When Conventional Heart Failure Therapy is Not Enough: Angiotensin Receptor Blocker, Direct Renin Inhibitor, or Aldosterone Antagonist?

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1 ORIGINAL PAPER When Conventional Heart Failure Therapy is Not Enough: Angiotensin Receptor Blocker, Direct Renin Inhibitor, or Aldosterone Antagonist? Sripal Bangalore, MD, MHA; 1 Sunil Kumar, MD; 2 Franz H. Messerli, MD 1 From the New York University School of Medicine, New York, NY; 1 the University of Nebraska Medical Centre, Omaha, NE; 2 and St Luke s Roosevelt Hospital and Columbia University, New York, NY 3 In patients on conventional heart failure therapy including angiotensin-converting enzyme (ACE) inhibitors, the addition of angiotensin receptor blockers (ARBs), direct renin inhibitors (DRIs), or aldosterone antagonists are therapeutic options to further reduce the risk of cardiovascular events. However, whether one is preferable over the other is not known. PubMed, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched for randomized clinical trials (RCTs), until March 2011, of trials testing either an ARB, DRI, or an aldosterone antagonist in patients with heart failure who were on conventional heart failure therapy with follow-up of at least 3 months. Efficacy (death, cardiovascular death, nonfatal myocardial infarction, heart failure hospitalization and composite of cardiovascular death or heart failure hospitalization) and safety (hyperkalemia, hypotension, renal failure) outcomes were compared. The authors identified 16 RCTs involving 31,429 participants that satisfied the inclusion criteria. When compared with placebo (reference rate ratio [RR] of 1), aldosterone antagonists reduced the rate of death (RR, 0.79; 95% credibility interval [CrI], ), cardiovascular death (RR, 0.78; 95% CrI, ), heart failure hospitalization (RR, 0.74; 95% CrI, ), and the composite of cardiovascular death or heart failure hospitalization (RR, 0.73; 95% CrI, ) with no difference for other efficacy outcomes. However, ARBs and DRIs did not result in any significant reduction in the rate of any of the efficacy outcomes when compared with placebo. When compared with placebo (RR=1), ARBs increased the rate of hyperkalemia (138% increase), renal failure (126% increase), and hypotension (63% increase). Similarly, aldosterone antagonists resulted in a 110% increase in hyperkalemia and DRIs with a 98% increase in hypotension. In patients with heart failure and reduced systolic function on conventional heart failure medications, the risk benefit ratio favors the addition of aldosterone antagonists over ARBs or DRIs. Ó2012 Wiley Periodicals, Inc. Address for correspondence: Sripal Bangalore, MD, MHA, Director of Research, Cardiac Catheterization Laboratory, Director, Cardiovascular Outcomes Group, Assistant Professor of Medicine, New York University School of Medicine, New York, NY sripalbangalore@gmail.com Manuscript received: August 15, 2012; revised: September 19, 2012; accepted: September 30, 2012 DOI: /chf The American College of Cardiology American Heart Association (ACC AHA) guidelines for the diagnosis and management of heart failure (HF) in adults state that the addition of an angiotensin receptor blocker [ARB] may be considered in persistently symptomatic patients with reduced left ventricular ejection fraction [LVEF] who are already treated with conventional therapy. 1 This was regarded as a class IIb recommendation with a level of evidence B. In contrast, the 2008 European Society of Cardiology (ESC) guidelines consider the addition of an ARB in patients with heart failure and an LVEF of equal or less than 40% who remain symptomatic despite optimal treatment with an angiotensin-converting enzyme [ACE] inhibitor and a beta-blocker as a class I recommendation with a level of evidence A. 2 The recently updated 2012 ESC guidelines, however, have revised the above recommendation restricting it to patients who are unable to tolerate a mineralocorticoid receptor antagonist and for the prevention of HF hospitalization. 