Heart Failure With Preserved Left Ventricular Systolic Function Among Patients With Non–ST-Segment Elevation Acute Coronary Syndromes

Heart Failure With Preserved Left Ventricular Systolic Function Among Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Kyla M. Bennett, MDa, Adrian F. Hernandez, MD, MHSa,*, Anita Y. Chen, MSa, Jyotsna Mulgund, MSa, L. Kristin Newby, MD, MHSa, John S. Rumsfeld, MD, PhDc, Judith S. Hochman, MDd, James W. Hoekstra, MDb, E. Magnus Ohman, MDa, W. Brian Gibler, MDe, Matthew T. Roe, MD, MHSa, and Eric D. Peterson, MD, MPHa Previous studies of non–ST-segment elevation acute coronary syndromes (NSTE ACSs) complicated by heart failure (HF) have focused primarily on patients with left ventricular systolic dysfunction defined by an ejection fraction (EF) <40%. Little is known about HF with preserved systolic function (EF >40%) in the NSTE ACS population. We identified high-risk patients with NSTE ACS (ischemic electrocardiographic changes and/or positive cardiac markers) from the CRUSADE quality improvement initiative who had an EF recorded and who had information on HF status. Management and outcomes were analyzed and compared based on the presence or absence of HF and whether left ventricular EF was >40%. Of 94,558 patients with NSTE ACS, 21,561 (22.8%) presented with signs of HF, and most had HF with preserved systolic function (n ⴝ 11,860, 55%). Mortality rates were 10.7% for HF/systolic dysfunction, 5.8% for HF/preserved systolic function, 5.7% for no HF/systolic dysfunction, and 1.5% for no HF/preserved systolic function. Use of guideline-recommended medical therapies and interventions was frequently significantly lower in those with HF regardless of EF compared with those without HF, except for use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. In conclusion, NSTE ACS complicated by HF with preserved systolic function is common and associated with a 2.3-fold higher mortality compared with NSTE ACS without HF or systolic dysfunction. Guideline-recommended therapies and interventions are under-utilized in patients with NSTE ACS and HF, with and without preserved systolic function, compared with those without HF. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;99: 1351–1356)

The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association (ACC/AHA) Guidelines (CRUSADE) initiative is a national quality improvement program designed to improve adherence to the ACC/AHA guidelines for the treatment of patients with non–ST-elevation acute coronary syndromes (NSTE ACSs).1 It also provides 1 of the few contemporary datasets of in-hospital outcomes and practice a

Duke Clinical Research Institute, Duke University Medical Center, Durham, and bWake Forest University Health Sciences, Winston-Salem, North Carolina; cDenver VA Medical Center/University of Colorado Health Sciences Center, Denver, Colorado; dNew York University School of Medicine, New York, New York; and eUniversity of Cincinnati School of Medicine, Cincinnati, Ohio. Manuscript received July 6, 2006; revised manuscript received and accepted December 21, 2006. CRUSADE is a National Quality Improvement Initiative of the Duke Clinical Research Institute, Durham, North Carolina. CRUSADE is funded by the Schering-Plough Corporation, Kenilworth, New Jersey. BristolMyers Squibb/Sanofi-Aventis Pharmaceuticals Partnership, New York, New York, provides additional funding support. Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, also funded this work. *Corresponding author: Tel: 919-668-7515; fax: 919-668-7058. E-mail address: [email protected] (A.F. Hernandez). 0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2006.12.057

