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Original Contribution |

Decline in Rates of Death and Heart Failure in Acute Coronary Syndromes, 1999-2006 FREE

Keith A. A. Fox, MB, ChB, FRCP; Philippe Gabriel Steg, MD; Kim A. Eagle, MD; Shaun G. Goodman, MD, MSc; Frederick A. Anderson, PhD; Christopher B. Granger, MD; Marcus D. Flather, MBBS, FRCP; Andrzej Budaj, MD, PhD; Ann Quill, MA; Joel M. Gore, MD; for the GRACE Investigators
[+] Author Affiliations

Author Affiliations: Cardiovascular Research, Division of Medical and Radiological Sciences, The University of Edinburgh, Edinburgh, Scotland (Dr Fox); Hospital Bichat, Paris, France (Dr Steg); University of Michigan Health System, Ann Arbor (Dr Eagle); Canadian Heart Research Centre and Terrence Donnelly Heart Centre, Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, Ontario (Dr Goodman); University of Massachusetts Medical School, Worcester (Drs Anderson and Gore and Ms Quill); Royal Brompton & Harefield NHS Trust, London, England (Dr Flather); Postgraduate Medical School, Grochowski Hospital, Warsaw, Poland (Dr Budaj); and Duke University Medical Center, Durham, NC (Dr Granger).

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JAMA. 2007;297(17):1892-1900. doi:10.1001/jama.297.17.1892.
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Context Randomized trials provide robust evidence for the impact of pharmacological and interventional treatments in patients with ST-segment elevation and non–ST-segment elevation acute coronary syndromes (NSTE ACS), but whether this translates to changes in clinical practice is unknown.

Objective To determine whether changes in hospital management of patients with ST-segment elevation myocardial infarction (STEMI) and NSTE ACS are associated with improvements in clinical outcome.

Design, Setting, and Patients In the Global Registry of Acute Coronary Events (GRACE), a multinational cohort study, 44 372 patients with an ACS were enrolled and followed up in 113 hospitals in 14 countries between July 1, 1999, and December 31, 2006.

Main Outcome Measures Temporal trends in the use of evidence-based pharmacological and interventional therapies; patient outcomes (death, congestive heart failure, pulmonary edema, cardiogenic shock, stroke, myocardial infarction).

Results Use of pharmacological medications increased over the study period (β-blockers, statins, angiotensin-converting enzyme inhibitors, thienopyridines with or without percutaneous coronary intervention [PCI], glycoprotein IIb/IIIa inhibitors, low-molecular-weight heparin; all P<.001). Pharmacological reperfusion declined in patients with STEMI by −22 percentage points (95% confidence interval [CI], −27 to −17), whereas primary PCI increased by 37 percentage points (95% CI, 33-41). In patients with non-STEMI, rates of PCI increased markedly by 18 percentage points (95% CI, 15-20). Rates of congestive heart failure and pulmonary edema declined in both populations: STEMI, −9 percentage points (95% CI, −12 to −6) and NSTE ACS, −6.9 percentage points (95% CI, −8.4 to −4.7). In patients with STEMI, hospital deaths decreased by 18 percentage points (95% CI, −5.3 to −1.9) and cardiogenic shock by −24 percentage points (95% CI, −4.3 to −0.5). Risk-adjusted hospital deaths declined −0.7 percentage points (95% CI, −1.7 to 0.3) in NSTE ACS patients. Six-month follow-up rates declined among STEMI patients: stroke by −0.8 percentage points (95% CI, −1.7 to 0.1) and myocardial infarction by −2.8 percentage points (95% CI, −6.4 to 0.9). In NSTE ACS, 6-month death declined −1.6 percentage points (95% CI, −3.0 to −0.1) and stroke by 0.7 percentage points (95% CI, −1.4 to 0.1).

Conclusions In this multinational observational study, improvements in the management of patients with ACS were associated with significant reductions in the rates of new heart failure and mortality and in rates of stroke and mycoardial infarction at 6 months.

Figures in this Article

Randomized trials provide robust evidence for the impact of pharmacological and interventional treatments in patients with ST-segment elevation and non–ST-segment elevation acute coronary syndromes (NSTE ACS), leading to changes in practice guidelines.14 However, the extent and time course of changes in clinical practice are uncertain, and it is unknown whether such changes are associated with improved outcome. Previous studies have documented substantial gaps between guideline recommendations and clinical practice.57 Thus, there is a clinical priority to determine the extent to which evidence is applied in practice, whether this is changing over time, and whether such changes are associated with improved outcomes.

Few studies in acute coronary disease offer a sufficiently long sampling interval with sufficiently robust sampling techniques to reveal changes in practice and outcome over time.810 The Global Registry of Acute Coronary Events (GRACE)7 is the only large-scale, multinational, observational study of the spectrum of patients hospitalized with an ACS, with continuous recruitment of patients for more than 6 years. Results from earlier studies suggest that hospital characteristics, access to resources, and geographic factors influence uptake of new therapies into practice.7,11 The Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE)11 quality improvement initiative involves centers throughout the United States and provides valuable insights into selected care processes and patient outcomes as measures of hospital quality.

