Time course of events in acute coronary syndromes: implications for clinical practice from the GRACE registry
Keith AA Fox*, Frederick A Anderson Jr, Shaun G Goodman, P Gabriel Steg, Karen Pieper, Ann Quill and Joel M Gore for the GRACE Investigators About the authors
Correspondence *Cardiovascular Research, University of Edinburgh, Chancellor's Building, 49 Little France Crescent, Edinburgh EH16 4SB, UK
Tel: +44 (0)131 242 6378
Email k.a.a.fox@ed.ac.uk
Summary
Background The time course of events after acute coronary syndromes might influence the timing and duration of therapeutic interventions. We investigated the impact of risk status and ST-segment category at presentation.
Methods The timing of death, reinfarction, stroke and major bleeding within 6 months of acute coronary syndromes was determined in 46,829 patients enrolled in the Global Registry of Acute Coronary Events (GRACE). Acute coronary syndromes were classified by elevation (n = 17,668), depression (n = 8,542), or neither (n = 20,619) in the ST segment. GRACE risk scores and hazard ratios (HR) were determined for three time periods: 0–4, 5–15 and 16–180 days.
Results ST-segment elevation was associated with a higher early risk of death than was ST-segment depression (0–4 days, HR 1.89, 95% CI 1.60–2.24 versus 5–15 days, HR 1.26, 95% CI 1.05–1.50), but after 15 days the risk was reversed (16–180 days, HR 0.85, 95% CI 0.75–0.97). Throughout the study, patients with ST-segment deviation had a higher mortality risk than those without. Within each ST category, the highest GRACE risk scores were associated with a 10–40-fold greater risk of death than the lowest scores (all categories P <0.0001). Most deaths occurred after day 4 (57%, 74%, and 78% for ST-segment elevation, depression and neither, respectively).
Conclusion The timing of events after acute coronary syndromes was affected by ST category and influenced by GRACE risk score within each electrocardiographic category of acute coronary syndromes. Risk stratification should, therefore, include multiple risk factors rather than ST shift alone.
Keywords:
acute coronary syndrome, death, major bleeding, myocardial infarction, stroke
Introduction
Acute coronary syndromes (ACS) encompass a spectrum of clinical conditions ranging from ST-segment elevation myocardial infarction (STEMI) to non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina. While these conditions share a common pathophysiological mechanism1—atherosclerotic plaque rupture complicated by various degrees of thrombosis and distal embolization2, 3, 4—the long-term clinical outcomes are dependent on various factors, such as the extent of myocyte necrosis and the development of arrhythmic and hemodynamic complications.5
The early risk of death following presentation with STEMI has been well characterized, but in patients with non-ST-segment elevation ACS (ST-segment depression or no ST-segment deviation [NSTE-ACS]), the time course of events and risk predictors have been less clearly defined. Patients presenting with a presumptive diagnosis of infarction and with persistent ST-segment elevation shown on electrocardiography are likely to have a complete occlusion of a major coronary artery and are candidates for emergency recanalization by reperfusion therapy.6 By contrast, the degree of coronary occlusion is variable in patients with NSTE-ACS, and the extent of infarction is dependent on the volume of myocardium at risk, collateral and antegrade perfusion, and myocardial oxygen demand.
In clinical practice, triage of patients with suspected ACS and management strategies are most frequently based on the clinical syndrome and electrocardiographic characteristics, without taking into account other risk factors or obtaining a formal risk score.9 This approach might, however, mask the true risk of complications, especially in patients with NSTE-ACS. For example, the ACC/AHA and the European Society of Cardiology guidelines recommend that patients with NSTE-ACS undergo early and repeated risk stratification (e.g. using the GRACE risk score) during hospitalization to guide decisions on treatment.7, 8 In the GRACE score, eight variables contain 90% of the predictive information.9 Various studies have, however, indicated a continuing risk of events after discharge and the raised risk of late mortality among patients with NSTEMI.5, 6, 10, 11, 12 Insights into the timing of events, such as infarction or reinfarction, stroke, and major bleeding, across the spectrum of ACS might, therefore, improve risk stratification and highlight key pathophysiological mechanisms before and after discharge, thereby aiding decision-making about the timing and duration of therapeutic interventions.