patterns in patients with NSTE ACSs. We examined the frequency, characteristics, treatment patterns, and outcomes of patients with NSTE ACS complicated by heart failure (HF) and preserved systolic function. Methods Study population: CRUSADE is a voluntary observational quality improvement initiative. CRUSADE began in January 2001; data collection is ongoing. Patients in the CRUSADE initiative have ischemic symptoms at rest within 24 hours before presentation and high-risk features, including ST-segment depression ⱖ0.5 mm, transient STsegment elevation of 0.5 to 1.0 mm (lasting ⬍10 minutes), and/or positive cardiac markers (increased troponin I or T and/or creatinine kinase-MB level higher than the upper limit of normal for the local laboratory assay). In total, 129,054 patients from 509 hospitals were included in the CRUSADE database from January 2001 to December 2004. For our analyses, we excluded 33,545 patients (25.8%) who did not have ejection fraction (EF) measured and 1,158 (⬍1.0%) with missing data on signs of HF at presentation. In addition, we excluded 8,366 (8.9%) from all analyses of in-hospital and discharge treatments and outcomes due to transfer to another institution. Patients www.AJConline.org

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Table 1 Patient characteristics by heart failure status Characteristic

Age (yrs)* Women White Body mass index (kg/m2)* Systolic blood pressure (mm Hg)* Heart rate (beats/min)* ST depression Transient ST elevation Positive cardiac markers Hypertension† Diabetes mellitus Current/recent smoker Hyperlipidemia‡ Previous myocardial infarction Previous percutaneous intervention Previous coronary artery bypass surgery Previous HF Previous stroke Renal insufficiency§

HF

No HF

EF ⱖ40% (n ⫽ 11,860)

EF ⬍40% (n ⫽ 9701)

EF ⬍40% (n ⫽ 12,919)

EF ⱖ40% (n ⫽ 60,078)

75 (64, 82) 53.1% 79.1% 27.8 (24.1, 32.6) 148 (126, 172) 90 (75, 108) 40.3% 5.0% 91.7% 78.7% 44.3% 21.4% 46.5% 30.5% 18.8% 19.6% 36.5% 15.3% 23.1%

75 (65, 82) 40.0% 79.6% 26.6 (23.3, 30.9) 139 (118, 162) 98 (82, 115) 36.0% 4.8% 94.5% 74.7% 46.7% 22.7% 46.6% 43.2% 20.8% 26.5% 49.4% 16.4% 26.6%

69 (58, 78) 33.8% 80.8% 27.3 (23.9, 31.3) 139 (119, 159) 85 (72, 100) 34.3% 8.3% 91.9% 68.5% 35.3% 28.3% 49.0% 41.8% 25.5% 28.3% 20.6% 11.9% 14.6%

64 (54, 75) 37.5% 81.7% 28.1 (24.9, 32.2) 146 (127, 167) 79 (68, 92) 35.7% 7.9% 87.6% 66.1% 26.9% 30.9% 50.0% 23.1% 19.4% 15.5% 6.1% 7.5% 7.3%

All p values ⬍0.0001 for comparisons across columns. * Medians (25th, 75th percentiles). † Systolic blood pressure ⬎140 mm Hg, or diastolic blood pressure ⬎90 mm Hg on repeated measurements or long-term treatment with antihypertensive medications. ‡ Known total cholesterol level ⬎200 mg/dl & (5.2 mmol/L) or long-term treatment with a lipid-lowering agent. § Serum creatinine level ⬎2.0 mg/dl, calculated creatinine clearance ⬍30 ml min, or need for dialysis.

were classified as having HF if signs or symptoms of HF were evident at presentation. The analytic cohort therefore consisted of 94,558 patients from 507 hospitals, i.e., 21,561 with HF and 72,997 without HF who had an EF measured by left ventriculography during cardiac catheterization or by noninvasive imaging. Data collection: Data are collected in anonymous fashion during patient hospitalization only and are submitted electronically. Because no patient identifiers are used, informed consent is not necessary, and the institutional review board of each institution approves participation in CRUSADE. Data collected include presenting clinical characteristics, acute medications (within 24 hours of presentation), implementation and timing of invasive cardiac procedures, laboratory results, clinical outcomes, and discharge therapies. Decisions regarding the use of invasive procedures and medications are made by the treating physicians. Contraindications to specific therapies given class IA/IB recommendations by the ACC/AHA guidelines are recorded.2 Data quality has been examined previously by randomly selecting sites and records. The overall accuracy of data collected is 94.8% and the overall degree of missing data in CRUSADE is low, averaging ⬃5% across all collected data elements. Notably, data on patient age and gender are missing in ⬍0.5% of all cases. Variable definitions: HF on presentation was defined as signs of HF on initial physical examination (jugular venous distention, rales, S3 gallop, or pulmonary edema on initial chest x-ray) or symptoms of HF on initial history (exertional