A total of 62 935 patients have been enrolled in GRACE since it was launched in 1999, and there is a sufficiently large sample size (16 814 patients with ST-segment elevation myocardial infarction [STEMI]; 27 558 with NSTE ACS; and 2067 in-hospital deaths) and sufficient study duration (6.5 years of recruitment) to define changes in management and outcome. The hypothesis for this analysis is that changes in hospital management of patients with ACS are associated with improvements in clinical outcome, and that these changes are independent of the risk status of the study population on presentation to hospital.

Full details of the GRACE methods have been published.12,13 To be eligible, patients (≥18 years) had to be admitted for ACS as a presumptive diagnosis and have at least 1 of the following: electrocardiographic changes consistent with ACS, serial increases in serum biochemical markers of cardiac necrosis, documented coronary artery disease, or both. The qualifying patient with ACS must not have been precipitated by significant noncardiovascular comorbidity. Where required, study investigators received approval from their local hospital ethics or institutional review board for the conduct of this study and signed informed consent for follow-up contact was obtained from the patients at enrollment.

Consistency of Sampling Techniques, End Point Definitions, and Methods of Analysis

The aim was to enroll an unselected population of patients with an ACS, irrespective of geographic region. Sites were encouraged to recruit the first 10 to 20 consecutive eligible patients each month, and regular audits were performed. Data were collected by trained study coordinators using standardized case report forms. Demographic characteristics, medical history, presenting symptoms, duration of prehospital delay, biochemical and electrocardiographic findings, treatment practices, and outcomes were collected. Patients with a non-ACS discharge diagnosis and patients transferred into a GRACE site from a non-GRACE site were excluded from the analysis. All cases were assigned to 1 of the following categories: STEMI (including left bundle-branch block), non-STEMI, unstable angina, and other cardiac or noncardiac diagnoses.13 Hospital-specific feedback was provided to each center on a quarterly basis.

The primary outcomes for this study were in-hospital death, recurrent myocardial infarction, heart failure, stroke, and cardiogenic shock. At approximately 6 months after hospital discharge, patients were followed up for death, stroke or myocardial infarction. Of the patients who were alive at discharge from hospital, 2435 (16%) of 15 569 of those with STEMI and 3883 (15%) of 26 736 with NSTE ACS did not complete follow up. Standardized definitions of all patient-related variables, diagnoses, and in-hospital outcomes were used13 (details available at http://www.outcomes.org/grace). We applied guideline-based criteria for identifying patients eligible for pharmacological treatments or mechanical interventions; specifics are available from the authors on request.

Statistical Analysis

The analysis focuses on the populations of patients diagnosed with STEMI or NSTE ACS (non-STEMI and unstable angina). Data used were collected from July 1, 1999, through December 31, 2006. Data are summarized as frequencies and percentages for categorical variables. Continuous variables are presented as medians and 25th and 75th percentiles. The period of patient enrollment into GRACE was divided into 13 periods of 6 months each. Six-month follow-up data for each patient were reported under the same period as their enrollment. The double-sided Cochran-Armitage test for trend or logistic regression was used to evaluate time trends at a significance level of α = .05. The analysis was performed using SAS software version 9.1 (SAS Institute Inc, Cary, NC).

To account for possible changes in patients' baseline risk characteristics, the probability of in-hospital death was calculated for each patient using the GRACE in-hospital risk score.14 The average risk score for each time period was then calculated. Although patients with STEMI showed no change in predicted risk of mortality over time, there was a slight increase in risk for those with NSTE ACS. To account for this, adjusted rates were computed and normalized to those of the first time period. To calculate the adjusted rate, a difference between the observed and predicted death rates was computed for each time period.

This study is based on data from 44 372 patients enrolled at 113 hospitals in 14 countries between July 1, 1999, and December 31, 2005, and were followed up for approximately 6 months after discharge. Of these patients, 27 558 were diagnosed with NSTE ACS and 16 814 with STEMI. Patients with STEMI were more often male and were slightly younger than those with NSTE ACS (Table 1). Patients with NSTE ACS had a more complex medical history than patients with STEMI but were less likely to be current smokers and more likely to be past smokers.

Table Graphic Jump LocationTable 1. Patients' Baseline Characteristics According to Type of Acute Coronary Syndrome and Enrollment Period
ST-Segment Elevation Myocardial Infarction

Temporal Trends in Pharmacological Management (Class 1A Indications). Temporal trends in medication use and interventions in eligible STEMI patients are shown in Figure 1 and Table 2. Over the study period, the use of aspirin exceeded 94% in eligible patients (Figure 1) and the use of any oral antiplatelet drug (aspirin or thienopyridine) did not change (97% in 1999 to 99% in 2005; 4% increase; 95% confidence interval [CI], 0.5-3.2 for percentage difference in rates). Treatment with β-blockers increased by 11 percentage points (95% CI, 7.6-14), statins by 48 percentage points (95% CI, 45-52), and angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) by 22 percentage points (95% CI, 18-25) (Figure 1 and Table 2).