3 Both sets of guidelines are unanimous in that they strongly recommend adding an aldosterone antagonist in symptomatic patients but warn against the triple combination of an ACE inhibitor, ARB, and an aldosterone antagonist. Neither of the guidelines recommend direct renin inhibitors (DRIs). These recommendations leave the practicing clinician in a predicament of how exactly to proceed in a HF patient who remains symptomatic despite optimal conventional therapy. Since a triple blockade of the renin angiotensin aldosterone system (RAAS) is not considered safe, should the next step be an aldosterone antagonist, 4,5 an ARB, or a DRI? METHODS Eligibility Criteria We conducted PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) searches for randomized clinical trials (RCTs) using the terms: angiotensin receptor blockers, angiotensin receptor antagonists, ARBs, aldosterone antagonists, direct renin inhibitors, DRI, and using the names of individual ARBs, aldosterone antagonists, or DRIs, in patients with HF, until March 2011 (week 2). There was no language restriction for the search. We checked the reference list of published Congest Heart Fail. 2013;19: Vol. 19 No. 3 May. June

2 review articles, meta-analyses, and randomized trials identified by the searches to find other eligible trials. We excluded studies that were only in abstract format without a manuscript published. In addition, for studies that did not report the outcomes of interest, we contacted the authors via . We also searched Food and Drug Administration (FDA) dockets by performing a hand search of all documents submitted for drug approval labeling change as well as the FDA meeting minutes available on the FDA Web site. Eligible trials had to fulfill the following criteria: (1) RCTs comparing the above drug classes; (2) cohort with HF and reduced systolic function on conventional HF therapy (including diuretics, b-blockers, and angiotensin-converting enzyme inhibitors); (3) follow-up of at least 3 months; (4) enrolling at least 100 patients; and (5) able to report the outcomes of interest (below). Selection and Quality Assessment Two authors (S.B. and S.K.) independently assessed trial eligibility and trial bias risk and extracted data (j=0.96). Disagreements were resolved by consensus. The bias risk of trials were assessed using the components recommended by the Cochrane Collaboration: 6 sequence generation of the allocation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. Trials with high or unclear risk for bias for any one of the first 3 components were considered as trials with a high risk of bias. Otherwise, they were considered as trials with a low risk of bias. Data Extraction and Synthesis The following outcomes were evaluated: efficacy outcomes were death, cardiovascular (CV) death, nonfatal myocardial infarction, stroke, HF hospitalization, and the composite of CV death or HF hospitalization. Safety outcomes evaluated were hyperkalemia, renal failure, and hypotension. Statistical analyses Mixed Treatment Comparisons. Mixed treatment comparison methods on all available networks of treatment comparisons were used to compare the different treatment regimens using WinBUGS code published by the UK Medical Research Council Health Services Research Collaboration. 7 The network meta-analysis allows for comparisons of agents not directly addressed within any of the individual trials such that in addition to analyzing the direct within-trial comparisons between two treatments (such as treatment A vs B), the network framework enabled us to incorporate the indirect comparisons from two trials that have one treatment in common (such as comparison of treatment A vs C using trials comparing A vs B and B vs C). The analysis has the advantage of maintaining the within-trial randomized treatment comparison of each trial while combining all available comparisons between treatments. Moreover, the network meta-analysis produces tighter confidence intervals, implying greater precision of the estimates. For the purpose of analysis, the trials were grouped into four categories: placebo, ARBs aldosterone antagonists, and DRIs. The analysis compared ARBs, aldosterone antagonists, or DRIs with placebo, which was used as the reference. A random-effects Poisson regression model was fitted after taking into account the correlation structure induced by the multi-arm trials. 