Long-Term Mortality of Patients Undergoing Cardiac Catheterization for ST-Elevation and Non-ST-Elevation Myocardial Infarction
Background— There are limited contemporary data comparing long-term outcomes after cardiac catheterization for ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI).
Methods and Results— We studied patients undergoing cardiac catheterization for STEMI (n=2413) and NSTEMI (n=1974) between 1999 and 2005 with at least 1 significant coronary lesion ≥75%. We compared adjusted mortality rates over restricted time intervals and the differential impact of early revascularization on mortality stratified by ST-elevation status. Between 1999 and 2007, 1274 patients died, with a median follow-up of 4 years. A piece-wise analysis showed a higher adjusted mortality risk for STEMI during the first 2 months (adjusted hazard ratio, 1.85; 95% confidence interval, 1.45 to 2.38) and a lower adjusted mortality risk for STEMI after 2 months (adjusted hazard ratio, 0.68; 95% confidence interval, 0.59 to 0.83). Compared with late or no revascularization, early revascularization was associated with a lower adjusted risk of mortality for both STEMI (adjusted hazard ratio, 0.73; 95% confidence interval, 0.58 to 0.90) and NSTEMI (adjusted hazard ratio, 0.76; 95% confidence interval, 0.65 to 0.89) (P for interaction=0.22).
Conclusions— Among a contemporary cohort of acute MI patients with significant coronary disease during cardiac catheterization, STEMI was associated with a higher risk of short-term mortality, but NSTEMI was associated with a higher risk of long-term mortality. Early revascularization was associated with a similar improvement in long-term outcomes for both STEMI and NSTEMI. These data suggest that in clinical investigations of early revascularization among patients with NSTEMI, extended follow-up may be necessary to demonstrate treatment benefit.
- acute coronary syndrome
- coronary disease
- myocardial infarction
Received June 19, 2008; accepted April 24, 2009.
Myocardial infarction (MI) remains a leading cause of mortality worldwide.1 ST-elevation MI (STEMI) is associated with a higher incidence of persistent and total coronary occlusion, whereas non-STEMI (NSTEMI) is associated with a greater severity and burden of coronary artery disease (CAD).2 The contemporary definition of MI, introduced in 19993 and revised in 20074, focused on circulating biomarkers, predominantly troponin, that detect myocardial necrosis with high sensitivity. However, most of the prior studies that investigated long-term outcomes on the basis of MI classification focused on non-Q-wave MI versus Q-wave MI comparisons,5–20 whereas fewer contemporary studies have used the newer troponin-based MI definition and classification system (STEMI versus NSTEMI).21–24
Clinical Perspective on p 3117
Several other potential differences exist between patients in current practice and those in historical studies. In contemporary practice, the diagnosis is often based on a history of chest pain and elevated biomarkers rather than ECG findings.25–27 In contrast, several historical studies specified ST-segment depression and T-wave inversion as major diagnostic criteria for non-Q-wave MI.11,17 An increasing number of patients with NSTEMI in contemporary practice have received treatment with evidence-based medications and have undergone coronary revascularization before presentation.23,28 Because recent data have shown a decline in the 6-month mortality of patients with STEMI with no change in the mortality of patients with NSTEMI despite an increasing use of cardiac catheterization and revascularization for both types of patients, the long-term prognosis by MI classification is uncertain in contemporary practice.28
Therefore, we identified patients with biomarker-defined acute MI who had least 1 significant coronary lesion during cardiac catheterization to compare differences in long-term mortality between STEMI and NSTEMI. Additionally, we evaluated the differential impact of early revascularization on the long-term mortality of patients with STEMI and NSTEMI.
