Review. Renin Inhibitors in Chronic Heart Failure: The Aliskiren Observation of Heart Failure Treatment Study in Context

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1 Review Renin Inhibitors in Chronic Heart Failure: The Aliskiren Observation of Heart Failure Treatment Study in Context Address for correspondence: HenryKrum,MBBS,PhD,FRACP Centre of Cardiovascular Research and Education in Therapeutics Department of Epidemiology and Preventive Medicine Monash University/The Alfred Centre Melbourne, Victoria 3004, Australia Henry Krum, PhD, FRACP, FESC and Aldo Maggioni, MD Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine (Krum), Monash University, Melbourne, Australia; ANMCO Research Centre (Maggioni), Florence, Italy Renin-angiotensin aldosterone system (RAAS) activation is a key neurohormonal contributor to the progression of chronic heart failure. Strategies that block this activation have consistently demonstrated major beneficial impacts on morbidity and mortality in this setting. Direct renin inhibitors (DRIs) present a novel opportunity to block at an additional or alternative step in this pathway, that being conversion of angiotensinogento angiotensini. Theoreticalbenefits of blocking at the level of renin include: inhibition of the reflex activation of plasma renin activity induced by conventional downstream RAAS blockers. Minimization of angiotensin II and/or aldosterone escape and blocking upstream at the rate-limiting step of angiotensin I production. Preclinical and early-phase clinical studies have largely supported this hypothesis. In the Aliskiren Observation of Heart Failure Treatment study, patients with systolic chronic heart failure receiving background angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers and β-blockers benefited from aliskiren in reduction vs placebo of plasma levels of brain natriuretic peptide, the primary efficacy endpoint of that study. Large-scale outcome trials are, however, required to definitively determine the benefits of a DRI strategy additional to, or as an alternative to, conventional approaches such as ACE inhibitors in the systolic chronic heart failure setting. Introduction Chronic heart failure remains a major public health problem with high mortality and frequent hospital admission, as well as representing a large healthcare cost to the community. This is despite recent advances in therapy that have made major inroads into morbidity and mortality associated with the disease. Chief among these therapeutic successes has been blockade of the renin-angiotensin aldosterone system (RAAS) that is markedly activatedin this syndrome.various strategies have been employed to block the RAAS in the chronic heart failure context (Figure 1). These include use of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and aldosterone antagonists,either as lone RAAS blockersor in combination. The advent of orally bioavailable direct renin inhibitors (DRIs) offers both an alternative and complementary strategy of upstream RAAS blockade to these existing therapies.this review will focus on the therapeuticrationale for renin inhibition in chronic heart failure with a focus on the Aliskiren Observation of Heart Failure Treatment (ALOFT) study results, as well as a summary of the features The authors have no funding, financial relationships, or conflicts of interest to disclose. of the ongoing Aliskiren Trial to Minimise Outcomes in Patients With Heart Failure (ATMOSPHERE) study. RAAS Blockade in Chronic Heart Failure The RAAS is activated early in heart failure, although somewhat later than that of sympathetic activation. 1 Renin activation in this setting occurs in response to reduced urinary sodium excretion, decreased afferent glomerular arteriolarpressure,as well as in response to the sympathetic activation that is particularly prominent in the kidney. 2 Strategies to block RAAS activation in heart failure have revolutionized the treatment of this condition. These approaches have until now all been downstream of renin conversion of angiotensinogen to angiotensin I. The evidence base for ACE inhibitors is particularly strong, with clear-cut morbidity and mortality benefits having been observed in the Studies of Left Ventricular Dysfunction (SOLVD)-Treatment study 3 in patients with symptomatic (New York Heart Association [NYHA] Class II-III) chronic heart failure. Furthermore, the SOLVD- Prevention 4 study supported early intervention with ACE inhibition even in patients who were not symptomatic but had objective evidence of left ventricular (LV) systolic dysfunction. Strategies directed at blocking the angiotensin II type I receptor directly (ie, ARBs) have also been demonstrated 536 Clin. Cardiol. 33, 9, (2010) Received: May 28, 2010 Accepted with revision: July 12, 2010

