Influence of Beta-Blocker Continuation or Withdrawal on Outcomes in Patients Hospitalized With Heart Failure

Findings From the OPTIMIZE-HF Program

Methods

Results

The OPTIMIZE-HF program enrolled a total of 48,612 patients hospitalized for HF at 259 U.S. hospitals. This analysis was confined to those patients from 91 hospitals participating in the hospital registry and pre-specified 60- to 90-day post-discharge follow-up. Of the 5,791 patients in the pre-specified cohort with 60- to 90-day follow-up data collection, left ventricular function was assessed in 5,117 patients, and 2,720 patients had documented LVSD. Patient demographics for the hospital and follow-up cohort with LVSD are shown in Table 1. The mean patient age in the follow-up group was 69.5 ± 14.5 years; 63% of the patients were men, and 75% were Caucasian. The HF etiology was ischemic in 52% of the patients; the mean LVEF was 24.3 ± 7.8%, and 89.3% of patients had known HF before admission. At hospital admission, pulmonary rales were present in 62% of patients, an S₃ gallop was present in 18%, and lower extremity edema was found in 63%. Medications on admission included a beta-blocker in 57% of patients, an angiotensin-converting enzyme inhibitor in 47%, an angiotensin receptor blocker in 12%, an aldosterone antagonist in 10%, and digoxin in 30%.

Patients were hospitalized for a mean of 6.4 days (median 5.0 days). Of the 2,720 patients with LVSD, 2,373 (87.2%) were eligible for beta-blocker therapy at the time of hospital discharge, with no documented contraindications or intolerance. There were 347 patients (12.8%) ineligible because of contraindications or intolerance to beta-blocker therapy at hospital discharge (n = 299) or discharge to skilled nursing care facility, transfer, or hospice (n = 48). Of the 2,373 patients eligible for beta-blocker therapy at hospital discharge, 1,350 patients (56.9%) were continued on beta-blocker therapy, 79 (3.3%) were withdrawn from beta-blocker therapy, and 303 (12.8%) were not treated. There were 632 patients (26.6%) newly started on beta-blocker therapy and 9 patients with missing treatment data (0.4%). Among the 1,537 patients receiving beta-blocker therapy before hospital presentation, 1,350 (87.8%) were continued on beta-blocker therapy and 187 (12.2%) were withdrawn (108 with documented contraindications or intolerance and 79 without). Patient characteristics for the 4 treatment groups included in this study (continued, newly started, withdrawn, eligible but not treated) are shown in Table 2. Patients in the group continued on beta-blockers were of similar age to those withdrawn but younger than those not treated. Vital signs and lab values were similar in those continued and withdrawn from beta-blocker therapy. The LVEF was lower in patients withdrawn from beta-blockers.

Beta-blocker use and clinical outcomes

Unadjusted Analyses

In the overall cohort of beta-blocker–eligible patients with HF and LVSD, mortality at 60 to 90 days after hospital discharge was 8.7% (Table 3). Readmission within the 60- to 90-day follow-up period was 30.2%, and death/rehospitalization occurred in 34.8%. Patients continued on beta-blocker therapy from the time of admission had shorter hospital length of stay compared with eligible patients who were not treated with beta-blockers (Table 3). Continued patients were found to have significantly lower post-discharge mortality rates during follow-up compared with those eligible but not treated with beta-blockers (8.7% vs. 13.8%, p = 0.046) (Table 3). The Kaplan-Meier actuarial mortality curves for eligible patients continued, newly started, withdrawn, and not treated with beta-blocker therapy are shown in Figure 1. The unadjusted hazard ratios (HRs) for post-discharge mortality with beta-blocker continuation compared to nonuse among eligible patients was 0.60 (95% confidence interval [CI]: 0.38 to 0.94, p = 0.027). Furthermore, there was no evidence that continuation of beta-blocker therapy was associated with increased risk of early rehospitalization (32.2% vs. 35.6%; HR: 0.86; 95% CI: 0.66 to 1.12, p = 0.25). Continuation of beta-blocker therapy was associated with a significantly lower risk of the combined mortality and/or rehospitalization end point (36.1% vs. 43.2%; odds ratio [OR]: 0.70; 95% CI: 0.54 to 0.91, p = 0.007). In unadjusted analyses, withdrawal of beta-blocker therapy was associated with substantially increased risk of post-discharge death compared with continuation of beta-blocker therapy (24.4% vs. 8.7%, HR: 2.82; 95% CI: 1.46 to 5.48, p = 0.002), but the death/rehospitalization rates were similar (Fig. 1, Table 3). When patients withdrawn from beta-blocker therapy were compared with patients eligible but not treated, mortality risk tended to be higher (HR: 1.69; 95% CI: 0.81 to 3.52, p = 0.16) (Table 3). Patients ineligible for beta-blocker therapy owing to contraindications or intolerance were also at high risk for adverse outcomes, with post-discharge mortality 13.1%, rehospitalization 30.8%, and death/rehospitalization 43.4%.

