Accepted Manuscript Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-Up Sami M.A. Alnasser, MD, Wei Huang, MS, Joel M. Gore, MD, Ph. Gabriel Steg, MD, Kim A. Eagle, MD, Frederick A. Anderson, Jr., PhD, Keith A.A. Fox, MB ChB, Enrique Gurfinkel, MD, David Brieger, MD, Werner Klein, MD, Frans van de Werf, MD, PhD, Álvaro Avezum, MD, PhD, Gilles Montalescot, MD, PhD, Dietrich C. Gulba, MD, Andrzej Budaj, MD, PhD, Jose Lopez-Sendon, MD, PhD, Christopher B. Granger, MD, Brian M. Kennelly, MB, ChB, PhD, Robert J. Goldberg, PhD, Emily Fleming, S.G. Goodman, MD, MSc PII:
S0002-9343(14)01225-X
DOI:
10.1016/j.amjmed.2014.12.007
Reference:
AJM 12819
To appear in:
The American Journal of Medicine
Received Date: 12 September 2014 Revised Date:
1 December 2014
Accepted Date: 8 December 2014
Please cite this article as: Alnasser SMA, Huang W, Gore JM, Steg PG, Eagle KA, Anderson FA Jr., Fox KAA, Gurfinkel E, Brieger D, Klein W, van de Werf F, Avezum Á, Montalescot G, Gulba DC, Budaj A, Lopez-Sendon J, Granger CB, Kennelly BM, Goldberg RJ, Fleming E, Goodman SG, on behalf of the GRACE Investigators, Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-Up, The American Journal of Medicine (2015), doi: 10.1016/ j.amjmed.2014.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-Up Sami M.A. Alnasser, MDa,b, Wei Huang, MSc, Joel M. Gore, MDc, Ph. Gabriel Steg, MDd, Kim A.
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Eagle, MDe, Frederick A. Anderson, Jr., PhDf, Keith A.A. Fox, MB ChBg, Enrique Gurfinkel, MDh†, David Brieger, MDi, Werner Klein, MDj†, Frans van de Werf, MD, PhDk, Álvaro Avezum, MD, PhDl, Gilles Montalescot, MD, PhDm, Dietrich C. Gulba, MDn, Andrzej Budaj, MD, PhDo,
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Jose Lopez-Sendon, MD, PhDp, Christopher B. Granger, MDq, Brian M. Kennelly, MB, ChB, PhDr, Robert J. Goldberg, PhDs, Emily Flemingt, S.G. Goodman, MD, MSca,t, on behalf of the
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GRACE Investigators*
†deceased
From the aTerrence Donnelly Heart Centre, Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, ON; bKing Fahad Cardiac Center, King Saud University, Riyadh,
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Saudi Arabia; cDivision of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA; dINSERM U-698, Université Paris 7, AP-HP, Centre Hospitalier BichatClaude Bernard, Paris, France; eUniversity of Michigan Health System, Ann Arbor, MI; fCenter
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for Outcomes Research, University of Massachusetts Medical School, Worcester, MA; gCentre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; hICYCC
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Favaloro Foundation, Buenos Aires, Argentina; iConcord Hospital and University of Sydney, Sydney, Australia; jDepartment of Internal Medicine, Krankenhaus der Barmherzigen Bruder, Teaching Hospital of the Karl Franzens University Graz, Graz, Austria; kDepartment of Cardiovascular Medicine, University Hospitals Leuven, Belgium; lDante Pazzanese Institute of Cardiology, São Paulo, SP, Brazil; mInstitut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, (AP-HP), Univ Paris 06, Paris, France; nDepartment of Cardiology, KKO St. Marien-Hospital, Oberhausen, Germany; oPostgraduate Medical School, Grochowski Hospital,
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Warsaw, Poland; pHospital Universitario La Paz, Instituto de Investigación La PAZ, IdiPaz, Universidad Autónoma de Madrid, UAM Madrid, Spain; qDuke Clinical Research Institute, Duke University Medical Center, Durham, NC; rHoag Memorial Hospital Presbyterian, Newport Beach,
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CA; sDivision of Epidemiology of Chronic Diseases and Vulnerable Populations, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA; t
Canadian Heart Research Centre, Toronto, ON
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Word count: 4,352
Brief title: Late Consequences of Acute Coronary Syndromes (40 characters)
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Key Words: acute coronary syndromes; prognosis; coronary revascularization; risk stratification
* A list of the GRACE Investigators and Coordinators may be found in Am Heart J 2009; 157:642-650; GRACE Investigators and Coordinators participating in the 2-year follow-up project are listed in the Appendix
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Corresponding author: Dr Shaun G. Goodman, St. Michael’s Hospital, Division of Cardiology, 30 Bond Street, Room 6-034 Donnelly, Toronto, Ontario, Canada M5B 1W8; Fax 416-864-5407
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Telephone 416-864-5722. E-mail [email protected]
Funding Source: GRACE was supported by an unrestricted grant from Sanofi-Aventis (Paris,
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France) to the Center for Outcomes Research, University of Massachusetts Medical School. The sponsor had no involvement in the conception or design; collection, analysis, and interpretation of data; in the writing, review, or approval of the manuscript; and in the decision to submit the manuscript for publication. Potential Conflicts of Interest: Sami MA Alnasser, Wei Huang, and Emily Fleming: None; Joel M Gore, Ph Gabriel Steg, Kim A Eagle, Frederick A Anderson, Keith AA Fox, Enrique Gurfinkel, David Brieger, Werner Klein, Frans Van de Werf, Alvaro Avezum, Gilles Montalesco, Dietrich C Gulba, Andrzej Budaj, Jose Lopez-Sendon, Christopher B Granger, Brian M Kennelly, Robert J 2
