Hypertension is an independent risk factor for cardiovascular (CV) and renal disease–related events. Activation of neurohormonal systems such as the renin-angiotensin-aldosterone system (RAAS) has been strongly implicated in hypertension and the inexorable progression to end-organ damage. The pathophysiologic role of the RAAS continues to expand. It is now being increasingly recognized that the RAAS pathway plays a central part not only in blood pressure (BP) regulation but also in the pathophysiology of CV and renal diseases.1,2 In this regard, angiotensin (Ang) II is a major regulator of CV remodeling, atherosclerosis, vascular aging, intraglomerular pressure, and glomerular filtration rate. The scope of this review is to discuss the merits of comprehensive RAAS blockade on reducing the risk of CV and renal outcomes in the context of currently available RAAS inhibitors.
J Clin Hypertens (Greenwich). 2011;13:848–855. ©2011 Wiley Periodicals, Inc.
Interruption of the renin-angiotensin-aldosterone system (RAAS) cascade with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or more recently direct renin inhibitors (DRIs) is a safe and effective antihypertensive strategy that is in routine clinical use. The clinical utility of these agents in cardiorenal end-organ protection is increasingly being recognized. Although both ACE inhibitors and ARBs demonstrate substantial benefit in patients with cardiovascular and/or renal disease, considerable evidence indicates that they only partially suppress the RAAS pathway due to feedback upregulation of plasma renin activity. With the goal of providing more comprehensive RAAS blockade, combination ACE inhibitor/ARB therapy has been evaluated. However, this approach has not shown the anticipated improvements in composite cardiovascular and renal outcomes and appears to be associated with significant toxicity. Due to a unique mechanism of action, the combination of a DRI with an ACE inhibitor or ARB may represent an effective end-organ–protective therapeutic strategy.
Pathobiology of the RAAS
Following conversion from its inactive precursor pro-renin in the renal juxtaglomerular cells, the aspartate protease renin cleaves angiotensinogen to generate the inactive decapeptide Ang I, which is converted to the active octapeptide Ang II by angiotensin-converting enzyme (ACE) (Figure 1).3,4 In addition, renin and the RAAS have been localized in various tissues including the brain and adipose tissue, for example. Ang II interacts with 2 major receptors, Ang II receptor type 1 (AT1) and Ang II receptor type 2 (AT2). Its interaction with the former primarily regulates BP via vasoconstriction and increased aldosterone release from the adrenal cortex. Renin secretion is regulated by multiple factors, including renal perfusion pressure and sodium chloride delivery to the kidneys, changes in sympathetic activity, and negative feedback by Ang II.
Several novel components and functions of the RAAS network may have profound implications for progression of cardiorenal diseases.1,5 Chymase and cathepsin G are alternate Ang II-generating enzymes that may be upregulated under pathologic conditions. ACE 2, expressed in vascular endothelial cells of the kidneys and heart, cleaves Ang I to form Ang 1-9, which is further cleaved by ACE to form the Ang 1-7 peptide, impacting vasodilation, apoptosis, and suppression of hypertrophy. Ang II can be metabolized to Ang 2-8 (Ang III) and Ang 3-8 (Ang IV) peptides, which exhibit diverse biological functions. Moreover, alternate proteolytic cleavage-independent production of Ang I via pro-renin binding to renin/pro-renin receptors has been described. Finally, aldosterone, a terminal effector of the RAAS pathway, plays a direct role in the pathogenesis of CV and renal disease independent of Ang II.
Several steps of the RAAS cascade serve as targets for therapeutic BP reduction.6 ACE inhibitors, including the second-generation dicarboxylate-containing agents such as lisinopril, ramipril, and enalapril, inhibit the conversion of Ang I to Ang II and are in routine clinical use. Other strategies include inhibition of AT1 using angiotensin receptor blockers (ARBs), 8 of which are available in the United States, and mineralocorticoid receptor blockers (MRBs), such as spironolactone and eplerenone. More recently, direct renin inhibitors (DRIs) have emerged as alternate antihypertensive agents. DRIs block renin at the first and rate-limiting step of the RAAS pathway and thus provide strong potential for more comprehensive RAAS inhibition.