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Figure 1

Post-Discharge Survival by Beta-Blocker Treatment Groups

Kaplan-Meier survival curves by beta-blocker treatment groups. Log-rank test: p < 0.001.

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Table 3

Clinical Outcomes of Follow-Up Cohort With LVSD by Beta-Blocker Treatment Group: Unadjusted

Aadjusted Analyses

The influence of beta-blocker treatment on follow-up outcomes was tested in risk- and propensity-adjusted models. After adjustment for multiple variables predictive of post-discharge mortality as well as propensity for beta-blocker use and correlation of data within the same hospital, continuation of beta-blocker therapy, when compared with no beta-blocker use among eligible patients, was still associated with a reduced risk of all-cause mortality in the first 60 to 90 days after hospital discharge (HR: 0.60; 95% CI: 0.37 to 0.99, p = 0.044) (Table 4). Continuation of beta-blocker therapy was also associated with lower post-discharge mortality/rehospitalization. Newly started beta-blocker therapy was also associated with improved outcomes compared to no beta-blocker use among eligible patients (Table 4). In contrast, after risk and propensity adjustment, withdrawal of beta-blocker therapy was associated with a substantially higher risk of death compared with continuation of beta-blocker therapy (HR: 2.34; 95% CI: 1.20 to 4.55, p = 0.013). However, these withdrawal patients were at similar post-discharge risk to those eligible but not treated with beta-blockers (Table 4).

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Table 4

Effect of Beta-Blocker Treatment Group on All-Cause Mortality and Death/Rehospitalization at 60 to 90 Days After Discharge: Risk- and Propensity-Adjusted Analyses

Tolerability

During the 60- to 90-day post-discharge follow-up period, continuation of beta-blocker therapy was very well tolerated, as evidenced by 93.6% of patients remaining on beta-blocker therapy after discharge. Newly starting beta-blocker therapy was also well tolerated, with 91.9% of patients remaining on therapy. Of the cohort of eligible patients who were not prescribed beta-blocker therapy either before admission or at time of hospital discharge, only 23.9% were started on beta-blocker therapy after discharge within the 60- to 90-day follow-up period (continued cohort 93.6% vs. not-treated cohort 23.9%, OR: 46.7, 95% CI: 32.1 to 68.0, p < 0.0001). Eligible patients in whom beta-blocker therapy was withdrawn during hospitalization were also less likely to be receiving treatment during 60- to 90-day post-discharge follow-up, with only 56.5% restarted on therapy (continued cohort 93.6% vs. withdrawn cohort 56.5%; OR: 11.3, 95% CI: 6.5 to 19.7, p < 0.0001). For patients continued on beta-blockers, 88.2% were maintained on at least their admission dose of medication (72.9% same dose and 15.3% increased) during the hospitalization and 11.8% had their dosage reduced. During the first 60 to 90 days of post-discharge follow-up, the discharge dose of beta-blockers was reduced in only 11.7% of patients, maintained in 73.4%, and increased in 15%.