We performed a retrospective study of 4606 consecutive patients undergoing diagnostic cardiac catheterization from 1999 to 2005 for the indication of acute MI who were found to have at least 1 significant coronary lesion ≥75% on angiography at the Duke University Medical Center (Durham, NC). We relied on the treating physician’s diagnosis of MI without the use of central adjudication, including all patients >18 years of age with MI diagnosed on the basis of a troponin T level ≥0.1 ng/mL, the decision limit in effect during the study period, or creatine kinase-MB level >9 ng/mL, the 99th percentile of a reference control population. We evaluated the individual troponin and creatine kinase-MB measurements of all identified subjects to confirm the presence of at least 1 elevated biomarker measurement during the index hospitalization. Classification of NSTEMI and STEMI was determined by the treating physician and based on interpretation of the ECG assessment of the patient’s clinical status. The cardiology fellow completing the electronic case report form for each patient independently verified, using a computer-assisted quality-control feedback system, all clinical, ECG, and angiographic data, including the final diagnoses of STEMI and NSTEMI.
We excluded patients without troponin or creatine kinase MB data, patients with incomplete angiograms, and to limit the contribution of nonvascular causes to overall mortality, patients with conditions likely to affect long-term survival independently of coronary disease (Figure 1).
Baseline characteristics, medical history, physical examination, initial cardiac catheterization results, and revascularization procedures performed within the first 30 days were collected prospectively as previously described.29,30 Severity of CAD was scored angiographically with the Duke CAD severity index31 (see the online-only Data Supplement). All data were stored in the Duke Databank for Cardiovascular Diseases. The Duke University Medical Center Institutional Review Board approved the study with waiver of the requirement for written informed consent.
As part of the standard follow-up for the Duke Databank for Cardiovascular Diseases, all patients with a coronary lesion ≥75% on angiography were followed up at 6 months and annually thereafter for mortality status by telephone contact, mailed questionnaire, and National Death Index search. Follow-up was considered complete if the mortality committee confirmed the patient’s death or if the patient was successfully contacted at the scheduled follow-up interval. Follow-up for mortality status was 97% complete for all scheduled contacts as of December 1, 2007. All periprocedural and perioperative fatalities were counted as end points. Patients with incomplete follow-up were censored at the time of last contact.
All statistical analyses were performed with SAS version 8.2 (SAS Institute Inc, Cary, NC). All probability values were 2 tailed with α=0.05, and all confidence intervals (CIs) were calculated to the 95th percentile. No adjustments were made for multiple comparisons. Categorical data were displayed as proportions and continuous data as medians and 25th to 75th percentiles. Comparison of baseline characteristics, angiographic results, revascularization rates, and medication use between STEMI and NSTEMI patients was performed with the Pearson χ2 test for categorical variables, the 2-sample t test for normally distributed continuous variables, and the Wilcoxon rank-sum test for nonnormally distributed data. To study the impact of early revascularization in both STEMI and NSTEMI groups, we stratified patients within each group into early and late/no revascularization. Early revascularization was defined as percutaneous coronary intervention (PCI)/coronary artery bypass graft surgery (CABG) within 48 hours of admission; late revascularization was defined as PCI/CABG after 48 hours but within 30 days of admission.
Survival by MI classification (STEMI versus NSTEMI) was evaluated with the Kaplan-Meier method, and relative survival was compared by use of Cox proportional hazards with stepwise and backward variable selection methods. A value of P=0.05 was used as the criterion for variables to remain in the model. The proportional-hazards assumption was assessed with Schoenfeld residuals; the assumption of linearity was evaluated for continuous variables with restricted cubic splines. When the relationship was found to be nonlinear, appropriate transformations were applied (see the online-only Data Supplement). We analyzed MI classification and baseline demographic, clinical, and angiographic variables as covariates to determine the adjusted risk of long-term mortality with a median follow-up of 4 years. Because historical data on the differential survival in Q-wave versus non-Q-wave MI patients have shown higher short-term mortality in Q-wave MI but higher long-term mortality in non-Q-wave MI,2 we included a 2-piecewise proportional-hazards model that allowed us to stratify outcomes by 2 time periods from the index catheterization: an early time period (0 to 2 months) and a late time period (2 months to 8 years). The 2-month time point was selected through visual assessment of the inflection point in the cumulative hazard function. To assess the validity of using a piecewise model with a cut point at 2 month, we reanalyzed the data using different cut points on either side of the 2-month cut point (range, 24 hours to 6 months). Because these sensitivity analyses consistently showed an early hazard with STEMI and late hazard with NSTEMI, only the 2-month piecewise model is shown.
