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Ther Adv Chronic Dis. Sep 2013; 4(5): 232–241.
PMCID: PMC3752183
Aliskiren: review of efficacy and safety data with focus on past and recent clinical trials
Selçuk Şen,corresponding author Soner Sabırlı, Tolga Özyiğit, and Yağız Üresin
Selçuk Şen, Department of Pharmacology, Istanbul Faculty of Medicine, Turgut Ozal Street 34390, Capa, Istanbul, Turkey;
corresponding authorCorresponding author.
slcsen/at/istanbul.edu.tr
Aliskiren is the newest antihypertensive drug and the first orally active direct renin inhibitor to become available for clinical use. Clinical data have substantiated that the antihypertensive effectiveness of aliskiren is similar to that of the other major antihypertensive agents. Furthermore, aliskiren has a similar safety profile to placebo. Combination treatment with aliskiren showed significant blood pressure and proteinuria reductions compared with monotherapy. Aliskiren decreases plasma renin activity in contrast to other renin–angiotensin–aldosterone related drugs. The efficacy of aliskiren in treating major cardiovascular events and the prevention of end-organ damage are being investigated in the ASPIRE HIGHER program. Although the first studies of the ASPIRE HIGHER program such as ALOFT, AVOID, AGELESS showed favorable findings, ASPIRE and AVANT-GARDE studies provided contradictory results. Subsequently, the ALTITUDE study was terminated early because of safety issues and lack of beneficial effects. Most recently, the ASTRONAUT trial showed no reduction in cardiovascular death or heart failure rehospitalization with the addition of aliskiren to standard therapy in patients who were hospitalized for heart failure and with reduced left-ventricular ejection fraction. The results of ongoing studies in other patient groups such as the ATMOSPHERE trial are awaited.
Keywords: aliskiren, hypertension, renin inhibitor
Aliskiren, the first orally active direct renin inhibitor, was approved by the US Food and Drug Administration in March 2007. It has demonstrated effective blood pressure (BP) control and is generally well tolerated as monotherapy or in combination with other antihypertensive drugs [Frampton and Curram, 2007]. Aliskiren is a potent inhibitor of renin, thereby inhibiting the renin–angiotensin–aldosterone system (RAAS) at its rate-limiting step by reducing the plasma renin activity (PRA).
As with other antihypertensive agents that target the RAAS, such as angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme inhibitors (ACEIs), aliskiren interferes with the negative feedback loop of the RAAS, thus stimulating a reactive rise in plasma renin concentration (PRC) [Azizi et al. 2006]. The major difference with aliskiren is that it decreases the PRA levels despite the increase in PRC, whereas the other antihypertensive drugs increase the PRA, except β blockers [Gradman and Traub, 2007]. Thus, low baseline PRA levels or inadequate reduction or reactive increase in PRA levels might reduce the treatment efficacy of aliskiren [Stanton et al. 2009].
We know that there is an association between high PRA and cardiovascular (CV) risk [Alderman et al. 1991, 1997] and also greater BP control provides greater reductions in CV events [Turnbull, 2003]. Therefore, reaching target BP levels is the main target of antihypertensive therapy. Aliskiren has proven its effectiveness in reducing BP in patients with hypertension when given as monotherapy or in combination with other antihypertensive drugs. However, the long terminal elimination half life of aliskiren, which is approximately 40 h, provides a sustained BP reduction over the entire 24 h period [Verdecchia et al. 2010].
Aliskiren is generally well tolerated, with a placebo-like profile at doses of 150 and 300 mg. The hepatic elimination of aliskiren also makes this drug suitable for patients with impaired renal function. Moreover, aliskiren does not interfere with several agents, including warfarin and statins. Pregnancy and bilateral renal artery stenosis are the two main contraindications in using aliskiren.
This review summarizes the place of aliskiren in hypertension management, its use as either monotherapy or in combination, its effectiveness in preventing end-organ damage, and current issues on dual RAAS blockage with aliskiren, in the light of recent studies.
