New Definition of Myocardial Infarction: Impact on Long-term Mortality
Article Outline
Abstract
Background
The use of cardiac troponin allows the identification of additional patients developing myocardial necrosis during an acute coronary syndrome. Novel guidelines of European and American cardiac societies recommend labeling these events as myocardial infarction. Our study evaluated the long-term mortality in the group of patients with non-ST segment elevation myocardial infarction not meeting the older World Health Organization (WHO) criteria (creatine phosphokinase) but additionally identified by the novel definition of myocardial infarction.
Methods
This cohort study included 1024 consecutive patients with non-ST segment elevation acute coronary syndrome classified into “unstable angina,” myocardial infarction according to the WHO definition (“WHO criteria”), and myocardial infarction additionally identified by the novel definition (“additional criteria”). All patients were treated with an early invasive strategy. The primary end point was all-cause mortality during follow-up of up to 36 months.
Results
During long-term follow-up (median 16 months, interquartile range 6-29 months), 67 deaths occurred. Kaplan-Meier analysis showed cumulative 3-year mortality rates of 5.6% in patients with “unstable angina,” 9.1% in patients identified by “WHO criteria,” and 17.5% in patients identified by “additional criteria” (P <.001). Cox regression analysis confirmed the “additional criteria” as a significant predictor of mortality (hazard ratio 3.1; 95% confidence interval, 1.9-5.0; P <.001).
Conclusions
The new definition of myocardial infarction based on cardiac troponin testing identifies a high-risk group of additional patients with acute coronary syndrome that is, therefore, appropriately classified as myocardial infarction. In fact, long-term mortality in “additional criteria” patients is higher than in “WHO criteria” patients.
Keywords: Coronary angiography, Coronary disease, Guidelines, Myocardial infarction, Prognosis, Unstable angina
Cardiac troponins are currently the most sensitive and specific biochemical markers of myocyte necrosis,1, 2 with demonstrated clinical utility in emergency settings.3, 4 Moreover, a close relationship between increasing concentrations of cardiac troponins and the risk of death in acute coronary syndromes has been observed.5, 6, 7 Subsequently, the Joint European Society of Cardiology/American College of Cardiology Committee classified cardiac troponin as a major criterion in their consensus document redefining myocardial infarction in the year 2000.8 Further amelioration of this definition was published recently by the Global Task Force of European and American cardiac societies.9
The new definition results in a substantial increase in the number of patients diagnosed with myocardial infarction,10, 11, 12, 13, 14 as a more sensitive marker for myocardial necrosis is used in this definition (troponin) compared with the World Health Organization (WHO) definition from the early 1980s (creatine phosphokinase).15 As anticipated in the European Society of Cardiology/American College of Cardiology consensus document, the change in myocardial infarction definition was associated with a substantial increase in the number of patients transferred to coronary care units and catheter laboratories.10, 12 This sparked considerable controversy over whether the prognosis of patients additionally identified by the new definition justifies their labeling as “myocardial infarction.”16, 17, 18, 19, 20, 21 This controversy could not be settled by the available data, as previous studies had several methodological limitations and yielded inconsistent results.11, 12, 13, 14 Therefore, we examined the long-term mortality in a large cohort of consecutive unselected patients with acute coronary syndrome treated with a contemporary early invasive strategy.
Methods
Study Population
This cohort study enrolled consecutive patients admitted to the Heart Center Bad Krozingen with symptoms of myocardial ischemia at rest from January 1996 to December 1999. We excluded patients with persistent ST-elevation, patients with de novo angina pectoris on exertion or worsening angina during exertion only, and patients in whom angiography was not performed due to patient refusal (n
=6) or extremely severe concomitant disease (n=9 with severe dementia or advanced malignancy). All patients were treated with an early invasive strategy. Patients were classified into 3 groups (Figure 1): patients with non ST-segment elevation myocardial infarction according to the WHO definition15—typical ischemic chest pain associated with a significant increase in creatine phosphokinase and creatine phosphokinase MB—were labeled as “WHO criteria.” Those additionally classified as non-ST-segment elevation myocardial infarction according to the newer definitions8, 9—typical signs as ischemic chest pain associated with an increase in cardiac troponin above the cut-off for myocardial infarction—but not meeting WHO criteria for myocardial infarction were characterized as “additional criteria.” All other patients were indicated as “unstable angina.”
Figure 1.
Classification of study patients. *New definition of myocardial infarction according to the universal definition published in 2007 by the European Society of Cardiology, American College of Cardiology, American Heart Association, and the World Heart Federation. WHO
=World Health Organization; MI=myocardial infarction.
The study was carried out according to the principles of the Declaration of Helsinki and was approved by the institutional review board. Informed consent was obtained from all participating patients. At hospital discharge, all patients were counseled to use a low-cholesterol diet, and statins were recommended.
Patient Management
Patients with persistent chest pain underwent immediate coronary angiography. In patients asymptomatic while on medical therapy, coronary angiography was performed within 24 hours of admission. Whenever possible, coronary stenting of the culprit lesion was performed immediately after angiography. Stenting was not restricted to patients with 1- and 2-vessel disease, but also was favored in patients with 3-vessel disease with suitable lesions. Patients underwent electrocardiographic recordings and determination of cardiac markers at 8-24 hours after the intervention, and additionally whenever ischemic symptoms developed. Dual antiplatelet therapy with aspirin and ticlopidine was restricted to patients receiving coronary stents and did not exceed 4 weeks in duration. If revascularization was indicated, but percutaneous coronary intervention was not considered the optimal treatment option (unprotected left main disease, diffuse 3-vessel disease), patients were scheduled for urgent coronary artery bypass grafting.
