 |
|
Diabetes and Mortality Following Acute Coronary Syndromes
Sean M. Donahoe, MD;
Garrick C. Stewart, MD;
Carolyn H. McCabe, BS;
Satishkumar Mohanavelu, MS;
Sabina A. Murphy, MPH;
Christopher P. Cannon, MD;
Elliott M. Antman, MD
JAMA. 2007;298:765-775.
ABSTRACT
| |
Context The worldwide epidemic of diabetes mellitus is increasing the burden of cardiovascular disease, the leading cause of death among persons with diabetes. The independent effect of diabetes on mortality following acute coronary syndromes (ACS) is uncertain.
Objective To evaluate the influence of diabetes on mortality following ACS using a large database spanning the full spectrum of ACS.
Design, Setting, and Patients A subgroup analysis of patients with diabetes enrolled in randomized clinical trials that evaluated ACS therapies. Patients with ACS in 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials from 1997 to 2006 were pooled, including 62 036 patients (46 577 with ST-segment elevation myocardial infarction [STEMI] and 15 459 with unstable angina/non-STEMI [UA/NSTEMI]), of whom 10 613 (17.1%) had diabetes. A multivariable model was constructed to adjust for baseline characteristics, aspects of ACS presentation, and treatments for the ACS event.
Main Outcome Measures Mortality at 30 days and 1 year following ACS among patients with diabetes vs patients without diabetes.
Results Mortality at 30 days was significantly higher among patients with diabetes than without diabetes presenting with UA/NSTEMI (2.1% vs 1.1%, P < .001) and STEMI (8.5% vs 5.4%, P < .001). After adjusting for baseline characteristics and features and management of the ACS event, diabetes was independently associated with higher 30-day mortality after UA/NSTEMI (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.24-2.56) or STEMI (OR, 1.40; 95% CI, 1.24-1.57). Diabetes at presentation with ACS was associated with significantly higher mortality 1 year after UA/NSTEMI (hazard ratio [HR], 1.65; 95% CI, 1.30-2.10) or STEMI (HR, 1.22; 95% CI, 1.08-1.38). By 1 year following ACS, patients with diabetes presenting with UA/NSTEMI had a risk of death that approached patients without diabetes presenting with STEMI (7.2% vs 8.1%).
Conclusion Despite modern therapies for ACS, diabetes confers a significant adverse prognosis, which highlights the importance of aggressive strategies to manage this high-risk population with unstable ischemic heart disease.
INTRODUCTION
The presence of elevated blood glucose levels, diabetes mellitus, or both contributes to more than 3 million cardiovascular deaths worldwide each year.1 With the increase in obesity, insulin resistance, and the metabolic syndrome, the worldwide prevalence of diabetes is expected to double by the year 2030.2-4 This burgeoning diabetes epidemic will increase the burden of cardiovascular disease attributable to diabetes.
In the United States, one-third of the population born in 2000 will develop diabetes, with an estimated 30% reduction in life expectancy, mostly related to atherosclerosis.5-6 More than 1.5 million adults in the United States were newly diagnosed with diabetes in 2005 alone.7 Nearly 65% of individuals with diabetes die from cardiovascular disease in the United States, establishing it as the leading cause of death among this growing segment of the population.8
More than 30 years ago, the Framingham Heart Study followed 239 patients with diabetes and observed a 3-fold increase in age-adjusted cardiovascular mortality.9 Subsequent studies demonstrated patients with type 2 diabetes without prior myocardial infarction (MI) have a similar risk of death from coronary artery disease as patients without diabetes with prior MI.10 Diabetes is now considered to be a risk equivalent of coronary artery disease for future MI and cardiovascular death.11 The acute and long-term management of acute coronary syndromes (ACS) does not differ for persons with diabetes, yet previous studies have suggested patients with diabetes have not had a similar reduction in cardiovascular mortality as patients without diabetes despite receiving modern therapies.12-13
In addition to being a risk factor for the development of coronary disease, diabetes influences outcomes following ACS. Subgroup analysis of patients with diabetes with ST-segment elevation MI (STEMI) in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial14 demonstrated significantly higher all-cause mortality at 30 days compared with patients without diabetes (10.5% vs 6.2%). Similarly, the Organization to Assess Strategies for Ischemic Syndromes (OASIS) registry15 of patients with unstable angina/non-STEMI (UA/NSTEMI) observed an increased rate of post-MI complications and mortality among patients with diabetes compared with patients without diabetes (odds ratio [OR], 1.57) during 2 years of follow-up. Both the GUSTO-1 and OASIS studies were conducted more than 10 years ago in a different era of coronary care and before the modern definition of diabetes. Moreover, a large, prospective multinational registry, Global Registry of Acute Coronary Events (GRACE),16 revealed in-hospital case fatality rates for patients with diabetes with ACS were almost twice as high as those of patients without diabetes. In this same registry, however, diabetes was not a significant risk score predictor of 6-month postdischarge death or MI for patients hospitalized with an ACS.17-18
The independent association of diabetes with mortality following ACS in the present era of coronary care remains uncertain. Our study evaluated the independent effect of diabetes on mortality following ACS at 30 days and 1 year from a large clinical trial database spanning the full spectrum of ACS.