Figure 1. Temporal Trends in Patients With ST-Segment Elevation Myocardial Infarction or Left Bundle-Branch Block, July 1999-December 2005
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 2 for the first and last periods. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass graft; Gp, glycoprotein; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Table Graphic Jump LocationTable 2. Changes in Therapy of 44372 Patients Treated for STEMI and NSTE ACS, 1999 and 2005
Other Guideline-Indicated Medications

The use of low-molecular-weight heparin increased by 20 percentage points (95% CI, 16-24), whereas the use of unfractionated heparin declined by 19 percentage points (95% CI, −24 to −15) over the same period (Figure 1). Some patients received both low-molecular-weight heparin and unfractionated heparin during hospitalization.15 Thienopyridine usage increased by 49 percentage points (95% CI, 45-53) overall, and by 56 percentage points (95% CI, 50-61) in the absence of percutaneous coronary intervention (PCI). Glycoprotein IIb/IIIa (GpIIb/IIIA) usage, overall, increased by 24 percentage points (95% CI, 20-27) over the course of the study, but among patients whose care was managed noninvasively, less than 1 in 10, received this therapy (2.3%-9.0%; 6.7 percentage points; 95% CI, 3.3-10). The use of calcium channel blockers, with no guideline-supported indication in STEMI, declined by 9.9 percentage points (95% CI, −13 to −6.9) between 1999 and 2005 (Figure 1B; Table 2).

Reperfusion and Interventional Therapy

Use of pharmacological reperfusion declined by 22 percentage points (95% CI, −27 to −17) (Figure 1; Table 2), whereas the rate of primary PCI increased by 37 percentage points (95% CI, 33-41) over the same interval (Figure 1; Table 2). Approximately one third of patients received primary or other PCI in 1999 and this increased to 64% of patients in 2005 (32.5 percentage points; 95% CI, 27-35). The proportion of patients with STEMI who did not receive pharmacological reperfusion therapy or primary rescue or facilitated PCI declined by 5.5 percentage points (95% CI, −9.8 to −1.2; Figure 1; Table 2).

Outcome Measures Over Time in Patients With STEMI

The rates of death in hospital and cardiogenic shock declined in parallel, whereas the rate of stroke did not change significantly (Figure 2). Hospital deaths decreased by 3.9 percentage points (95% confidence interval [CI] −5.3 to −1.9) and cardiogenic shock by 2.4 percentage points (95% CI, −4.3 to −0.5; Table 3). The rate of in-hospital congestive heart failure or pulmonary edema declined by 9.0 percentage points (95% CI, −12 to −6; Table 3). Myocardial infarction diagnosed more than 24 hours after presentation to hospital or recurrent myocardial infarction were collected systematically in the revised case report form July 2002. The rate of these events declined by 1.6 percentage points (95% CI, −3.6 to 0.5). A linear regression of mean risk scores at hospital presentation, over time, was nonsignificant (data available from authors on request).

Figure 2. In-Hospital and 6-Month Outcomes in Patients With ST-Segment Elevation Myocardial Infarction or Left Bundle-Branch Block
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 3 for the first and last periods. CHF indicates congestive heart failure; MI, myocardial infarction. For in-hospital outcomes, P<.01 for recurrent MI or MI diagnosed 24 hours after presentation to hospital; P=.02 for shock; and P<.001 for death. For 6-month outcomes, P=.01 for MI and P=.04 for stroke.

Table Graphic Jump LocationTable 3. Changes in Clinical Outcomes in 44372 Patients Treated for STEMI or NSTE ACS, 1999 and 2005

The rate of myocardial infarction occurring between hospital discharge and 6-month follow-up decreased by 2.8 percentage points (95% CI, −6.4 to 0.9) and stroke by 0.8 percentage points (95% CI, −1.7 to 0.1; Figure 2; Table 3).

Non-STEMI and Unstable Angina

Temporal Trends in Pharmacological Therapies (Class 1A Recommendations). Temporal trends in medication use in NSTE ACS patients without contraindications to these drugs are shown in Figure 3 and Table 2. The use of aspirin was high and increased modestly during the study by 2.6 percentage points (95% CI, 1.1-4.1). Similarly, the use of β-blockers increased by 9.9 percentage points (95% CI, 7.5-12). Use of ACE inhibitors (or ARBs) increased by 23 percentage points (95% CI, 20-26), statins by 42 percentage points (95% CI, 40-45), and thienopyridines by 51 percentage points (95% CI, 48-54). In contrast, the use of unfractionated heparin fell by 19 percentage points (95% CI, −22 to −16), whereas that of low-molecular-weight heparin increased by 23 percentage points (95% CI, 20-26; some patients received both low-molecular-weight heparin and unfractionated heparin during hospitalization15). Treatment with calcium-channel blockers (no class 1 recommendation) declined by 12 percentage points (95% CI, −15 to −9.4).