Because of a possible interaction between ST-segment elevation status and age and the presence of prior infarction,32 comparisons between STEMI and NSTEMI were further stratified according to first MI or subsequent MI. Interaction terms between ST-segment elevation status and the presence of diabetes, sex, and CAD index also were computed to assess whether a differential association of ST-segment elevation status with survival existed within these subgroups.
Finally, to study the impact of early revascularization on long-term outcomes, we determined the adjusted hazard ratio (HR) of early revascularization versus late/no revascularization within the STEMI and NSTEMI groups.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
During the 6-year patient accrual period (1999 to 2005), we identified 4387 patients who met the eligibility criteria for the study (Figure 1). A total of 1974 patients (45%) were classified by the treating physician as having STEMI, and 2413 patients (55%) were classified as having NSTEMI. On a yearly basis, the proportion of patients with NSTEMI increased and the proportion of patients with STEMI decreased (Figure 2).
Patients with NSTEMI were older, were more likely to be women, and had a greater burden of comorbidities (Table 1). Furthermore, patients with NSTEMI were more likely to have left main and multivessel coronary disease and higher left ventricular ejection fraction values compared with patients with STEMI (Table 2). Patients with NSTEMI were more likely to undergo CABG within 30 days of presentation, whereas patients with STEMI were more likely to undergo PCI. A total of 412 STEMI patients received fibrinolytic therapy; 83 had PCI for failed fibrinolysis or recurrent ischemia within 24 hours of fibrinolysis, and the remainder of patients underwent nonurgent PCI without preceding recurrent ischemia.
Mortality in the Overall Patient Cohort
Over a period of 8 years, 1274 patients died. Unadjusted mortality at 1 year was lower among STEMI patients than NSTEMI patients (9.5% versus 14.3%, respectively), as was long-term mortality (median 4-year follow-up, 28.9% versus 44.9%, respectively). Visual assessment of the Kaplan-Meier curves demonstrated an initially higher unadjusted mortality risk in STEMI patients followed by consistently higher unadjusted mortality after 2 months in NSTEMI patients (Figure 3). The long-term mortality difference persisted after adjustment for baseline characteristics, clinical presentation features, and angiographic disease severity, with an adjusted HR of 0.84 (95% CI, 0.74 to 0.97; Table 3). Other covariates retained in the final model are listed in the online-only Data Supplement.
Mortality Stratified by Time From Catheterization
The piecewise model used to assess adjusted mortality over 2 restricted time intervals, 0 to 2 months and 2 months to 8 years, showed an inversion in the relative mortality risk over time with a higher adjusted early mortality for STEMI (adjusted HR from 0 to 2 months, 1.85; 95% CI, 1.45 to 2.38) and a lower adjusted late mortality for STEMI (adjusted HR from 2 months to 8 years, 0.68; 95% CI, 0.59 to 0.83; Table 3).
Mortality Stratified by Use of Revascularization Procedures
Table 4 compares the baseline and angiographic characteristics of patients undergoing early revascularization with those receiving late or no revascularization within 30 days. Compared with late or no revascularization, early revascularization was associated with an adjusted long-term mortality hazard of 0.73 (95% CI, 0.58 to 0.90) for STEMI and 0.76 (95% CI, 0.65 to 0.89) for NSTEMI (Table 3). There was no interaction between early revascularization status and the differential long-term mortality among the STEMI versus NSTEMI groups (P for interaction=0.22).