The large-scale multinational observational GRACE registry was established in 1999 to provide reliable and precisely defined data on the treatment, practice patterns, and long-term outcomes of patients with ACS.13 As part of this program, risk scores for patients with ACS have been developed. These risk scores aim to guide the triage and early management of ACS and are based on clinical characteristics and markers of ischemia and cell necrosis measured at initial presentation. The hypothesis on which we based the present study was that although the temporal distribution of cardiac complications differs according to electrocardiographic features (ST-segment deviation), within each category the spectrum of risk is determined by characteristics at presentation (i.e. the GRACE risk score). To test this hypothesis, we used GRACE data to investigate the relation between ST category, GRACE risk score, and the complication rates (e.g. death, myocardial infarction, and stroke) before and after discharge from hospital.
Methods
Study population
Full details of the GRACE protocol can be found elsewhere.13, 14 GRACE was designed to enroll an unselected population of patients with ACS, irrespective of geographic region. A total of 115 hospitals, located in 14 countries (Australia, New Zealand and various countries in North and South America and Europe) have contributed data to this observational study.
Eligible patients were adults (
18 years old) admitted to participating hospitals with a presumptive diagnosis of ACS and a clinical history of ACS accompanied by at least one of the following: electrocardiographic changes consistent with ACS, serial increases in levels of biochemical markers of cardiac necrosis (creatine kinase myocardial fraction, creatine phosphokinase, or troponin) and documented coronary artery disease (i.e. history of myocardial infarction, congestive heart failure believed to be due to ischemia or resuscitated sudden cardiac death; history of or new positive stress test or angina, with or without imaging; prior or new cardiac catheterization documenting coronary artery disease, percutaneous coronary intervention, or CABG). Patients with noncardiovascular causes for the clinical presentation, such as trauma, surgery, or aortic aneurysm, were excluded. In order to ascertain the occurrence of several long-term outcomes, such as death, myocardial infarction, or stroke, patients were followed up at approximately 6 months. Data were gathered by telephone, at clinic visits, and/or through calls to the patient's primary care physician. Where required, study investigators received approval from their local hospital ethics or institutional review board for the conduct of this study.
To ensure enrollment of an unselected ACS population to GRACE, sites were encouraged to recruit the first 10–20 consecutive eligible patients each month. Regular audits to confirm conformance to eligibility criteria and correct interpretation of data requested on the case report form were performed at all participating hospitals. Patient data were collected by trained study coordinators on standard case report forms. The case report form was revised twice ("second" and "third" versions) during the course of this study to include addition detail. Revisions were relevant for reinfarction data, which are available only in the third version, and the date of postdischarge stroke, which was collected in the first and third versions; the second version captured only time intervals in which a stroke may have occurred. Demographic characteristics, medical history, presenting symptoms, duration of prehospital delay, biochemical and electrocardiographic findings, treatment practices, and a variety of hospital outcome data were collected. Standard definitions of all patient-related variables, clinical diagnoses, and hospital complications and outcomes were used. On the basis of electrocardiographic features at presentation, all cases were assigned to one of the following categories: ST-segment elevation (with or without ST-segment depression), ST-segment depression without ST-segment elevation, or neither.
Identification of recurrent myocardial infarction is challenging in this and in other studies, especially during the period when cardiac markers remain elevated from the index event, and, therefore, we included only recurrent myocardial infarctions beyond the first 24 h after the index event.