2 Direct renin inhibitor Bradykinin ACE inhibitor peptides AT 1 receptor blocker Angiotensinogen (liver) Angiotensin I Angiotensin II AT 1 AT 2 PRA 5.26 ng/ml/h Aldosterone > 101 pg/ml PRA 5.26 ng/ml/h Aldosterone > 101 pg/ml Mortality Hazard ratio Mortality and morbidity Hazard ratio Figure 2. Baseline plasma renin activity (PRA) and aldosterone as predictors of outcome in heart failure in the Valsartan Heart Failure Trial. Aldosterone receptor antagonist Aldosterone Figure 1. Renin-angiotensin aldosterone system and various points where pharmacological blockade can be achieved. Abbreviations: ACE, angiotensin converting enzyme; AT, angiotensin. to be successful in chronic heart failure. Both the Valsartan Heart Failure Trial (Val-HeFT) 5 and Candesartan in Heart Failure Assessment of Reduction of Mortality and Morbidity (CHARM)-Added 6 studiesdemonstratedthat addition of an ARB to patients already receiving background ACE inhibitors could reduce combined morbidity and mortality (but not mortality alone in either study). More recently, the Heart Failure Endpoint Evaluation of AII- Antagonist Losartan study 7 compared losartan 150 mg/day to 50 mg/day in symptomatic systolic chronic heart failure patients unable to tolerate ACE inhibitors. Fewer major events were observed at the higher ARB dose, supporting the contentionthat greaterraas blockade resultsin greater impact on cardiovascularoutcomes.it is on this background that consideration of a DRI strategy in chronic heart failure is discussed. Rationale for DRI Use in Heart Failure Plasma renin concentration and activity are a fundamental component of the RAAS activation that occurs in response to the failing left ventricle. A number of studies have demonstrated a close relationship between levels of plasma renin activity (PRA) and subsequent major cardiovascular eventsin patientswith chronic heart failure. In the Val-HeFT study (Figure 2), PRA above the median was a powerful independent prognostic indicator of such events. 8 Specifically, the independent association between elevated PRA and subsequent morbidity and mortality in Val-HeFTwas demonstratedtaking into accountnot only the clinicalvariables,but also laboratoryexaminationsincluding plasma levels of brain natriuretic peptide (BNP), aldosterone, and norepinephrine levels. The impact of PRA on prognosis was shown in a similar way in patients treated or not with β-blockers and/or ACE-inhibitors, documenting that the prognostic role of PRA is relevant in different contexts with low or high PRA levels at baseline. More recently, Vergaro et al 9 showed that elevated PRA was significantlyassociatedwith cardiac eventsin nearly700 patients with chronic heart failure treated with current best practice therapies. What is uncertain is whether lowering of PRA using a DRI strategy confers a reduction in such events. However, given the recent advent of these agents, this hypothesis is now able to be formally tested. Development of DRIs Development of orally bioavailable, once-daily DRIs has been somewhat of a holy grail in cardiovascular pharmacotherapy. Earlier agents, such as enalkiren and remikiren, were effective peptidergic agents but required intravenous administration. 10 The DRI aliskirenalso has very low overall bioavailability (2.6%); however, it appears to confer consistent PRA and downstream RAAS inhibition and blood pressure-lowering in the preclinical and clinical trial setting. Furthermore, its pharmacokinetics make it suitable for once-daily administration. It additionally has minimal p450 metabolism,and therefore drug interactions occurring via this mechanisms are unlikely to be of major clinical significance. 11 Newer agents with greater bioavailability have been developed; however, they do not seem to have advanced to the stage of late phase clinical testing as yet. DRI Studies in Heart Failure Preclinical Studies There has been limited preclinical evaluation of DRIs in animal models of heart failure. Westermann et al 12 evaluated C57J/b/6 mice who underwent coronary ligation. Ten Clin. Cardiol. 33, 9, (2010) 537

3 Review continued days of aliskiren therapy resulted in improved (vs placebo) systolic and diastolic function, evaluated by pressure-volume loop analysis. Furthermore, LV dilatation, cardiac hypertrophy, lung weights, and relevant cell signaling kinases were all restored toward normal values with aliskiren. In a double transgenic (RAAS overexpression) rat model, 13 aliskiren appeared to produce similar if not greater beneficialimpact on cardiac hypertrophy,lv wall thickness, and diastolic dysfunction than the ARB, valsartan. A small study of aliskiren, in a rat diabetic cardiomyopathy (ren- 2) model of heart failure with preserved ejection fraction (HFPEF), demonstrated improved diastolic parameters vs control. 