Mortality Among Subgroups
In a further analysis examining differential survival among NSTEMI versus STEMI within several subgroups, we found a significant interaction of MI classification with age (P for interaction=0.01) and CAD index (P for interaction=0.02) and a trend toward statistical significance for the interaction between MI classification and a history of prior MI (P for interaction=0.09) (see Table 3) There was no significant interaction of MI classification with sex (P for interaction=1.0) or a history of diabetes mellitus (P for interaction=0.5). Women had a higher long-term mortality than men within both the STEMI and NSTEMI groups (see the online-only Data Supplement). Within the STEMI group, women were less likely to undergo revascularization at 30 days than men (81% versus 87.5%). Similarly, within the NSTEMI group, only 66% of women underwent revascularization within 30 days compared with 73% of men.
Among patients undergoing cardiac catheterization for acute MI defined with troponin-based criteria, STEMI was associated with a lower late mortality risk compared with NSTEMI. Although early (0 to 2 months) mortality was higher for STEMI, late (beyond 2 months) mortality remained consistently lower for STEMI through 8 years of follow-up.
Comparisons With Prior Studies
Although the majority of studies point toward a similar or higher long-term mortality with non-Q-wave MI compared with Q-wave MI,2 there are conflicting data on the prognosis of contemporary patients with STEMI versus NSTEMI identified using the current consensus MI definition.23,24 Our study showed that long-term mortality was almost 30% for STEMI and 45% for NSTEMI, a finding that is consistent with other studies comparing long-term survival in Q-wave versus non-Q-wave MI in the prereperfusion era.2
Reasons for Differences in Outcomes
There are several possible reasons for the time-dependent differences in outcomes among patients with STEMI and NSTEMI observed in our study. First, the greater prevalence of comorbidities among patients with NSTEMI accounts for much of the excess long-term mortality in this group, as evidenced by substantial attenuation of the HR after adjustment for differences in the composite Charlson comorbidity index and other comorbidities. Patients with NSTEMI have consistently been shown to receive fewer guideline-recommended medications on discharge compared with patients with STEMI,34 a discrepancy with potentially greater impact on long-term outcomes than differences in early revascularization. Second, other investigators have shown that patients with NSTEMI have higher rates of recurrent ischemia and late mortality.35 Our angiographic data showed that patients with NSTEMI had a greater prevalence of left main and double- and triple-vessel disease, as well as a higher Duke CAD index, compared with patients with STEMI. Although we did not assess recurrent ischemia, we hypothesize that the greater CAD severity among NSTEMI patients compared with STEMI patients may have led to more recurrent ischemia.
Third, early revascularization for STEMI and NSTEMI was associated with lower long-term mortality, even after adjustment for a comprehensive set of covariates. Although patients with STEMI clearly benefit from early reperfusion,36 the benefit from early catheterization followed by early revascularization among patients with NSTEMI has been less consistent26; the most recent randomized comparison of early invasive management among patients with non-ST-elevation acute coronary syndrome, the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial, failed to show an improvement in the primary end point at 6 months in the overall study population,37 although the early invasive strategy was associated with better outcomes among the highest-risk subgroup. Our nonrandomized study is the first to show a similar survival advantage with early revascularization among patients with STEMI and NSTEMI (P for interaction=0.22) over a median follow-up period of 4 years, indicating that among patients with NSTEMI, an extended period of follow-up may be necessary to show a treatment effect in randomized trials investigating the early invasive strategy.
A recent meta-analysis by O'Donoghue et al38 showed that the early invasive strategy did not benefit women with low-risk NSTEMI, possibly because of an increased prevalence of normal coronaries in this subgroup. Our study shows that even among patients with acute MI and flow-limiting disease on angiography, women were less likely than men to undergo revascularization at 30 days. Further research is needed to better understand the physician and patient decision-making process underlying this important treatment disparity. Moreover, the association between early revascularization and lower long-term mortality among the high-risk troponin-positive NSTEMI population in our study is consistent with the results of the TIMACS trial37 and the meta-analysis by O'Donoghue et al,38 and supports the use of this strategy among high-risk patient subsets.