Need for Comprehensive Blockade of the RAAS
Single-site interruption of the RAAS may not lead to comprehensive RAAS inhibition, potentially resulting in suboptimal clinical outcomes.3,4,7 For example, Ang II “escape” and aldosterone “breakthrough” may occur during long-term ACE inhibitor or ARB therapy and can contribute to target organ damage. This escape of inhibition has been attributed in part to an increase in plasma renin concentration and, importantly, plasma renin activity (PRA) due to dysregulation of the normal feedback suppression of renin production in the kidneys. The prevalence of non–ACE-dependent pathways, including chymase and cathepsin G, provide alternate routes for RAAS escape. Although ARBs block AT1, Ang II may still be able to mediate its effects via other Ang II receptor subtypes such as AT2 or AT4.
Supramaximal doses of RAAS inhibitors have been evaluated in an effort to provide more comprehensive RAAS blockade and reduce the rate of progression to target organ damage.8–11 While treatment of heart failure (HF) patients with high doses of ACE inhibitors or ARBs conferred some clinical benefits compared with a standard dosage group, particularly with regard to HF hospitalizations, higher doses were also associated with significantly greater rates of renal impairment, hypotension, and hyperkalemia.8,11 Taken together, these results suggest that the risk-benefit ratio with dose-intensified ACE inhibitor or ARB strategies does not lend itself to routine use in clinical practice.
Alternatively, initial evidence suggested that combination therapy might further reduce cardiorenal risk. In order to achieve comprehensive RAAS inhibition, it was hypothesized that combination therapy with agents that target different steps of the RAAS cascade might provide additional clinical benefits. The current US hypertension guidelines acknowledge that a combination of ≥2 antihypertensive agents is often required to achieve target BP.12 For example, combination therapy with an ACE inhibitor and calcium channel blocker or diuretic has proven effective in recent clinical trials (eg, the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT], Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension [ACCOMPLISH] trial) and such an approach is commonly prescribed. However, the benefit of such combinations may be less than optimal. The remainder of this review discusses the clinical evidence for cardiorenal risk reduction with comprehensive RAAS blockade, with a particular focus on using combination therapy incorporating the first-in-class DRI aliskiren.
Combinations Involving ACE Inhibitors, ARBs, and MRBs
Clinically, the addition of an ARB to ACE inhibitor therapy in HF patients has been shown to reduce the combined end point of mortality and morbidity compared with placebo.13–15 For example, during a median follow-up of 41 months, the addition of candesartan to ACE inhibitor therapy in 2548 patients with HF significantly reduced the combined end point of CV death or hospital admission for HF (37.9% vs 42.3%), as well as the individual end points of CV death (23.7% vs 27.3%) and hospital admission for HF (24.2% vs 28.0%) (all P<.05).14 All-cause mortality was nonsignificantly reduced (30% vs 32%). In contrast, the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) in patients with CV disease or high-risk diabetes showed that no CV outcomes benefit was realized with combination ramipril/telmisartan therapy vs ramipril alone.2 Moreover, combination therapy was associated with higher rates of adverse events (AEs), including hypotension, syncope, renal dysfunction, and hyperkalemia, compared with the component monotherapies, leading to higher rates of discontinuation. Similar results were reported in a postmyocardial infarction (MI) population treated with both captopril and valsartan.16 These latter findings argue against the use of combination ACE inhibitor/ARB therapy in these high-risk patients.
In terms of relative benefits of combination ACE inhibitor/ARB therapy in hypertensive patients with established renal disease, results from a meta-analysis of 49 randomized trials showed that this treatment approach reduced proteinuria to a greater extent than either monotherapy.17 Disconcertingly, long-term results of the ONTARGET study demonstrated that combination ramipril/telmisartan therapy worsened major renal outcomes such as need for dialysis, doubling of serum creatinine, and mortality compared with monotherapy, despite a greater reduction in proteinuria in dual-therapy recipients.18 These results argue against a nephroprotective role for combination ACE inhibitor/ARB therapy in patients with hypertension in the absence of renal or heart disease, and caution against extrapolation that proteinuria reduction predicts improvement in overall renal function.19 While highlighting the need for better surrogate end points that would translate into improved clinical outcomes, these results also underscore the need for more effective strategies to lower renal risk.