8 The analysis used the rate of efficacy and safety outcomes per 1000 person-years to obtain the log rate ratios of one treatment relative to another treatment. Rates, rather than number of events, were considered the most appropriate outcome for this analysis because they incorporate the duration of the trials. Patientyears of follow-up were calculated by multiplying the sample size with the mean follow-up duration. Calculation of the probability that each treatment is best (lowest event proportion) was performed using a Bayesian Markov chain Monte Carlo method, adapted to apply to a connected network set of treatment comparisons. Minimally informative prior distributions were used for comparisons of treatments, so the findings and interpretation are close to those obtained with frequentist methods. All network analyses were conducted using WinBUGS Sensitivity analyses were performed after excluding trials that included patients with post myocardial infarction left ventricular systolic dysfunction. Role of the Funding Source This work was not funded and hence there was no role of any funding source in the conception, data synthesis, analysis, data interpretation, or drafting of the manuscript. RESULTS Study Selection We identified 16 RCTs that satisfied our inclusion criteria (Figure 1). The network of treatment comparisons is shown in Figure 2. Trials that compared ACE inhibitor+arb vs an ACE inhibitor were considered as ARB vs placebo trials for the purpose of this analysis (the Randomized Evaluation of Strategies for Left Ventricular Dysfunction [RESOLVD], Valsartan in Acute Myocardial Infarction [VALIANT], Yashumura and colleagues trials). We excluded the ARBs-only arm of the RESOLVD and VALIANT trials because these patients were not taking ACE inhibitors by design. Of the 16 trials, 6 trials compared ARBs vs placebo, 8 trials compared aldosterone antagonists vs placebo, and 2 trials compared DRIs vs placebo. The network of available treatment comparisons is shown in Figure 1. Of these, 4 trials (the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study [EPHESUS], VALIANT, Weir and colleagues, Aliskiren Study in Post-MI Patients to Reduce Remodeling [ASPIRE] trials) enrolled patients with post myocardial 108 Congest Heart Fail Vol. 19 No. 3 May. June 2013

3 Records identified through database searching using terms Heart failure, RCT and Human = 5702 Record screened=5702 Trials excluded (based on title and/abstract) not involving an ARB, DRI or AA=5502 Full-text articles assessed for eligibility (n = 200) Full-text articles excluded due to total number of patients less than 100 or total duration of study less than 3 months (n = 169) Studies included in qualitative synthesis (n = 31) Trials excluded (N=15) Outcome of interest not reported (n=6) Case control studies (n=3) Duplicate publication (n=3) Meta-analysis (n=3) Trial included in the meta-analysis = 16 FIGURE 1. Study selection. RCT indicates randomized controlled trial; ARB, angiotensin receptor blocker, DRI, direct renin inhibitor; AA, aldosterone antagonist. FIGURE 2. Network of treatment comparisons. The link between the treatments are trials representing either direct comparison (solid line) or indirect comparison (dotted lines). The numbers along the link represents the number of trial arms providing direct comparison between the drug classes. ARB indicates angiotensin receptor blocker, DRI, direct renin inhibitor; AA, aldosterone antagonist. infarction left ventricular systolic dysfunction. This later group was excluded in a sensitivity analysis. Baseline Characteristics Baseline characteristics and quality analysis are summarized in Table I and Table II. The 16 RCTs enrolled 31,429 participants who were followed up for a mean of 16.2 months (range: 3 41 months). The average age was 6311 years, and an average left ventricular ejection fraction of 31%7%. Table II shows the conventional HF treatment used in the included trials. While the proportion of patients taking ACE inhibitors was high in most of the trials, the proportion of patients taking b-blockers was variable and dismally low in a few trials. Similarly, the use of implantable cardioverterdefibrillators (ICDs) or cardiac resynchronization therapy (CRT) was low in the few trials that reported these data (Table II). Efficacy Outcomes When compared with placebo (reference rate ratio of 1), aldosterone antagonists reduced the rate of death (21% reduction) (Figure 3a), cardiovascular death (22% reduction) (Figure 3b), HF hospitalization (26% reduction) (Figure 3c), and the composite of cardiovascular death or HF hospitalization (27% reduction) (Figure 3d), with no difference for other efficacy outcomes (data not shown). However, ARBs did not result Congest Heart Fail Vol. 19 No. 3 May. June