Discussion

The OPTIMIZE-HF program provides an important opportunity to evaluate the influence of continuation and withdrawal of beta-blocker therapy during hospitalization for HF. This registry contains substantially more detailed information on patient characteristics, presenting symptoms, treatments, and outcomes than has previously been available in administrative datasets or other registries (12). In this detailed analysis, the vast majority of hospitalized HF patients who were treated with beta-blockers before admission were able to be continued on beta-blocker therapy during the hospitalization. Continuation of beta-blocker therapy was associated with substantially lower risk and propensity adjusted post-discharge mortality risk. Withdrawal of beta-blockers was associated with excess adjusted mortality risk. In addition, continuation of beta-blocker therapy was well tolerated after discharge, and substantially more patients were treated as outpatients with this strategy. These findings extend the results of prior observational analyses among select participants in randomized clinical trials to a diverse cohort of patients hospitalized with HF in the usual care setting from all regions of the country and have significant clinical implications.

Neurohormonal inhibition is the foundation of modern systolic HF management. A meta-analysis of 22 placebo-controlled randomized beta-blocker trials involving 10,132 chronic systolic HF patients demonstrated an OR for total mortality of 0.65 (95% CI: 0.53 to 0.80) in favor of beta-blocker use (19). Accordingly, national practice guidelines (5,6) recommend use of beta-blockers in all stable outpatients with systolic HF in the absence of contraindications on the basis of their proven ability to significantly reduce mortality in these patients. In contrast to the compelling evidence for beta-blocker use in the chronic stable setting, whether beta-blocker therapy should be continued during hospitalization among decompensated HF patients is a commonly encountered and important clinical issue for which little data exist.

There have been no randomized clinical trials and relatively little observational data on the impact of continuing or withdrawing beta-blocker therapy after hospitalization for worsening HF. A retrospective analysis of patients enrolled in the OPTIME-CHF (Outcomes of the Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure) study (8) reported worse outcomes for the 47 patients in whom beta-blocker were withdrawn of the 212 patients treated with beta-blockers at the time of the admission for acute decompensated HF. A retrospective analysis of patients enrolled in FIRST (Flolan International Randomized Survival Trial) (9) reported no excess risk for patients treated with beta-blockers at the time of hospital presentation for HF. A study of patients receiving beta-blockers at the time of HF hospitalization in the ESCAPE (Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization) trial showed that 268 of 432 patients who remained on beta-blocker therapy had a shorter length of stay and lower 6-month mortality rate (11). Continuation versus withdrawal of beta-blocker therapy remained independently associated with lower mortality in a multivariable analysis (11). In an analysis of COMET (Carvedilol or Metoprolol European Trial), 752 of 3,029 patients had a nonfatal HF hospitalization while receiving study beta-blocker treatment (10). Of these, 529 (70%) of patients were continued on beta-blocker therapy at the same dose, 162 (22%) had a dose reduction, and 61 patients (8%) had beta-blocker treatment withdrawn. The risk of death was higher in patients in whom beta-blocker therapy was discontinued or for whom the dose was reduced compared with those patients who were continued on beta-blocker therapy (10).

Each of these prior analyses included select patients enrolled and followed in randomized clinical trials. The mean age of the patients was approximately 64 years, 75% were men, and comorbidities were relatively infrequent (8–11). As these patients were treated in clinical trials with investigators and coordinators with considerable experience in managing patients with HF, these studies cannot provide information as to whether similar results can be expected in the general group of patients hospitalized with HF. Our results in real-world patients in the usual care setting involving clinicians and hospitals from all regions of the country show that discontinuation of beta-blocker therapy during a HF hospitalization is associated with substantially worse risk-adjusted outcomes compared to continuation. These findings were derived from a broad cohort with a high proportion of older HF patients with multiple comorbidities who are more representative of those seen in general practice (12,13).

The decision to discontinue beta-blocker therapy in certain patients hospitalized with HF may be related to a greater state of patient decompensation, which may account for poor outcomes among these patients rather than the withdrawal of beta-blocker therapy per se (10). Though withdrawal of beta-blockers was associated with a few indicators of more severe HF, it remained significantly and independently associated with increased mortality after adjustment for multiple covariates and propensity score. In the absence of symptomatic bradycardia, symptomatic hypotension, or cardiogenic shock, the decision to discontinue beta-blocker therapy among these patients is based primarily on clinical judgment, likely influenced by individual clinician experience (11). Patients who were continued on beta-blocker therapy had similar admission vital signs, physical exam findings, and laboratories to those in whom beta-blocker therapy was discontinued. In this study, improved outcomes with continued beta-blocker therapy persisted after controlling for factors associated with the decision to discontinue beta-blocker therapy and those associated with post-discharge outcomes. However, with an observational analysis, it is possible that not all factors that may have influenced the decision to continue, withdraw, or not initiate beta-blocker therapy have been fully captured, and these unmeasured factors may influence the findings.