METHODS
Patient Population
Patients in our analysis were pooled from 11 independent Thrombolysis in Myocardial Infarction (TIMI) Study Group clinical trials. The methods of each individual trial has been previously reported.19-29 The number of patients enrolled in each trial, type of ACS evaluated, prespecified duration of follow-up, and randomized interventions are summarized in Table 1. Trials were included in the pooled analysis if they began enrollment after 1997 when the American Diabetes Association created the latest guidelines for the diagnosis of diabetes mellitus.30 Pooled trials also had to be completed by 2006, to collect information on both ACS and diabetes status, and must have included at least 30 days of clinical follow-up (Figure 1).30-31
|
|
|
|
Table 1. Pooled TIMI Trials
|
|
|
|
|
|
|
Figure 1. Flow Diagram of the TIMI Diabetes Database
TIMI indicates Thrombolysis in Myocardial Infarction.
|
|
|
This established a cohort of 62 036 patients from 55 countries and more than 900 clinical sites. Each patient gave written informed consent to participate in a clinical trial and none were enrolled in more than 1 TIMI trial. Observations began at trial randomization following the index coronary event and each patient was followed up until cessation of the trial or death.
Definitions
Study participants were classified as having diabetes or not having diabetes by self-report, then stratified by ACS type. Patients who controlled their diabetes by diet were included. Patients diagnosed with diabetes mellitus after trial enrollment were not considered to have diabetes for purposes of this analysis. Recorded baseline characteristics were age, sex, height, weight, geographic region, and prerandomization medications (aspirin,  -blockers, angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs], and hypolipidemic therapy, mostly statins). Relevant past medical history included smoking, hypertension, known prior hyperlipidemia, previous MI, prior coronary artery bypass graft (CABG) surgery, or heart failure.
The index ACS event was further characterized by systolic blood pressure and heart rate at enrollment, creatinine clearance, location of infarction if STEMI, Killip class, and TIMI risk index. The TIMI risk index is a triage tool to risk stratify patients at presentation with ACS using heart rate, age, and systolic blood pressure, and has been validated in both STEMI and UA/NSTEMI.32-33 In-hospital treatment included fibrinolytics, glycoprotein IIb/IIIa inhibitors, thienopyridines, aspirin, -blockers, ACE inhibitors or ARBs, and hypolipidemic therapy, as well as revascularization by percutaneous coronary intervention or CABG surgery. Coronary angiography was performed among a subset of study participants according to individual trial design or at the discretion of the treating physician. Major epicardial coronary arteries were considered diseased if they had 70% or more stenosis. Multivessel disease was defined as 70% or more stenosis in at least 2 major epicardial arteries or 50% or more stenosis of the left main coronary artery. Discharge medications were examined to determine if there were disparities in management between patients with and without diabetes after the ACS event.
Main Outcome Measures
The coprimary outcomes measured were 30-day and 1-year post-ACS mortality. Mortality rates were compared between patients with diabetes and patients without diabetes in all patients with ACS, and then derived separately for patients with UA/NSTEMI and STEMI. After multivariable adjustment, the risk of all-cause mortality based on the presence of diabetes was calculated.
Statistical Methods
All analyses were performed in 3 populations: all patients with ACS, patients with UA/NSTEMI, and patients with STEMI. Mortality rates at 30 days were calculated for patients with and without diabetes and then stratified by baseline characteristics, features of the index ACS event, and ACS management. These groups were compared using the Pearson  2 test for categorical variables and the Kruskal-Wallis test for continuous variables. Candidate covariates for entry into the multivariable model were identified by focusing on factors that differed significantly (P < .05) in the univariate analyses between patients with and without diabetes. All analyses were performed using Stata version 9.2 (StataCorp LP, College Station, Texas).
Logistic regression was used to construct the 30-day mortality model. The ORs for mortality at 30 days were adjusted for age, sex, region of enrollment, smoking status, history of hypertension, prior MI, congestive heart failure, CABG surgery, heart rate, systolic blood pressure, creatinine clearance, use of aspirin, -blockers, ACE inhibitors or ARBs, hypolipidemic therapy before randomization, and the administration of aspirin, -blockers, ACE inhibitors or ARBs, glycoprotein IIb/IIIa inhibitors, thienopyridines, and hypolipidemic therapy during hospitalization for ACS.
A separate multivariable model was generated for 1-year mortality using Cox proportional hazards regression models. At 1 year, the use of aspirin, -blockers, ACE inhibitors or ARBs, thienopyridines, and hypolipidemic therapy at time of discharge was added into the model. Infarct location and administration of fibrinolytics were also included in the STEMI models. A term was introduced for each individual TIMI trial to account for intertrial variability. These multivariable models had the power to accommodate these variables given the large number of outcome events.34
Survival analysis through the first year following ACS was performed using the Kaplan-Meier method. Mortality curves were generated separately for patients with and without diabetes with either STEMI or UA/NSTEMI, and then compared using the log-rank test. An interaction of diabetes on mortality by ACS type was tested at the prespecified time points of 30 days and 1 year following ACS presentation. The numbers at risk are included to indicate the completeness of follow-up through 1 year, which was primarily determined by the individual trial design.