In contrast, aldosterone antagonism with MRBs such as spironolactone in combination with ARBs and/or ACE inhibitors has shown substantial benefit in terms of end-organ protection.20,21 The Randomized Aldactone Evaluation Study (RALES), for example, demonstrated that the addition of spironolactone to an ACE inhibitor in patients with severe HF significantly reduced the relative risk of death by 30%. This was attributable to reductions in death from both progressive HF and cardiac sudden death.20 However, there is a definite risk of hyperkalemia with MRBs, which is exacerbated during concomitant treatment with ACE inhibitors/ARBs and may preclude the routine use of this combination. A population-based analysis showed that the rate of hospitalizations and mortality attributed to hyperkalemia increased significantly after the RALES publication.22 These results suggest that rates of hyperkalemia found in clinical studies are lower than those encountered in clinical practice, possibly reflecting closer laboratory monitoring, restriction of risk-aggravating agents, and/or patient selection in clinical trials, and that safe use of MRBs in combination with other RAAS agents might be more problematic than expected.
Role of DRIs
Of all antihypertensive drug classes, DRIs appear to provide the most comprehensive inhibition of the RAAS, reducing PRA, Ang I, Ang II, and aldosterone. The DRI aliskiren distinguishes itself from ACE inhibitors and ARBs in its ability to lower PRA, thereby inhibiting the production of both Ang I and Ang II. Initial evaluations of aliskiren-mediated neurohormonal and hemodynamic effects showed significant dose-dependent reductions in PRA and plasma concentrations of Ang I and Ang II, while ACE inhibitors or ARBs resulted in elevations in PRA and plasma Ang I concentrations in patients on sodium-depleted or sodium-repleted diets.23–25 PRA may be an independent risk factor for mortality and morbidity in CV disease, even in patients currently taking ACE inhibitor or ARB therapy, and also may be independent of BP control.26,27
Several studies have demonstrated the antihypertensive efficacy of aliskiren monotherapy compared with ACE inhibitors or ARBs. This efficacy was further augmented when aliskiren was used concomitantly with these agents.28–32 Aliskiren-based combination therapy in hypertensive patients, with or without concomitant diabetes, provided superior BP control compared with ACE inhibitor, ARB, or aliskiren monotherapy (eg, additional reductions in systolic BP of approximately 4–5 mm Hg with combination therapy over monotherapy29,31). Importantly, long-term treatment with aliskiren-based combination therapy was well tolerated, with headache, dizziness, and nasopharyngitis occurring in about 7% of patients and hyperkalemia (≥6.0 mmol/L) in only 1 of 588 patients (0.2%).32
Surrogate End Point for Cardioprotection
In the 3-month Aliskiren Observation of Heart Failure Treatment (ALOFT) study, the addition of aliskiren to the combination of an ACE inhibitor (or ARB) and β-blocker in patients with HF resulted in significant reductions in plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP), a measure of left ventricular (LV) stress, compared with the addition of placebo (Table I).33 In addition, significantly greater reductions in PRA and urinary aldosterone excretion, and improvements in mitral regurgitation, were achieved with aliskiren-based therapy. The incidences of renal dysfunction, symptomatic hypotension, and hyperkalemia, all prespecified safety assessments, were similar in both treatment cohorts.