Diagnosis and clinical outcomes
A discharge diagnosis of STEMI was made if a new ST-segment elevation greater than 1 mm in any location was seen or if a new (or presumed new) left-bundle-branch block was indicated on the index or a subsequent electrocardiogram, with the level of at least one positive cardiac biochemical marker of necrosis being raised. Patients were diagnosed as having NSTEMI if the level of at least one cardiac biochemical marker of necrosis was raised without new ST-segment elevation being seen on the index or subsequent electrocardiogram. Deaths were recorded during and after hospitalization. Hospital-specific feedback regarding patient characteristics, presentation, management, and outcomes were provided by GRACE to each center on a quarterly basis in the form of written reports. The temporal distribution of events between admission and 6-month follow-up was determined and GRACE risk scores were calculated based upon presentation characteristics.9 The events analyzed were death, infarction or reinfarction—particularly for NSTE-ACS patients—new stroke (irrespective of type) and major bleed (including hemorrhagic stroke). Three time periods for assessment were decided a priori: 0–4 days, 5–15 days, and 16–180 days. These were selected to reflect the time period within which most patients are hospitalized, the period immediately after discharge and longer follow-up.
Statistical analysis
Baseline characteristics are summarized as frequencies and percentages for categorical data and as median and 25th and 75th percentile values for continuous variables. Kaplan–Meier curves reflect the cumulative unadjusted mortality function.
Unadjusted rates (hazards) were calculated for different outcomes in either 2 day or 5 day time periods using the life-table method (Figure 1a and Figure 2). For postdischarge stroke, the exact date was not recorded in the second version of the case record form (36% of patients) but was interval censored (recorded as <1 month, 1 to <3 months, or 3 to 
6 months). In this case, strokes were estimated to have occurred at the midpoint of the respective intervals. Major bleeds were reported during the hospitalization; hazards were calculated for each 2 day period. Adjusted hazard ratios (HR) were calculated from Cox's proportional hazards models. The models consisted of baseline characteristics from the GRACE in-hospital risk model (age, Killip class, creatinine, positive cardiac markers, cardiac arrest, systolic blood pressure and pulse rate),9 hospital cluster (as a covariate) and the interactions of time period with ST category. Separate HR were estimated from these time period–ST category interactions for the periods 0–4, 5–15, and 16–180 days from admission.
Figure 1 Empirical hazard function for mortality and Kaplan–Meier curves showing cumulative incidence of death in patients presenting with acute coronary syndromes.
![Figure 1 : Empirical hazard function for mortality and Kaplan|[ndash]|Meier curves showing cumulative incidence of death in patients presenting with acute coronary syndromes. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com](/ncpcardio/journal/v5/n9/thumbs/ncpcardio1302-f1.jpg)
(A) Empirical rate per 2 days. (B) Mortality from hospital admission to 180 days. (C) Mortality from 16 to 180 days.
Full figure and legend (79K)Figures & Tables indexDownload Power Point slide (283K)Figure 2 Event rates by time interval in patients presenting with acute coronary syndromes.
(A) Death. (B) Myocardial infarction or reinfarction. (C) Stroke. (D) Major bleed, including hemorrhagic stroke. Abbreviation: MI, myocardial infarction.
Full figure and legend (103K)Figures & Tables indexDownload Power Point slide (308K)Additional analyses with Cox's models for death were performed for each ST category to assess whether the GRACE risk score added further prognostic information. Patients in each group were divided into four predefined categories of risk score: from low to highest (<135, 135 to <160, 160 to <180, and 180). The models were adjusted for hospital cluster and included interaction terms for GRACE risk score category and time, using the same predefined time periods from admission. Cox's proportional hazards regression models showed that the HR for ST elevation compared with either of the other ST groups changed over time; therefore, HR are presented by time periods. All statistical analyses were performed with SAS software version 9.1 (SAS Institute Inc., Cary, NC). Statistical significance was set at P <0.05.
