Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure

: BACKGROUND Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m 2 ; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m 2 , and 2,286 (13.7%) 30 to 44 ml/min/1.73 m 2 . Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m 2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m 2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m 2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m 2 ) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction. ABSTRACT BACKGROUND Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES This study sought to investigate patient prognosis and the ef ﬁ cacy of beta-blockers according to renal function using estimated glomerular ﬁ ltration rate (eGFR). METHODS Analysis of 16,740 individual patients with left ventricular ejection fraction < 50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and strati ﬁ ed by heart rhythm. RESULTS Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m 2 ; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m 2 , and 2,286 (13.7%) 30 to 44


Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure
H eart failure (HF) is associated with numerous comorbidities, of which renal dysfunction is both common and of particular importance due to its impact on mortality as well as on the use of guideline-recommended therapies (1). Patients with HF have a higher incidence of renal dysfunction due to shared pathophysiological pathways and mutual risk factors. In We examined the effect of renal dysfunction on outcomes in patients with HF and reduced ejection fraction (HFrEF) using the totality of individual patient data (IPD) from the landmark, double-blind, randomized controlled trials (RCTs) comparing betablockers with placebo (11). The Beta-Blockers in Heart Failure Collaborative Group is a multinational project that has systematically harmonized clinical trial data to improve management and outcomes in patients with HF (12)(13)(14)(15). In this study, we tested the hypothesis that compared with placebo, betablockers reduce mortality in patients with moderate and moderately severe renal dysfunction. Further, we looked at the prognostic impact of renal dysfunction and associated variables, and how change in renal function affects mortality.

METHODS
The Beta-Blockers in Heart Failure Collaborative  (11). IPD were obtained for all 11 trials identified in the systematic review, and data were extracted from original source OUTCOME. The outcome for this analysis was allcause mortality, which included additional deaths reported after the censor date for 7 studies (18)(19)(20)24,25,27,28). There were no patients with missing vital status. STATISTICAL ANALYSIS. A statistical analysis plan was generated and finalized by the Collaborative Group in advance of data analysis. Summary results are presented as percentages, or median and interquartile range (displayed as 25th to 75th quartiles).
Group comparisons were made using the Kruskal Wallis nonparametric rank test. Fractional polynomials were used to find the best transformation of eGFR in adjusted analysis, including nonlinear relationships (for sinus rhythm, the best fit was the inverse square root, and for AF the inverse squared eGFR).
All analyses of beta-blockers versus placebo followed the principle of intention to treat. Outcomes were analyzed using a Cox proportional hazards regression model stratified by study and grouped by heart rhythm and eGFR category. This is a 1-stage fixed-effects approach and assumes that all trials are estimating a common treatment effect with baseline hazards that vary across studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) are presented, along with corresponding p values. We pre-specified adjustment in Cox models for baseline age, sex, LVEF, history of myocardial infarction, systolic blood pressure, heart rate, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and diuretic therapy. Only a minority of patients were followed for an extended period, and therefore data were censored at 1,200 days (3.3 years) from randomization.
Effect modification was assessed using p values from interaction terms fitted in the multivariable models. The interactions of continuous eGFR with mortality or beta-blocker efficacy were assessed using cubic splines in the Cox model and the Royston-Parmar flexible parametric survival model (30).
There was no evidence of violation of the proportional hazards assumption in any multivariable model as determined by Schoenfeld residuals. Kaplan-Meier plots were used to graph the pooled, unadjusted data 3) exclusion of CAPRICORN (the only post-infarct trial) and BEST (utilizing a pharmacologically distinct beta-blocker). We also performed sensitivity analyses using all available eGFR measurements for interaction analyses, rather than just the central 99%.
Heterogeneity for pooled outcomes was assessed using the I 2 statistic from a fixed-effects 2-stage model.
We performed post hoc analyses: 1) according to dose achieved at interim follow-up; 2) to assess the relationship between proteinuria and worsening renal function; and 3) using the CKD-EPI (Chronic Kidney     Table 4). In 2,879 patients with AF at baseline, there was no significant reduction in mortality with beta-blockers in any category of eGFR, and no interaction of beta-blocker efficacy with continuous eGFR (p for interaction ¼ 0.18) ( Table 3, Figure 2).    Table 2). eGFR ¼ estimated glomerular filtration rate.
In patients with sinus rhythm and moderate or moderately severe renal impairment, 77% managed to reach one-half of the target dose of beta-blocker or greater (compared with 80% with eGFR 60 to 89 ml/ min/1.73 m 2 and 84% with eGFR $90 ml/min/1.73 m 2 ) (Online Table 6). These patients had substantially better prognosis than those at lower dose levels (Online Figure 3); however, the same pattern was also seen in patients randomized to placebo. Across both sinus rhythm and AF, discontinuation of betablockers was similar to that seen with placebo in patients with moderate and moderately severe renal dysfunction. This was the case for all adverse events leading to therapy discontinuation, and also those specifically related to renal impairment (Online Table 7). Overall, discontinuation rates for both beta-blockers and placebo were higher in those with more advanced renal dysfunction.