Abrupt cessation of beta-blockers has been reported to be associated with ischemia, hypertension, ventricular arrhythmias, and, in some cases, myocardial infarction (20,21). Withdrawal of beta-blocker therapy in patients hospitalized with HF thus could be associated with outcomes worse than having never been treated in the first place. In this study, HF patients in whom beta-blocker therapy was withdrawn were at higher risk for mortality and death/rehospitalization in the first 60 to 90 days compared with those continued, but this risk was not significantly different from those eligible but not treated. However, as there was a trend for worse outcomes, further study will be necessary to determine whether withdrawal of beta-blockers is associated with increased risk beyond that of not deriving the benefits on ongoing beta-blocker treatment in this patient population.

Several recent studies (22–24) have reported that many HF patients who are candidates for beta-blockers do not receive them. In addition, the rate of beta-blocker prescriptions at hospital discharge is lowest for patients at the greatest risk of death, who in fact derive the most benefit from their use (24). In an analysis of 103 acute-care hospitals in Ontario, Canada, comprising 1,418 patients with LVEF ≤40%, beta-blockers were prescribed to 40% of the lowest-risk patients but to only 23% with the highest risk of death on the basis of a previously derived and validated 1-year mortality risk prediction model (24). Medication prescription at the time of discharge has been shown to be the strongest predictor of long-term adherence to drug therapy (25,26). Discontinuation of evidence-based HF medications during hospital admission, when not absolutely necessary, thus can have deleterious effects on treatment rates and long-term clinical outcomes. As shown in this study, when beta-blocker therapy was disrupted during hospitalization, a substantial proportion of patients did not have this therapy re-initiated after discharge. In a prospective longitudinal follow-up study in a cohort of consecutive patients with chronic HF seen at a specialized HF outpatient clinic (23), the most common reason for systolic HF patients not to be treated with beta-blocker therapy was discontinuation during hospitalization and failure to restart treatment despite the absence of contraindications. Continuation of beta-blocker therapy during HF hospitalization, whenever possible, represents an important strategy to improve overall treatment rates with this guideline-recommended therapy.

Conclusions

Data from this study of a large, representative cohort of HF patients indicate that continuation of beta-blocker therapy among patients hospitalized with HF is associated with better outcomes than those in whom beta-blocker therapy is withdrawn or never initiated. These results persisted even after controlling for differences between the patient groups. In addition, continuation of beta-blocker therapy was very well tolerated, with 93.6% of those continued and discharged on beta-blocker therapy remaining on treatment during follow-up. The HF patients withdrawn from beta-blockers during hospitalization were substantially less likely to be treated with beta-blockers after discharge, which likely contributed to these patients' poor outcomes. These findings suggest that routine discontinuation of beta-blocker therapy on hospital admission is neither necessary nor advisable, and the majority of patients hospitalized for HF are eligible for beta-blocker therapy to be continued. The present study provides real-world support of recent guideline recommendations that, whenever possible, beta-blocker therapy should be continued in patients hospitalized with HF.