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Goldberg, and Shaun G Goodman: Research grant support, consulting honoraria from Sanofi Aventis. In addition Dr Gulba reports speaker/consulting honoraria from Daiichi Sankyo, Bayer, Boehringer Ingelheim, Pfizer, Astra Zeneca and Eli Lilly; Dr Anderson reports research grants
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from The Medicines Company, and consulting honoraria from GlaxoSmithKline and Millennium; Dr Van de Werf reports speaker/consulting honoraria from AstraZeneca and The Medicines
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Company.
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All authors had access to the data and a role in writing the manuscript.
3
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Abstract Objectives. To describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-
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month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality.
Background. Short term outcomes have been well characterized in acute coronary
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syndromes; however, longer-term follow up for the entire spectrum of these patients, including ST-segment elevation myocardial infarction , non-ST elevation myocardial
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infarction, and unstable angina, is more limited.
Methods. Between 1999-2007, 70,395 patients with a suspected acute coronary syndrome were enrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronary syndrome diagnosis in 57 sites.
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Results. From 2004-7, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge, 14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery, and 24.2% were rehospitalized. In patients with 2-year
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follow-up, ASA (88.7%), beta-blocker (80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heart failure occurred in 6.3%,
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(re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE risk score was highly predictive of all-cause mortality at 2 years (c-statistic 0.80). Conclusion. In this large multinational cohort of acute coronary syndrome patients, there were important later adverse consequences including frequent morbidity and mortality. These findings were seen in the context of additional coronary procedures and despite continued use of evidence-based therapies in a high proportion of patients. 4
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 The discriminative accuracy of the GRACE risk score in hospital survivors for predicting longer-term mortality was maintained.
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Word Count: 245
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352
While the early risks of death and recurrent myocardial infarction have been well characterized following presentation with an acute coronary syndrome1-10, the later
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evidence-based management and consequences in a contemporary patient population remain less clearly defined.11-15 Risk scores are available to predict short term
outcome9,16,17 from the Global Registry of Acute Coronary Events (GRACE) an
observational study of more than 70,000 acute coronary syndrome patients from 123
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hospitals in 14 countries from 1999-2007.18-20 Given the considerable variability that
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exists among patients across the entire spectrum of acute coronary syndromes (including myocardial infarction and unstable angina), estimation of risk, including beyond the shorter term, may assist in determining optimal longer term management. Further, the value of risk predictors of short-term outcome (e.g., in-hospital16 and 6month9,17) from the GRACE models in predicting longer-term outcome (e.g., ≥1 year)
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has been limited to-date.9,13,14,21-24 The purpose of this paper is to describe the longerterm outcomes and receipt of coronary intervention procedures and evidence-based medication in selected GRACE patients undergoing 6-month and 2-year follow-up. Our
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secondary study objective was to determine the value of the GRACE risk score17 in
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hospital survivors in predicting 2-year mortality.
Methods:
From 2001 to 2007, 70,395 patients with a suspected acute coronary syndromewere enrolled in the GRACE program. Patients ≥18 years old admitted with a presumptive diagnosis of an acute coronary syndrome and electrocardiographic changes consistent
6
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 with an acute coronary syndrome, abnormal cardiac biomarker and/or documentation of coronary artery disease, were included.18,20
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Data were collected at each site by a trained coordinator using a standardized case report form. Demographic characteristics, medical history, presenting symptoms,
biochemical and electrocardiographic findings, treatment practices, and a variety of
SC
hospital outcome data were collected. Standardized definition of all patient-related
variables and clinical diagnoses were used.18 Completed case report forms were faxed
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to, or entered into an electronic, web-based case report form developed by, the data coordinating center.