dyspnea, orthopnea, shortness of breath, labored breathing, fatigue at rest or with normal exertion). HF/preserved systolic function was defined for this analysis as signs and symptoms of HF on presentation with an EF ⱖ40% by any technique. HF/systolic dysfunction was defined as signs and/or symptoms of HF and an EF ⬍40%. Renal insufficiency was defined as a known creatinine level ⬎2 mg/dl, a calculated creatinine clearance ⬍30 ml/ min, or need for renal dialysis. Statistical analysis: We examined patient and hospital characteristics and management patterns across 4 groups of patients with NSTE ACS, i.e., HF/preserved systolic function, HF/systolic dysfunction, no HF/systolic dysfunction, and no HF/preserved systolic function. The primary comparison analyzed was differences observed between the HF/ preserved systolic function group and the no-HF/preserved systolic function group. To test for independence of type of HF and patient characteristics, clinical presentation, in-hospital care patterns, and outcomes, Kruskal-Wallis multisample tests were used to compare continuous variables, and chi-square tests were used for categorical variables. To explore the association between type of HF and management strategies or outcomes, we used a generalized estimating equation logistic regression method to account for the effect of potential confounders and within-hospital clustering of responses.3 All odds ratios (ORs) were determined using the no-HF/preserved systolic function as a comparator group. Variables evaluated in these models included age, race, gender, body mass index categories (un-

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Table 2 Acute medications by heart failure status* Medications

HF

No HF

EF ⱖ40% (n ⫽ 11,860)

Aspirin Clopidogrel Glycoprotein IIb/IIIa Heparin, any ␤-Blockers ACE inhibitor Statins Angiotensin receptor blocker

EF ⬍40% (n ⫽ 9701)

EF ⬍40% (n ⫽ 12,919)

EF ⱖ40% (n ⫽ 60,078)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

91.1% 38.5% 29.7% 83.7% 81.2% 52.6% 46.5% 10.9%

0.69 (0.64–0.75) 0.82 (0.78–0.86) 0.80 (0.75–0.85) 0.89 (0.84–0.95) 0.77 (0.72–0.82) 1.29 (1.22–1.36) 0.90 (0.86–0.95) 0.97 (0.87–1.09)

90.9% 36.8% 28.2% 84.8% 81.4% 60.9% 46.5% 8.2%

0.70 (0.63–0.76) 0.79 (0.75–0.84) 0.82 (0.76–0.87) 0.99 (0.92–1.06) 0.78 (0.73–0.83) 1.82 (1.71–1.94) 0.90 (0.85–0.95) 0.75 (0.65–0.86)

93.7% 44.8% 43.3% 87.8% 85.3% 53.9% 50.4% 7.4%

0.88 (0.82–0.96) 0.88 (0.84–0.92) 1.09 (1.03–1.15) 1.05 (0.98–1.11) 1.03 (0.97–1.09) 1.49 (1.42–1.56) 0.93 (0.88–0.97) 0.88 (0.78–1.02)

95.0% 48.9% 46.1% 87.9% 84.7% 42.1% 51.7% 7.4%

All p values ⬍0.0001 for comparisons across columns. The reference group consists of patients without HF and an EF ⱖ40%. * Medications administered within 24 hours of hospital presentation for patients without listed contraindications.

