Impact of Acute Beta-Blocker Therapy for Patients with Non–ST-Segment Elevation Myocardial Infarction

The American Journal of Medicine (2007) 120, 685-692

CLINICAL RESEARCH STUDY

Impact of Acute Beta-Blocker Therapy for Patients with Non–ST-Segment Elevation Myocardial Infarction Chadwick D. Miller, MD,a Matthew T. Roe, MD, MHS,b Jyotsna Mulgund, MS,b James W. Hoekstra, MD,a Renato Santos, MD,a Charles V. Pollack, Jr., MD, MA,c E. Magnus Ohman, MD,b W. Brian Gibler, MD,d Eric D. Peterson, MD, MPHb a

Wake Forest University Health Sciences, Winston-Salem, NC; bDuke Clinical Research Institute, Duke University Medical Center, Durham, NC; cPennsylvania Hospital, University of Pennsylvania School of Medicine, Philadelphia; dUniversity of Cincinnati College of Medicine, Cincinnati, Ohio. ABSTRACT PURPOSE: Early use of beta-blockers is a quality indicator for the treatment of patients with non–STsegment elevation myocardial infarction (NSTEMI), despite limited data from randomized clinical trials in this population. We sought to determine the impact of acute beta-blocker therapy on outcomes in patients with NSTEMI. SUBJECTS AND METHODS: We examined acute (⬍24 hours) beta-blocker use in 72,054 patients with NSTEMI from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) initiative at 509 US hospitals from 2001-2004. We analyzed patient and provider factors associated with beta-blocker use and the impact of beta-blocker therapy on unadjusted, risk-adjusted, and propensity matched outcomes in the overall sample and among selected high-risk subgroups. RESULTS: A total of 82.5% of patients without documented contraindications received acute betablocker therapy. Factors strongly associated with acute beta-blocker use included prior beta-blocker use, higher presenting systolic blood pressure, lower heart rate, lack of signs of heart failure, and cardiology care. Acute beta-blocker use was associated with lower in-hospital mortality (unadjusted 3.9% vs 6.9%, P ⬍.001, adjusted odds ratio 0.66, 95% confidence interval 0.60-0.72), lower adjusted mortality among most of 6 subgroups determined by propensity to receive acute beta-blockers, and lower adjusted mortality in patients with and without signs of heart failure and in those ⬍80 years and those ⱖ80 years old. CONCLUSIONS: The majority of NSTEMI patients receive acute beta-blocker therapy. Certain patient subgroups remain undertreated. Because treatment with acute beta-blockers was associated with improved clinical outcomes in nearly all patient subgroups assessed, broader use in patients with NSTEMI appears warranted. © 2007 Elsevier Inc. All rights reserved. KEYWORDS: Acute coronary syndromes; Beta blockers; Guidelines; Patient care

Medications that inhibit the ␤-adrenergic receptor have become widely accepted therapy for the management of patients with acute myocardial infarction and congestive heart CRUSADE is funded by the Schering-Plough Corporation. BristolMyers Squibb/Sanofi Pharmaceuticals Partnership provides additional funding support. Millennium Pharmaceuticals, Inc. also funded this work. Requests for reprints should be addressed to Eric Peterson, MD, MPH, Duke Clinical Research Institute, 2400 Pratt Street, Room 7009, Durham, NC 27705. E-mail address: [email protected]

0002-9343/$ -see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2007.04.016

failure. Randomized clinical trials performed before the reperfusion era for acute ST-segment elevation myocardial infarction demonstrated that beta-blockers improved early clinical outcomes.1,2 A subsequent trial in patients with non–ST-segment myocardial infarction treated with fibrinolytics demonstrated that immediate beta-blocker use was associated with a lower incidence of recurrent ischemic events compared with delayed use.3 A more contemporary trial demonstrated that beta-blockers significantly reduce mortality and other adverse clinical outcomes in patients

