Renin–angiotensin–aldosterone system inhibition in heart failure with mid-ranged ejection fraction: A systematic review and meta-analysis

Heart failure with mid-ranged ejection fraction (HFmrEF) has emerged as a new clinical entity in heart failure), encompassing the left ventricular ejection fraction range of 40–49%. This positions it squarely between heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), making up to 20% of all heart failure patients.1 The likeness of HFmrEF to either HFpEF or HFrEF in terms of clinical characteristics, outcomes and treatment options has been a topic of great debate in recent times. Renin–angiotensin–aldosterone system (RAAS) inhibitors, which have been shown to be clearly effective in HFrEF,2 but not in HFpEF,3 have yet to be proven efficacious in HFmrEF. We performed a systematic review and meta-analysis to address this question. This systematic review and meta-analysis was conducted in compliance with Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA).4 Two independent investigators (MMM and MSK) queried Medline, Scopus, Embase and Cochrane CENTRAL using a comprehensive search strategy from database inception dates to 9 October 2018 for randomized controlled trials (RCTs) or observational studies. The detailed search strategy employed in each database is provided in Supplementary Material Table S1 online. Studies reporting outcomes in HFmrEF patients receiving RAAS inhibitors (angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) or aldosterone antagonists) were included. Hazard ratios with 95% confidence intervals (CIs) were extracted and pooled using a random-effects model to assess the association of RAAS inhibition and adverse events. In cases where hazard ratios were not provided, raw event rates and totals were used to calculate risk ratios and were pooled with hazard ratios. Publication bias was assessed using Egger’s regression test. Quality of included studies was evaluated using the Newcastle–Ottawa scale for observational studies and Cochrane Risk of Bias Tool (CRBT) for RCTs. Heterogeneity in effect estimates was quantified using Higgin’s I2 statistic; I2 > 75% was considered significant. Review Manager (Version 5.3; Cochrane Collaboration, Oxford, UK) was used for meta-analysis. Two RCTs3,5 (1842 patients) and four observational studies6,,–9 (three prospective; one retrospective) (5682 patients) enrolling a total of 7524 HFmrEF patients (37% female, mean age 71 years) were included in our meta-analysis. Supplementary Figure S1 illustrates the PRISMA flowchart outlining the search procedure. Patient demographics and study characteristics of the included studies are listed in Table 1. Egger’s regression test did not indicate any evidence of publication bias (p = 0.476). Newcastle–Ottawa scale (Supplementary Table S2) and CRBT (Supplementary Figure S2) showed an overall low risk of bias among observational studies and RCTs respectively. Study characteristics and patient demographics of the included studies. Heart failure patients without coronary artery disease. ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; HFmrEF: heart failure with mid-range ejection fraction; LVEF: left ventricular ejection fraction; RCT: randomized controlled trial; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist; SwedeHF: Swedish Heart Failure Registry; CHART-2: Chronic Heart Failure Analysis and Registry in the Tohoku District-2; KorAHF: Korean Acute Heart Failure; CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; N/S: not specified Study characteristics and patient demographics of the included studies. Heart failure patients without coronary artery disease. ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin receptor blocker; HFmrEF: heart failure with mid-range ejection fraction; LVEF: left ventricular ejection fraction; RCT: randomized controlled trial; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist; SwedeHF: Swedish Heart Failure Registry; CHART-2: Chronic Heart Failure Analysis and Registry in the Tohoku District-2; KorAHF: Korean Acute Heart Failure; CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; N/S: not specified Forest plot assessing the association between renin–angiotensin–aldosterone system inhibition and adverse cardiac events. IV: inverse variance; CI: confidence interval; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; SwedeHF: Swedish Heart Failure Registry;CHART-2: Chronic Heart Failure Analysis and Registry in the Tohoku District-2; KorAHF: Korean Acute Heart Failure; CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Forest plot assessing the association between renin–angiotensin–aldosterone system inhibition and adverse cardiac events. IV: inverse variance; CI: confidence interval; ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin II receptor blocker; SwedeHF: Swedish Heart Failure Registry;CHART-2: Chronic Heart Failure Analysis and Registry in the Tohoku District-2; KorAHF: Korean Acute Heart Failure; CHARM: Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; TOPCAT: Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist This meta-analysis suggests that RAAS inhibition using ACEIs and ARBs is associated with lower risk of all-cause mortality and heart failure hospitalization in HFmrEF. Aldosterone antagonists did not show any significant association with all-cause mortality or heart failure hospitalization, suggesting that the pathophysiology of HFmrEF may have greater involvement with the renin and angiotensin components of RAAS than aldosterone. In addition, blood pressure reduction is a major effect of RAAS blockade, independent of the level at which it is carried out.10 HFmrEF patients have been shown to exhibit systolic blood pressures higher than HFrEF but lower than HFpEF,1 potentially explaining why RAAS inhibitors are more effective in these patients. These findings favor the argument that HFmrEF is an intermediate phenotype of HFrEF and HFpEF, as opposed to a completely distinct entity. Given the dearth of established treatment strategies for HFmrEF, ACEIs and ARBs may serve as effective therapeutic options for this sizable population. This meta-analysis is not without limitations. First, the low number of studies reduces the power of this meta-analysis. Second, subgroup analyses specific to dosages and drugs within each class (ACEI, ARB or aldosterone antagonists) could not be carried out due to lack of reported information in included studies. Additionally, ACEIs and ARBs could not be evaluated individually as they were reported as a unified group by most studies. Third, the effect of RAAS inhibition in heart failure patients with changing ejection fraction (improved or deteriorated) could not be studied. Last, difficulty in identifying HFmrEF due to differences in clinical characteristics of patients with improved or deteriorated ejection fraction limits the generalizability of our findings.11 An abstract of this study has been accepted for presentation in American College of Cardiology Scientific Sessions 2019.