derweight, normal, overweight, obese I and II, and extremely obese), family history of coronary artery disease, hypertension, diabetes, current/recent smoker, hypercholesterolemia, previous myocardial infarction, previous percutaneous coronary intervention, previous coronary artery bypass grafting, previous HF, previous stroke, renal insufficiency, ST-segment depression, ST-segment elevation, ST-segment depression and ST-segment elevation, positive cardiac markers, heart rate and systolic blood pressure at admission, insurance status (Medicare/Medicaid, self-pay/ none, and health maintenance organization/private), total number of hospital beds, region (west, northeast, midwest, and south), hospital capabilities to perform invasive procedures (no services, diagnostic catheterization only, percutaneous coronary intervention without coronary artery bypass grafting surgery, and percutaneous coronary intervention with coronary artery bypass grafting surgery), academic/ nonacademic status, and cardiology inpatient care. In addition, an association between mortality and presence of systolic dysfunction versus preserved systolic function were explored in the HF and no-HF groups using generalized estimating equation logistic regression models where preserved systolic function is the reference group. A p value ⬍0.05 was considered statistically significant for all tests. All analyses were performed with SAS 8.2 (SAS Institute, Cary, North Carolina). Results Patient characteristics: Of the 94,558 patients who had an EF value and HF status recorded included in the study, 21,561 (22.8%) had HF. In total 11,860 patients (55%) with NSTE ACS complicated by HF had preserved systolic function, whereas 9,701 patients (45%) with NSTE ACS and HF had systolic dysfunction. Of the 72,997 patients without HF, 60,078 (82.3%) had preserved systolic function and 12,919 (17.7%) had systolic dysfunction. Compared with patients without HF, those with HF with and without systolic dysfunction were more likely to have high-risk features (e.g., advanced age, diabetes mellitus, previous HF, renal insufficiency, and previous stroke) (Table 1). Of patients with HF, those with preserved systolic function were more likely to be women and have a history of hypertension than those

with systolic dysfunction. Patients with HF and systolic dysfunction were more likely to have diabetes mellitus, previous myocardial infarction, renal insufficiency, previous coronary artery bypass grafting, and previous HF than those without HF or systolic dysfunction. Treatment patterns: Use of medications within 24 hours of arrival and treatments varied across groups. Patients with HF/preserved systolic function received clopidogrel, glycoprotein IIb/IIIa inhibitors, and statins less frequently than patients without HF and with preserved systolic function. Patients with HF/preserved systolic function more frequently received angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers than those without HF or systolic dysfunction (Table 2). Use of in-hospital interventions also varied significantly across the 4 groups (Table 3). Compared with those without HF and/or systolic dysfunction, patients with HF/preserved systolic function were less likely to receive early cardiac catheterization, early percutaneous coronary intervention, or any revascularization. All reported rates of cardiac catheterization reflect only those patients who were considered eligible for catheterization. Rate of coronary artery bypass graft surgery was similar in those with HF/preserved systolic function and those without HF. Use of discharge medications also varied across groups. Compared with patients without HF and with preserved systolic function, patients with HF/preserved systolic function were less likely to receive discharge clopidogrel or statins; patients with HF/preserved systolic function were more likely to receive ACE inhibitors and angiotensin receptor blockers (Table 4). Clinical outcomes: Mortality was higher in patients with HF/preserved systolic function (5.8%) than in those with no HF/preserved systolic function (1.5%). Patients with HF/preserved systolic function also had higher rates of adverse events compared with patients with NSTE ACS without HF (Figure 1). After adjustment for patient and hospital factors using patients without HF or systolic dysfunction as the reference group, mortality was higher in all groups with HF, including patients with HF/preserved systolic function (adjusted OR 2.30, 95% confidence interval [CI] 2.05 to 2.59),

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Table 3 Invasive cardiac procedures by heart failure status* Procedure

HF

No HF

EF ⱖ40% (n ⫽ 11,860)

Cardiac catheterization Cardiac catheterization within 48 h Percutaneous coronary intervention Percutaneous coronary intervention within 48 h Coronary artery bypass surgery Any revascularization