All cases were assigned to one of the following mutually exclusive categories based on
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presenting electrocardiographic characteristics, cardiac biomarker status during hospitalization, and final hospital diagnosis: ST-segment elevation or new left bundle branch block myocardial infarction, non-ST-segment elevation myocardial infarction or
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unstable angina.18,20 Patients were diagnosed with ST elevation myocardial infarction if they had new or presumed new ST-segment elevation ≥1 mm in any
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electrocardiographic location, or new left bundle branch block on the index or qualifying electrocardiogram with at least one positive cardiac biomarker of necrosis (i.e., troponin and/or creatine kinase and/or creatine kinase-MB elevated above the upper limit of normal/reference limit according to each hospital’s laboratory). Non-ST elevation myocardial infarction was diagnosed in the cases of at least one positive cardiac biomarker of necrosis without new ST-segment elevation seen on the index or qualifying
7
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 electrocardiogram. Unstable angina was diagnosed when serum cardiac biomarkers of necrosis were within the normal range.
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Follow-up at 6 months was prospective and based primarily on individual patient
contact; reliance on information from the patient’s family, physician(s), and on hospital or central records was used only when direct patient contact was unavailable.18,20,25 A
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one-page standardized data collection form was collected by trained study physicians or coordinators. Questions were asked about rehospitalization for heart disease,
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development of subsequent stroke, receipt of diagnostic and interventional procedures, and medications currently taken. Subsequent morbidity and mortality, including causespecific death, were not adjudicated. In 2004, 2-year follow-up was undertaken in a similar fashion to that at 6 months in patients with a discharge acute coronary syndrome
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diagnosis at 57 sites where ethics approval, patient consent, and logistics allowed; retrospective follow-up was undertaken for some patients in 2004 but was otherwise
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prospective.
Statistical analysis
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Continuous data are summarized as medians, with 25th and 75th percentiles, and categorical data as frequencies and percentages. The chi-square test, Wilcoxon Rank Sum, and Kruskal-Wallis test were used for group comparisons of categorical and continuous variables, respectively. Multivariable logistic regression was used to examine post-discharge events rates according to final discharge diagnosis. The discriminatory performance of the GRACE risk score was evaluated by the c-statistic
8
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 (area under the receiver-operating characteristic curve). Cox proportional hazards analysis was used to determine if the GRACE risk score that was previously predictive of death within 6 months of discharge was predictive of death within 2 years of
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discharge. Patients were divided into three predefined categories of risk scores from lowest to highest (140).14 Kaplan-Meier curves reflect the cumulative
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unadjusted mortality. All statistical analyses were performed using SAS software 9.1.
Role of the Sponsor
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GRACE was sponsored by an educational grant from Sanofi-Aventis to the Center for Outcomes Research (COR; University of Massachusetts Medical School, Worcester, MA); COR serves as the International Scientific Coordinating Center for GRACE. The sponsor did not participate in data collection or analysis. The design and conduct of the
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study and the selection of the topics for analysis and publication were entirely the responsibility of the steering and publications committees.
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Results:
From 2004-7, 28,449 patients in the entire GRACE sample were diagnosed with an
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acute coronary syndrome, including 22,937 from the 57 sites participating in the 2-year follow-up initiative (Figure 1). After excluding 1,009 (4.4%) patients who died during the index hospitalization, 21,928 patients were eligible to be included in post-hospitalization follow-up; 2806 (12.8%) had neither 6-month nor 2-year follow-up.
9
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Characteristics of patients with and without follow-up Patients with (n=19,122) and without (n=2,806) additional post-discharge follow-up had some differences in their baseline characteristics such as more frequent prior angina,
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MI, heart failure, coronary artery bypass surgery, hypertension, and hyperlipidemia in patients with follow-up (Table 1). Patients with additional follow-up had a numerically higher GRACE risk score. In addition, patients with follow-up more frequently had non-
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ST elevation myocardial infarction whereas those without follow-up had more ST
segment myocardial infarction as their final diagnosis. The in-hospital use of some
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medications (e.g., acetylsalicylic acid [ASA], beta-blocker) was higher while some were lower (e.g., adenosine diphosphate [ADP] receptor inhibitor, angiotensin converting enzyme [ACE] inhibitor) in patients with compared to those without additional follow-up.