A landmark analysis was performed between 30 days and 1 year. Landmark analysis is a form of survival analysis that classifies patients based on an intermediate event during follow-up, and prognosis is then evaluated from that time point. The landmark used in our analysis was survival at 30 days to discriminate the early vs longer-term influence of diabetes. Patients who survived 30 days after the index ACS event were evaluated for mortality through 1 year on the basis of diabetes status and type of ACS.
RESULTS
Baseline Characteristics
Of the 62 036 patients in this analysis, 46 577 presented with STEMI and 15 459 with UA/NSTEMI. In total, 10 613 patients (17.1%) had diabetes (Table 1). Baseline characteristics at the time of ACS for patients with and without diabetes are shown in Table 2. Consistent with prior observations, patients with diabetes at ACS presentation were older, more often women, had higher body mass index (calculated as weight in kilograms divided by height in meters squared), and were more likely to have a history of hypertension, known hyperlipidemia, MI, CABG surgery, and heart failure compared with patients without diabetes. However, patients with diabetes were less likely to be current smokers. Patients with diabetes had a higher TIMI risk index, especially those patients with STEMI, and were more likely to have heart failure (Killip classes 2-4) at ACS presentation. There was little difference in creatinine clearance between patients with and without diabetes.
|
|
|
|
Table 2. Baseline Characteristics of Patients With and Without Diabetes and Presenting With UA/NSTEMI or STEMI
|
|
|
The majority of patients with UA/NSTEMI were enrolled in North America whereas the patients with STEMI were predominantly from regions other than North America (Table 2). Furthermore, there was a higher prevalence of diabetes at enrollment in North American sites compared with sites in other regions of the world. Patients with UA/NSTEMI had diabetes more often than those presenting with STEMI (22.4% vs 15.4%, P < .001). The UA/NSTEMI population also had significantly more comorbid conditions than the STEMI population, including an increased prevalence of hypertension, known hyperlipidemia, prior MI, and a history of heart failure.
Therapies for ACS
Medical therapies prerandomization, in-hospital, and at discharge along with revascularization rates during the index hospitalization for both patients with and without diabetes are shown in Table 3. When compared with patients without diabetes prerandomization, patients with diabetes were treated more frequently with proven risk-modifying therapies, including aspirin (37.2% vs 24.8%, P < .001), -blockers (29.2% vs 22.1%, P < .001), ACE inhibitors or ARBs (35.1% vs 17.7%, P < .001), and hypolipidemic therapy (18.8% vs 10.9%, P < .001). When stratified by a history of previous MI, percutaneous coronary intervention, or CABG surgery, there were higher rates of prior ischemic heart disease in patients with diabetes and presenting with UA/NSTEMI, likely explaining the disparities in medication use before randomization (data available upon request). Also, patients with diabetes presenting with UA/NSTEMI were more frequently taking insulin than those patients who presented with STEMI (26.8% vs 19.3%, P < .001).
|
|
|
|
Table 3. Medical Therapies Prerandomization, In-hospital, and at Discharge in Patients With and Without Diabetes Presenting With UA/NSTEMI or STEMI
|
|
|
While hospitalized for ACS, patients with diabetes received -blockers less frequently (76.1% vs 80.0%, P < .001), but received ACE inhibitors or ARBs more frequently (65.8% vs 57.5%, P < .001). Patients with diabetes were more likely to undergo revascularization procedures during index hospitalization than patients without diabetes irrespective of presentation (for UA/NSTEMI, 35.6% vs 33.0%; P = .003; and for STEMI, 27.9% vs 26.0%; P = .001). The higher revascularization rate among patients with diabetes was a consequence of more frequent CABG surgery following ACS.
Extent of Coronary Artery Disease
Coronary angiography data from the index ACS hospitalization were available for 15 574 patients (25.1%). Among this subset, patients with diabetes were more likely to have multivessel coronary disease than patients without diabetes (62.0% vs 48.1%, P < .001) (Table 4). More multivessel coronary disease was present among patients with diabetes compared with patients without diabetes presenting with UA/NSTEMI (65.9% vs 50.8%, P < .001) or STEMI (56.5% vs 45.4%, P < .001). There was a corresponding tendency for angiography among patients without diabetes to reveal either no obstructive disease or only single-vessel disease.
|
|
|
|
Table 4. Angiographic Data in Patients With and Without Diabetes Presenting With UA/NSTEMI or STEMI
|
|
|
Mortality at 30 Days
Mortality was significantly higher among patients with diabetes than among patients without diabetes at 30 days following either UA/NSTEMI (2.1% vs 1.1%, P < .001) or STEMI (8.5% vs 5.4%, P < .001) (Table 5). The unadjusted 30-day mortality risk for patients with diabetes was consistently higher than for patients without diabetes across key subgroups in the UA/NSTEMI and STEMI cohorts (Figure 2). Patients older than 75 years, with Killip classes 2-4, decreased creatinine clearance, and increased TIMI risk index had the highest absolute mortality at 30 days regardless of whether they had STEMI or UA/NSTEMI. There was no significant interaction between diabetes status and type of ACS at 30 days. There was also no significant difference in 30-day mortality between patients with diabetes taking insulin and those not taking insulin before ACS among both STEMI (7.8% vs 8.7%, P = .26) and UA/NSTEMI (2.4% vs 1.8%, P = .31) cohorts.