In a study by Gradman and coworkers, 652 patients with mild to moderate hypertension were randomized to receive double-blind treatment with once-daily oral doses of aliskiren (150 mg, 300 mg or 600 mg), irbesartan 150 mg or placebo. Systolic BP (SBP) and diastolic BP (DBP) were significantly decreased in patients receiving once-daily treatment with aliskiren (150 mg, 300 mg and 600 mg) compared with those receiving placebo (p < 0.001). The antihypertensive effect of aliskiren 150 mg was comparable to that of irbesartan 150 mg (9.3 ± 0.8 and 11.4 ± 1.3 versus 8.9 ± 0.7 and 12.5 ± 1.2 mmHg reduction in mean DBP and SBP, respectively). Aliskiren 300 mg and 600 mg lowered mean DBP (11.8 ± 0.8 and 11.5 ± 0.8 mmHg, respectively) significantly more than irbesartan 150 mg (p < 0.05). However, the dose–response curve for aliskiren reached a plateau at 300 mg, with no further significant DBP or SBP reductions observed at 600 mg. Furthermore, aliskiren treatment was well tolerated at all doses administered in the same study. The most common adverse effects reported were headache, dizziness and diarrhea. The incidence of headache was 2.4%, 6.2% and 4.6% with aliskiren 150, 300 and 600 mg respectively compared with 5.3% of patients treated with placebo and 3.0% of patients treated with irbesartan 150 mg. Dizziness was reported by a total of 19 patients (2.9%) and diarrhea by 16 patients (2.5%) during the study [Gradman et al. 2005].
In several clinical studies, aliskiren monotherapy has shown similar or slightly higher antihypertensive effectiveness compared with that of hydrochlorothiazide (HCTZ), amlodipine, ramipril, valsartan, irbesartan or losartan monotherapies [Gradman et al. 2005; Uresin et al. 2007; Oparil et al. 2007; Schmieder et al. 2009; Andersen et al. 2008; Solomon et al. 2009; Brown et al. 2011; Duprez et al. 2008]. In a pooled analysis of three studies, which compared aliskiren and ramipril monotherapies, overall SBP was lower with aliskiren than with ramipril (weighted mean difference between the treatments 1.84 mmHg, fixed effect model, p < 0.0001; and 1.87 mmHg, random effect model, p = 0.0055) [Verdecchia et al. 2010].
In a randomized double-blind clinical study comparing the 24 h mean ambulatory BP reductions from baseline after a missed dose of aliskiren, ramipril or irbesartan in 654 patients with hypertension, the antihypertensive effect of aliskiren 300 mg persisted for more than 24 h. Aliskiren showed greater maintenance of the BP lowering effect (91/91% of the mean ambulatory SBP and DBP respectively) than the irbesartan 300 mg (73/77%) and ramipril 10 mg (64/65%) treatment arms [Palatini et al. 2010]. These data provide further evidence that aliskiren monotherapy provides a sustained BP reduction over 24 h, probably due to the longer terminal elimination half life of aliskiren (about 40 h).
Aliskiren has a favorable tolerability profile in the hypertensive population, including older patients. In a recent meta-analysis, White and coworkers pooled data from 12 randomized controlled trials with aliskiren in more than 12,000 patients with hypertension. They analyzed the incidence of adverse effects with aliskiren compared with those with ACEI and ARB treatments. In the long-term studies, the incidence of adverse effects observed with 150 and 300 mg of aliskiren were 33.7% and 43.2% respectively, significantly lower than those with ACEIs (60.1%) and ARBs (53.9%). Serious adverse effects with aliskiren monotherapy occurred slightly more than those with ACEIs but significantly less than those with ARBs (3.4%, 2.4% and 8.4% respectively). Hypotension (7.6%) and peripheral edema (4.8%) were the most common adverse effects observed with aliskiren. The incidence of angioedema and urticaria was quite low (0.4%) and the incidence of cough was 3.7%, which is lower than that seen with ACEIs (12%). The other rare adverse effects seen with aliskiren were renal dysfunction (0.4%) and hyperkalemia (0.1%). Furthermore, treatment with 600 mg of aliskiren was reported to be associated with diarrhea [White et al. 2010].