Results
Study population
Between the start of July 1999 and the end of June 2006, 59,536 patients were admitted with a presumptive diagnosis of ACS; 4,925 patients who were discharged with non-ACS diagnoses and 7,782 patients who were transferred from non-GRACE hospitals were excluded. ACS diagnoses were confirmed in the remaining 46,829 patients, and they were enrolled in the study and either died or were discharged from hospital. After classification by ST category, 38% had ST-segment elevation, 18% had ST-segment depression, and 44% had neither. They differed significantly in terms of baseline characteristics (Table 1). Of included patients, 8,843 (19%) did not have 6-month follow-up information but were included in the analysis.
Table 1 Baseline characteristics in patients presenting with an acute coronary syndrome.
Full tableFigures & Tables indexDownload Power Point slide (344K)
Temporal distribution of events
Mortality
In the ST-segment elevation group, 43% (826 of 1,901) of deaths occurred within the first 4 days; for patients with ST-segment depression, this proportion was 26% (215 of 822), and for patients without ST deviation it was 22% (217 of 970, Table 2 and Figure 1a).
Table 2 Absolute event rates (per 5 days) from admission to 180 days in patients presenting with an acute coronary syndrome.
Full tableFigures & Tables indexDownload Power Point slide (256K)
After adjustment for age, Killip class, creatinine, positive initial cardiac markers, cardiac arrest status, systolic blood pressure, pulse, and hospital cluster, the HR for ST-segment elevation versus ST-segment depression were 1.89 (95% CI 1.60–2.24) for 0–4 days, 1.26 (95% CI 1.05–1.50) for 5–15 days, and 0.85 (95% CI 0.75–0.97) for 16–180 days (Table 3). The risk of death was significantly higher for patients in both these ST-category groups than in those without ST-segment deviation (P <0.001 for all time periods, Table 3).
Table 3 Hazard ratios for mortality, re-infarction, and stroke from admission to 180 days, and for major bleed from admission to 15 days in patients presenting with an acute coronary syndrome.
Full tableFigures & Tables indexDownload Power Point slide (302K)
The greatest number of deaths was observed in the early period following admission (0–15 days; Tables 2 and 4, Figure 1b and Figure 2a) compared with later. Those with no ST-segment deviation at presentation had the lowest cumulative incidence of death throughout the study (Figure 1b). The death rates (by time interval) also changed markedly in the first 15 days (Table 2, Figure 1a and 2a). For patients who survived to day 16, the rate of death during the period of 16–180 days (per 2 day interval; Figure 1a) in the ST-segment depression category exceeded that in the ST-segment elevation category by approximately day 24. Figure 1c illustrates this change in rate by depicting the cumulative mortality after day 15. Table 3 shows that the change persisted even after adjustment for GRACE risk factors. Patients with neither ST elevation nor depression also retained the lowest mortality rate throughout the study.
Table 4 Absolute event rates from admission to 6 months in patients presenting with an acute coronary syndrome.
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Infarction, reinfarction, stroke and major bleeding
The rates of infarction and reinfarction (by time interval) for each of the three groups are shown in Figure 2b. In patients with ST-segment elevation at presentation, 40% (146 of 361) of the reinfarctions occurred within the first 4 days; the proportions were similar for patients presenting with ST depression and no ST deviation (40% [90 of 221] and 42% [168 of 402], respectively; Table 2). The adjusted HR of infarction or reinfarction after presentation was higher throughout the study for patients with ST-segment depression than for patients with no ST-segment deviation (P 0.04 for each period; Table 3). The adjusted HR for patients with ST elevation compared with those with ST-segment depression did not differ (Table 3).
In patients with ST-segment elevation at presentation, 47% (131 of 277) of strokes occurred within the first 4 days; the proportion of early strokes was lower for patients with ST-segment depression and no deviation (29% [35 of 119] and 32% [66 of 207], respectively; Table 2 and Figure 2c).
During the first 4 days after presentation, the adjusted rate of stroke was higher in the ST-segment elevation category than in the ST-segment depression category. Thereafter, this difference disappeared. Patients in the ST-segment elevation category also had a higher adjusted HR for stroke in days 0–4 than did the group with no ST-segment deviation; thereafter, the HR decreased until there is no difference for days 16–180 (Table 3).