4 TABLE I. Baseline Characteristics of Included Trials Study Year Total, No. Treatment Groups Follow- Up, mo Mean Age, y Men, % Diabetes, % Ischemic Etiology, % NYHA Class III IV, % LVEF, % ALOFT Aliskiren vs placebo AREA IN-CHF Canrenone vs placebo NA 0 40 ASPIRE Aliskiren vs placebo NA 38 CHARM-added Candesartan vs placebo Cice et al Telmisartan vs placebo NA Cicoira et al Spironolactone vs placebo NA 64 NA 33 EMPHASIS-HF Eplerenone vs placebo EPHESUS Eplerenone vs placebo NA 33 Gao et al Spironolactone vs placebo NA RALES Spironolactone vs placebo NA RESOLVD Enalapril+candesartan NA vs enalapril Udelson et al Eplerenone vs Placebo Val-HeFT Valsartan vs placebo VALIANT Captopril+valsartan vs NA 35 captopril Weir et al Eplerenone vs placebo NA 34 Yasumura et al ACE inhibitor + ARB vs ACE inhibitor or ARB NA 43 NA NA Abbreviations: ACE, angiotensin-converting enzyme; ALOFT, Aliskiren Observation of Heart Failure Treatment; AREA IN-CHF, Anti-Remodelling Effect of Canrenone in Patients With Mild Chronic Heart Failure; ARBs, angiotensin receptor blockers; ASPIRE, Aliskiren Study in Post-MI Patients to Reduce Remodeling; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; EMPHASIS-HF, Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure; EPHESUS, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study; HTN, hypertension; LVEF, left ventricular ejection fraction; NA, not available; NYHA, New York Heart Association; RALES, Randomized Aldactone Evaluation Study; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction. TABLE II. Inclusion and Exclusion Criteria and Bias-Risk Assessment of Trials Study Baseline ACE Inhibitor, a % Baseline BB, % Baseline Diuretics, % Baseline Digitalis, % Baseline ICD CRT, % Risk of Bias b ALOFT NA NA NA +++ AREA IN-CHF ASPIRE NA NA NA +++ CHARM-Added Cice et al NA 51.5 NA +++ Cicoira et al NA NA NA +) EMPHASIS-HF EPHESUS NA NA +++ Gao et al RALES RESOLVD NA ++ Udelson et al NA NA +++ Val-HeFT NA +++ VALIANT NA Weir et al NA NA NA ++ Yasumura et al NA NA NA +)) Abbreviations: ACE, angiotensin-converting enzyme; BB, b-blockers; CRT, cardiac resynchronization therapy; ICD, implantable-cardioverter defibrillator; NA, not available. See footnote of Table I for expansion of trial names. a Trials evaluating ACE inhibitor+arb vs ACE inhibitor (considered as ARB vs placebo for this analysis) were considered to have baseline ACE inhibitor usage of 100%. b Based on sequence generation, allocation concealment, and blinding. +, ) and represents low, high and unclear risk of bias, respectively. in any significant reduction in the rate of any of the efficacy outcomes (Figure 3a d). DRIs, when compared with placebo, did not result in any significant reduction in the rate of any of the efficacy outcomes (Figure 3a d). In the head-to-head comparisons of active comparators, there was no difference for any of the efficacy 110 Congest Heart Fail Vol. 19 No. 3 May. June 2013

5 significant increase in the rate of either renal failure or hypotension when compared with placebo, although the point estimates suggested similar increased risk (Figure 4a c). In addition, DRIs were associated with a 98% increase in the rate of hypotension, although there was no significant increase in the rate of either hyperkalemia or renal failure when compared with placebo although the point estimates suggested a similar increased risk (Figure 4a c). In the head-to-head comparisons of active comparators, there was no difference for any of the safety outcomes for any combination of comparators (Figure 4a c). Table IV summarizes the event rate per 1000 patient-years of follow-up and the probability that each treatment is the best (lowest event proportion). When compared with placebo, ARBs resulted in 22 excess cases of hyperkalemia, 15 excess cases of renal failure, and 18 excess cases of hypotension (Table IV) for every 1000 patient-years of