Our study has several limitations. First, we evaluated only acute MI patients found to have significant CAD on angiography because longitudinal follow-up was available only for these patients. Second, because the majority of STEMI patients in our study received primary PCI and all patients in the NSTEMI group underwent cardiac catheterization, survival among both the STEMI and NSTEMI groups may be better than that in an unselected acute MI population. Third, all patients were managed in a tertiary academic healthcare setting in a single-center practice, so generalizability to the general community is uncertain. Fourth, information on discharge medications was lacking because of technical problems with extracting discharge medication lists before 2002, so we could not ascertain how long-term secondary prevention medications influenced mortality rates. Fifth, we could not evaluate cause of death, so we could not delineate how differences in cardiovascular versus noncardiovascular mortality rates influenced the overall mortality rates among STEMI versus NSTEMI. Finally, we did not account for differences in the success of PCI procedures among STEMI versus NSTEMI patients.
Among patients with significant CAD found on angiography for acute MI identified by the use of a troponin-based definition, STEMI was associated with a higher risk of short-term mortality compared with NSTEMI, but NSTEMI was associated with a higher risk of long-term mortality. Early revascularization was associated with a similar reduction in long-term mortality for both STEMI and NSTEMI. These data suggest that in clinical investigations of early revascularization among patients with NSTEMI, measuring outcomes over an extended period of follow-up may be necessary to demonstrate a positive treatment effect.
We would like to thank Emily Honeycutt for her help with database programming.
Source of Funding
This study was funded internally by the Duke Clinical Research Institute, Durham, NC. Dr Chan receives salary support from the National Medical Research Council, Singapore, Singapore, and the National University Hospital, Singapore, Singapore; research support from the Ralph Snyderman Foundation, Durham, NC, and the Duke Clinical Research Institute, Durham, NC; and tuition fee and research support from the Montreal Heart Institute, Montreal, Quebec.
Dr Peterson holds research grants from Bristol Myers Squibb/Sanofi, Schering Plough, and Merck/Schering, The other authors report no conflicts.
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In this study of outcomes over a median follow-up period of 4 years among a contemporary cohort of patients undergoing cardiac catheterization for ST-elevation myocardial infarction (STEMI; n=1974) and non-STEMI (NSTEMI; n=2413) at an academic medical center, we compared mortality rates over restricted time intervals and the differential impact of early revascularization on mortality stratified by ST-elevation status. The long-term mortality rates of 29% and 45% for STEMI and NSTEMI, respectively, remain very similar to historical mortality rates among patients with Q-wave and non-Q-wave MI in the era before reperfusion and early invasive therapy, indicating a critical need to develop more efficacious treatment strategies for both types of MI. The adjusted mortality risk was greater for STEMI during the first 2 months (hazard ratio for STEMI versus NSTEMI, 1.85; 95% confidence interval, 1.45 to 2.38) but greater for NSTEMI after 2 months (hazard ratio for STEMI versus NSTEMI, 0.68; 95% confidence interval, 0.59 to 0.83). Compared with late or no revascularization, early revascularization was associated with a lower adjusted risk of long-term mortality for both STEMI (hazard ratio, 0.73; 95% confidence interval, 0.58 to 0.90) and NSTEMI (hazard ratio, 0.76; 95% confidence interval, 0.65 to 0.89) (P for interaction=0.22). These data suggest that the relative mortality among patients managed invasively for STEMI and NSTEMI is time dependent, with NSTEMI imparting a delayed but substantial enhancement of mortality risk; moreover, early revascularization may improve very late survival to a similar extent for both infarct types. In clinical investigations of early revascularization among patients with NSTEMI, extended follow-up may therefore be necessary to demonstrate treatment benefit.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.799981/DC1.