|
|
|
|
Table 5. The Risk of Death Attributable to Diabetes Following ACS
|
|
|
|
|
|
|
Figure 2. Unadjusted Odds of Mortality at 30 Days After Acute Coronary Syndromes in UA/NSTEMI and STEMI
STEMI indicates ST-segment elevation myocardial infarction; UA/NSTEMI, unstable angina/non-STEMI; CI, confidence interval. The overall unadjusted odds of death associated with diabetes is shown by the diamond (edges represent upper and lower 95% CIs) and the dotted vertical line. For each subgroup, the square is proportional to the number of patients and represents a point estimate of mortality risk conferred by diabetes, with the horizontal lines representing 95% CIs.
|
|
|
After multivariable modeling, the independent risk conferred by diabetes at 30 days among patients with UA/NSTEMI was higher (OR, 1.78; 95% confidence interval [CI], 1.24-2.56) than among patients with STEMI (OR, 1.40; 95% CI, 1.24-1.57) (Table 5). Results were similar with the inclusion of body mass index, Killip class, known prior hyperlipidemia, or a term for the individual trial interventions in the model.
Mortality at 1 Year
Mortality at 1 year was significantly higher among patients with diabetes than in patients without diabetes presenting with UA/NSTEMI (7.2% vs 3.1%, P < .001) or STEMI (13.2% vs 8.1%, P < .001) (Figure 3). The unadjusted risk of death at 1 year associated with diabetes among patients presenting with UA/NSTEMI was higher (hazard ratio [HR], 2.24; 95% CI, 1.86-2.70; P < .001) than among patients presenting with STEMI (HR, 1.64; 95% CI, 1.51-1.78; P < .001), with a significant interaction between diabetes and ACS type on mortality (P = .004) (Figure 3).
|
|
|
|
Figure 3. Cumulative Incidence of All-Cause Mortality Through 1 Year After ACS
ACS indicates acute coronary syndromes; STEMI, ST-segment elevation myocardial infarction; UA/NSTEMI, unstable angina/non-STEMI. Vertical dotted line represents 30 days after ACS. Patients with diabetes are at higher risk of death at 30 days following either UA/NSTEMI (2.1% vs 1.1%, P < .001) or STEMI (8.5% vs 5.4%, P < .001). By 1 year after ACS, the cumulative mortality in patients with diabetes vs without diabetes was higher in UA/NSTEMI (7.2% vs 3.1%, P < .001) and STEMI (13.2% vs 8.1%, P < .001), and accrues at a higher rate in patients with diabetes than in patients without diabetes. The relative increase in mortality for the patients with diabetes following UA/NSTEMI exceeds that of STEMI (P = .004 for interaction between diabetes status and ACS stratum).
|
|
|
There was an early mortality risk associated with STEMI among both patients with and without diabetes. However, mortality during the first year following ACS accrued at a higher rate among patients with diabetes and presenting with UA/NSTEMI than with STEMI. In a landmark analysis between 30 days and 1 year, there was an interaction between diabetes status and ACS type on mortality (P = .049). By 1 year following ACS, patients with diabetes and presenting with UA/NSTEMI had a mortality that approached patients without diabetes and presenting with STEMI (7.2% vs 8.1%).
At 1 year, diabetes remained a significant independent factor associated with all-cause mortality for patients presenting with UA/NSTEMI (HR, 1.65; 95% CI, 1.30-2.10) and for patients presenting with STEMI (HR, 1.22; 95% CI, 1.08-1.38) (Table 5).
COMMENT
Our analysis demonstrates a statistically robust association between diabetes at time of presentation with ACS and all-cause mortality at 30 days and at 1 year, even after adjusting for baseline characteristics as well as features and management of the index event. Despite advances in the treatment of ACS, the magnitude of excess mortality among patients with diabetes was considerable and observed among all of the major subgroups within both the UA/NSTEMI and STEMI populations.
Diabetes had an even greater adverse impact on long-term mortality following UA/NSTEMI than STEMI. The burden of cardiovascular risk inherent among the patients presenting with UA/NSTEMI marked the index ACS presentation as a sentinel event in a chronic, progressive course that was more accelerated among patients with diabetes. By 1 year, the mortality of patients with diabetes presenting with UA/NSTEMI approached that of patients without diabetes presenting with STEMI. As demonstrated in our study, the UA/NSTEMI population is enriched with this high-risk diabetic population.
Our study was systematically conducted from prospectively collected data within the context of a randomized clinical trial. We analyzed patients from centers throughout the world implementing modern therapies across the full spectrum of ACS. Our findings extend prior observations on the adverse effect of diabetes on STEMI from the GUSTO-1 data and from the OASIS registry of patients with UA/NSTEMI. The GRACE multinational registry also demonstrated diabetes at ACS to be a significant contributor to in-hospital and 6-month out-of-hospital mortality. Diabetes did not meet criteria for inclusion in the GRACE risk prediction tool, which excluded in-hospital mortality and was by necessity simplified to maintain its utility.18
Diabetes status, however, was included in the TIMI risk scores for both UA/NSTEMI and STEMI.35-36 Neither score attempted to quantify the independent impact of diabetes at the initial presentation with ACS. By pooling these 11 TIMI trials with a large cumulative number of outcome events, we had the statistical power to determine the independent effect of diabetes on all-cause mortality.