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Characteristics and in-hospital procedures and events according to final diagnosis
Of the 19,122 patients with post-discharge follow-up, 6,719 (35.1%) were diagnosed
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with ST elevation myocardial infarction, 6,994 (36.6%) were diagnosed with non-ST elevation myocardial infarction and 5409 (28.3%) were diagnosed with unstable angina
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(Table 2). In hospital procedures (cardiac catheterization, percutaneous coronary intervention, and bypass surgery) and events (myocardial infarction, cardiogenic shock, heart failure, stroke, and major bleeding) by acute coronary syndrome diagnosis are shown in Table 3.
Medical therapy at discharge and 2-year follow-up according to final diagnosis
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Selected medical therapies in the patient population with 2-year post-discharge followup (n=12044) by final diagnosis are shown in Table 4. The use of medical therapies varied by geographic region; for example, statin use at 2 years was highest in
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Australia/New Zealand/Canada (82%-89% in unstable angina, non-ST elevation, and ST elevation myocardial infarction) and Europe (86%-90%) when compared to the
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United States (72%-81%) and South America (71%-77%).
Post-discharge procedures according to final diagnosis
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Procedures performed from the time of discharge to up to 2-year follow-up are listed in Table 5. The use of procedures varied by geographic region; for example, unscheduled cardiac catheterization post-discharge was highest in the United States (19%-24% in ST elevation and non-ST elevation myocardial infarction, and unstable angina) and South
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America (14%-17%) when compared to Europe (11%-14%) and Australia/New Zealand/Canada (9%-12%).
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Post-discharge event rates according to final diagnosis From discharge to up to 2 years, the overall rate of death was 7.1% (1,334 of 18,690
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patients; Table 5). Unadjusted mortality rates varied by geographic region. Death postdischarge in unstable angina, ST elevation and non-ST elevation myocardial infarction patients, respectively, was observed in South America (4.3%, 4.7%, and 5.7%), Europe (4.3%, 5.1%, and 5.7%), Australia/New Zealand/Canada (5.4%, 6.0%, and 9.8%), and the United States (5.7%, 11.4%, and 15.1%).
11
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 When compared to non-ST elevation myocardial infarction patients, those with ST elevation myocardial infarction had lower age- and gender-adjusted rates of death (odds ratio [OR] 0.88; 95% CI 0.77-1.01), recurrent MI (OR 0.68; 95% CI 0.56-0.81), heart
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failure (OR 0.78; 95% CI 0.65-0.93) and unscheduled cardiovascular rehospitalization (OR 0.80; 95% CI 0.74-0.88). Compared to non-ST elevation myocardial infarction
patients, those with ST elevation myocardial infarction had comparable gender- and 6-
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month GRACE risk score-adjusted rates of death (OR 1.11; 95% CI 0.96-1.28) and heart failure (OR 0.95; 95% CI 0.78-1.14), but lower adjusted rates of recurrent MI (OR
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0.78; 95% CI 0.65-0.94) and unscheduled cardiovascular rehospitalization (OR 0.86; 95% CI 0.78-0.94).
Cause of mortality by final diagnosis
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Among the 1,334 deaths in the patients with post-discharge follow-up, the presumed cause of death was reported in 1,179 patients. Cardiovascular causes accounted for 758 (64.3%) deaths, 14 (1.2%) were related to pulmonary embolism, 22 (1.9%) to
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trauma, 12 (1.0%) to suicide, with the remaining 373 deaths (31.6%) being non-cardiac in nature. Cause of death and additional outcomes by acute coronary syndrome
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diagnosis are shown in Table 5. Six-month mortality was 4.0% (700 of 17,598 patients), with the majority (71.3%) due to cardiovascular causes. Mortality between 6 months and 2 years was 5.7% (634 of 11,066 patients), with the majority (56.0%) due to cardiovascular causes; however, the proportion of non-cardiac-related deaths was greater in this second time window (41.1% compared with 23.3% in the first 6 months post-discharge).