|ALOFT33||302 patients with hypertension, HF, and BNP >100 pg/mL||Addition of aliskiren 150 mg or placebo to ACE inhibitor (or ARB) and β-blocker for 3 months||Aliskiren associated with greater reductions in NT-proBNP (25% vs placebo; P=.011), BNP (25%; P=.016), PRA (77%; P<.0001), and urinary aldosterone excretion (21%; P=.015)|
No significant between-group difference in BP reduction
Safety/tolerability similar between groups, including incidence of renal dysfunction (AE or serum creatinine >3.0 mg/dL), symptomatic hypotension, and/or hyperkalemia (AE or serum potassium >5.5 mmol/L) (10.9% aliskiren, 7.5% placebo; P=NS)
|ALLAY34||465 patients with hypertension, increased LV wall thickness, and BMI >25 kg/m2||Aliskiren 300 mg, losartan 100 mg, or aliskiren/losartan 300/100 mg for 9 months||Aliskiren noninferior to losartan in reducing LV mass index (mean, 4.9 vs 4.8 g/m2; P<.0001)|
Greater reduction in LV mass index with aliskiren/losartan (mean, 5.8 g/m2), but not significant vs losartan
No significant between-group difference in BP reduction
Safety/tolerability similar among groups, including incidence of hypotension (1.3% aliskiren, 1.3% losartan, 1.9% aliskiren/losartan), serum potassium ≥6.0 mmol/L (2.0%, 0.7%, 0.7%), BUN >40.0 mg/dL (0.7%, 1.3%, 0%), and serum creatinine >2.0 mg/dL (0%, 0.7%, 0.7%) (all P=NS)
|ASPIRE36||820 patients post-MI and LV ejection fraction ≤45%||Addition of aliskiren 300 mg or placebo to standard therapy (statins, β-blockers, antiplatelets, and ACE inhibitors [or ARBs]) for 36 weeks||No significant between-group difference in LV end systolic volume reduction|
No significant between-group difference in combined rates of CV death, HF hospitalization, recurrent MI, stroke, and resuscitated sudden deatha
Aliskiren associated with greater incidences of hyperkalemia (5.2% vs 1.3%), hypotension (8.8% vs 4.5%), and renal dysfunction (2.4% vs 0.8%)
In the 9-month Aliskiren in Left Ventricular Hypertrophy (ALLAY) study, aliskiren, losartan, and combination aliskiren/losartan therapy significantly reduced LV mass index from baseline in overweight hypertensive patients with increased ventricular wall thickness (Table I).34 Reductions in LV mass with aliskiren monotherapy were noninferior to losartan monotherapy while those in the combination group were numerically larger but not significantly different from those in the losartan monotherapy group (Figure 2). The safety profile was similar across all treatment groups with respect to occurrence of hypotension, hyperkalemia, and renal dysfunction (Table I). It is conceivable that BP lowering and reduction in LV mass was lower than in earlier trials of RAAS inhibition (eg, Losartan Intervention for Endpoints Reduction [LIFE]35) due to the lower LV mass at baseline, modestly elevated average baseline BP (145/89 mm Hg), and shorter duration of treatment.
The recently reported results of the Aliskiren Study in Post-MI Patients to Reduce Remodelling (ASPIRE) showed that the addition of aliskiren or placebo to an ACE inhibitor or ARB for 36 weeks did not alter ventricular remodeling as assessed by similar mean changes in LV end-systolic volume, reflecting competence of cardiac emptying related to systolic function.36 There was also no difference in the combined rates of CV death, HF hospitalization, recurrent MI, stroke, and resuscitated sudden death between the two treatment cohorts, although the study was not powered to assess clinical outcomes. Regarding safety, aliskiren therapy was associated with a higher rate of AEs, including hyperkalemia, hypotension, and renal dysfunction (Table I).
The ongoing 8-week Aliskiren and Valsartan to Reduce NT-proBNP via Renin-Angiotensin-Aldosterone System Blockade (AVANT-GARDE) study is evaluating the effects of aliskiren 300 mg/d alone or in combination with valsartan 320 mg/d in a proposed 1100 hospitalized patients with preserved LV systolic function who were stabilized after acute coronary syndrome.37 The primary efficacy outcome is change from baseline in NT-proBNP at the end of the study.