During the first 4 days, the adjusted rate of major bleeding was higher among patients with any type of ST-segment deviation than among patients without ST-segment deviation (Table 3). During days 5–15, the adjusted rate of major bleeding was higher in patients with ST depression than among patients with ST-segment elevation and patients without ST-segment deviation (Table 3).
Application of GRACE risk score
Analysis of the mortality data by GRACE risk score demonstrated a wide range of HR for mortality within each category of ST deviation, up to 30–40 times higher than the lowest HR during the first 5 days of admission (Table 5) and at least a 10-fold range thereafter. Thus, a broad spectrum of risk exists within each category of ST-segment deviation, influenced by the eight components of the GRACE score that convey 90% of the predictive risk of death.9
Table 5 Hazard ratios for mortality according to category of GRACE risk score in patients presenting with an acute coronary syndrome
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Discussion
In this multinational, observational cohort study of patients with an ACS, we found that the temporal distribution of clinical events during 6 months of follow-up differed not only according to ST category of ACS but also within each electrocardiographic category, according to GRACE risk score at presentation.
Three-quarters of all deaths in patients with ST-segment depression occurred after the first 4 days, during the period when most patients have been discharged from hospital. Although the rates of death in days 0–15 and stroke on days 0–4 were highest among patients with ST-segment elevation on admission, the risk of a major bleed on days 5–15 was highest in patients with ST-segment depression on admission. The adjusted risks of all outcomes were lowest in the group without ST-segment deviation.
These data provide insights into key pathophysiological mechanisms of ACS. The high incidence and steep increase in major cardiac complications occurring on days 0–4, including death, are consistent with the impact of arrhythmic and hemodynamic complications associated with ACS-related myocardial injury.8 The rise in risk-adjusted incidence of death and of major bleeding, and trends towards more strokes and recurrent myocardial infarctions among patients who presented with ST-segment depression, indicate further occult and overt coronary occlusions that concur with observations in other studies of multiple sites of plaque rupture in patients with NSTE-ACS.15, 16
Our data have potentially important clinical implications, since aggressive antithrombotic and revascularization strategies have focused mainly on the in-hospital phase of management and have had most emphasis on the urgency of treatment for patients presenting with STEMI. For NSTE-ACS patients, international guidelines recommend early interventional strategies and antithrombotic therapies only in those classified as high risk (i.e. recurrent chest pain, ST-segment depression, dynamic ST-segment changes, elevated cardiac biomarkers, thrombus on angiography, advanced age, history of previous myocardial infarction, prior CABG, diabetes, congestive heart failure, hypertension, renal dysfunction, inflammatory markers, left ventricular dysfunction, extensive coronary artery disease).17, 18 Data from several registries suggest that systematic risk stratification is not done to guide therapy for the majority of these patients.19, 20, 21 We noted, however, that risk of reinfarction and death in ST depression–ACS patients is also highest (2.3% and 2.7%, respectively), during the first 4 days following presentation compared with the following 5 to 15 days (0.7% and 1.2%, respectively), suggesting that prompt initiation of antithrombotic therapies is more useful than waiting until the anatomy is defined by angiography. Similarly, delayed intervention (with rehospitalization) for higher-risk but apparently "stabilized" patients with NSTE-ACS might miss the period with the most marked increase in cardiac events.