Figure 3. Temporal Trends in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes, July 1999-December 2005
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 2 for the first and last periods. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass graft; GP, glycoprotein; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Temporal Trends in Interventional Therapy

There was a modest decrease in the use of coronary artery bypass graft (CABG) surgery of 1.7 percentage points (95% CI, −3.2 to −0.3; Figure 3). The frequency of angiography increased markedly by 21 percentage points (95% CI, 18 to 24). The use of PCI increased substantially by 18 percentage points (95% CI, 15-20). Glycoprotein IIb/IIIa inhibitors exhibited an increase, with increasing usage between 1999 (9.0%, 194/2157) and 2003 (23%, 435/1859), then about 20% through 2005 (Figure 3) with an overall increase of 11 percentage points (95% CI, 8.3-13; Table 2). Glycoprotein IIb/IIIa usage in patients whose care was managed noninvasively was low, increasing from 2.7% (49/1792) in 1999 to 9.3% in 2002 and decreasing to 6.1% (123/2013) in 2005.

Outcome Measures Over Time in Patients With NSTE ACS

Risk-adjusted hospital deaths declined by 0.7 percentage points (95% CI, −1.7 to 0.3) in NSTE ACS patients (Figure 4; Table 3). The rate of stroke did not change significantly over time (Figure 4; Table 3). The rate of cardiogenic shock decreased slightly, but significantly, while the rate of congestive heart failure and pulmonary edema decreased by 6.5 percentage points (95% CI, −8.4 to −4.7). Myocardial infarction diagnosed more than 24 hours after presentation to hospital or recurrent myocardial infarction (recorded systematically in case report forms from July 2002) declined by 1.3 percentage points (95% CI, −2.7 to 0.1).

Figure 4. In-Hospital and 6-Month Outcomes in Patients With Non–ST-Segment Elevation Myocardial Infarction or Unstable Angina
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 3 for the first and last periods. CHF indicates congestive heart failure; MI, myocardial infarction. For in-hospital outcomes, P<.001 for CHF or pulmonary edema and P=.03 for shock; recurrent MI or MI diagnosed 24 hours after presentation to hospital, and stroke. For 6-month outcomes, P=.03 for stroke.

The rate of death between hospital discharge and 6-month follow-up decreased by 1.6 percentage points (95% CI, −3.0 to −0.1). Stroke decreased by 0.7 percentage points (95% CI, −1.4 to 0.1; Figure 4; Table 3).

Risk Scores and Death Adjusted for Risk at the Start of the Study

The mean in-hospital risk score14 for patients with NSTE ACS showed a significant (P<.01) increasing trend over the study period, from 120 (95% CI, 118-121) in 1999 to 125 (95% CI, 123-127) in 2007. Hence, if all else remained unchanged, the expected risk of death would have risen from 2.5% to 3.2%. Thus, although the unadjusted death rate remained unchanged, when adjusted for risk, deaths decreased by 0.7 percentage points (95% CI, −1.7 to 0.3) from 1999, a relative change of 24% (Figure 4; Table 3).

These data, from the largest multinational observational cohort study of patients with an ACS, demonstrate evidence of a change in practice for both pharmacologic and interventional treatments in patients with either STEMI or NSTE ACS. These changes in practice are accompanied by significant decreases in the rates of in-hospital death, cardiogenic shock, recurrent myocardial infarction, and heart failure in patients presenting with STEMI and significant decreases in hospital death, heart failure, cardiogenic shock, and new myocardial infarction among patients with NSTE ACS. The risk status of patients at presentation with STEMI did not change over the course of the present study, so it is highly plausible that the changes in clinical outcomes are the direct consequence of changes in practice. The hospital death rate for patients with NSTE ACS showed a significant decrease after adjustment for baseline risk. It is disappointing that the proportion of patients who received no reperfusion therapy has not significantly improved over time.

The use of evidence-based therapies and PCI interventions increased in the STEMI population. This included the use of ACE inhibitors (or ARBs) and Gp IIb/IIIa inhibitors in patients undergoing PCI. This increase was matched by a statistically significant decrease in the rates of death, cardiogenic shock, and heart failure or pulmonary edema.