686

The American Journal of Medicine, Vol 120, No 8, August 2007

with left ventricular systolic dysfunction within 3-21 days one of the following high-risk features: ST-segment depresof an acute myocardial infarction.4 Despite the broad bension ⱖ0.5 mm, transient ST-segment elevation 0.5-1.0 mm efits demonstrated across these studies, the recently com(lasting for ⬍10 minutes), or positive cardiac markers (elpleted Clopidogrel and Metoprolol in Myocardial Infarction evated troponin I or T or creatine kinase-MB greater than Trial/Second Chinese Cardiac Study (COMMIT/CCS-2) the upper limit of normal for the local laboratory assay). demonstrated an early hazard and Patients transferring into a particno mortality benefit when betaipating hospital ⬎ 24 hours after blockers were administered within their last ischemic episode are not CLINICAL SIGNIFICANCE 24 hours of acute ST-segment eleligible for inclusion. 5 evation myocardial infarction. Of 115,950 patients included in ● The use of beta-blockers in patients with The updated American College CRUSADE between 2001 and 2004 non–ST-segment elevation myocardial of Cardiology/American Heart at 509 US hospitals, the following infarction is associated with reduced Association (ACC/AHA) guidewere excluded from this analysis: mortality and improved outcomes. lines for the management of pa35,399 who transferred into or out tients with unstable angina and of a participating hospital, 13,104 ● Although the majority of patients with non–ST-segment myocardial inwithout positive cardiac markers, non–ST-segment elevation myocardial farction designate acute (⬍24 hours) 1019 who did not have acute medinfarction receive beta-blockers, highuse of beta-blockers as a class I ications recorded, 209 who had inrisk patients are less likely to receive recommendation. This is largely complete information on acute this therapy. based on extrapolation from earbeta-blocker use, and 7269 with ● Further efforts are needed to reduce lier beta-blocker studies that prilisted contraindications to betamarily enrolled patients with STblockers (bradycardia, ⬎1st degree treatment gaps for the use of ␤ blockers segment elevation myocardial atrioventricular block, cardiogenic for acute myocardial infarction. infarction, because few randomshock, hypotension, and chronic ized trials of beta-blocker use for obstructive pulmonary disease or acute myocardial infarction have asthma). The remaining analysis included patients with non–ST-segment elevation myocarpopulation included 72,054 patients. dial infarction.1-7 However, given the concerns raised by the Clinical Endpoint Definitions findings of the COMMIT/CCS-2 trial about the early use of Clinical endpoints included all-cause mortality during the beta-blockers for acute myocardial infarction, we evaluated index hospitalization, post-admission infarction, in-hospital the use of acute beta-blockers for patients with non–STheart failure, and cardiogenic shock. Post-admission infarcsegment elevation myocardial infarction. Using data from tion was defined as patients who: the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementa● Demonstrated no cardiac biomarker evidence of infarction of the ACC/AHA Guidelines (CRUSADE) Initiative, tion at the time of presentation but then had subsequent we sought to: describe contemporary patterns of acute use cardiac biomarker elevation or electrocardiographic eviof beta-blockers in patients with non–ST-segment elevation dence of infarction; myocardial infarction; determine patient, provider, and hos● Had initial infarction at presentation and then experienced pital factors associated with acute beta-blocker use; and a second increase of biomarkers greater than the upper determine the impact of acute beta-blocker use on clinical limit of normal (if most recent biomarkers were less than outcomes in the overall sample, among propensity groups, the upper limit of normal) or experienced a biomarker and among specific high-risk subgroups. increase ⬎50% above the most recent value if most recent biomarkers were greater than the upper limit of normal; METHODS ● Within 24 hours of percutaneous coronary intervention, Patients meeting inclusion criteria for CRUSADE were experienced a 50% increase in preprocedural biomarker identified locally by each site. Data collected included palevels or an increase in biomarkers ⬎3 ⫻ upper limit of tient and hospital characteristics, use of acute medications normal (if preprocedural biomarkers were less than the (within 24 hours of presentation), medication contraindicaupper limit of normal); or tions, use and timing of invasive cardiac procedures, labo● Within 24 hours of coronary artery bypass grafting, exratory results, in-hospital outcomes, and discharge therapies perienced an increase in biomarkers ⬎5 ⫻ upper limit of and interventions. normal or develop new Q waves on ECG.