Therapeutic Implications
The magnitude of risk conferred by diabetes following ACS demands a major research effort to reduce the influence of diabetes on coronary artery disease.37 Reducing coronary risk from diabetes requires a multifactorial approach to manage all atherogenic influences.38 Long-term, targeted, intensive use of proven therapies for the traditional coronary risk factors must be widely promoted for patients with diabetes, particularly following ACS. As with lipids levels, more stringent targets for patients with diabetes may be better all around.
In the United States, a reduction in coronary deaths has been observed during the past 2 decades from the prevention and modification of high blood pressure, high cholesterol, and tobacco use. But these gains have been partially offset by the increased burden of cardiovascular disease attributable to diabetes.39 There must be ongoing reevaluation of traditional guidelines for diabetes management to further mitigate this critical, independent risk factor.40-41 Collaboration between medical societies, national health care organizations, and industry will be vital to halt the epidemic of diabetes-related cardiovascular disease.42-43
Novel targets for diabetes management in patients with coronary artery disease must be identified and tested. For example, glucagon-like peptide-1 receptor agonists reduce both fasting and postprandial glucose concentrations and may even improve myocardial function following an acute MI, as demonstrated in a small, nonrandomized pilot study.44 Such agents are worthy of investigation in large, longitudinal clinical trials to assess their efficacy on cardiovascular end points.
An important ongoing clinical trial, Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D),45 will study whether insulin replacement or an insulin-sensitizing agent will improve mortality following ACS among patients with diabetes. This study will also compare medical management and revascularization in patients with diabetes with multivessel coronary artery disease. Meanwhile, the FREEDOM trial will provide data to guide the choice between percutaneous coronary intervention and CABG surgery among patients with diabetes requiring revascularization.46
Study Limitations
Our analysis has several limitations. The database merged several clinical trials and intertrial variability in care could have influenced patient enrollment, administered therapies, and outcome. We focused on a subgroup of patients with diabetes that was not prespecified at the individual trial design. Fasting glucose measurements were not universally collected, so our study was unable to evaluate the subgroup of patients who had previously unrecognized diabetes, which might have been discovered during the qualifying presentation.47 It is also possible that each site enrolling patients had adopted varying diagnostic guidelines for diabetes.48 These factors, along with diabetes definition by self-report, could bias the risk assessment of diabetes to the null. We were unable to assess the type and duration of diabetes, features of diabetes management, and degree of glycemic control. Measurement of glycated hemoglobin, serial blood glucoses during ACS, or insulin resistance may identify a gradient of risk among patients with diabetes with coronary artery disease.49-50 Cause of death data was not available for each patient so it was impossible to determine whether reinfarction, stroke, cardiovascular death, or noncardiovascular death was driving mortality in the first year following ACS.
Conclusion
Despite modern therapies for ACS, diabetes conferred a significant independent excess mortality risk at 30 days and 1 year following ACS. Current strategies are insufficient to ameliorate the adverse impact of diabetes. Given the increasing burden of cardiovascular disease attributable to diabetes worldwide, our study highlights the need for a major research effort to identify aggressive new strategies to manage unstable ischemic heart disease among this high-risk population.
AUTHOR INFORMATION
Corresponding Author: Elliott M. Antman, MD, The TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115 (eantman{at}rics.bwh.harvard.edu).
Author Contributions: Drs Donahoe and Antman had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of its analysis. Drs Donahoe and Stewart contributed equally as primary coauthors.
Conception and design: Donahoe, Stewart, Murphy, Antman.
Acquisition of data: Donahoe, McCabe, Murphy, Cannon, Antman.
Analysis and interpretation of data: Donahoe, Stewart, McCabe, Mohanavelu, Murphy, Cannon, Antman.
Drafting of the manuscript: Donahoe, Stewart.
Critical revision of the manuscript for important intellectual content: Donahoe, Stewart, McCabe, Mohanavelu, Murphy, Cannon, Antman.
Statistical analysis: Donahoe, Stewart, Mohanavelu, Murphy, Cannon, Antman.
Obtaining funding: McCabe, Cannon.
Administrative, technical, or material support: McCabe, Cannon, Antman.
Supervision: McCabe, Murphy, Cannon, Antman.
Financial Disclosures: The TIMI Study Group has received research/grant support in the last 2 years through the Brigham and Women's Hospital with funding from (in alphabetical order): Accumetrics, Amgen, AstraZeneca, Baxter, Bayer Healthcare LLC, Beckman Coulter, Biosite Incorporated, Bristol-Myers Squibb, CardioKinetix, CV Therapeutics, Eli Lilly and Company, FoldRx, GlaxoSmithKline, INO Therapeutics LLC, Inotek Pharmaceuticals, National Institutes of Health, Integrated Therapeutics Corporation, KAI Pharmaceuticals, Merck, Millennium Pharmaceuticals, Novartis, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics Corporation, Roche Diagnostics GmbH, Sanofi-Aventis, Sanofi-Synthelabo Recherche, Schering-Plough Research Institute, and St Jude Medical. Dr Cannon reported receiving research grant support from Accumetrics, AstraZeneca, GlaxoSmithKline, Merck, Merck/Schering Plough Partnership, Sanofi-Aventis/Bristol-Myers Squibb Partnership, and Schering Plough.