14 Given the putative patho-physiological role of the RAAS in HFPEF, together with the paucity of effective therapies for the condition, DRIs should be examined clinically in this setting. Clinical Studies With regard to clinical evaluation, again this has been somewhat limited. A small mechanistic proof-of-concept study 15 was conducted in 27 patients randomized to the ACE inhibitor ramipril or the DRI aliskiren, 300 mg/day for 7 days. In addition to the expected reduction in PRA, there was a greater reduction in angiotensin II (Figure 3) and aldosterone plasma levels in the DRI group. These data would suggest (but are far from conclusive) that a DRI strategy might be a better approach to reduce so called angiotensin and aldosterone escape that occurs with downstream blockade of the RAAS. On the other hand, plasma BNP levels were somewhat higher (nonsignificantly increased) in DRI compared to ramipril. The ALOFT study 16 has been the major proof-of-concept evaluation of DRIs in chronic heart failure patients conducted thus far. The study compared aliskiren 150 mg/day vs placebo in addition to background ACE inhibitor or ARB Mean change from baseline in Ang II (%) Week 0 Week 2 Week 4 Week 6 Ramipril (n=14) Aliskiren (n=13) Figure 3. Effect of direct renin inhibitor vs angiotensin converting enzyme inhibitor on plasma angiotensin (ANG) II levels in patients with chronic heart failure. Ramipril was force-titrated from 5 mg to 7.5 mg at the end of week 2, and from 7.5 mg to 10 mg at the end of week 4. Aliskiren was force-titrated from 75 mg to 150 mg at the end of week 2, and from 150 mg to 300 mg at the end of week 4. Randomization Placebo Placebo once daily Aliskiren 150 mg once daily Standard therapy for HF continued throughout study in all patients, which could include a b-blocker with either an ACEI or ARB, but not both 2 weeks single-blind 12 weeks double-blind Figure 4. The Aliskiren Observation of Heart Failure Treatment study design overview. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; HF, heart failure. The key patient enrollment features of the ALOFT study were that there was no left ventricular ejection cut-off in these patients, NYHA Class II-IV heart failure symptoms, a requirement for a current or past history of hypertension, plasma BNP level of >100 pgm/ml, and prior treatment with ACE inhibitor (or ARB) and β-blocker (Figure 4). Key exclusion criteria were systolic blood pressure <90 mm Hg, serum creatinine >177 μmol/l, and the patient being 6 months remote from a major cardiovascular event. These are fairly routine exclusions in a chronic heart failure study, but might somewhat limit generalizability of results to the entire population of such patients. The primary objective of the ALOFT study was to assess the tolerability and safety of aliskiren, specifically the incidence of renal dysfunction, symptomatic hypotension, and hyperkalemia. Efficacy assessments were also prespecified, BNP being the primary efficacy end point. BNP is increasingly being utilized as a surrogate end point for phase II trials in patients with heart failure based on its utility as an independent prognostic marker and also its seeming ability to track the progression of the heart failure disease process. Thus, reductions in plasma BNP could be seen as a surrogate marker for retardation of the disease process as well as reduction in future major cardiovascular and mortality events. The main efficacy finding was a significant reduction in plasma BNP levels with aliskiren compared with placebo, thus meeting the study s primary efficacy end point (Figure 5). Urinary aldosterone levels were also significantly reduced by aliskiren vs placebo. Furthermore, a number of echocardiographic parameters indicative of attenuation of the left ventricular remodeling process were improved with aliskiren compared to placebo. This includes the mitral regurgitantarea, the peak early (e) transmitralflow velocity, E to A ratio, deceleration time, and ratio of mitral velocity to early diastolic velocity of the mitral annulus. These findings are noteworthy given that the remodeling process does take 538 Clin. Cardiol. 33, 9, (2010)

4 Change from baseline (pg/ml) mean±sem n = Optimal HF therapy + placebo p = n = Optimal HF therapy + aliskiren 150 mg Figure 5. Effect of aliskiren vs placebo on plasma brain natriuretic peptide levels in chronic heart failure patients in Aliskiren Observation of Heart Failure Treatment study. Reprinted with permission; McMurray JJ et al. 15 Abbreviations: HF, heart failure; SEM, standard error of mean. many months to affect with pharmacological therapy, and this study was only 3 months in duration. The adverse event profile is also important to consider. The major adverse events that are typically observed in studies of RAAS blockade are clinically significant hypotension, hyperkalemia, and renal impairment. In the ALOFT trial, all of these were somewhat greater in the aliskiren group compared to placebo, although none reached statistical significance (Figure 6). No evidence of an excess of these predefined adverse events were observed even in the subgroups of patients at high risk, such as the elderly, those with diabetes, those treated with spironolactone, and those with lower estimated