Patients with hypertension mostly need combination therapy, including two or more antihypertensive drugs to reach target BP levels. Therefore, current treatment guidelines recommend that combination therapy should be considered as a priority for patients who have high initial BP [Chobanian et al. 2003; Mancia et al. 2007]. The antihypertensive efficacy of aliskiren is increased by combining it with drugs that produce a reactive increase in PRA, such as diuretics, ACEIs and ARBs [Andersen et al. 2008; Oparil et al. 2007; Villamil et al. 2007; Uresin et al. 2007; Gradman et al. 2005]. In this section, studies of aliskiren in combination with HCTZ, ACEIs, ARBs and calcium channel blockers (CCBs) are summarized.
Aliskiren, which is longer acting in comparison with HCTZ, may be advantageous. In a large comparative study by Schmieder and colleagues, aliskiren provided a significantly greater BP reduction than HCTZ, which has a half life of only 6–9 h after a single dose and 8–15 h after chronic dosing [Schmieder et al. 2009]. The long duration of action of aliskiren is also consistent with the maintenance of its antihypertensive effect following a missed dose. In a randomized study with 24 h ambulatory BP monitoring, aliskiren maintained more than 90% of its antihypertensive effect after a missed dose versus 73–77% with irbesartan and 64–65% with ramipril [Palatini et al. 2010].
In a trial by Villamil and colleagues, 2776 patients with hypertension were randomized to receive aliskiren (75 mg, 150 mg or 300 mg), HTCZ (6.25 mg,12.5 mg or 25 mg), their combination or placebo for 8 weeks. Combination treatment was superior to both monotherapies in reducing mean DBP (p < 0.0001) and mean SBP (p < 0.05), with the exception of aliskiren/HCTZ 75 mg/12.5 mg versus HCTZ monotherapy. Aliskiren monotherapy reduced PRA by up to 65% from baseline whereas HCTZ monotherapy increased PRA up to 72%. However, when HCTZ was combined with aliskiren, decreases in PRA of 46.1–63.5% were observed [Villamil et al. 2007]. In a different study, aliskiren/HCTZ combination at a dose of 300 mg/25 mg or 300 mg/12.5 mg provided significantly greater SBP/DBP reductions (15.9/11.0 mmHg and 13.5/10.5 mmHg respectively) than aliskiren 300 mg alone (8.0/7.4 mmHg; both p < 0.001). Moreover aliskiren/HCTZ combination treatment showed similar tolerability to aliskiren monotherapy [Nickenig et al. 2008]. Aliskiren/HCTZ combination treatment at doses of 300 mg/25 mg and 150 mg/25 mg both improved BP control rates in patients whose condition was nonresponsive to HCTZ 25 mg alone (58%, 49% versus 26%; both p value < 0.001) in a clinical trial in which 722 patients with hypertension were randomized for 8 weeks [Blumenstein et al. 2009].
The efficacy, safety and tolerability of combination therapy with aliskiren and ACEIs have also been tested in several studies. In the study by Uresin and colleagues, treatment with aliskiren/ramipril combination for 8 weeks produced significantly greater reductions in mean DBP than either aliskiren (p = 0.043) or ramipril (p = 0.004) monotherapy, and also in mean SBP than ramipril (p < 0.0001), but not aliskiren (p = 0.088). For the change in mean SBP, aliskiren monotherapy was found to be superior (p = 0.021) to ramipril. Furthermore there was no statistically significant tolerability and safety difference between the treatment arms. The most common adverse effects with aliskiren monotherapy were headache (3.2%), cough (2.1%), nasopharyngitis (3.2%) and diarrhea (1.1%). Although cough is not uncommon with the use of ramipril (4.7%), it was reported in only 1.8% of patients in the aliskiren/ramipril combination arm. However, hyperkalemia was reported more often in the combination group (5.5%) than in those receiving monotherapy with aliskiren (2.2%) or ramipril (2.6%). The rate of significant increase in serum creatinine levels was quite low in all groups [Uresin et al. 2007].
In a clinical study, after 26 weeks of an active treatment period, ramipril-based therapy and aliskiren-based therapy were compared in a 4-week blind withdrawal phase. During the withdrawal period, BP was rapidly increased with ramipril-based therapy rather than aliskiren-based therapy [Andersen et al 2008]. In the study by Duprez and colleagues, decreases from baseline mean SBP and mean DBP with aliskiren monotherapy (−14.0 and −5.1 mmHg respectively) were noninferior (p < 0.001 for both values) and superior to ramipril monotherapy (−11.6, −3.6 mmHg; p = 0.02, p < 0.01 respectively) in older patients with hypertension (aged ≥65 years) and more patients achieved BP control with aliskiren (42%) than with ramipril (33%; p < 0.01) [Duprez et al. 2010].