In patients with NSTE ACS, increases were observed in in-hospital treatment with low-molecular-weight heparin, thienopyridines, ACE inhibitors (or ARBs), and statins. Similarly, the rate of cardiac intervention (cardiac catheterization and PCI) increased. In contrast, the use of Gp IIb/IIIa inhibitors increased between 1999 and 2003 but changed little thereafter; a similar pattern was observed for Gp IIb/IIIa inhibitors without PCI. This change in practice may reflect a response to the findings from the Global Use of Strategies to Open Occluded Coronary Arteries-IV Acute Coronary Syndrome (GUSTO-IV ACS,16 published in June 2001) and guidelines for managing patients with NSTE ACS (published in 200017,18 and 20024,19). In the update, the use of Gp IIb/IIIa inhibitors was limited in patients who were to undergo PCI.

In NSTE ACS the rates of new heart failure or pulmonary edema, in hospital, decreased significantly. The risk score for patients with NSTE ACS increased modestly over the course of the study. After adjustment for risk status, the rate of hospital death declined by approximately a quarter. More marked changes may be evident with longer follow-up because the beneficial impact of interventional therapy may be seen with later follow-up.2023 The results of a meta-analysis of trials of interventional therapy suggest an additional hazard of death or myocardial infarction during the hospital phase that is subsequently overcome by postdischarge benefit.23,24

Since GRACE was launched in 1999, NSTE ACS guidelines from both the American College of Cardiology/American Heart Association (ACC/AHA)1,2 and the European Society of Cardiology (ESC)3,4 have been updated to include data from recent clinical trials. In an earlier study from the GRACE registry, data from nearly 13 000 patients with an ACS were analyzed to evaluate the uptake of selected cardiac medications and invasive therapies between 1999 and 2001 and to assess the impact of geographical and hospital characteristics on this pattern.7 During this period, new guidelines were released by the ESC and the ACC/AHA, and the results of 2 major clinical trials (Fragmin during Instability in Coronary Artery Disease [FRISC] II,25,26 GUSTO IV-ACS27) were published. The results of our earlier study suggest that hospital status, access to resources, and geographical factors, rather than the publication of guidelines, influence the uptake of new therapies into practice.7 We also reported increases in the use of evidence-based cardiac medications between July 1999 and December 2001 but no significant decline in death rates was observed over that interval.7 Data from the present study (1999 to 2006) demonstrate substantial temporal changes in the use of pharmacological and interventional therapies in ACS and clear evidence for a reduction in new heart failure and in-hospital deaths especially in patients with STEMI. Our multinational data, combined with those from CRUSADE,28 suggest the potential for further reductions in patient outcomes with greater uptake of evidence-based therapies and interventions.

Strengths and Limitations

GRACE is the largest multinational observational cohort study to include the spectrum of patients with ACS. GRACE is designed to be representative of regional communities and uses standardized criteria for defining ACS and hospital outcomes, rigorous quality control, and audit measures. The participating clusters reflect regional practices and outcomes but do not necessarily reflect practice for specific countries. Participating hospitals are sent feedback on a 6-month basis, so we cannot determine whether improvements in adherence to evidence-based medication are taking place nationwide or are limited to participating sites. Increasing use of troponin measurement throughout the study may have led to underestimation of the detection of small reinfarctions if troponin was already elevated at presentation and if the patient did not evolve new electrocardiographic changes of myocardial infarction.

Conclusions

These contemporary multinational observational data show substantial changes in the management of patients with STEMI or NSTE ACS studied between 1999 and 2006. The main changes demonstrate a marked increase in interventional therapy in both ST elevation and NSTE ACS and changes in pharmacological therapy, including increases in use of β-blockers, statins, ACE inhibitors (or ARBs), and thienopyridines in patients with an ACS, and Gp IIb/IIIa inhibitors in patients with STEMI. The changes are consistent with trial evidence and national and international guidelines. The risk profile for patients with STEMI has not changed significantly over this interval, whereas the risk for patients with NSTE ACS has increased slightly. This study population is the first demonstration of significant reductions observed in hospital rates of new heart failure in ACS patients, over time, and of reductions in mortality.

Corresponding Author: Keith A. A. Fox, MB, ChB, FRCP, Cardiovascular Research, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK (k.a.a.fox@ed.ac.uk).

Author Contributions: Dr Fox had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fox, Steg, Eagle, Goodman, Anderson, Granger, Budaj, Gore.

Acquisition of data: Fox, Steg, Eagle, Goodman, Anderson, Granger, Budaj, Gore.

Analysis and interpretation of data: Fox, Steg, Eagle, Goodman, Anderson, Granger, Flather, Budaj, Quill, Gore.

Drafting of the manuscript: Fox.

Critical revision of the manuscript for important intellectual content: Fox, Steg, Eagle, Goodman, Anderson, Granger, Flather, Budaj, Quill, Gore.

Statistical analysis: Fox, Anderson, Quill.

Obtained funding: Anderson.

Administrative, technical, or material support: Steg, Eagle, Goodman, Anderson, Flather, Budaj, Quill, Gore.

Study supervision: Fox, Steg, Anderson, Gore.