12
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Survival status according to final diagnosis and discharge GRACE risk score Survival status by ACS diagnosis at discharge is shown in Figure 2. The median duration of follow-up was 728 (25th, 75th percentiles: 212, 730) days. The risk continued
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at an approximately linear rate for the 2 years of follow-up. The discharge GRACE risk score (n=10,320) was highly predictive of all-cause mortality at 2 years (c-statistic 0.80; Figure 3a). Patients with a higher (>140) and intermediate (109-140) GRACE risk score
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had a relatively higher risk of death at 2-years compared to those with a lower (≤108)
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score (HR 15.2 and 3.9, respectively; log-rank p
S0002-9343(14)01225-X
DOI:
10.1016/j.amjmed.2014.12.007
Reference:
AJM 12819
To appear in:
The American Journal of Medicine
Received Date: 12 September 2014 Revised Date:
1 December 2014
Accepted Date: 8 December 2014
Please cite this article as: Alnasser SMA, Huang W, Gore JM, Steg PG, Eagle KA, Anderson FA Jr., Fox KAA, Gurfinkel E, Brieger D, Klein W, van de Werf F, Avezum Á, Montalescot G, Gulba DC, Budaj A, Lopez-Sendon J, Granger CB, Kennelly BM, Goldberg RJ, Fleming E, Goodman SG, on behalf of the GRACE Investigators, Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-Up, The American Journal of Medicine (2015), doi: 10.1016/ j.amjmed.2014.12.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Late Consequences of Acute Coronary Syndromes: Global Registry of Acute Coronary Events (GRACE) Follow-Up Sami M.A. Alnasser, MDa,b, Wei Huang, MSc, Joel M. Gore, MDc, Ph. Gabriel Steg, MDd, Kim A.
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Eagle, MDe, Frederick A. Anderson, Jr., PhDf, Keith A.A. Fox, MB ChBg, Enrique Gurfinkel, MDh†, David Brieger, MDi, Werner Klein, MDj†, Frans van de Werf, MD, PhDk, Álvaro Avezum, MD, PhDl, Gilles Montalescot, MD, PhDm, Dietrich C. Gulba, MDn, Andrzej Budaj, MD, PhDo,
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Jose Lopez-Sendon, MD, PhDp, Christopher B. Granger, MDq, Brian M. Kennelly, MB, ChB, PhDr, Robert J. Goldberg, PhDs, Emily Flemingt, S.G. Goodman, MD, MSca,t, on behalf of the
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GRACE Investigators*
†deceased
From the aTerrence Donnelly Heart Centre, Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, ON; bKing Fahad Cardiac Center, King Saud University, Riyadh,
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Saudi Arabia; cDivision of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA; dINSERM U-698, Université Paris 7, AP-HP, Centre Hospitalier BichatClaude Bernard, Paris, France; eUniversity of Michigan Health System, Ann Arbor, MI; fCenter
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for Outcomes Research, University of Massachusetts Medical School, Worcester, MA; gCentre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; hICYCC
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Favaloro Foundation, Buenos Aires, Argentina; iConcord Hospital and University of Sydney, Sydney, Australia; jDepartment of Internal Medicine, Krankenhaus der Barmherzigen Bruder, Teaching Hospital of the Karl Franzens University Graz, Graz, Austria; kDepartment of Cardiovascular Medicine, University Hospitals Leuven, Belgium; lDante Pazzanese Institute of Cardiology, São Paulo, SP, Brazil; mInstitut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, (AP-HP), Univ Paris 06, Paris, France; nDepartment of Cardiology, KKO St. Marien-Hospital, Oberhausen, Germany; oPostgraduate Medical School, Grochowski Hospital,
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Warsaw, Poland; pHospital Universitario La Paz, Instituto de Investigación La PAZ, IdiPaz, Universidad Autónoma de Madrid, UAM Madrid, Spain; qDuke Clinical Research Institute, Duke University Medical Center, Durham, NC; rHoag Memorial Hospital Presbyterian, Newport Beach,
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CA; sDivision of Epidemiology of Chronic Diseases and Vulnerable Populations, Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA; t
Canadian Heart Research Centre, Toronto, ON
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Word count: 4,352
Brief title: Late Consequences of Acute Coronary Syndromes (40 characters)
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Key Words: acute coronary syndromes; prognosis; coronary revascularization; risk stratification
* A list of the GRACE Investigators and Coordinators may be found in Am Heart J 2009; 157:642-650; GRACE Investigators and Coordinators participating in the 2-year follow-up project are listed in the Appendix
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Corresponding author: Dr Shaun G. Goodman, St. Michael’s Hospital, Division of Cardiology, 30 Bond Street, Room 6-034 Donnelly, Toronto, Ontario, Canada M5B 1W8; Fax 416-864-5407
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Telephone 416-864-5722. E-mail [email protected]
Funding Source: GRACE was supported by an unrestricted grant from Sanofi-Aventis (Paris,
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France) to the Center for Outcomes Research, University of Massachusetts Medical School. The sponsor had no involvement in the conception or design; collection, analysis, and interpretation of data; in the writing, review, or approval of the manuscript; and in the decision to submit the manuscript for publication. Potential Conflicts of Interest: Sami MA Alnasser, Wei Huang, and Emily Fleming: None; Joel M Gore, Ph Gabriel Steg, Kim A Eagle, Frederick A Anderson, Keith AA Fox, Enrique Gurfinkel, David Brieger, Werner Klein, Frans Van de Werf, Alvaro Avezum, Gilles Montalesco, Dietrich C Gulba, Andrzej Budaj, Jose Lopez-Sendon, Christopher B Granger, Brian M Kennelly, Robert J 2
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Goldberg, and Shaun G Goodman: Research grant support, consulting honoraria from Sanofi Aventis. In addition Dr Gulba reports speaker/consulting honoraria from Daiichi Sankyo, Bayer, Boehringer Ingelheim, Pfizer, Astra Zeneca and Eli Lilly; Dr Anderson reports research grants
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from The Medicines Company, and consulting honoraria from GlaxoSmithKline and Millennium; Dr Van de Werf reports speaker/consulting honoraria from AstraZeneca and The Medicines
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Company.