Inclusion Criteria and Analysis Population For inclusion in CRUSADE, patients must present to a participating institution with acute ischemic symptoms lasting ⱖ10 minutes in the preceding 24 hours, and have at least

In-hospital heart failure was defined as signs, symptoms, and radiographic findings of heart failure that began after the initial history and physical examination or heart failure that recurred after initial signs of heart failure at presenta-

Miller et al

Beta-Blocker Therapy in NSTEMI

tion resolved. Cardiogenic shock was defined as persistent hypotension (systolic blood pressure ⬍90 mm Hg) with signs of end-organ dysfunction such as oliguria, altered mental status, or poor peripheral perfusion. Nonfatal endpoints were reported by sites and were not centrally adjudicated.

Statistical Methods For the descriptive analysis, patient baseline demographics, clinical characteristics, care patterns, and in-hospital outcomes were compared between patients who received betablockers versus those who did not. Medians and 25th and 75th percentiles were reported for continuous variables, and percentages were reported for categorical variables. The Wilcoxon test for continuous variables and the chisquared test for categorical variables were used to test for differences. We analyzed variables associated with acute use of betablockers using a logistic generalized estimating equations method.8 The generalized estimating equation method is used to adjust for correlations among clustered responses (ie, within hospital correlations for responses) where patients at the same hospital were more likely to have similar responses relative to patients in other hospitals. Variables in the model included patient demographics, presentation factors including prior use of beta-blockers, medical history, and certain hospital characteristics. Heart rate and age were entered into the model as continuous variables with linear splines to account for variations in the effect of the variable on beta-blocker use within different ranges of the continuous variables. Univariate analyses were then conducted to determine which of these factors could be expected to have an independent effect on beta-blocker use. All variables were then tested in multivariable analyses and results were evaluated in a stepwise fashion, sequentially eliminating nonsignificant variables considered clinically unimportant by the investigators and retaining significant variables considered to be of explanatory importance. Finally, the association between acute beta-blocker therapy and in-hospital clinical outcomes also was assessed using the logistic generalized estimating equation method. Results were analyzed in 3 ways— overall, within high-risk subgroups, and within 6 strata of patients determined by the propensity to receive acute beta-blockers. The models used to determine adjusted clinical outcomes included patient demographics (age, sex, race), presenting characteristics (congestive heart failure, positive cardiac markers, systolic blood pressure, heart rate), medical history (family history, dyslipidemia, hypertension, renal insufficiency, prior myocardial infarction, prior coronary artery bypass grafting, prior percutaneous coronary intervention, prior stroke, prior congestive heart failure, current smoking, diabetes), and hospital characteristics (bed size, region, capabilities for invasive cardiac procedures and academic, teaching status). A P value ⬍.05 was considered statistically significant for all tests. All statistical analyses were performed using SAS software (version 8.2, SAS Institute, Cary, NC).

687

RESULTS A total of 82.5% of patients received acute beta-blockers. Patients who received acute beta-blockers were younger, more commonly male, had prior myocardial infarction, were more commonly taking prior beta-blockers, were cared for by cardiologists at academic hospitals, and less commonly had prior or current heart failure (Table 1). The independent factors associated with acute beta-blocker use are listed in Table 2. Patients treated with acute beta-blockers more commonly received other acute medical therapies and more commonly underwent invasive cardiac procedures (Table 3). In the overall sample, patients treated with acute betablockers had lower rates of unadjusted and adjusted in-hospital mortality (3.9% vs 6.9%, adjusted odds ratio [AOR] 0.66, 95% confidence interval [CI], 0.60-0.72), reinfarction (3.0% vs 3.6%, AOR 0.80, 95% CI, 0.72-0.89), and cardiogenic shock (2.1% vs 3.2%, AOR 0.76, 95% CI, 0.67-0.87) compared with patients not treated with acute beta-blockers. No difference in the unadjusted or adjusted risk of congestive heart failure was demonstrated (9.0% vs 9.7%, AOR 1.00, 95% CI, 0.92-1.08). Similar findings were noted in subgroups such as those with and without signs of congestive heart failure on presentation and those ⬍80 years of age and those ⱖ80 years of age (Figure 1). Acute beta-blocker use was associated with a significantly lower risk of adjusted mortality across groups of patients categorized based upon the propensity to receive acute beta-blockers, except for the group with the greatest propensity to receive acute beta-blockers where a nonsignificant reduction in adjusted mortality was demonstrated (Figure 2).