Financial Disclosures: Dr Fox reports receiving research grant funding from the British Heart Foundation, Medical Research Council, and the Wellcome Trust and research grants and lecture fees from Sanofi-Aventis, GlaxoSmithKline, and Bristol-Myers Squibb. Dr Steg reports receiving consulting fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck, GlaxoSmithKline, Sanofi-Aventis, Pfizer, Servier, and Takeda; lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Novartis, Nycomed, Sanofi-Aventis, Sankyo, Servier, and ZLB-Behring; and grant support from Sanofi-Aventis. Dr Eagle reports receiving research grants from Biosite, Bristol-Myers Squibb, Cardiac Sciences, Blue Cross/Blue Shield of Michigan, the Hewlett Foundation, the Mardigian Fund, Pfizer, Sanofi-Aventis, Varbedian Fund, the National Institutes of Health's National Heart, Lung, and Blood Institute, and the Robert Wood Johnson Foundation and serving as a consultant for and on the advisory board for the National Heart, Lung, and Blood Institute, Pfizer Inc, and Sanofi-Aventis. Dr Goodman reports receiving research grants from Sanofi-Aventis, Bristol-Myers Squibb, Hoffmann-LaRoche Pharmaceuticals, Merck & Co Inc, Schering Corp, and the Medicines Co and serving as a speaker for or receiving advisory board member fees from Sanofi-Aventis, Bristol-Myers Squibb, Hoffmann-LaRoche Pharmaceuticals, Boehringer Ingelheim, and GlaxoSmithKline. Dr Anderson reports receiving research grants from Sanofi-Aventis. Dr Granger reports receiving research grants from Alexion, AstraZeneca, Sanofi-Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, deCode Genetics, Genentech, GlaxoSmithKline, Novartis, Procter and Gamble, and the Medicines Co and receiving consulting fees from Alexion, AstraZeneca, Sanofi-Aventis, Genentech, GlaxoSmithKline, INO Therapeutices, Medicure, Novartis, Procter and Gamble, and the Medicines Co. Dr Flather reports receiving grants from Sanofi-Aventis, GlaxoSmithKline, Bristol-Myers Squibb, Boehringer Ingelheim, and Lilly; serving as a consultant and an advisory board member for Sanofi-Aventis, Eisai, and CSL Behring; and receiving speaker bureau fees for Menarini, CSL Behring, Sanofi-Aventis, and Bristol-Myers Squibb. Dr Budaj reports receiving research grants from Sanofi-Aventis, GlaxoSmithKline, AstraZeneca, and Boehringer Ingelheim and serving as an advisory board member for Sanofi-Aventis, GlaxoSmithKline, and AstraZeneca. Dr Gore reports receiving a research grant from Sanofi-Aventis, and Ms Quill reported no disclosures.

Funding/Support: This research was supported by an unrestricted grant from Sanofi-Aventis, Paris, France. GRACE is supported by an unrestricted educational grant from Sanofi-Aventis to the Center for Outcomes Research, University of Massachusetts Medical School.

Role of the Sponsor: Sanofi-Aventis had no involvement in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. The design, conduction, and interpretation of GRACE were undertaken by an independent steering committee.

Acknowledgment: We thank the physicians and nurses participating in GRACE, and Sophie Rushton-Smith, PhD, who provided editorial support and was funded by Sanofi-Aventis.