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All authors had access to the data and a role in writing the manuscript.
3
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Abstract Objectives. To describe the longer-term outcomes, procedures, and medication use in Global Registry of Acute Coronary Events (GRACE) hospital survivors undergoing 6-
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month and 2-year follow-up, and the performance of the discharge GRACE risk score in predicting 2-year mortality.
Background. Short term outcomes have been well characterized in acute coronary
SC
syndromes; however, longer-term follow up for the entire spectrum of these patients, including ST-segment elevation myocardial infarction , non-ST elevation myocardial
M AN U
infarction, and unstable angina, is more limited.
Methods. Between 1999-2007, 70,395 patients with a suspected acute coronary syndrome were enrolled. In 2004, 2-year prospective follow-up was undertaken in those with a discharge acute coronary syndrome diagnosis in 57 sites.
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Results. From 2004-7, 19,122 (87.2%) patients underwent follow-up; by 2 years postdischarge, 14.3% underwent angiography, 8.7% percutaneous coronary intervention, 2.0% coronary bypass surgery, and 24.2% were rehospitalized. In patients with 2-year
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follow-up, ASA (88.7%), beta-blocker (80.4%), renin-angiotensin system inhibitor (69.8%), and statin (80.2%) therapy was used. Heart failure occurred in 6.3%,
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(re)infarction in 4.4%, and death in 7.1%. Discharge-to-6-month GRACE risk score was highly predictive of all-cause mortality at 2 years (c-statistic 0.80). Conclusion. In this large multinational cohort of acute coronary syndrome patients, there were important later adverse consequences including frequent morbidity and mortality. These findings were seen in the context of additional coronary procedures and despite continued use of evidence-based therapies in a high proportion of patients. 4
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 The discriminative accuracy of the GRACE risk score in hospital survivors for predicting longer-term mortality was maintained.
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Word Count: 245
5
ACCEPTED MANUSCRIPT Goodman Submission 14-1352
While the early risks of death and recurrent myocardial infarction have been well characterized following presentation with an acute coronary syndrome1-10, the later
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evidence-based management and consequences in a contemporary patient population remain less clearly defined.11-15 Risk scores are available to predict short term
outcome9,16,17 from the Global Registry of Acute Coronary Events (GRACE) an
observational study of more than 70,000 acute coronary syndrome patients from 123
SC
hospitals in 14 countries from 1999-2007.18-20 Given the considerable variability that
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exists among patients across the entire spectrum of acute coronary syndromes (including myocardial infarction and unstable angina), estimation of risk, including beyond the shorter term, may assist in determining optimal longer term management. Further, the value of risk predictors of short-term outcome (e.g., in-hospital16 and 6month9,17) from the GRACE models in predicting longer-term outcome (e.g., ≥1 year)
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has been limited to-date.9,13,14,21-24 The purpose of this paper is to describe the longerterm outcomes and receipt of coronary intervention procedures and evidence-based medication in selected GRACE patients undergoing 6-month and 2-year follow-up. Our
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secondary study objective was to determine the value of the GRACE risk score17 in
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hospital survivors in predicting 2-year mortality.
Methods:
From 2001 to 2007, 70,395 patients with a suspected acute coronary syndromewere enrolled in the GRACE program. Patients ≥18 years old admitted with a presumptive diagnosis of an acute coronary syndrome and electrocardiographic changes consistent
6
ACCEPTED MANUSCRIPT Goodman Submission 14-1352 with an acute coronary syndrome, abnormal cardiac biomarker and/or documentation of coronary artery disease, were included.18,20
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Data were collected at each site by a trained coordinator using a standardized case report form. Demographic characteristics, medical history, presenting symptoms,
biochemical and electrocardiographic findings, treatment practices, and a variety of
SC
hospital outcome data were collected. Standardized definition of all patient-related
variables and clinical diagnoses were used.18 Completed case report forms were faxed
M AN U
to, or entered into an electronic, web-based case report form developed by, the data coordinating center.