DISCUSSION Our results show that more than 80% of eligible patients with non–ST-segment elevation myocardial infarction were treated with acute beta-blockers within 24 hours of hospital presentation. Patients who received acute beta-blockers were more likely to have been receiving beta-blockers prior to hospitalization, have stable hemodynamic features, and receive care on a cardiology inpatient service. Use of acute beta-blockers was associated with a lower adjusted risk of adverse outcomes across different patient subgroups and propensity groups. Recent clinical trials include the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial that evaluated the use of oral betablockers within 3-21 days after acute myocardial infarction (both ST-segment elevation myocardial infarction and non– ST-segment elevation myocardial infarction) complicated by left ventricular systolic dysfunction and demonstrated a significant reduction in long-term (⬎1 year) mortality, reinfarction, and arrhythmias.4,9-12 In contrast, the COMMIT/ CCS-2 trial demonstrated an early hazard (increased risk of hypotension, bradycardia, CHF, and cardiogenic shock)

688

The American Journal of Medicine, Vol 120, No 8, August 2007

Table 1

Patient and Hospital Characteristics by Acute Beta-Blocker Use

Patient Characteristics Demographics Age (years)* Women (%) White (%) Body mass index* Medical history Hypertension (%) Diabetes mellitus (%) Current smoking (%) Hyperlipidemia (%) Family history of coronary artery disease (%) Renal insufficiency (%)† Prior stroke (%) Prior myocardial infarction (%) Prior congestive heart failure (%) Prior percutaneous coronary intervention (%) Prior coronary artery bypass grafting (%) Presenting characteristics ST depression (%) Transient ST-elevation (%) Signs of CHF (%) Systolic blood pressure (mm Hg)* Heart rate (beats per minute)* Other features Cardiology service (%)‡ Academic hospital (%)§ Prior beta-blocker use (%) Insurance status (%) HMO/Private Medicare Medicaid

No Acute Beta-Blockers (n ⫽ 12,612)

Acute Beta-Blockers (n ⫽ 59,442)

P Value

71 (58, 80) 42.5 79.1 27.3 (23.7, 31.5)

69 (57, 79) 40.1 78.9 27.6 (24.3, 31.9)

⬍.001 ⬍.001 .12 ⬍.001

66.5 33.8 24.7 41.0 32.4 14.6 12.0 27.8 22.3 19.3 18.8

71.5 33.7 25.5 48.8 34.4 15.1 11.3 31.8 19.4 21.3 21.1

⬍.001 .95 .10 ⬍.001 ⬍.001 .022 .024 ⬍.001 ⬍.001 ⬍.001 ⬍.001

28.7 6.5 28.3 141 (120, 161) 84 (70, 100)

32.3 5.9 24.0 147 (128, 168) 84 (72, 100)

⬍.001 ⬍.001 ⬍.001 ⬍.001 .003

48.4 25.7 21.0

53.7 30.5 44.6

⬍.001 ⬍.001 ⬍.001 ⬍.001

41.3 44.1 7.9

44.7 41.3 6.4

CHF ⫽ congestive heart failure; HMO ⫽ health maintenance organization. *Presented as median (25th, 75th percentile). †Creatinine ⬎2.0 mg/dL, calculated creatinine clearance ⬍30 mL/min, or need for chronic renal dialysis. ‡Admission to a cardiology inpatient service. §Member of the Council of Teaching Hospitals.

coupled with early benefits (decreased risk of ventricular fibrillation and reinfarction) with immediate use of betablockers for patients with acute myocardial infarction (93% had ST-segment elevation myocardial infarction).8 However, follow-up in the COMMIT/CCS-2 trial was limited to the hospitalization period, which was no longer than 28 days; close to half of the patients did not receive reperfusion therapy, use of catheterization and revascularization procedures was not permitted, and no mortality benefit was demonstrated.5 In contrast to randomized clinical trials that often include patients with both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction, our patient population represents a true non–ST-segment elevation myocardial infarction cohort. In this analysis we have shown improved in-hospital outcomes with acute betablockers in a contemporary population of patients with non–ST-segment elevation myocardial infarction treated in routine practice who commonly received other evidencebased medications and underwent revascularization proce-