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Goldberg RJ, Spencer FA, Yarzebski J.  et al.  A 25-year perspective into the changing landscape of patients hospitalized with acute myocardial infarction (the Worcester Heart Attack Study).  Am J Cardiol. 2004;94:1373-1378
PubMed   |  Link to Article
Spencer FA, Lessard D, Yarzebski J, Gore JM, Goldberg RJ. Decade-long changes in the use of combination evidence-based medical therapy at discharge for patients surviving acute myocardial infarction.  Am Heart J. 2005;150:838-844
PubMed   |  Link to Article
Peterson ED, Roe MT, Mulgund J.  et al.  Association between hospital process performance and outcomes among patients with acute coronary syndromes.  JAMA. 2006;295:1912-1920
PubMed   |  Link to Article
Steg PG, Goldberg RJ, Gore JM.  et al.  Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE).  Am J Cardiol. 2002;90:358-363
PubMed   |  Link to Article
The GRACE Investigators.  Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes.  Am Heart J. 2001;141:190-199
PubMed   |  Link to Article
Granger CB, Goldberg RJ, Dabbous O.  et al.  Predictors of hospital mortality in the Global Registry of Acute Coronary Events.  Arch Intern Med. 2003;163:2345-2353
PubMed   |  Link to Article
Gore JM, Spencer FA, Goldberg RJ.  et al.  Use of heparins in non-ST-elevation acute coronary syndromes.  Am J Med. 2007;120:63-71
PubMed   |  Link to Article
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes.  N Engl J Med. 1996;335:775-782
PubMed   |  Link to Article
Bertrand ME, Simoons ML, Fox KA.  et al.  Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation; recommendations of the Task Force of the European Society of Cardiology.  Eur Heart J. 2000;21:1406-1432
PubMed   |  Link to Article
Braunwald E, Antman EM, Beasley JW.  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: 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. 2000;36:970-1062
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Fox KA, Poole-Wilson P, Clayton TC.  et al.  5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial.  Lancet. 2005;366:914-920
PubMed   |  Link to Article
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E.FRISC II Investigators: Fast Revascularisation During Instability in Coronary Artery Disease.  Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial.  Lancet. 2000;356:9-16
PubMed   |  Link to Article
Cannon CP, Weintraub WS, Demopoulos LA, Robertson DH, Gormley GJ, Braunwald E.Treat Angina With Aggrastat and determine Cost of Therapy With an Invasive or Conservative Strategy—Thrombolysis In Myocardial Infarction.  Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial.  Am J Cardiol. 1998;82:731-736
PubMed   |  Link to Article
Mehta SR, Cannon CP, Fox KA.  et al.  Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials.  JAMA. 2005;293:2908-2917
PubMed   |  Link to Article
Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials.  J Am Coll Cardiol. 2006;48:1319-1325
PubMed   |  Link to Article
FRagmin and Fast Revascularisation During InStability in Coronary Artery Disease Investigators.  Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet. 1999;354:708-715
PubMed   |  Link to Article
FRagmin and Fast Revascularisation during InStability in Coronary Artery Disease Investigators.  Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet. 1999;354:701-707
PubMed   |  Link to Article
Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet. 2001;357:1915-1924
PubMed   |  Link to Article
Bhatt DL, Roe MT, Peterson ED.  et al.  Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative.  JAMA. 2004;292:2096-2104
PubMed   |  Link to Article

Figures

Figure 1. Temporal Trends in Patients With ST-Segment Elevation Myocardial Infarction or Left Bundle-Branch Block, July 1999-December 2005
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 2 for the first and last periods. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass graft; Gp, glycoprotein; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Figure 2. In-Hospital and 6-Month Outcomes in Patients With ST-Segment Elevation Myocardial Infarction or Left Bundle-Branch Block
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 3 for the first and last periods. CHF indicates congestive heart failure; MI, myocardial infarction. For in-hospital outcomes, P<.01 for recurrent MI or MI diagnosed 24 hours after presentation to hospital; P=.02 for shock; and P<.001 for death. For 6-month outcomes, P=.01 for MI and P=.04 for stroke.

Figure 3. Temporal Trends in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes, July 1999-December 2005
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 2 for the first and last periods. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CABG, coronary artery bypass graft; GP, glycoprotein; LMWH, low-molecular-weight heparin; PCI, percutaneous coronary intervention; UFH, unfractionated heparin.

Figure 4. In-Hospital and 6-Month Outcomes in Patients With Non–ST-Segment Elevation Myocardial Infarction or Unstable Angina
Graphic Jump Location

The sample size of the ST-segment elevation myocardial infarction cohort varied over time. Percentages are based on eligible patients for respective treatments in each period, shown in Table 3 for the first and last periods. CHF indicates congestive heart failure; MI, myocardial infarction. For in-hospital outcomes, P<.001 for CHF or pulmonary edema and P=.03 for shock; recurrent MI or MI diagnosed 24 hours after presentation to hospital, and stroke. For 6-month outcomes, P=.03 for stroke.

Tables

Table Graphic Jump LocationTable 1. Patients' Baseline Characteristics According to Type of Acute Coronary Syndrome and Enrollment Period
Table Graphic Jump LocationTable 2. Changes in Therapy of 44372 Patients Treated for STEMI and NSTE ACS, 1999 and 2005
Table Graphic Jump LocationTable 3. Changes in Clinical Outcomes in 44372 Patients Treated for STEMI or NSTE ACS, 1999 and 2005