Combination therapy with aliskiren and various ARBs has also been investigated in different clinical studies [Oparil et al. 2007; Pool et al. 2007; Parving et al. 2008; Nakamura et al. 2011]. A randomized clinical trial in 1797 patients with hypertension was performed to examine the antihypertensive effect of aliskiren and valsartan alone or in combination. The mean DBP was significantly reduced with the highest dose combination (300 mg of aliskiren and 320 mg of valsartan) than either monotherapy (12.2 mmHg decrease with combination versus 9.0 mmHg with aliskiren 300 mg, p < 0.0001; 9.7 mmHg with valsartan 320 mg, p < 0.0001 and 4.1 mmHg decrease with placebo, p < 0.0001), without any increase in the rate of adverse effects. Incidents of hyperkalemia and increased serum creatinine levels were similar in all groups and did not demand discontinuation of treatment [Oparil et al. 2007].
In the ACCELERATE (Aliskiren and the CCB Amlodipine Combination as an Initial Treatment Strategy for Hypertension Control) study, patients were randomized to treatment with aliskiren 150 mg plus placebo (n = 315) or 5 mg amlodipine plus placebo (n = 315) or 150 mg aliskiren plus 5 mg amplodipine (n = 617). Within 8–16 weeks the dose was doubled to aliskiren 300 mg or amlodipine 10 mg or aliskiren 300 mg plus amlodipine 10 mg. Within 16–32 weeks all patients were given therapy with 300 mg aliskiren plus 10 mg amlodipine. At week 24, HCTZ or placebo was added to the therapy if BP was uncontrolled. Patients given initial combination therapy had a 6.5 mmHg [95% confidence interval (CI) 5.3–7.7] greater reduction in mean SBP than the monotherapy groups (p < 0.0001). Peripheral edema was the most common reason for withdrawal from therapy, with the 11.4% discontinuation rate in the initial amlodipine group twice that of the other groups. Hypotension was reported as an adverse event for five (0.8%) patients in the combination group, one (0.3%) in the aliskiren group and two (0.6%) in the amlodipine group [Brown et al. 2011].
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 0.8%, p = 0.09), hypotension (8.8% versus 4.5%, p = 0.02) and hyperkalemia (5.2% versus 1.3%, p = 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.
In 2003, the CHARM-added trial (Effects of Candesartan in Patients with CHF and Reduced Left-ventricular Systolic Function Taking Angiotensin-converting-enzyme Inhibitors) showed that the addition of candesartan to an ACEI in patients with HF leads to a significant reduction in CV events, including CV death or hospital admissions for worsening HF. In the same year, the COOPERATE trial (Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-converting-enzyme Inhibitor in Nondiabetic Renal Disease) suggested that combination therapy in comparison with monotherapy safely retards the progression of nondiabetic renal disease. Both of those trials encouraged the use of dual RAAS blockade in patients with HF or nondiabetic renal disease [McMurray et al. 2003; Nakao et al. 2003]. However, in 2008, the results of the ONTARGET trial (Renal Outcomes with Telmisartan, Ramipril, or Both, in People at High Vascular Risk) revealed that although combination therapy with ramipril and telmisartan reduced proteinuria more than monotherapy, the number with secondary renal outcomes, dialysis or doubling serum creatinine was higher with this combination therapy [Mann et al. 2008]. These findings sparked an argument concerning the use of dual RAAS blockade and skepticism on surrogate endpoints, such as microalbuminuria.
