A Comparative Study of Carvedilol Versus Metoprolol Initiation and 1-Year Mortality Among Individuals Receiving Maintenance Hemodialysis

Abstract

Background: Carvedilol and metoprolol are the β-blockers most commonly prescribed to US hemodialysis patients, accounting for ∼80% of β-blocker prescriptions. Despite well-established pharmacologic and pharmacokinetic differences between the 2 medications, little is known about their relative safety and efficacy in the hemodialysis population.

Study design: A retrospective cohort study using a new-user design.

Setting & participants: Medicare-enrolled hemodialysis patients treated at a large US dialysis organization who initiated carvedilol or metoprolol therapy from January 1, 2007, through December 30, 2012.

Predictor: Carvedilol versus metoprolol initiation.

Outcomes: All-cause mortality, cardiovascular mortality, and intradialytic hypotension (systolic blood pressure decrease ≥ 20mmHg during hemodialysis plus intradialytic saline solution administration) during a 1-year follow-up period.

Measurements: Survival models were used to estimate HRs and 95% CIs in mortality analyses. Poisson regression was used to estimate incidence rate ratios (IRRs) and 95% CIs in intradialytic hypotension analyses. Inverse probability of treatment weighting was used to adjust for several demographic, clinical, laboratory, and dialysis treatment covariates in all analyses.

Results: 27,064 individuals receiving maintenance hemodialysis were included: 9,558 (35.3%) carvedilol initiators and 17,506 (64.7%) metoprolol initiators. Carvedilol (vs metoprolol) initiation was associated with greater all-cause (adjusted HR, 1.08; 95% CI, 1.02-1.16) and cardiovascular mortality (adjusted HR, 1.18; 95% CI, 1.08-1.29). In subgroup analyses, similar associations were observed among patients with hypertension, atrial fibrillation, heart failure, and a recent myocardial infarction, the main cardiovascular indications for β-blocker therapy. During follow-up, carvedilol (vs metoprolol) initiators had a higher rate of intradialytic hypotension (adjusted IRR, 1.10; 95% CI, 1.09-1.11).

Limitations: Residual confounding may exist.

Conclusions: Relative to metoprolol initiation, carvedilol initiation was associated with higher 1-year all-cause and cardiovascular mortality. One potential mechanism for these findings may be the increased occurrence of intradialytic hypotension after carvedilol (vs metoprolol) initiation.

Keywords: Beta-blocker; blood pressure; cardiovascular; carvedilol; dialyzability; end-stage renal disease (ESRD); hemodialysis; hypotension; intradialytic hypotension (IDH); metoprolol; mortality; pharmacoepidemiology.

Figure 1.. Study design

Carvedilol and metoprolol initiators were defined as hemodialysis patients who had no record of a beta-blocker prescription in the previous 180 days (beta-blocker washout period). Among these patients, the index date was defined as the date of carvedilol or metoprolol initiation. Baseline covariates were identified in the 180-day period prior to the index date. Study follow-up began immediately after the index date. To ensure all potential study patients were eligible for Medicare coverage regardless of their age, individuals needed to have a dialysis vintage > 90 days at the start of the baseline period. Abbreviations: Rx, prescription

Figure 2.. Flow diagram depicting the assembly of the study cohort

Abbreviations: LDO, large dialysis organization

Figure 3.. Association between carvedilol versus metoprolol initiation and 1-year mortality: intent-to-treat analysis

An intent-to-treat design was employed in all analyses. Cox proportional hazards models were used to estimate the association between carvedilol (versus metoprolol) initiation and 1-year all-cause mortality. Fine and Gray proportional subdistribution hazards models were used to estimate the association between carvedilol (versus metoprolol) initiation and 1-year cardiovascular mortality. In cardiovascular mortality analyses, non-cardiovascular death was treated as a competing risk. Inverse probability of treatment weighting was used in adjusted analyses to control for all the baseline covariates listed in Table 1. Abbreviations: CI, confidence interval; HR, hazard ratio; ref., referent

Figure 4.. Association between carvedilol versus metoprolol initiation and 1-year cardiovascular mortality among individuals with and without a recent history of intradialytic hypotension: intent-to-treat analysis

An intent-to-treat design was employed in all analyses. Fine and Gray proportional subdistribution hazards models were used to estimate the association between carvedilol (versus metoprolol) initiation and 1-year cardiovascular mortality. In these analyses, non-cardiovascular death was treated as a competing risk. Inverse probability of treatment weighting was used in adjusted analyses to control for all the baseline covariates listed in Table 1. Abbreviations: CI, confidence interval; HR, hazard ratio; ref., referent