References

Antman EM, Anbe DT, Armstrong PW.  et al.  ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).  Circulation. 2004;110:588-636
PubMed   |  Link to Article
Braunwald E, Antman EM, Beasley JW.  et al.  ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—2002: 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).  Circulation. 2002;106:1893-1900
PubMed   |  Link to Article
Van de Werf F, Ardissino D, Betriu A.  et al. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology.  Management of acute myocardial infarction in patients presenting with ST-segment elevation.  Eur Heart J. 2003;24:28-66
PubMed   |  Link to Article
Bertrand ME, Simoons ML, Fox KA.  et al. The Task Force on the management of acute coronary syndromes of the European Society of Cardiology.  Management of acute coronary syndromes in patients presenting without persistent ST-segment elevation.  Eur Heart J. 2002;23:1809-1840
PubMed   |  Link to Article
Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, Lopez-Sendon J. Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE).  Lancet. 2002;359:373-377
PubMed   |  Link to Article
Carruthers KF, Dabbous OH, Flather MD.  et al. The Global Registry of Acute Coronary Events (GRACE).  Contemporary management of acute coronary syndromes: does the practice match the evidence?  Heart. 2005;91:290-298
PubMed   |  Link to Article
Fox KA, Goodman SG, Anderson FA Jr.  et al. The Global Registry of Acute Coronary Events (GRACE).  From guidelines to clinical practice: the impact of hospital and geographical characteristics on temporal trends in the management of acute coronary syndromes.  Eur Heart J. 2003;24:1414-1424
PubMed   |  Link to Article
Rogers WJ, Canto JG, Lambrew CT.  et al.  Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3.  J Am Coll Cardiol. 2000;36:2056-2063
PubMed   |  Link to Article
Goldberg RJ, Spencer FA, Yarzebski J.  et al.  A 25-year perspective into the changing landscape of patients hospitalized with acute myocardial infarction (the Worcester Heart Attack Study).  Am J Cardiol. 2004;94:1373-1378
PubMed   |  Link to Article
Spencer FA, Lessard D, Yarzebski J, Gore JM, Goldberg RJ. Decade-long changes in the use of combination evidence-based medical therapy at discharge for patients surviving acute myocardial infarction.  Am Heart J. 2005;150:838-844
PubMed   |  Link to Article
Peterson ED, Roe MT, Mulgund J.  et al.  Association between hospital process performance and outcomes among patients with acute coronary syndromes.  JAMA. 2006;295:1912-1920
PubMed   |  Link to Article
Steg PG, Goldberg RJ, Gore JM.  et al.  Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE).  Am J Cardiol. 2002;90:358-363
PubMed   |  Link to Article
The GRACE Investigators.  Rationale and design of the GRACE (Global Registry of Acute Coronary Events) Project: a multinational registry of patients hospitalized with acute coronary syndromes.  Am Heart J. 2001;141:190-199
PubMed   |  Link to Article
Granger CB, Goldberg RJ, Dabbous O.  et al.  Predictors of hospital mortality in the Global Registry of Acute Coronary Events.  Arch Intern Med. 2003;163:2345-2353
PubMed   |  Link to Article
Gore JM, Spencer FA, Goldberg RJ.  et al.  Use of heparins in non-ST-elevation acute coronary syndromes.  Am J Med. 2007;120:63-71
PubMed   |  Link to Article
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators.  A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes.  N Engl J Med. 1996;335:775-782
PubMed   |  Link to Article
Bertrand ME, Simoons ML, Fox KA.  et al.  Management of acute coronary syndromes: acute coronary syndromes without persistent ST segment elevation; recommendations of the Task Force of the European Society of Cardiology.  Eur Heart J. 2000;21:1406-1432
PubMed   |  Link to Article
Braunwald E, Antman EM, Beasley JW.  et al.  ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: 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. 2000;36:970-1062
PubMed   |  Link to Article
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
PubMed   |  Link to Article
Fox KA, Poole-Wilson P, Clayton TC.  et al.  5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomised trial.  Lancet. 2005;366:914-920
PubMed   |  Link to Article
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E.FRISC II Investigators: Fast Revascularisation During Instability in Coronary Artery Disease.  Outcome at 1 year after an invasive compared with a non-invasive strategy in unstable coronary-artery disease: the FRISC II invasive randomised trial.  Lancet. 2000;356:9-16
PubMed   |  Link to Article
Cannon CP, Weintraub WS, Demopoulos LA, Robertson DH, Gormley GJ, Braunwald E.Treat Angina With Aggrastat and determine Cost of Therapy With an Invasive or Conservative Strategy—Thrombolysis In Myocardial Infarction.  Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial.  Am J Cardiol. 1998;82:731-736
PubMed   |  Link to Article
Mehta SR, Cannon CP, Fox KA.  et al.  Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials.  JAMA. 2005;293:2908-2917
PubMed   |  Link to Article
Bavry AA, Kumbhani DJ, Rassi AN, Bhatt DL, Askari AT. Benefit of early invasive therapy in acute coronary syndromes: a meta-analysis of contemporary randomized clinical trials.  J Am Coll Cardiol. 2006;48:1319-1325
PubMed   |  Link to Article
FRagmin and Fast Revascularisation During InStability in Coronary Artery Disease Investigators.  Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet. 1999;354:708-715
PubMed   |  Link to Article
FRagmin and Fast Revascularisation during InStability in Coronary Artery Disease Investigators.  Long-term low-molecular-mass heparin in unstable coronary-artery disease: FRISC II prospective randomised multicentre study.  Lancet. 1999;354:701-707
PubMed   |  Link to Article
Simoons ML. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet. 2001;357:1915-1924
PubMed   |  Link to Article
Bhatt DL, Roe MT, Peterson ED.  et al.  Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative.  JAMA. 2004;292:2096-2104
PubMed   |  Link to Article

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