All cases were assigned to one of the following mutually exclusive categories based on
TE D
presenting electrocardiographic characteristics, cardiac biomarker status during hospitalization, and final hospital diagnosis: ST-segment elevation or new left bundle branch block myocardial infarction, non-ST-segment elevation myocardial infarction or
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unstable angina.18,20 Patients were diagnosed with ST elevation myocardial infarction if they had new or presumed new ST-segment elevation ≥1 mm in any
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electrocardiographic location, or new left bundle branch block on the index or qualifying electrocardiogram with at least one positive cardiac biomarker of necrosis (i.e., troponin and/or creatine kinase and/or creatine kinase-MB elevated above the upper limit of normal/reference limit according to each hospital’s laboratory). Non-ST elevation myocardial infarction was diagnosed in the cases of at least one positive cardiac biomarker of necrosis without new ST-segment elevation seen on the index or qualifying
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 electrocardiogram. Unstable angina was diagnosed when serum cardiac biomarkers of necrosis were within the normal range.
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Follow-up at 6 months was prospective and based primarily on individual patient
contact; reliance on information from the patient’s family, physician(s), and on hospital or central records was used only when direct patient contact was unavailable.18,20,25 A
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one-page standardized data collection form was collected by trained study physicians or coordinators. Questions were asked about rehospitalization for heart disease,
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development of subsequent stroke, receipt of diagnostic and interventional procedures, and medications currently taken. Subsequent morbidity and mortality, including causespecific death, were not adjudicated. In 2004, 2-year follow-up was undertaken in a similar fashion to that at 6 months in patients with a discharge acute coronary syndrome
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diagnosis at 57 sites where ethics approval, patient consent, and logistics allowed; retrospective follow-up was undertaken for some patients in 2004 but was otherwise
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prospective.
Statistical analysis
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Continuous data are summarized as medians, with 25th and 75th percentiles, and categorical data as frequencies and percentages. The chi-square test, Wilcoxon Rank Sum, and Kruskal-Wallis test were used for group comparisons of categorical and continuous variables, respectively. Multivariable logistic regression was used to examine post-discharge events rates according to final discharge diagnosis. The discriminatory performance of the GRACE risk score was evaluated by the c-statistic
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 (area under the receiver-operating characteristic curve). Cox proportional hazards analysis was used to determine if the GRACE risk score that was previously predictive of death within 6 months of discharge was predictive of death within 2 years of
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discharge. Patients were divided into three predefined categories of risk scores from lowest to highest (140).14 Kaplan-Meier curves reflect the cumulative
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unadjusted mortality. All statistical analyses were performed using SAS software 9.1.
Role of the Sponsor
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GRACE was sponsored by an educational grant from Sanofi-Aventis to the Center for Outcomes Research (COR; University of Massachusetts Medical School, Worcester, MA); COR serves as the International Scientific Coordinating Center for GRACE. The sponsor did not participate in data collection or analysis. The design and conduct of the
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study and the selection of the topics for analysis and publication were entirely the responsibility of the steering and publications committees.
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Results:
From 2004-7, 28,449 patients in the entire GRACE sample were diagnosed with an
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acute coronary syndrome, including 22,937 from the 57 sites participating in the 2-year follow-up initiative (Figure 1). After excluding 1,009 (4.4%) patients who died during the index hospitalization, 21,928 patients were eligible to be included in post-hospitalization follow-up; 2806 (12.8%) had neither 6-month nor 2-year follow-up.
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Characteristics of patients with and without follow-up Patients with (n=19,122) and without (n=2,806) additional post-discharge follow-up had some differences in their baseline characteristics such as more frequent prior angina,
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MI, heart failure, coronary artery bypass surgery, hypertension, and hyperlipidemia in patients with follow-up (Table 1). Patients with additional follow-up had a numerically higher GRACE risk score. In addition, patients with follow-up more frequently had non-
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ST elevation myocardial infarction whereas those without follow-up had more ST
segment myocardial infarction as their final diagnosis. The in-hospital use of some
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medications (e.g., acetylsalicylic acid [ASA], beta-blocker) was higher while some were lower (e.g., adenosine diphosphate [ADP] receptor inhibitor, angiotensin converting enzyme [ACE] inhibitor) in patients with compared to those without additional follow-up.