Combination therapy with a direct renin inhibitor, thus decreasing the PRA, added to the other blockers of the system, which increase PRA, is a promising way of dual RAAS blockade. Indeed, aliskiren in combination with ACEIs or ARBs showed significantly greater BP reduction than monotherapy alone in a few trials, as previously discussed. However, the ASPIRE study, and more recently, the ALTITUDE study revealed somewhat disappointing results as discussed above. In both of these studies, adverse events were seen more frequently with dual RAAS blockade including aliskiren. However, the two meta-analyses did not show a significant rise in adverse events with dual RAAS blockade including aliskiren. White and colleagues pooled the safety data from 13 randomized, double-blind clinical trials of which nine were short-term (8-week) studies and assessed the safety of aliskiren in combination with ARBs or HCTZ in more than 12,000 patients. In the short-term studies, the rates of reported serious adverse events (defined as fatal or life threatening, resulting in persistent or significant disability or incapacity, constituting a congenital anomaly or birth defect, requiring inpatient hospitalization or prolongation of existing hospitalization, or is otherwise medically significant) were similar in patients who received aliskiren in combination with valsartan (0.6%), aliskiren monotherapy (150 mg, 0.5%; 300 mg, 0.4%), ARB monotherapy including valsartan, irbesartan, losartan (0.8%) or placebo (0.7%). However, the incidence of serious adverse events with aliskiren/HCTZ combination therapy (1.1%) was similar to that with HCTZ monotherapy (0.9%) and slightly higher than that with aliskiren monotherapy (150 mg, 0.5%; 300 mg, 0.4%) or placebo (0.7%). In the longer-term studies, combination therapy with aliskiren/losartan resulted in fewer serious adverse events than losartan monotherapy and a similar incidence to aliskiren monotherapy (5.2%, 8.4%, and 3.4% respectively). Moreover, the incidence of serious adverse events did not differ in patients who received aliskiren/HCTZ combination therapy (2.5%) or each of the individual monotherapies (3.4% and 1.7% for aliskiren and HCTZ monotherapy respectively). The other most common adverse events related to combination therapy of aliskiren with HCTZ, valsartan and losartan were headache (6.5%, 4.5% and 6.5% respectively), nasopharyngitis (3.8%, 2.4% and 7.1% respectively), diarrhea (1.6%, 1.4% and 4.5% respectively) and dizziness (2.3%, 1.6% and 5.2% respectively) [White et al. 2011].
Although the findings indicate that using aliskiren in combination with either HCTZ or ARBs would be perfectly safe, another meta-analysis reported the risk of hyperkalemia and suggested carefully monitoring serum potassium levels with dual RAAS blockade using aliskiren. This meta-analysis included 10 randomized controlled studies with 4814 enrolled participants. The results showed that combination therapy with aliskiren and ACEIs or ARBs significantly increased the risk of hyperkalemia compared with ACEI/ARB monotherapy (relative risk 1.58, 95% CI 1.24–2.02) or aliskiren alone (1.67, 1.01–2.79). The risk of acute kidney injury did not differ significantly between the combination therapy and monotherapy groups (1.14, 0.68–1.89) [Harel et al. 2012].
The populations of the studies discussed above are more or less distinct from each other. The main study population of the CHARM study included patients with advanced HF, while the ON-TARGET study population consisted of patients with established atherosclerotic vascular disease or diabetes with end-organ damage. The ALTITUDE study included patients with type 2 diabetes at high risk of fatal or nonfatal CV and renal events, and ASPIRE was a post-MI study. Thus, the results of each study should be evaluated in their own context and not under the common concept of dual RAAS blockade. For now we may conclude that dual RAAS blockade with either an ACEI/ARB combination or a combination of the direct renin inhibitor aliskiren with any of them does not seem beneficial for patients with diabetes or those who have had a MI when the additional risks which are natural consequences of such a combination such as hypotension or hyperkalemia are considered. However, in the light of meta-analyses showing no additional burden for the pooled populations, the results of ongoing studies should be awaited for conclusions relating to patients with other indications.
The Aliskiren Trial of Minimizing Outcomes for Patients with Heart Failure (ATMOSPHERE) study results will evaluate and clarify the effect of both aliskiren and enalapril monotherapy and aliskiren/enalapril combination therapy on important clinical outcomes such as CV death and HF hospitalization in patients with chronic systolic HF, New York Heart Association functional class II–IV symptoms, and elevated plasma levels of BNP [Krum et al. 2011]. The findings of the ATMOSPHERE study may bring some insight to the use of dual RAAS blockade with aliskiren in patients with HF. Furthermore the patient population of ATMOSPHERE is different to that of ALTITUDE. Whereas 29% of the patients randomized in ATMOSPHERE have diabetes, all of the ALTITUDE study participants have diabetes. Importantly just 11% of patients had HF and only 62 patients had an EF less than 35% in ALTITUDE. The median baseline SBP levels of the patients in ALTITUDE and ATMOSPHERE are 135 and 120 mmHg respectively. One of the key differences between the two studies lies in the estimated glomerular filtration rate (eGFR). Patients with an eGFR less than 35 ml/min/1.73 m2 were excluded from ATMOSPHERE. Also, ATMOSPHERE is a study which has open-label active run-in periods [McMurray et al. 2012]. Although the risk of some adverse events such as hyperkalemia and hypotension may be present, characteristics of the ATMOSPHERE study population and design ensure avoidance of serious adverse events such as CV death, resuscitated death, MI, unplanned HF hospitalization, end-stage renal disease or renal death, or doubling of baseline serum creatinine.