Author Disclosures

Dr. Fonarow has received research grants from Amgen, Biosite, Bristol-Myers Squibb, Boston Scientific/Guidant, GlaxoSmithKline, Medtronic, Merck, Pfizer, Sanofi-Aventis, Scios, Inc., and the National Institutes of Health; is or has been on the Speaker's Bureau or has received honoraria in the past 5 years from Amgen, AstraZeneca, Biosite, Bristol-Myers Squibb, Boston Scientific, GlaxoSmithKline, Medtronic, Merck, NitroMed, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, Scios, Inc., St. Jude Medical, Takeda, and Wyeth; and is or has been a consultant for Biosite, Bristol-Myers Squibb, Boston Scientific, GlaxoSmithKline, Medtronic, Merck, NitroMed, Pfizer, Sanofi-Aventis, Schering-Plough, Scios, Inc., and Wyeth. Dr. Abraham has received research grants from Amgen, Biotronik, CHF Solutions, GlaxoSmithKline, HFSA, Medtronic, Myogen, National Institutes of Health, Orqis Medical, Otsuka Maryland Research Institute, Paracor, and Scios, Inc.; is or has been a consultant/on the Speaker's Bureau for Amgen, AstraZeneca, Boehringer-Ingelheim, CHF Solutions, GlaxoSmithKline, Guidant, Medtronic, Merck, Pfizer, ResMed, Respironics, Scios, Inc., and St. Jude Medical; is on the advisory board of CardioKine, CardioKinetix Inc., CHF Solutions, Department of Veterans Affairs Cooperative Studies Program, Inovise, National Institutes of Health, and Savacor, Inc.; and has received honoraria from AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Guidant, Medtronic, Merck, Pfizer, ResMed, Respironics, Scios, Inc., and St. Jude Medical. Dr. Albert is a consultant for GlaxoSmithKline and Medtronic; is on the Speaker's Bureau for GlaxoSmithKline, NitroMed, and Scios, Inc.; and is employed by the Cleveland Clinic Foundation. Dr. Gattis Stough has received research grants from Actelion, GlaxoSmithKline, Medtronic, Otsuka, and Pfizer; is a consultant or on the Speaker's Bureau for Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, Novacardia, Otsuka, Protein Design Labs, RenaMed, Sigma Tau, and Scios, Inc.; and has received honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, and Pfizer. Dr. Gheorghiade has received research grants from the National Institutes of Health, Otsuka, Sigma Tau, Merck, and Scios, Inc.; is or has been a consultant for Debbio Pharm, Errekappa Terapeutici, GlaxoSmithKline, PDL, and Medtronic; and has received honoraria from Abbott, AstraZeneca, GlaxoSmithKline, Medtronic, Otsuka, Protein Design Lab, Scios, Inc., and Sigma Tau. Dr. Greenberg has received research grant support from Amgen, Cardiodynamics, GlaxoSmithKline, Millennium, Novacardia, Otsuka, Pfizer, Sanofi-Aventis, and Titan; is on the Speaker's Bureau or is a consultant for Amgen, AstraZeneca, GlaxoSmithKline, Guidant Corp., Medtronic, Merck & Co., NitroMed, Pfizer, Remon Medical Technologies, and Scios, Inc.; is an advisory board member for CHF Solutions, GlaxoSmithKline, and NitroMed; and has received honoraria from AstraZeneca, GlaxoSmithKline, Medtronic, Merck & Co., NitroMed, Novartis, Pfizer, and Scios, Inc. Dr. O'Connor has received research grant support from the National Institutes of Health; is on the Speaker's Bureau and/or is a consultant for Amgen, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Guidant, Medtronic, Merck, NitroMed, Novartis, Otsuka, Pfizer, and Scios, Inc.: and he has received honoraria from GlaxoSmithKline, Pfizer, and Otsuka. Jie Lena Sun is an employee of DCRI. Dr. Yancy has received research grants from Cardiodynamics, GlaxoSmithKline, Medtronic, NitroMed, and Scios, Inc.; is a consultant or on the Speaker's Bureau for AstraZeneca, Cardiodynamics, GlaxoSmithKline, Medtronic, NitroMed, Novartis, and Scios, Inc.; is on the advisory board for CHF Solutions, FDA cardiovascular device panel, and the National Institutes of Health; and has received honoraria from AstraZeneca, Cardiodynamics, GlaxoSmithKline, Medtronic, Novartis, and Scios, Inc. Dr. Young has received research grants from Abbott, Acorn, Amgen, Artesion Therapeutics, AstraZeneca, Biosite, GlaxoSmithKline, Guidant, Medtronic, MicroMed, the National Institutes of Health, Scios, Inc., Vasogen, and World Heart; and is a consultant for Abbott, Acorn, Amgen, Biomax Canada, Biosite, Boehringer-Ingelheim, Bristol-Myers Squibb, Cotherix, Edwards Lifescience, GlaxoSmithKline, Guidant, Medtronic, MicroMed, Novartis, Paracor, Proctor & Gamble, Protemix, Scios, Inc., Sunshine, Thoratec, Transworld Medical Corporation, Vasogen, Viacor, and World Heart.