follow-up. Similarly, when compared with placebo, aldosterone antagonists resulted in 18 excess cases of hyperkalemia, 5 excess cases of renal failure, and 10 excess cases of hypotena b c d FIGURE 3. (a) Results from a mixed treatment comparison analysis on the outcome of death. (b) Results from a mixed treatment comparison analysis on the outcome of cardiovascular death. (c) Results from a mixed treatment comparison analysis on the outcome of heart failure hospitalization. (d) Results from a mixed treatment comparison analysis on the composite outcome of cardiovascular death or heart failure hospitalization. The numbers represent rate ratio and 95% credibility intervals. AA indicate aldosterone antagonist; ARBs, angiotensin receptor blockers; DRI, direct renin inhibitor. outcomes for any combination of comparators, although the point estimate favored aldosterone antagonists compared with either ARBs or DRIs (Figure 3a d). Table III summarizes the rate per 1000 patient-years of follow-up and the probability that each treatment is the best (lowest event proportion). When compared with placebo, aldosterone antagonists resulted in 9 fewer deaths, 6 fewer cardiovascular deaths, 25 fewer HF hospitalizations, and 44 fewer CV deaths or HF hospitalizations (Table III) per 1000 patient-years of follow-up, and there was >70% to 90% probability that aldosterone antagonists were the best (lowest event proportion) compared with ARBs, DRIs, or placebo (Table III) for these outcomes. Safety Outcomes When compared with placebo (reference rate ratio of 1), ARBs increased the rate of hyperkalemia (138% increase) (Figure 4a), renal failure (126% increase) (Figure 4b), and hypotension (63% increase) (Figure 4c). Similarly, aldosterone antagonists resulted in a 110% increase in the rate of hyperkalemia, with no Congest Heart Fail Vol. 19 No. 3 May. June

6 TABLE III. Rate of Selected Efficacy Outcomes (Per 1000 Patient-Year Follow-Up) and the Probability That Each Treatment Is the Best (Lowest Rate Ratio) From Mixed Treatment Comparison Analysis Probability Best, % CV death or HF Hospitalization Rate (95% CrI) Probability Best, % HF Hospitalization Rate (95% CrI) CV Death Rate (95% CrI) Probability Best Death Rate Treatment Rate (95% CrI) Probability Best, % Placebo ( ) ( ) ( ) ( ) 0.1 ARBs ( ) ( ) ( ) ( ) 3.1 AA ( ) ( ) ( ) ( ) 86.9 DRIs ( ) ( ) ( ) ( ) 9.9 Abbreviations: AA, aldosterone antagonists; ARBs, angiotensin receptor blockers; CrI, credibility interval; CV, cardiovascular; DRIs, direct renin inhibitors; HF, heart failure. Higher the % probability best, lower the rate of outcomes (and better is the treatment for that outcome). Rates are for 1000 patient-years of follow-up. sion (Table IV) for every 1000 patient-years of followup. As expected, for all of these adverse safety outcomes, placebo had a greater probability of being the best treatment (lowest event proportion) compared with aldosterone antagonists, ARBs, and DRIs. Sensitivity Analysis In a sensitivity analysis, even after excluding trials of post myocardial infarction left ventricular systolic dysfunction, the above results were largely unchanged (Table V). DISCUSSION We assessed the risk benefit ratio of addition of an ARB, aldosterone antagonist, or DRI in patients with HF on conventional HF therapy. When compared with placebo, we found a significant benefit of addition of an aldosterone antagonist rather than ARBs or DRIs for the reduction of death, cardiovascular death, HF hospitalization, or the composite of cardiovascular death or HF hospitalization. When compared with placebo, ARBs were associated with a significant increase in the rate of hyperkalemia, renal failure, and hypotension. Similarly, when compared with placebo, aldosterone antagonists were associated with an increase in hyperkalemia and DRI with an increase in hypotension, with the point estimate suggesting a similar increase in other safety outcomes (although statistically nonsignificant). The risk-benefit profile therefore seems to favor the addition of an aldosterone antagonist rather than ARB or DRI in patients with systolic HF who continue to be symptomatic on conventional HF therapy. HF Treatment Previous randomized trials have shown the beneficial effect of b-blockers and ACE inhibitors in patients