EF ⬍40% (n ⫽ 9701)

EF ⬍40% (n ⫽ 12,919)

EF ⱖ40% (n ⫽ 60,078)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

68.4% 38.8% 35.3% 21.2% 14.0% 49.7%

0.72 (0.67–0.77) 0.62 (0.58–0.67) 0.73 (0.69–0.78) 0.65 (0.60–0.70) 1.12 (1.04–1.21) 0.76 (0.72–0.81)

64.5% 36.2% 26.5% 14.6% 14.6% 40.7%

0.68 (0.63–0.72) 0.66 (0.61–0.70) 0.54 (0.51–0.58) 0.49 (0.45–0.53) 1.35 (1.23–1.48) 0.62 (0.58–0.67)

80.4% 57.5% 41.9% 30.8% 16.6% 57.5%

0.89 (0.84–0.95) 0.99 (0.94–1.04) 0.75 (0.71–0.79) 0.81 (0.77–0.86) 1.36 (1.27–1.45) 0.82 (0.78–0.87)

86.6% 64.8% 53.1% 40.9% 15.4% 68.3%

All p values ⬍0.0001 for comparisons across columns. * Excluded patients with contraindications to catheterization and those transferred when reporting percutaneous coronary intervention and coronary artery bypass surgery. Table 4 Discharge medications by heart failure statusⴱ Medications

HF

No HF

EF ⱖ40% (n ⫽ 11,860)

Aspirin Clopidogrel ␤-Blockers ACE inhibitor† Angiotensin receptor blocker† Statins

EF ⬍40% (n ⫽ 9701)

EF ⬍40% (n ⫽ 12,919)

EF ⱖ40% (n ⫽ 60,078)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

Adjusted OR (95% CI)

%

89.4% 53.0% 86.0% 62.7% 11.9% 63.5%

0.79 (0.73–0.85) 0.78 (0.74–0.83) 0.92 (0.86–0.98) 1.20 (1.13–1.27) 0.99 (0.88–1.11) 0.88 (0.83–0.93)

89.1% 47.4% 87.1% 76.8% 10.5% 62.2%

0.77 (0.70–0.85) 0.66 (0.62–0.70) 1.00 (0.92–1.09) 2.32 (2.13–2.53) 0.87 (0.76–1.01) 0.87 (0.82–0.93)

92.2% 58.4% 89.0% 72.7% 9.0% 69.8%

0.89 (0.82–0.96) 0.79 (0.75–0.82) 1.17 (1.09–1.25) 1.93 (1.81–2.06) 0.97 (0.84–1.10) 0.93 (0.89–0.98)

93.4% 65.5% 87.0% 58.4% 8.3% 72.9%

Figure 1. In-hospital clinical outcomes by presence/absence of HF/systolic dysfunction (black bars), HF/preserved systolic function (hatched bars), no HF/systolic dysfunction (gray bars), and no HF/preserved systolic function (horizontally striped bars). MI ⫽ myocardial infarction.

those with HF/systolic dysfunction (adjusted OR 3.93, 95% CI 3.48 to 4.44), and those with systolic dysfunction but no HF (adjusted OR 2.76, 95% CI 2.48 to 3.07). Similar trends were seen for recurrent myocardial infarction in patients with HF/preserved systolic function (adjusted OR 1.18, 95% CI 1.03 to 1.35), those with HF/systolic dysfunction (adjusted OR 1.27, 95% CI 1.08 to 1.49), and those with systolic dysfunction but no HF (adjusted OR 1.20, 95% CI 1.07 to 1.34). Adjusted ORs for cardiogenic shock were 2.99 (95% CI 2.58 to 3.48) for patients with HF/preserved systolic function, 6.44 (95% CI 5.59 to 7.43) for those with