Funding/Support: The TIMI Study Group has received research/grant support in the last 2 years through the Brigham and Women's Hospital with funding from (in alphabetical order): Accumetrics, Amgen, AstraZeneca, Baxter, Bayer Healthcare LLC, Beckman Coulter, Biosite Incorporated, Bristol-Myers Squibb, CardioKinetix, CV Therapeutics, Eli Lilly and Company, FoldRx, GlaxoSmithKline, INO Therapeutics LLC, Inotek Pharmaceuticals, National Institutes of Health, Integrated Therapeutics Corporation, KAI Pharmaceuticals, Merck, Millennium Pharmaceuticals, Novartis, Nuvelo, Ortho-Clinical Diagnostics, Pfizer, Roche Diagnostics Corporation, Roche Diagnostics GmbH, Sanofi-Aventis, Sanofi-Synthelabo Recherche, Schering-Plough Research Institute, and St Jude Medical.
Role of the Sponsors: None of the granting agencies or companies listed had any role in the design and conduct of the analysis, in the collection, management, or analysis of the data, or in the preparation, review, or approval of the manuscript.
Additional Contributions: We thank C. Michael Gibson, MS, MD, at the TIMI Study Group for his assistance with the conception of this project and his guidance at many steps along the way. The genesis of the TIMI diabetes database and preliminary analysis would not have been possible without the efforts of Amy Shui, MA, of the TIMI Data Coordinating Center. We also thank Jie Qin, MS, at the TIMI Data Coordinating Center for her help with the statistical analysis. No additional financial compensation was provided to the acknowledged individuals for their participation in this project.
Author Affiliations: The TIMI Study Group; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (Drs Stewart, Cannon, and Antman, and Mr Mohanavelu and Mss McCabe and Murphy); and Department of Medicine, Division of Cardiology, Cornell University Medical Center, New York, New York (Dr Donahoe).
REFERENCES
| |
1. Danaei G, Lawes CM, Vander Hoorn S, Murray CJ, Ezzati M. Global and regional mortality from ischaemic heart disease and stroke attributable to higher-than-optimum blood glucose concentration: comparative risk assessment. Lancet. 2006;368(9548):1651-1659.
FULL TEXT
| PUBMED
2. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases, part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies. Circulation. 2001;104(23):2855-2864.
FREE FULL TEXT
3. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-1053.
FREE FULL TEXT
4. Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study. Lancet. 2007;369(9563):750-756.
FULL TEXT
|
ISI
| PUBMED
5. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290(14):1884-1890.
FREE FULL TEXT
6. Franco OH, Steyerberg EW, Hu FB, Mackenbach J, Nusselder W. Associations of diabetes mellitus with total life expectancy and life expectancy with and without cardiovascular disease. Arch Intern Med. 2007;167(11):1145-1151.
FREE FULL TEXT
7. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published online ahead of print December 28, 2006]. Circulation. 2007;115(5):e69-e171.
FREE FULL TEXT
8. Thom T, Haase N, Rosamond W, et al, American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):e85-e151.
FREE FULL TEXT
9. Garcia MJ, McNamara PM, Gordon T, Kannel WB. Morbidity and mortality in diabetics in the Framingham population: sixteen year follow-up study. Diabetes. 1974;23(2):105-111.
ISI
| PUBMED
10. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
FREE FULL TEXT
11. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421.
FREE FULL TEXT
12. Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA. 1999;281(14):1291-1297.
FREE FULL TEXT
13. Fox CS, Coady S, Sorlie PD, et al. Trends in cardiovascular complications of diabetes. JAMA. 2004;292(20):2495-2499.
FREE FULL TEXT
14. Mak KH, Moliterno DJ, Granger CB, et al. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction: GUSTO-I Investigators (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries). J Am Coll Cardiol. 1997;30(1):171-179.
ABSTRACT
15. Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) registry. Circulation. 2000;102(9):1014-1019.
FREE FULL TEXT
16. Franklin K, Goldberg RJ, Spencer F, et al. Implications of diabetes in patients with acute coronary syndromes: the Global Registry of Acute Coronary Events. Arch Intern Med. 2004;164(13):1457-1463.
FREE FULL TEXT
17. Eagle KA, Lim MJ, Dabbous OH, et al. A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry. JAMA. 2004;291(22):2727-2733.
FREE FULL TEXT
18. Fox KA, Dabbous OH, Goldberg RJ, et al. Prediction of risk of death and myocardial infarction in the six months after presentation with acute coronary syndrome: prospective multinational observational study (GRACE) [published online ahead of print October 10, 2006]. BMJ. 2006;333(7578):1091.
FREE FULL TEXT
19. Cannon CP, McCabe CH, Wilcox RG, et al. Oral glycoprotein IIb/IIIa inhibition with Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) trial. Circulation. 2000;102(2):149-156.