dures. Although our results may be limited by the lack of follow-up after discharge, other observational studies have shown discharge use of beta-blockers in elderly patients with acute myocardial infarction (both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction) is associated with reduced mortality, even among those who underwent revascularization procedures.13,14 Results from CRUSADE supplement evidence from randomized clinical trials by showing that acute beta-blockers are beneficial for patients with non–ST-segment elevation myocardial infarction and are consistent with other registry data. The National Cooperative Cardiovascular Project retrospectively evaluated the impact of beta-blocker prescribing at hospital discharge on long-term mortality among patients with acute myocardial infarctions. Among these Medicare patients, beta-blocker prescribing at discharge was associated with a 14% decrease in mortality at 1 year.13 Subgroup analysis of this population demonstrated a similar mortality benefit to beta-blocker use among patients with

Miller et al Table 2

Beta-Blocker Therapy in NSTEMI

689

Factors Associated with Acute Beta-Blocker Use

Variable

␹2

Adjusted OR

Prior beta-blocker use SBP (per 10 mm Hg increase) Signs of congestive heart failure Heart rate* Heart rate ⬍60 beats per minute Heart rate 60 to 100 beats per minute Heart rate ⬎100 beats per minute Prior congestive heart failure Cardiology inpatient service Prior PCI Insurance coverage Medicare† Medicaid† Self-insurance† Age* Age ⬍55 years Age 55-64 years Age 65-74 years Age 75-84 years Age ⱖ85 years ECG findings ST depression‡ Transient ST elevation‡ ST depression ⫹ Transient ST elevation‡ Academic hospital§ Male sex Hyperlipidemia Family history of CAD Renal insufficiency储

927 241 112

3.36 1.06 0.76

3.11-3.64 1.05-1.06 0.72-0.80

1.018

1.011-1.025

1.010

1.008-1.012

0.997

0.996-0.999

0.78 1.25 0.81

0.73-0.82 1.17-1.33 0.77-0.87

0.96 0.78 1.08

0.91-1.01 0.72-0.86 0.98-1.19

1.002 0.990 0.989 1.001 1.003

0.995-1.009 0.980-0.999 0.980-0.997 0.992-1.009 0.991-1.015

1.12 1.15 1.23

1.07-1.17 1.03-1.28 1.03-1.47

1.30 1.06 1.07 1.05 0.95

1.09-1.55 1.02-1.11 1.02-1.12 1.00-1.11 0.89-1.00

95% CI

108

75 46 45 30

30

23

8 8 7 4 4

CAD ⫽ coronary artery disease; CI ⫽ confidence interval; PCI ⫽ percutaneous coronary intervention. *Heart rate and age entered into model as continuous variables with no reference group, but linear splines were performed for each variable to account for variations in the slope of the distribution of the variables within each listed segment. ␹2 values represent strength of the association of the overall variable. †Compared with health maintenance organization/private insurance. ‡Compared with neither ST depression nor transient ST elevation. §Member of the Council of Teaching Hospitals. 储Creatinine ⬎2.0 mg/dL, calculated creatinine clearance ⬍30 mL/min, or need for chronic renal dialysis.

ST-segment elevation myocardial infarction and non–STsegment elevation myocardial infarction at 2 years.15 Previous analyses that showed enhanced benefit with betablockers among high-risk subgroups of patients with acute myocardial infarction led us to evaluate the benefit of acute beta-blocker use in patient subpopulations, including the elderly and those with congestive heart failure on arrival.1-4,15 In CRUSADE, we found similar benefits with acute betablocker therapy in younger vs. older patients and for patients with and without signs of congestive heart failure on presentation. Our results are similar to those from other