HF/systolic dysfunction, and 3.75 (95% CI 3.35 to 4.19) for those with systolic dysfunction but no HF. We also evaluated differences in mortality separately among the HF and no-HF categories based on the presence of systolic dysfunction versus preserved systolic function. In patients with HF, there was an approximate twofold increased risk of mortality in patients with systolic dysfunction compared with those with preserved systolic function (10.7% vs 5.8%, adjusted OR 1.73, 95% CI 1.54 to 1.95). In patients without HF, there was an approximate threefold increased risk of mortality in the group with systolic dysfunction (5.7% vs 1.5%, adjusted OR 2.61, 95% CI 2.33 to 2.93). Because we excluded patients with a missing EF, we examined the characteristics and outcomes for those who had missing EF values. Patients with missing EF values tended to be slightly older (median age 71 vs 67 years) and more likely to be women (41.6% vs 39.2%). In addition, patients with missing EF values were more likely to have renal insufficiency (16.8% vs 12.3%), previous myocardial infarction (34.0% vs 28.6%), previous congestive HF (22.5% vs 16.3%), and previous coronary artery bypass grafting (22.3% vs 18.9%). Those patients with missing EF values were also less likely to receive acute medications, such as aspirin (89.9% vs 93.9%), clopidogrel (38.3% vs 45.9%), glycoprotein IIB/IIIa inhibitors (30.4% vs 42.3%), ␤ blockers (77.7% vs 84.0%), and ACE inhibitors (40.5%

Coronary Artery Disease/Heart Failure and Preserved Function in ACS

vs 46.7%). Patients with missing EF values also had lower rates of procedures, such as cardiac catheterization (40.3% vs 81.6%), percutaneous intervention (35.8% vs 47.3%), or any revascularization (43.2% vs 62.3%). Unadjusted outcomes were different between those with missing EF values and those with recorded values (death/myocardial infarction 10.9% vs 5.8%). However, the incidence of in-hospital HF was higher in patients with an EF measured than in those without (9.0% vs 8.5%). Discussion This is the largest study to evaluate the frequency, management, and outcomes of NSTE ACS complicated by HF/ preserved systolic function. HF/preserved systolic function is common in the setting of NSTE ACS, affecting ⬎12% of patients with a recorded EF. More than 50% of patients with ACS and HF had an EF ⬎40%, although most ACS trials have focused on patients with systolic dysfunction. Although systolic function is preserved, these patients are at increased risk for in-hospital death and other complications. Despite this early mortality risk, treatment patterns of patients with NSTE ACS and HF/preserved systolic function fall short of ACC/AHA recommendations. Although current practice emphasizes the risk to patients with NSTE ACS complicated by HF/systolic dysfunction, the risk of mortality in such patients is significantly higher when signs or symptoms of HF are present even if systolic function is preserved. In our study, the adjusted OR for mortality was 2.3-fold higher in patients with HF/preserved systolic function compared with patients with NSTE ACS without HF or systolic dysfunction. Previous analyses of ACS have cited the adjusted OR for death as 2.2 to 3.8 for patients with versus those without HF.4,5 In addition to their higher risk of mortality, patients with NSTE ACS and HF/ preserved systolic function demonstrated higher rates of reinfarction and cardiogenic shock compared with patients with NSTE ACS without HF and with preserved systolic function. The ACC/AHA guidelines state that any patient with NSTE ACS and HF should receive an ACE inhibitor, as supported by randomized controlled trials of ACE inhibitors in ACS complicated by HF or high-risk coronary disease.2,6 –14 Only 60.9% of patients with HF/systolic dysfunction in this study received an ACE inhibitor as an acute medication (⬍24 hours); 76.8% received ACE inhibitors at discharge. Those with HF/preserved systolic function had an even lower rate of use. Additional concerns are related to the use of evidencebased therapies with class I recommendations by current ACC/AHA guidelines.2 Rates of aspirin, ␤-blocker, and statin use were lower in patients with than in those without HF. In particular, the high-risk HF/preserved systolic function group did not receive evidence-based medications (statins, clopidogrel, glycoprotein IIb/IIIa platelet inhibitors) at an adequate rate. Although studies may not be specific to HF, these therapies should be widely instituted, especially in patients with the highest risk of long-term mortality and morbidity. However, the timing of ␤-blocker use in ACS complicated by HF is based on clinical judg-