glomerular filtration rate at study entry. However, and as previously noted, the aliskiren 150 mg/day dose used in ALOFT is half the dose being used in subsequent major trials of aliskiren for various cardiovascular disease states, and therefore Proportion of patients (%) Standard HF therapy + aliskiren 150 mg/day + placebo p=ns 3.2 p=ns p=ns 6.4 n=156 n=146 n=156 n=146 n=156 n=146 Renal dysfunction Symptomatic hypotension 4.8 Hyperkalaemia Figure 6. Tolerability and side effect profile of aliskiren vs placebo in chronic heart failure (HF) patients in Aliskiren Observation of Heart Failure Treatment study. Abbreviation: NS = nonsignificant. might not be indicative of the adverse event profile that might occur at the higher dose. DRIs in Other Related Disorders Two important, related trials with aliskiren have been either published (Aliskiren Left Ventricular Assessment of Hypertrophy [ALLAY] trial) 17 or presented at a major meeting (Aliskiren Study in Post-MI Patients to Reduce Remodelling [ASPIRE]). 18 The ALLAY trial observed generally beneficial effects on cardiac hypertrophy with aliskiren compared to, as well as added to, the ARB losartan. In contrast, the recently presented ASPIRE trial randomized 820 predominantly male patients with large infarctions (left ventricular ejection fraction [LVEF] <45%) within 2 6 weeks of the acute event to aliskiren 300 mg/day or placebo. Patients could be receiving ACE inhibitor or ARB but not both in the post-myocardial infarction (MI) setting. The primary study endpoint was change in left ventricular end systolic volume. However, there was no change in this parameter nor in left ventricular end diastolic, LVEF, or infarct size between aliskiren and placebo, over the study duration of 36 weeks. Adverse effects were statistically significantly increased with aliskiren for hypotension and hyperkalemia. Adverse events for renal dysfunction were borderline increased. The study authors concluded that the results of this surrogate end-point study do not support the testing of aliskiren in a large-scale outcome trial in high-risk post-mi patients. It is somewhat difficult to reconcile the findings of the ASPIRE trial with those of ALOFT. Per protocol, ASPIRE patients were proximate temporally to a large MI. Thus, ASPIRE and ALOFT comprise somewhat different patient populations (ie, in subacute vs chronic settings, respectively).it is also worth notingthat in ALOFT,aliskiren was added to background ACE inhibitor or ARB. In contrast in ASPIRE, aliskiren was added to patients who in many cases would be naive to RAAS blockade prior to the index MI and thus have effectively had multiple RAAS blockers added over a relatively short period of time. In this regard there is a parallelism with the Valsartan in Acute Myocardial Infarction study, which compared a combined valsartan/captopril strategy to captopril alone. That comparison was neutral, potentially because of the rapid addition of multiple RAAS blocking agents rather than by them being sequentially added over a longer period of time.finally,it could be hypothesizedon pathophysiological grounds that the greatest RAAS activation post-mi occurs early, and therefore the greatest benefit of RAAS blockade might be to intervene early. Given the broad entry criteria (out to 6 weeks post-mi) for commencement of aliskiren therapy in ASPIRE, this might have been too late to maximize remodeling and other benefits. This is supported by analysis of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival study of Clin. Cardiol. 33, 9, (2010) 539

5 Review continued patients with post-mi, LV systolic dysfunction who received the aldosterone antagonist eplerenone (or placebo). In that study, patients who received active therapy early post-mi (ie, at days 3 7) derived greater benefit than those who received it later (ie, 7 14 days post-mi). 19 Large-Scale Outcome Trials With DRIs in Chronic Heart Failure The ATMOSPHERE trial 20 will definitively address the question of the benefits (or otherwise) of a DRI strategy in patients with systolic chronic heart failure, remote from an ischemic event. The key entry criteria for ATMOSPHERE are patients with a left ventricular ejection fraction <35% and a plasma BNP of >150 pg/ml (or >100 pg/ml if an unplanned hospitalization with heart failure had occurred within the last 12 months). Patients also need to be on an ACE inhibitor and tolerating at least a dose equivalent to 10 mg daily of enalapril. Patients can be on a maximum of 1 other RAAS blocker. This issue is relevant to safety and the increased risk of hypotension, hyperkalemia, and renal impairmentwith multiple RAAS blockers. In Val-HeFT there was an interaction effect such that patients on an ACE inhibitor, ARB, and β-blocker did worse than those on and ACE inhibitor, ARB, and no β-blocker. Although not seen in CHARM-Added (with candesartan), such a subgroup analysis will also be examined in ATMOSPHERE. The study design is