studies that found reduced long-term mortality with betablockers in the elderly and those with congestive heart failure or left ventricular systolic dysfunction, but we also have shown that older patients and those with congestive heart failure were less likely to receive acute beta-blockers.4,14,15 Clinicians may have concerns about using acute beta-blockers in these types of patients with acute myocardial infarction, given the increased risk of shock and hypotension seen with beta-blockers in prior trials, especially among patients with signs of congestive heart failure (who have high baseline risks of adverse outcomes) and very elderly patients (who were not commonly enrolled in randomized trials of acute beta-blockers).5,16,17 Although we acknowledge these concerns, our findings suggest that these high-risk patients benefit from acute beta-blocker use. However, it is important not to extrapolate these findings to patients with cardiogenic shock, as these patients were excluded from our analysis. In order to enhance patient care, further studies are needed to delineate factors limiting the use of beta-blockers in certain populations. Through this information, interventions can be designed to improve betablocker use in undertreated subgroups that may receive a greater relative benefit from this treatment.18 Significant knowledge deficits exist about the use of beta-blockers in patients with non–ST-segment elevation myocardial infarction. Most investigations have not evaluated only patients with non–ST-segment elevation myocardial infarction and, thus, the evidence for benefit in this population has been limited. Our results from over 72,000 patients with definite non–ST-segment elevation myocardial infarction prove the administration of beta-blockers in the first 24 hours is associated with mortality benefit at the time

Table 3 Concomitant Acute (⬍24 h) Medications and Invasive Procedures by Acute Beta-Blocker Use*

Variable Aspirin Clopidogrel Heparin (any) Glycoprotein IIb/IIIa inhibitor Cardiac catheterization Cath ⱕ24 h of arrival Arrival to cath (h)† PCI PCI ⱕ24 h of arrival Arrival to PCI (h)† Coronary artery bypass grafting

No Acute Beta-Blockers (n ⫽ 12,612)

Acute Beta-Blockers (n ⫽ 59,442)

84.3% 32.1% 73.1% 25.6%

94.7% 47.5% 86.7% 40.8%

62.2% 26.2% 27.3 (12.8, 53.9) 36.5% 16.5% 25.6 (8.8, 51.2) 11.4%

75.2% 34.5% 25.2 (11.9, 49.4) 45.5% 22.6% 23.0 (7.5, 47.3) 13.3%

Cath ⫽ catheterization; other abbreviations as in previous tables. *Only subjects without contraindications for each medication are included. †Values are median (25th, 75th percentile).

690

The American Journal of Medicine, Vol 120, No 8, August 2007

Figure 1 Adjusted risk of in-hospital clinical outcomes by acute beta-blocker use. Patients in the congestive heart failure (CHF) group had signs of CHF upon hospital presentation.

of hospital discharge. This information augments the results from the National Cooperative Cardiovascular Project showing that patients with non–ST-segment elevation myocardial infarction who are discharged on beta-blockers have

a lower mortality rate at 2 years.15 Although registry data cannot take the place of a randomized clinical trial, it represents the best available information at this time. Coupling these results together, patients with non–ST-segment eleva-

Figure 2 Adjusted risk of in-hospital mortality among propensity groups. Patients were categorized into 6 equal groups based upon the propensity to receive acute beta-blockers ranging from those with the lowest propensity (Group 1, 66.5%) to those with the highest propensity (Group 6, 92.4%).