Surrogate End Point for Renal Protection
In the Aliskiren in the Evaluation of Proteinuria in Diabetes (AVOID) study of hypertensive patients with type 2 diabetes and nephropathy, addition of aliskiren to losartan and standard antihypertensive therapy led to significant reductions in urinary albumin-to-creatinine ratio and overnight urinary albumin excretion rate compared with placebo (Table II and Figure 3).38 The observed aliskiren-mediated renoprotective effects might be independent of its BP-lowering effect since a systolic/diastolic BP difference of only 2/1 mm Hg was noted with aliskiren therapy compared with placebo. However, it must be noted that the baseline BP was well controlled in the study, which allowed for only a lower rate of BP decline. The overall incidence of AEs and laboratory abnormalities (eg, hyperkalemia, increased serum creatinine, and increased blood urea nitrogen) was generally similar between the 2 treatment groups (Table II). These results were consistent with those of an exploratory study in hypertensive patients with type 2 diabetes and albuminuria in which combination aliskiren/irbesartan therapy resulted in significant reductions in albuminuria compared with aliskiren or irbesartan monotherapy (Table II).39
|AVOID38||599 patients with hypertension, type 2 diabetes, and nephropathy||First 3 months: losartan 100 mg/placebo or losartan/aliskiren 100/150 mg; next 3 months: aliskiren dose doubled|
Patients also received optimal antihypertensive therapy
|Losartan/aliskiren associated with greater reductions in urinary albumin-to-creatinine ratio (20% at study end vs losartan/placebo; P<.001)|
Greater reduction in overnight urinary albumin excretion rate with losartan/aliskiren (18% at study end vs losartan/placebo; P<.001)
No significant between-group difference in BP reduction
Safety/tolerability generally similar between groups, including incidence of hypotension (4.0% losartan/aliskiren, 1.0% losartan/placebo), serum potassium ≥6.0 mmol/L (4.7%, 1.7%; P=.06), BUN >40.0 mg/dL (21.7%, 22.2%), and serum creatinine >2.0 mg/dL (12.4%, 18.2%)
|Persson39||26 patients with hypertension, type 2 diabetes, and albuminuria >100 mg/d||Aliskiren 300 mg, irbesartan 300 mg, aliskiren/irbesartan 300/300 mg, or placebo for four 2-month treatment periods (cross-over design)||Greater reduction in albuminuria with aliskiren (48% vs placebo; P<.001) and irbesartan (58% vs placebo; P<.001)|
Combination therapy resulted in 71% reduction in albuminuria compared with placebo, more than either monotherapy (P<.05)
No cases of hypotension or hyperkalemia (plasma potassium >5.5 mmol/L)
Future Trials: Morbidity and Mortality
The previously mentioned studies are limited in that they only evaluated the effects of aliskiren on surrogate end points for CV and renal protection. The findings do, however, warrant further study of the effects of aliskiren on cardiorenal morbidity and mortality outcomes, particularly in high-risk patients with diabetes or HF. Currently, a total of 4 ongoing randomized controlled trials are examining the potential benefits of aliskiren therapy on hard end points in high-risk populations (Table III). The Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) is assessing the cardiorenal effect of aliskiren plus conventional treatment in patients with high-risk type 2 diabetes.40 ALTITUDE will determine whether the addition of aliskiren to conventional treatment (including ACE inhibitors or ARBs), compared with placebo, delays the occurrence of CV and renal morbidity and mortality. The Aliskiren Trial to Minimize Outcomes in Patients With Heart Failure (ATMOSPHERE) is evaluating whether aliskiren monotherapy is superior/noninferior to enalapril monotherapy and/or whether combination aliskiren/enalapril therapy is superior to enalapril monotherapy in delaying the time to CV death or HF hospitalization in HF patients.37 The potential benefits of aliskiren, in addition to standard therapy, in reducing CV mortality and HF re-hospitalization in patients stabilized after hospitalization for acute decompensated HF is being studied in the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT).41 Lastly, the Aliskiren in Prevention of Later Life Outcomes (APOLLO) study is determining the effectiveness of aliskiren therapy on the prevention of CV morbidity and mortality in elderly patients with additional risk factors, with or without previous CV events.42