with systolic HF. 9,10 However, it has also been shown that chronic treatment with ACE inhibitors leads to continued production of angiotensin II (ACE escape) through non-ace pathways, thus mitigating the beneficial effects of ACE inhibitors to a certain extent. By blocking the AT1 receptors (downstream pathway), ARBs are not affected by ACE escape. Similarly, by blocking the upstream pathway of renin, DRIs are also not influenced by ACE escape. A combination of either ARBs or DRIs with an ACE inhibitor has thus been proposed to provide a more complete RAS blockade. Indeed, some trials have shown the beneficial effects of both an ARB 11 and an aldosterone antagonist 12 in symptomatic patients taking conventional HF medications including an ACE inhibitor. A major concern with dual RAAS blockade (either aldosterone antagonists, ARBs, or DRIs) in HF is the safety issue. In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Added, hyperkalemia was almost 5 times more common, and elevated creatinine occurred twice as much with the addition of candesartan than with 112 Congest Heart Fail Vol. 19 No. 3 May. June 2013

7 a b c FIGURE 4. (a) Results from a mixed treatment comparison analysis on the safety outcome of hyperkalemia. (b) Results from a mixed treatment comparison analysis on the safety outcome of renal failure. (c) Results from a mixed treatment comparison analysis on the safety outcome of hypotension. The numbers represents rate ratio and 95% credibility intervals. AA, aldosterone antagonist; ARBs, angiotensin receptor blocker; DRI, direct renin inhibitor. TABLE IV. Rate of Selected Safety Outcomes (Per 1000 Patient-Year Follow-Up) and the Probability That Each Treatment Is the Best (Lowest Rate Ratio) From Mixed Treatment Comparison Analysis Treatment Hyperkalemia Rate (95% CrI) Probability Best, % Renal Failure Rate (95% CrI) Probability Best, % Hypotension Rate (95% CrI) Probability Best, % Placebo ( ) ( ) ( ) 84.3 ARBs ( ) ( ) ( ) 0.1 AA ( ) ( ) ( ) 13.5 DRIs ( ) ( ) ( ) 2.1 Abbreviations: AA, aldosterone antagonists; ARBs, angiotensin receptor blockers; CrI, credibility interval; CV, cardiovascular; DRIs, direct renin inhibitors; HF, heart failure. Higher the percentage probability best, lower the rate of outcomes (and better is the treatment for that outcome). Rates are for 1000 patient-years of follow-up. TABLE V. Sensitivity Analyses of Selected Outcomes After Excluding Trials Enrolling Patients With Left Ventricular Systolic Dysfunction Post Myocardial Infarction Treatment Death CV Death HF Hospitalization CV Death or HF Hospitalization Hyperkalemia Renal Failure Hypotension Placebo (Reference) ARBs 0.94 ( ) 0.90 ( ) 0.78 ( ) 0.89 ( ) 3.87 ( ) 3.07 ( ) 1.89 ( ) AA 0.74 ( ) 0.73 ( ) 0.67 ( ) 0.67 ( ) 2.27 ( ) 1.48 ( ) 1.42 ( ) DRI 0.36 ( ) NR 1.62 ( ) 0.93 ( ) 1.40 ( ) 1.54 ( ) 2.91 ( ) ARBs (Reference) AA 0.78 ( ) 0.82 ( ) 0.86 ( ) 0.76 ( ) 0.59 ( ) 0.47 ( ) 0.75 ( ) DRI 0.37 ( ) NR 2.06 ( ) 1.02 ( ) 0.37 ( ) 0.48 ( ) 1.53 ( ) AA (Reference) DRI 0.49 ( ) NR 2.42 ( ) 1.39 ( ) 0.62 ( ) 1.02 ( ) 2.05 ( ) Abbreviations: AA, aldosterone antagonist; ARBs, angiotensin receptor blockers; CV, cardiovascular; DRI, direct renin inhibitor; HF, heart failure; NR, not reported. Values are expressed as rate ratio (95% credibility interval). placebo in patients taking ACE inhibitors. 11 A recent meta-analysis in more than 18,000 patients with left ventricular dysfunction showed a significantly increased risk of adverse events leading to the discontinuation of dual RAAS blockade (ARBs+ACE inhibitor) compared with monotherapy (ACE inhibitor). 13 Thus, hypotension, worsening of renal function, and hyperkalemia were more common with combination therapy than with ACE inhibitor therapy alone. Similarly, Kuenzli and colleagues 13 found no benefit of dual RAAS blockade (ARBs+ACE inhibitor) compared with ACE inhibitor but more hyperkalemia, renal dysfunction, and hypotension. The analysis found benefit for the outcome of hospitalization due to HF; however, there was significant heterogeneity in this analysis. Our analysis is concordant with this study in that Congest Heart Fail Vol. 19 No. 3 May. June