Previous experience has shown the beneficial effects of dual RAAS blockade in patients with HF, for example, the CHARM-added study. Dual RAAS blockade with the addition of valsartan to optimal HF therapy has demonstrated beneficial effects in the Val-HeFT study [Cohn and Tognoni, 2001]. Although it cannot be concluded that dual RAAS blockade has beneficial effects in patients with diabetes or in those after an MI, in the light of recent studies, patients with HF may be a potential population to derive benefit from dual RAAS blockade. However, independently from the other factors and in contrast to other RAAS blockers, aliskiren can provide beneficial effects for patients with HF by reducing PRA levels.
While most of the trials that studied the effectiveness and safety of aliskiren as either monotherapy or in combination with other antihypertensive drugs in the treatment of hypertension have shown encouraging results, there is still a lack of data regarding improved hard endpoints. However, recently the ALTITUDE trial has fueled concerns, mainly due to increased incidence of stroke with the use of aliskiren in patients with diabetes or moderate to severe renal dysfunction. Although aliskiren has not been associated with increased serious adverse events according to most study results, except the ALTITUDE trial, hyperkalemia should be taken into consideration, especially in the use of combination therapy with ACEIs or ARBs.
Despite these reservations, aliskiren has some unique advantages, which could make it favorable compared with other medications. For instance, aliskiren has a unique PRA reduction capacity, differing from other antihypertensive drugs such as ACEIs and ARBs. Furthermore, aliskiren has a long terminal elimination half life, as long as 40 h, providing sustained BP control over 24 h. Moreover, hepatic elimination could put this medicine one step ahead of other drugs in some cases.
Regarding dual RAAS blockade, after the results of the ONTARGET study were reported, a debate occurred on study design and surrogate endpoints. The ALTITUDE study, which was designed using hard endpoints such as CV death, resuscitated death, MI, stroke, unplanned HF hospitalization, end-stage renal disease or renal death, or doubling of baseline serum creatinine and investigated the dual RAAS blockage effect with aliskiren, showed that there was no beneficial effect of dual RAAS blockade with aliskiren. In addition, adverse events were more frequent in the aliskiren treatment arm. There will probably be further discussions concerning the ALTITUDE study design.
The results of current studies suggest that dual RAAS blockade with aliskiren should be avoided, at least in patients with diabetes. Ongoing studies are expected to shed light on whether there is a potential patient population who would benefit from this combination. Furthermore, there is still uncertainty as to whether the current surrogate endpoints, such as BNP levels or microalbuminuria, can really be predictive of hard outcomes. Surely new innovative predictive biomarkers should be investigated.
Also, many novel parameters of the complicated RAAS system, such as prorenin, angiotensin 1–7, angiotensin IV, angiotensin-converting enzyme 2, need to be considered in experimental or clinical trials. All of these components may have potential therapeutic benefits or be new targets of treatment.
Footnotes
Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflict of interest statement: The authors declare no conflict of interest in preparing this article.
Contributor Information
Selçuk Şen, Department of Pharmacology, Istanbul Faculty of Medicine, Turgut Ozal Street 34390, Capa, Istanbul, Turkey.
Soner Sabırlı, Department of Pharmacology, Istanbul Faculty of Medicine, Istanbul, Turkey.
Tolga Özyiğit, Department of Pharmacology, Istanbul Faculty of Medicine, Istanbul, Turkey.
Yağız Üresin, Department of Pharmacology, Istanbul Faculty of Medicine, Istanbul, Turkey.
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