 m2
or microalbuminuria). The primary endpoints of the study were time to first event for the composite endpoint of CV death, resuscitated death, myocardial infarction, stroke, unplanned hospitalization for HF, onset of end-stage renal disease or doubling of baseline serum creatinine concentration [Parving et al. 2009
]. However, the study was halted prematurely by the safety monitoring board due to increased adverse events, including nonfatal stroke, renal dysfunction, hyperkalemia and hypotension, with no apparent benefit. The major concern was increased stroke with aliskiren in comparison to placebo (2.6% versus 2%, unadjusted p
= 0.04) [McMurray et al. 2012
]. Based on these findings, dual aliskiren and ACEI/ARB therapy is not recommended in patients with hypertension and diabetes or at least moderate renal dysfunction.
The ASTRONAUT (Six Months Efficacy and Safety of Aliskiren Therapy on Top of Standard Therapy, on Morbidity and Mortality in Patients with Acute Decompensated Heart Failure) trial has recently completed. The trial investigated whether aliskiren, when added to standard therapy, would reduce the rate of CV death or HF rehospitalization at 6 or 12 months in patients with acute decompensated HF. In total, 1639 patients were randomized to aliskiren or placebo. At 6 months, 24.9% of the aliskiren group (77 CV deaths, 153 HF rehospitalizations) and 26.5% of the placebo group (85 CV deaths, 166 HF rehospitalizations) experienced the primary endpoint [hazard ratio (HR) 0.92; 95% CI 0.76–1.12; p
= 0.41]. At 12 months, the event rates were 35.0% for the aliskiren group (126 CV deaths, 212 HF rehospitalizations) and 37.3% for the placebo group (137 CV deaths, 224 HF rehospitalizations) (HR 0.93; 95% CI 0.79–1.09; p
= 0.36). The rates of hyperkalemia, hypotension and renal failure were higher in the aliskiren group compared with the placebo group. As a consequence, among patients hospitalized for HF with reduced LVEF, initiation of aliskiren in addition to standard therapy did not reduce CV death or HF rehospitalization at 6 months or 12 months after discharge [Gheorghiade et al. 2013
The other currently ongoing trials of the ASPIRE-HIGHER program are summarized briefly below.
The ATMOSPHERE trial, to evaluate the efficacy and safety of aliskiren and aliskiren/enalapril combination on morbi-mortality in patients with CHF, is planned to enroll over 5000 patients who have class II–IV congestive heart failure (CHF) with ejection fraction (EF) less than 35%. Monotherapy with aliskiren or enalapril or their combination therapy will be compared. The primary endpoint is delaying time to first occurrence of either CV death or HF hospitalization in patients with CHF. The duration of the study is 4 years and the estimated study completion date is August 2014.
The APOLLO (A Randomized Controlled Trial of Aliskiren in the Prevention of Major CV Events in Elderly People) trial will provide new information about the role of aliskiren with or without additional therapy with HCTZ or amlodipine in 1758 elderly patients (≥ 65 years) with SBP 130–159 mmHg in preventing major CV events such as CV death, nonfatal MI, nonfatal stroke and significant HF.
The AQUARIUS (Safety and Efficacy of Aliskiren on the Progression of Atherosclerosis in Coronary Artery Disease Patients) trial will assess the change in coronary atherosclerotic disease as determined by intravascular ultrasound (IVUS) for aliskiren compared with placebo when given in addition to standard therapy in approximately 592 patients with coronary artery disease and a BP in the prehypertensive range. The duration of the study was 104 weeks and the estimated study completion date was January 2013, but the results of the study not yet published.