|ALTITUDE40||Approximately 8600 patients with high-risk type 2 diabetes||Addition of aliskiren (150→300 mg) or placebo to conventional therapy during 4 years||Time to first event for the composite end point of CV death, resuscitated sudden death, nonfatal MI, nonfatal stroke, unplanned HF hospitalization, end-stage renal disease, renal death, or doubling of baseline serum creatinine concentration|
|ATMOSPHERE37||Approximately 7000 patients with HF||Addition of aliskiren (150→300 mg), enalapril 10 mg, or aliskiren/enalapril (150/10 mg→300/10 mg) to conven-tional therapy (except ACE inhibitor) during 2 to 4 years||Time to first occurrence of either CV death or HF hospitalization|
|ASTRONAUT41||Approximately 1800 patients stabilized after hospitalization for acute decompensated HF||Addition of aliskiren (150→300 mg) or placebo to conventional therapy (except combination ACE inhibitor/ARB)||Time to first occurrence of either CV death or HF re-hospitalization within 6 months|
|APOLLO42||Approximately 11,000 elderly patients with additional risk factors, with or without previous CV events||Combination therapy (aliskiren/HCTZ or aliskiren/amlodipine), monotherapy (aliskiren, HCTZ, or amlodipine), or placebo||Composite of CV death, nonfatal MI, nonfatal stroke, and significant HF|
RAAS blockade, particularly with ACE inhibitors and ARBs, has remained a cornerstone of treatment for the management of hypertension, CV and renal disease, and diabetes. Recent evidence suggests that combination aliskiren/ACE inhibitor or aliskiren/ARB therapy might provide more comprehensive RAAS suppression and potential end-organ protection in high-risk patient populations. However, the optimal therapeutic partner for aliskiren is currently unknown, although combinations with ARBs may yield more sustainable RAAS inhibition than combinations with ACE inhibitors. In many cases (eg, hypertension, HF, renal disease), concomitant diuretic use would also be recommended. RAAS inhibitors and diuretics (excluding MRBs and other potassium-sparing diuretics) have opposite effects on serum potassium levels, which could help minimize any changes to this laboratory parameter, whereas both drug classes can elevate serum creatinine levels. A prudent approach would be to monitor both serum potassium and creatinine levels during the initial 2 to 3 months of treatment with aliskiren/ACE inhibitor, aliskiren/ARB, or aliskiren/diuretic therapy, with further follow-up should dose up-titration be necessary.43 Although potential safety issues of long-term aliskiren combination therapy are not fully known at this time, aliskiren-based combinations have been well tolerated to date in carefully selected clinical trial patients. Rates of hyperkalemia and elevations in serum creatinine >2.0 mg/dL have been minimal. Aliskiren has only been available in the United States since 2007, and, thus, completed studies have been limited to those assessing BP lowering and other surrogate markers of cardiorenal protection. Results from ongoing and planned outcomes studies in high-risk patients, including those with type 2 diabetes or HF, should define the precise role of aliskiren as part of combination RAAS blockade.
Acknowledgments and disclosures: Technical assistance with editing, figure preparation, and styling of the manuscript for submission was provided by Oxford PharmaGenesis Inc, and was funded by Novartis Pharmaceuticals Corporation. The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of this manuscript. The opinions expressed in the manuscript are those of the authors and Novartis Pharmaceuticals had no influence on the contents. Dr Rastogi: speaker honoraria: Novartis Pharmaceuticals Corporation, Viiv, Genzyme, Cubist; Dr Rashid: nothing to disclose; Dr Wright: speaker honoraria: Novartis Pharmaceuticals Corporation, Boehringer-Ingelheim, Forest Pharmaceuticals, GlaxoSmithKline, LipoScience. Consultant: Novartis Pharmaceuticals Corporation, St. Jude Medical, LipoScience. Research support: Novartis Pharmaceuticals Corporation, Atritech, St. Jude Medical. Stock or options: none.