to take such patients, switch them all to enalapril during an open-label run-in phase, and then add aliskiren 75 mg/day additional to the highest tolerated dose of ACE inhibitor (up to 20 mg/day of enalapril). Patients are then randomized (double blind) to receive aliskiren, enalapril, or both. The coprimary objectives of the study are to test if aliskiren monotherapy is superior (or at least noninferior) to enalapril and/or if the aliskiren/enalapril combination is superior to enalapril monotherapy in delaying time to first occurrence of either cardiovascular death or heart failure hospitalization. Predefined secondary end points include evaluation of impact of these 3 arms on change in BNP levels as well as impact on the clinical summary score of the Kansas City Quality of Life Questionnaire. A number of tertiary end points are also included, focusing on the impact of components of the primary end point other major cardiovascular events and renal function. Stored blood has been taken for emerging cardiovascular biomarkers. A total of 7041 patients (2347 in each arm) are presently being recruited to ensure that the requisite number of endpoints are able to be achieved. It is worth noting in the trial design that considerable effort is made to ensure that patients receive a background dose of enalapril of at least 16.6 mg/day. This was the mean achieved dose in the SOLVD-Treatment study. 3 Achievement of a lower dose would complicate interpretation of the data, in particular making the enalapril monotherapy dose a potentially suboptimal comparator. Conclusion The utility of a direct renin inhibitory strategy in heart failure is underpinned by important epidemiological, pathophysiological, and early clinical data from the ALOFT study.it is, however,still uncertainas to whether superiority with a DRI strategy can be achieved compared to or additional to an ACE inhibitor strategy and whether this will occur with fewer side effects. The recent ALOFT study 16 does suggest that combining a DRI with an ACE inhibitor (and/or 1 other RAAS blocker) might provide significantadditional benefit in systolic chronic heart failure without a clinically significant increase in side effects and adverse events. However, considerable clinical equipoise still exists with regard to these hypotheses.fortunately, the ATMOSPHERE study will eventually provide definitive data in this regard. References 1. Packer M. Pathophysiology of chronic heart failure. Lancet. 1992;340: Krum H. Role of renin in heart failure and therapeutic potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst. 2008;9: SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. NEnglJMed. 1991;325: SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. 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Plasma renin activity is an independent prognostic factor in chronic heart failure. Eur Heart J. 2008;29((suppl):):393. Abstract. 10. Hollenberg NK. Direct renin inhibition and the kidney. Nat Rev Nephrol. 2010;6: Buczko W, Hermanowicz JM. Pharmacokinetics and pharmacodynamics of aliskiren, an oral direct renin inhibitor. Pharmacol Rep. 2008;60: Westermann D, Riad A, Lettau O, et al. Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure. Hypertension. 2008;52: Pilz B, Shagdarsuren E, Wellner M, et al. Aliskiren, a human renin inhibitor, ameliorates cardiac and renal damage in doubletransgenic rats. Hypertension. 2005;46: Clin. Cardiol. 33, 9, (2010)

6 14. Connelly KA, Kelly DJ, Kim S, et al. The direct renin inhibitor, aliskiren, improves cardiac function via direct renin inhibition and via renin receptor modulation in a rodent model of diabetic diastolic heart failure. Circulation. 2008;118:S1166. Abstract McMurray JJ, Pitt B, Latini R, et al; Aliskiren Observation of Heart Failure Treatment (ALOFT) Investigators. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail. 2008;1: Seed A, Gardner R, McMurray J, et al. Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure. Eur J Heart Fail. 2007;9: Solomon SD, Appelbaum E, Manning WJ, et al; Aliskiren in Left Ventricular Hypertrophy (ALLAY) Trial Investigators. Effect of the direct Renin inhibitor aliskiren, the Angiotensin receptor blocker losartan, or both on left ventricular mass in patients with hypertension and left ventricular hypertrophy. Circulation. 2009;119: Solomon SD. ASPIRE Study results. Paper presented at: American College of Cardiology 59th Scientific Sessions; March 16, 2010; Atlanta, GA. 19. Adamopoulos C, Ahmed A, Fay R, et al; EPHESUS Investigators. Timing of eplerenone initiation and outcomes in patients with heart failure after acute myocardial infarction complicated by left ventricular systolic dysfunction: insights from the EPHESUS trial. Eur J Heart Fail. 2009;11: Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbi-mortality in Patients With Chronic Heart Failure (ATMOSPHERE). Identifier: NCT clinicaltrials.gov. Accessed May 20, Clin. Cardiol. 33, 9, (2010) 541