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ment because of the potential risk for cardiogenic shock in patients who have not been stabilized.15 A common paradox in cardiovascular care is that patients with the highest risk for mortality or morbidity receive evidence-based therapies and interventions at a lower rate despite their greater potential for benefiting from them.16,17 Although previous studies have shown that invasive procedures are less likely in those with systolic dysfunction or in those with clinical HF, our study extends those findings to patients with HF and preserved systolic function to determine whether these procedures occur less often after adjusting for other factors.5,18 –21 The appropriate timing of invasive procedures and/or revascularization is not well understood for patients with HF, although guidelines recommend an early invasive strategy. Another important finding from our study is that the presence of systolic dysfunction without HF symptoms carries risks similar to those seen in patients with HF and preserved systolic function. Therefore, assessing for left ventricular function is important in the setting of ACS regardless of HF symptoms. Our results support previous work demonstrating that decreased systolic function, even without HF symptoms, is associated with substantial early morbidity and mortality.22,23 Even in patients who do not undergo cardiac catheterization, evaluation for systolic dysfunction is important and may alter clinical management.21 Moreover, systolic dysfunction carries significant implications for long-term outcomes and specific indications for therapies.24 Notably, 33,545 (25.8%) of the patients with NSTE ACS in the CRUSADE registry had to be excluded from this analysis due to lack of recorded EF values. Considering the importance of HF and systolic dysfunction in management and outcomes of patients with NSTE ACS, it is clear that EF needs to be assessed in such patients more frequently. Study limitations: Although the CRUSADE database, currently with ⬎180,000 patients, is large, the analysis is limited to information obtained clinically and reported through a standardized case-report form. As such, underreporting of events may occur. However, this would provide conservative estimates of outcomes. Patients without a measured EF were excluded, which may have resulted in the exact frequency for treatments and events being over- or under-reported. In general, patients missing EF values were older and had more co-morbidities. Unadjusted rates of treatments were lower in those missing EF values and unadjusted outcomes were worse. Similar findings have been reported by our group and likely reflect an overall pattern of care.21 In addition, only in-hospital outcomes were assessed, so we could not determine the influence of type of HF on longer term outcomes after hospitalization. The prespecified definition for HF for the CRUSADE includes symptoms that may overlap with ischemia, which may result in overreporting of HF. Further, although we observed disparities in treatment for patients with HF, we cannot quantify the influence of these differences on observed clinical outcomes. The analysis is observational and requires confirmation with other, prospectively designed studies.

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1. Hoekstra JW, Pollack CV Jr, Roe MT, et al. Improving the care of patients with non–ST-elevation acute coronary syndromes in the emergency department: the CRUSADE initiative. Acad Emerg Med 2002; 9:1146 –1155. 2. Braunwald E, Antman EM, Beasley JW, et al. 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. 3. Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika 1986;73:13–22. 4. Spencer FA, Meyer TE, Gore JM, Goldberg RJ. Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure: the National Registry of Myocardial Infarction. Circulation 2002;105:2605–2610. 5. Steg PG, Dabbous OH, Feldman LJ, et al. 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. 6. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821– 828. 7. Cleland JG, Erhardt L, Murray G, Hall AS, Ball SG. Effect of ramipril on morbidity and mode of death among survivors of acute myocardial infarction with clinical evidence of heart failure. A report from the AIRE Study Investigators. Eur Heart J 1997;18:41–51. 8. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet 2000;355:1575–1581. 9. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782–788. 10. Garg R, Yusuf S. Overview of randomized trials of angiotensinconverting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA 1995;273:1450 –1456. 11. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung

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13. 14.

15. 16. 17. 18.

19.

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