8 there was no benefit of ARBs when compared with placebo. However, for certain outcomes, such as hospitalization for HF, the point estimate favored ARBs over placebo (although not statistically significant). In addition, the adverse profile of this dual RAAS blockade (ARBs+ACE inhibitor) was not favorable in that it increased the risk of hyperkalemia, renal failure, and hypotension. In contrast, addition of aldosterone antagonists to patients already taking an ACE inhibitor not only reduced hospitalization for HF but also all-cause mortality and cardiovascular mortality. However, aldosterone antagonists were also associated with hyperkalemia. The pathogenesis of hyperkalemia with aldosterone inhibition is different from the one with the ACE inhibitor ARB combination. Aldosterone inhibition slows down the Na K exchange at the distal tubule and has little if any glomerular effects unless there is excessive diuresis. In contrast, the ACE inhibitor ARB combination only inconsistently affects aldosterone secretion but causes hyperkalemia predominantly by decreasing glomerular filtration rate secondary to dilating the efferent arteriole. Not surprisingly, renal failure was observed significantly more often with the ACE inhibitor ARB combination than with aldosterone antagonists. Similarly, the risk profile of the DRIs was also not favorable. Of note, in our efficacy analyses in the indirect head-to-head comparisons of active comparators, there was no difference for any of the outcomes for any combination of comparators, although the point estimate favored aldosterone antagonists compared with either ARBs or DRIs. Not only were aldosterone antagonists beneficial compared with placebo, but the point estimate favored it in comparison with active comparators. This, together with a probability of >70% to 90% to be the best among the four treatment comparators, allows us to reasonably conclude that the aldosterone antagonists are more effective than either ARBs or DRIs. From a safety perspective, however, any combination of dual RAAS blockade is associated with excess adverse events and these patients need to be closely monitored. LIMITATIONS As in other meta-analyses, given the lack of data in each trial, we did not adjust our analyses for dosage of medications used or with compliance to assigned treatment. All of the trials did not report each of the outcomes tested. Accordingly, we are not able to exclude outcome measure reporting bias. Of note, the percentage of patients taking b-blockers and those who received ICD CRT was low in a few trials that reported this. It is unknown whether the mortality benefit seen with aldosterone antagonists would persist in the presence of increased use of therapies known to reduce mortality. In addition, there were only a limited number of trials involving DRIs and it is possible that the results might change when newer trials with larger sample sizes show any beneficial effect of DRIs. CONCLUSIONS Given the adverse effects and lack of consistent cardiovascular benefits, the routine addition of an ARB or DRI to ACE inhibitor therapy in HF patients should be avoided or used only in select patients who cannot tolerate aldosterone blockade. The data in aggregate seem to favor aldosterone antagonists over ARBs or DRIs as preferred add-on therapy in these patients. Regardless of which drug class is added, dual RAAS blockade will require strict monitoring of potassium and renal function and a careful follow-up for symptoms and signs of hypotension. Acknowledgments and disclosures: Dr Bangalore had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis and had the final responsibility to submit for publication. Study concept and design: Drs Bangalore and Messerli. Acquisition of data: Drs Bangalore and Kumar. Analysis and interpretation of data: Drs Bangalore and Messerli. Drafting of manuscript: Dr Bangalore and Messerli. Critical revision of the manuscript for important intellectual content: Drs Bangalore, Kumar, and Messerli. Statistical analysis: Dr Bangalore. Study supervision: Drs Bangalore and Messerli. Sripal Bangalore: Advisory boards: Daiichi Sankyo and Boehringer Ingelheim; Sunil Kumar: None; Franz H. Messerli: Ad hoc consultant/speaker for the following organizations: Novartis, Daiichi Sankyo, Abbott. Grant support from Novartis, Forest, and Boehringer Ingelheim. 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