FREE FULL TEXT
20. InTIME-II Investigators. Intravenous tPA for the treatment of infarcting myocardium early: InTIME-II, a double blind comparison of single bolus lenoteplase vs. accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J. 2000;21(24):2005-2013.
FREE FULL TEXT
21. Cannon CP, Weintraub WS, Demopoulos LA, et al, TACTICS (Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy)-Thrombolysis in Myocardial Infarction 18 Investigators. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344((25)):1879-1887.
FREE FULL TEXT
22. Giugliano RP, Roe MT, Harrington RA, et al, INTEGRITI Investigators. Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) Phase II Angiographic Trial. J Am Coll Cardiol. 2003;41(8):1251-1260.
FREE FULL TEXT
23. de Lemos JA, Blazing MA, Wiviott SD, et al, A to Z Investigators. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes phase Z of the A to Z trial. JAMA. 2004;292(11):1307-1316.
FREE FULL TEXT
24. Cannon CP, Braunwald E, McCabe CH, et al, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.
FREE FULL TEXT
25. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 trial. Circulation. 2002;105(14):1642-1649.
FREE FULL TEXT
26. Ohman EM, Van de Werf F, Antman EM, et al, FASTER (TIMI 24) Investigators. Tenecteplase and tirofiban in ST-segment elevation acute myocardial infarction: results of a randomized trial. Am Heart J. 2005;150(1):79-88.
FULL TEXT
|
ISI
| PUBMED
27. Antman EM, Morrow DA, McCabe CH, et al, ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354(14):1477-1488.
FREE FULL TEXT
28. Wiviott SD, Antman EM, Winters KJ, et al, JUMBO-TIMI 26 Investigators. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111(25):3366-3373.
FREE FULL TEXT
29. Sabatine MS, Cannon CP, Gibson CM, et al, CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fribrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352(12):1179-1189.
FREE FULL TEXT
30. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20(7):1183-1197.
ISI
| PUBMED
31. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses. Lancet. 1999;354(9193):1896-1900.
FULL TEXT
|
ISI
| PUBMED
32. Morrow DA, Antman EM, Giugliano RP, et al. A simple risk index for rapid initial triage of patients with ST-elevation myocardial infarction: an InTIME II substudy. Lancet. 2001;358(9293):1571-1575.
FULL TEXT
|
ISI
| PUBMED
33. Wiviott SD, Morrow DA, Frederick PD, Antman EM, Braunwald E. Application of the thrombolysis in myocardial infarction risk index in non-ST-segment elevation myocardial infarction: evaluation of patients in the National Registry of Myocardial Infarction. J Am Coll Cardiol. 2006;47(8):1553-1558.
FREE FULL TEXT
34. Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number of events per variable in logistic regression analysis. J Clin Epidemiol. 1996;49(12):1373-1379.
FULL TEXT
|
ISI
| PUBMED
35. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-842.
FREE FULL TEXT
36. Morrow DA, Antman EM, Charlesworth A, et al. TIMI risk score for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of infarcting myocardium early II trial substudy. Circulation. 2000;102(17):2031-2037.
FREE FULL TEXT
37. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115(1):114-126.
FREE FULL TEXT
38. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med. 2003;348(5):383-393.
FREE FULL TEXT
39. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356(23):2388-2398.
FREE FULL TEXT
40. Canadian Diabetes Assocation Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2003 Clinical Practice Guidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2003;27(supp 2):S1-S140.
41. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(supp 1):S4-S36.
FREE FULL TEXT
42. American Diabetes Association. Make the Link! Diabetes, Heart Disease and Stroke Web site. http://www.diabetes.org/heart-disease-stroke.jsp. Accessibility verified July 17, 2007.43. Rydén L, Standl E, Bartnik M, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: the Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28(1):88-136.
FREE FULL TEXT
44. Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962-965.
FREE FULL TEXT
45. Brooks MM, Frye RL, Genuth S, et al. Hypotheses, design, and methods for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Am J Cardiol. 2006;97(12A):9G-19G.
FULL TEXT
|
ISI
| PUBMED
46. ClinicalTrials.gov Web site. Comparison of two treatments for multivessel coronary artery disease in individuals with diabetes (FREEDOM). http://clinicaltrials.gov/show/NCT00086450. Accessibility verified July 17, 2007.47. Norhammar A, Tenerz A, Nilsson G, et al. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Lancet. 2002;359(9324):2140-2144.
FULL TEXT
|
ISI
| PUBMED
48. Kim SH, Chunawala L, Linde R, Reaven GM. Comparison of the 1997 and 2003 American Diabetes Association classification of impaired fasting glucose: impact on prevalence of impaired fasting glucose, coronary heart disease risk factors, and coronary heart disease in a community-based medical practice. J Am Coll Cardiol. 2006;48(2):293-297.
FREE FULL TEXT
49. Pinto DS, Skolnick AH, Kirtane AJ, et al. U-shaped relationship of blood glucose with adverse outcomes among patients with ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2005;46(1):178-180.
FREE FULL TEXT
50. Suleiman M, Hammerman H, Boulos M, et al. Fasting glucose is an important independent risk factor for 30-day mortality in patients with acute myocardial infarction: a prospective study. Circulation. 2005;111(6):754-760.