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Characteristics and in-hospital procedures and events according to final diagnosis
Of the 19,122 patients with post-discharge follow-up, 6,719 (35.1%) were diagnosed
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with ST elevation myocardial infarction, 6,994 (36.6%) were diagnosed with non-ST elevation myocardial infarction and 5409 (28.3%) were diagnosed with unstable angina
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(Table 2). In hospital procedures (cardiac catheterization, percutaneous coronary intervention, and bypass surgery) and events (myocardial infarction, cardiogenic shock, heart failure, stroke, and major bleeding) by acute coronary syndrome diagnosis are shown in Table 3.
Medical therapy at discharge and 2-year follow-up according to final diagnosis
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Selected medical therapies in the patient population with 2-year post-discharge followup (n=12044) by final diagnosis are shown in Table 4. The use of medical therapies varied by geographic region; for example, statin use at 2 years was highest in
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Australia/New Zealand/Canada (82%-89% in unstable angina, non-ST elevation, and ST elevation myocardial infarction) and Europe (86%-90%) when compared to the
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United States (72%-81%) and South America (71%-77%).
Post-discharge procedures according to final diagnosis
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Procedures performed from the time of discharge to up to 2-year follow-up are listed in Table 5. The use of procedures varied by geographic region; for example, unscheduled cardiac catheterization post-discharge was highest in the United States (19%-24% in ST elevation and non-ST elevation myocardial infarction, and unstable angina) and South
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America (14%-17%) when compared to Europe (11%-14%) and Australia/New Zealand/Canada (9%-12%).
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Post-discharge event rates according to final diagnosis From discharge to up to 2 years, the overall rate of death was 7.1% (1,334 of 18,690
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patients; Table 5). Unadjusted mortality rates varied by geographic region. Death postdischarge in unstable angina, ST elevation and non-ST elevation myocardial infarction patients, respectively, was observed in South America (4.3%, 4.7%, and 5.7%), Europe (4.3%, 5.1%, and 5.7%), Australia/New Zealand/Canada (5.4%, 6.0%, and 9.8%), and the United States (5.7%, 11.4%, and 15.1%).
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 When compared to non-ST elevation myocardial infarction patients, those with ST elevation myocardial infarction had lower age- and gender-adjusted rates of death (odds ratio [OR] 0.88; 95% CI 0.77-1.01), recurrent MI (OR 0.68; 95% CI 0.56-0.81), heart
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failure (OR 0.78; 95% CI 0.65-0.93) and unscheduled cardiovascular rehospitalization (OR 0.80; 95% CI 0.74-0.88). Compared to non-ST elevation myocardial infarction
patients, those with ST elevation myocardial infarction had comparable gender- and 6-
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month GRACE risk score-adjusted rates of death (OR 1.11; 95% CI 0.96-1.28) and heart failure (OR 0.95; 95% CI 0.78-1.14), but lower adjusted rates of recurrent MI (OR
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0.78; 95% CI 0.65-0.94) and unscheduled cardiovascular rehospitalization (OR 0.86; 95% CI 0.78-0.94).
Cause of mortality by final diagnosis
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Among the 1,334 deaths in the patients with post-discharge follow-up, the presumed cause of death was reported in 1,179 patients. Cardiovascular causes accounted for 758 (64.3%) deaths, 14 (1.2%) were related to pulmonary embolism, 22 (1.9%) to
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trauma, 12 (1.0%) to suicide, with the remaining 373 deaths (31.6%) being non-cardiac in nature. Cause of death and additional outcomes by acute coronary syndrome
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diagnosis are shown in Table 5. Six-month mortality was 4.0% (700 of 17,598 patients), with the majority (71.3%) due to cardiovascular causes. Mortality between 6 months and 2 years was 5.7% (634 of 11,066 patients), with the majority (56.0%) due to cardiovascular causes; however, the proportion of non-cardiac-related deaths was greater in this second time window (41.1% compared with 23.3% in the first 6 months post-discharge).
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ACCEPTED MANUSCRIPT Goodman Submission 14-1352 Survival status according to final diagnosis and discharge GRACE risk score Survival status by ACS diagnosis at discharge is shown in Figure 2. The median duration of follow-up was 728 (25th, 75th percentiles: 212, 730) days. The risk continued
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at an approximately linear rate for the 2 years of follow-up. The discharge GRACE risk score (n=10,320) was highly predictive of all-cause mortality at 2 years (c-statistic 0.80; Figure 3a). Patients with a higher (>140) and intermediate (109-140) GRACE risk score
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had a relatively higher risk of death at 2-years compared to those with a lower (≤108)
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score (HR 15.2 and 3.9, respectively; log-rank p