The findings from this study also suggest that greater attention needs to be paid to the prevention of complications after NSTE-ACS patients are discharged. The median time of hospitalization was 6 days for patients with ST-segment deviation and 5 days in those without, but most of the deaths in all ST categories occurred beyond the first 4 days after presentation (57% for ST-segment elevation, 74% for ST-segment depression, and 78% for neither at presentation). Although the HR for complications was much lower than that observed during hospital stay, our findings demonstrate an ongoing risk of infarction, reinfarction, death, and stroke following discharge. Cumulatively, the overall rates for days 5–180 were higher than those for days 0–4 in hospital. Only a proportion of patients are discharged on evidence-based cardiac medications and, of those, only a small proportion adheres to therapy during follow-up,22, 23, 24 but our finding highlights the importance of adherence and monitoring, to therapy, particularly for NSTE-ACS patients.24 Furthermore, trial data suggest that the use of potent antithrombotic therapy beyond early in-hospital management might provide improved efficacy but also greater bleeding hazards.25 Long-term registry studies, including GRACE, have demonstrated that the application of evidence-based therapies is associated with substantial improvements in outcome, including reductions in death and new heart failure.26
GRACE is a large multinational observational cohort study that includes the complete spectrum of patients with ACS; furthermore, it is designed to be representative of the diversity of the ACS population rather than of practice in specific communities. We used standard criteria for defining ACS and hospital outcomes across sites, as well as rigorous quality control and audit of all participating centers. The timing of in-hospital events is recorded in detail in case report forms, but recording of the timing of events after discharge is dependent on individual patient review and case record review (85% completeness of 6 month follow-up). In terms of limitations of this study, the frequency of early recurrent myocardial infarction might be underestimated because it was assessed only after the first 24 h after presentation, but this limitation does not apply to the other endpoints. This study did not use the discharge diagnosis as the basis for comparisons (e.g. myocardial infarction, NSTEMI, or unstable angina), in order to avoid the confounding that would have been introduced by patients who presented without signs of infarction but developed these changes during hospitalization.
In patients presenting to hospital with an ACS, the temporal distribution of events reveals that almost two-thirds (66% of deaths, 59% of infarctions or reinfarctions) occurred in the period beyond the first 4 days after presentation. Our findings provide clues about the potential pathophysiological mechanisms of late events and have implications for the postdischarge management of the diagnostic categories of ACS—in particular, the timing of therapeutic interventions and the benefit–risk balance of oral antithrombotic therapies.
Key points
- The temporal distribution of postpresentation events (death, infarction, reinfarction, new stroke, and major bleed) in patients hospitalized for an acute coronary syndrome (ACS) varies according to ST category but is powerfully influenced by the GRACE risk score
- Our data demonstrate a 10–40-fold range of death within each category of ST deviation (ST elevation, ST depression, or no ST deviation); thus, ST segment deviation alone is an inadequate basis for risk prediction
- Within the first 15 days of presentation with ACS, patients with ST elevation at initial presentation are at greatest risk of death
- In contrast, in the postdischarge period, there is a higher risk of death in patients with ST depression at initial presentation
- Almost two-thirds of all events in the first 6 months after hospital presentation occur in the period beyond the first 4 days (66% of deaths, 59% of reinfarctions)
- For those with ST depression at initial presentation, three-quarters of all the deaths in the first 6 months occur beyond the median period of hospitalization (beyond 4 days)
Acknowledgments
This research was supported by an unrestricted grant from Sanofi-Aventis, Paris, France. We thank the physicians and nurses participating in GRACE. Further information about the project, along with the complete list of participants, can be found at http://www.outcomes.org/grace. The authors are grateful to S Rushton-Smith, who provided editorial support in the preparation of this paper. GRACE is supported by an unrestricted educational grant from Sanofi-Aventis to the Center for Outcomes Research, University of Massachusetts Medical School. Sanofi-Aventis had no involvement in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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Competing interests
KAA Fox is a consultant for and is funded by GlaxoSmithKline and Sanofi-Aventis. He is also funded by Merck.
FA Anderson is funded by Sanofi-Aventis, Scios and The Medicines Company. He is a consultant for GlaxoSmithKline.
PG Steg is funded by Sanofi-Aventis. He is a consultant for Astellas, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Endotis Pharma, GlaxoSmithKline, Medtronic, Merck, Nycomed, Sanofi-Aventis, Servier, Takeda and The Medicines Company.
JM Gore is funded by Sanofi-Aventis.
The other authors declared no competing interests.
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Subject areas under which this article appears: Acute coronary syndromes