Miller et al

Beta-Blocker Therapy in NSTEMI

tion myocardial infarction without contraindications should be treated acutely and over the long term with beta-blocker medications. As an observational, retrospective analysis, certain limitations were present. First, hospitals included in CRUSADE were actively seeking to improve performance and may not be representative of all US hospitals. Second, although we excluded patients with contraindications to acute betablocker use, undocumented contraindications may explain the nonuse of acute beta-blockers in at least a portion of the 17.5% of patients who did not receive them, especially because these patients were more likely to have lower blood pressure and signs of congestive heart failure. Furthermore, because prior beta-blocker use was the factor most strongly associated with acute beta-blocker use, previous tolerance to beta-blockers may have driven the continued use of beta-blockers during the acute care period, rather than specific indications for beta-blocker use from the new, acute ischemic event that prompted hospitalization. Third, although we evaluated the impact of acute betablockers on adjusted clinical outcomes with multiple techniques, our results were likely influenced by unmeasured confounders. Fourth, we did not collect data on the dose, type, or method of administration (intravenous or oral) of acute beta-blockers and, thus, could not ascertain how these features influenced the results. Furthermore, data collection was limited to the in-hospital period, so we could not determine the long-term impact of acute beta-blocker use. Fifth, post-admission infarction was defined as any elevation in cardiac biomarkers after admission. This definition does not discriminate between those patients presenting with a myocardial infarction in evolution and those who had an event after arrival to the hospital. An additional limitation is the exclusion of transferred patients, which could reduce the generalizability of our findings. Finally, hospitals were encouraged to submit data on consecutive patients, but privacy regulations prevented verification of consecutive patient inclusion. The majority of eligible patients with non–ST-segment elevation myocardial infarction in contemporary practice were treated with beta-blockers ⬍24 hours from arrival. High-risk patients were less likely to receive this therapy even though the beneficial impact of beta-blockers was seen across patient subgroups and did not vary significantly by the propensity to receive beta-blockers. Although quality indicators for acute myocardial infarction (both ST-segment elevation myocardial infarction and non–ST-segment elevation myocardial infarction) recommend beta-blockers within 24 hours, contraindications are not specified and the highest-risk patients with the greatest predicted benefit from beta-blockers may not be clearly targeted within these quality recommendations.19 Thus, further efforts are needed to reduce treatment gaps for the use of beta-blockers for acute myocar-

691 dial infarction, and additional studies are needed to clarify the optimal timing for initiating beta-blocker therapy based upon patient risk factors and hemodynamic status.

References 1. Randomised trial of intravenous atenolol among 16,027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group. Lancet. 1986;2:57-66. 2. Metoprolol in acute myocardial infarction (MIAMI). A randomised placebo-controlled international trial. The MIAMI Trial Research Group. Eur Heart J. 1985;6:199-226. 3. Roberts R, Rogers WJ, Mueller HS, et al. Immediate versus deferred beta-blockade following thrombolytic therapy in patients with acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) II-B Study. Circulation. 1991;83:422-437. 4. Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385-1390. 5. Chen ZM, Pan HC, Chen YP, et al; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005; 366:1622-1632. 6. Braunwald E, Antman EM, Beasley JW, et al; American College of Cardiology; American Heart Association. Committee on the Management of Patients with Unstable Angina. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction--summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40: 1366-1374. 7. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335-371. 8. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 1986;73:13-22. 9. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlledrelease metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283:1295-1302. 10. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999;353:9-13. 11. Packer M, Fowler MB, Roecker EB, et al; Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study Group. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106: 2194-2199. 12. McMurray J, Kober L, Robertson M, et al. Antiarrhythmic effect of carvedilol after acute myocardial infarction: results of the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) trial. J Am Coll Cardiol. 2005;45:525-530. 13. Krumholz HM, Radford MJ, Wang Y, et al. National use and effectiveness of ␤-blockers for the treatment of elderly patients after acute myocardial infarction: National Cooperative Cardiovascular Project. JAMA. 1998;280:623-629. 14. Chen J, Radford MJ, Wang Y, et al. Are ␤-blockers effective in elderly patients who undergo coronary revascularization after acute myocardial infarction? Arch Intern Med. 2000;160:947-952. 15. Gottlieb SS, McCarter RJ, Vogel RA. Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med. 1998;339:489-497.

692 16. Steg PG, Dabbous OH, Feldman LJ, et al; Global Registry of Acute Coronary Events Investigators. Determinants and prognostic impact of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation. 2004;109:494-499. 17. Forman DE, Bernal JL, Wei JY. Management of acute myocardial infarction in the very elderly. Am J Med. 1992;93:315-326. 18. Bradley EH, Holmboe ES, Mattera JA, et al. A qualitative study of increasing beta-blocker use after myocardial infarction: why do some hospitals succeed? JAMA. 2001;285:2604-2611.

The American Journal of Medicine, Vol 120, No 8, August 2007 19. Krumholz HM, Anderson JL, Brooks NH, et al; American College of Cardiology/American Heart Association Task Force on Performance Measures; Writing Committee to Develop Performance Measures on ST-Elevation and Non-ST-Elevation Myocardial Infarction. ACC/AHA clinical performance measures for adults with ST-elevation and non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on performance measures (writing committee to develop performance measures on ST-elevation and non-ST-elevation myocardial infarction). Circulation. 2006;113:732-761.