FREE FULL TEXT
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati
What's this?
RELATED LETTERS
Diabetes and Mortality Risk After Acute Coronary Syndromes
and
JAMA. ;298():2367-2367.
FULL TEXT
Diabetes and Mortality Risk After Acute Coronary Syndromes
JAMA. ;298():2367-2368.
FULL TEXT
Glucose-Insulin-Potassium Therapy in Patients With STEMI
, , and
JAMA. ;299():2385-2385.
FULL TEXT
RELATED ARTICLE
Acute Coronary Syndromes
, , and
JAMA. ;298():828-828.
FULL TEXT
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
Dysglycemia and acute myocardial infarction the role of echocardiography.
Verhaert and Thomas
J Am Coll Cardiol Img 2009;2:600-603.
FULL TEXT
Evaluation of the Glycometabolic Effects of Ranolazine in Patients With and Without Diabetes Mellitus in the MERLIN-TIMI 36 Randomized Controlled Trial
Morrow et al.
Circulation 2009;119:2032-2039.
ABSTRACT
| FULL TEXT
Ethnic differences in long-term improvement of angina following revascularization or medical management: a comparison between south Asians and white Europeans
Zaman et al.
J Public Health (Oxf) 2009;31:168-174.
ABSTRACT
| FULL TEXT
The hexosamine biosynthesis inhibitor azaserine prevents endothelial inflammation and dysfunction under hyperglycemic condition through antioxidant effects
Rajapakse et al.
Am. J. Physiol. Heart Circ. Physiol. 2009;296:H815-H822.
ABSTRACT
| FULL TEXT
Insulin as a cardiovascular therapeutic: improving glycemic control in patients with coronary artery disease.
Pepine
J Am Coll Cardiol 2009;53:S1-S2.
FULL TEXT
Heart Disease and Stroke Statistics--2009 Update: A Report From the American Heart Association Statistics Committee and Stroke Statistics Subcommittee
WRITING GROUP MEMBERS et al.
Circulation 2009;119:e21-e181.
FULL TEXT
Growth-differentiation factor-15 for risk stratification in patients with acute chest pain
Bouzas-Mosquera et al.
Eur Heart J 2008;29:2947-2947.
FULL TEXT
Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology:
Authors/Task Force Members et al.
Eur Heart J 2008;29:2909-2945.
FULL TEXT
American College of Endocrinology Pre-Diabetes Consensus Conference: Part Two
Bloomgarden
Diabetes Care 2008;31:2222-2229.
FULL TEXT
Acute Coronary Syndromes and Diabetes Mellitus: A Winning Ticket for Prasugrel
Fuster and Farkouh
Circulation 2008;118:1607-1608.
FULL TEXT
Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38
Wiviott et al.
Circulation 2008;118:1626-1636.
ABSTRACT
| FULL TEXT
Reduction in recurrent cardiovascular events with prasugrel compared with clopidogrel in patients with acute coronary syndromes from the TRITON-TIMI 38 trial
Murphy et al.
Eur Heart J 2008;29:2473-2479.
ABSTRACT
| FULL TEXT
The Year in Non-ST-Segment Elevation Acute Coronary Syndrome
Giugliano and Braunwald
J Am Coll Cardiol 2008;52:1095-1103.
FULL TEXT
Screening for Coronary Artery Disease in Patients With Diabetes
Roelker
Diabetes Spectr. 2008;21:166-171.
ABSTRACT
| FULL TEXT
Best Practices for Lowering the Risk of Cardiovascular Disease in Diabetes
Triplitt and Alvarez
Diabetes Spectr. 2008;21:177-189.
ABSTRACT
| FULL TEXT
Glucose-Insulin-Potassium Therapy in Patients With STEMI
Selker et al.
JAMA 2008;299:2385-2385.
FULL TEXT
LDL Cholesterol Lowering in Type 2 Diabetes: What Is the Optimum Approach?
Nesto
Clin. Diabetes 2008;26:8-13.
ABSTRACT
| FULL TEXT
Impact of Drug-Eluting Stents Among Insulin-Treated Diabetic Patients A Report from the NHLBI Dynamic Registry.
Mulukutla et al.
J Am Coll Cardiol Intv 2008;1:139-147.
ABSTRACT
| FULL TEXT
Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning
Ferdinandy et al.
Pharmacol. Rev. 2007;59:418-458.
ABSTRACT
| FULL TEXT
Diabetes and Mortality Risk After Acute Coronary Syndromes
Srinivasan and Bhagra
JAMA 2007;298:2367-2367.
FULL TEXT
Diabetes and Mortality Risk After Acute Coronary Syndromes
Parakh
JAMA 2007;298:2367-2368.
FULL TEXT
Diabetes Contributes to Acute Coronary Syndromes Death
DOC News 2007;4:15-15.
FULL TEXT
Diabetes Increases Short-Term Mortality Risk in Patients with Acute Coronary Syndromes
JWatch Emergency Med. 2007;2007:2-2.
FULL TEXT
Patients with Diabetes Fare Worse After MI Than Those Without Diabetes
Journal Watch Cardiology 2007;2007:4-4.
FULL TEXT
|