Cardiac Troponin Assay
On admission, serum samples were obtained and analyzed in a central laboratory within 1 hour. All troponin measurements were performed with a commercially available third-generation electrochemiluminescent immunoassay (Elecsys 2010 Troponin T STAT; Roche Diagnostics, Basel, Switzerland).22 The analytic range extends from 0.01 to 25 μg/L. The coefficient of variation (imprecision) of this assay is 10% at 0.03 μg/L. Therefore, we defined the cut-off value for the myocardial infarction diagnosis as 0.03 μg/L as recommended by the European Society of Cardiology/American College of Cardiology definition (99th percentile with an acceptable imprecision <10% at this point or, in case of a higher imprecision, increase above 10% coefficient of variation).8
Creatine Phosphokinase and Creatine Phosphokinase MB Assay
Creatine phosphokinase was measured using a photometric assay (creatine kinase liquid, Roche Diagnostics) on a Hitachi 917 autoanalyzer (Hitachi Ltd., Tokyo, Japan) according to the recommendations of the International Federation of Clinical Chemistry.23 The lower detection limit of this assay is 3 U/L. The analytic range extends from 3 to 25,300 U/L. The reference range is 38-174 U/L in men and 26-140 U/L in women. The coefficient of variation (imprecision) of this assay is 0.6% at 190 U/L.
Creatine phosphokinase MB was determined using an immunological ultraviolet-assay (creatine kinase-MB liquid, Roche Diagnostics) on a Hitachi 917 autoanalyzer. The lower detection limit of this assay is 3 U/L. The analytic range extends from 3 to 6,900 U/L. The reference range is below 24 U/L. The coefficient of variation (imprecision) of this assay is 3.8% at 20.8 U/L.
As cut-off for diagnosis of myocardial infarction, we used an increase in creatine phosphokinase beyond 2× the upper limit of normal with concomitant increase in creatine phosphokinase MB.
Follow-up
All patients were scheduled for outpatient visits at 6 months. In addition, patients were contacted by questionnaire on a regular basis for up to 60 months. For patients reporting cardiac symptoms, at least one clinical and electrocardiographic examination was performed at the outpatient clinic or by the referring physician. All information derived from contingent hospital readmission records or provided by the referring physician or by the outpatient clinic was reviewed and entered into a computer database.
End Points and Statistical Analysis
The prespecified primary end point was defined as death from all causes. As secondary end points we assessed nonfatal myocardial infarction and the composite of death and nonfatal myocardial infarction. The definition of myocardial infarction was prespecified in 1996 according to the WHO criteria for myocardial infarction. To meet this end point, patients who had initially presented with myocardial infarction had to have new ST-segment changes and an increase in creatine phosphokinase of at least 50% over the previous trough level in at least 2 samples reaching at least 3 times the upper limit of normal or 5× the upper limit of normal after coronary artery bypass grafting.
The statistical analyses were performed using the SPSS/PC (version 13.0, SPSS Inc., Chicago, Ill) software package; a statistical significance level of .05 was used. Comparisons were made using one-way analysis of variance, Kruskal-Wallis test, and chi-squared test, as appropriate. All hypothesis testing was 2-tailed. Cox regression analysis was performed to identify significant predictors of death in univariate and multivariable analysis. Multivariable analysis included all baseline variables with P <.05 in univariate analysis. The cumulative survival curves were constructed with the use of the Kaplan-Meier method.
Results
Baseline Characteristics
This cohort study comprised 1024 unselected consecutive patients with symptoms of myocardial ischemia at rest without persistent ST-segment elevation. The diagnosis was “unstable angina” in 578 patients, myocardial infarction according to “additional criteria” in 262 patients, and myocardial infarction according to “WHO criteria” in 184 patients (Figure 1). Table 1 describes the baseline demographic, clinical, angiographic, and procedural characteristics in the 3 groups. “Additional criteria” and “WHO criteria” patients had significantly higher blood levels of markers of inflammation, as well as more often ischemic electrocardiogram changes and impaired left ventricular function when compared with “unstable angina” patients. Further on, coronary angiography more often revealed multivessel coronary disease in “additional criteria” and “WHO criteria” patients. Accordingly, these patients underwent invasive treatment more frequently and earlier compared with “unstable angina” patients (median 3.5 and 2.8 hours vs 4.7 hours; P <.001). Comparing patients with “additional criteria” and “WHO criteria,” “additional criteria” patients were significantly older, and more often had impaired renal function and multivessel coronary disease. The blood levels of troponin T were comparable in both groups (P=.734).
Table 1. Baseline and Procedural Characteristics According to Diagnosis
| Unstable Angina n=578 | Additional Criteria n=262 | WHO Criteria n=184 | P Value | |
|---|---|---|---|---|
| Baseline characteristics | ||||
| Age (years) | 65.6(58.2-72.0) | 68.9(60.7-76.1) | 64.6(56.0-72.6) | <.001 |
| Female sex | 178(30.8) | 68(26.0) | 45(24.5) | .149 |
| Prior myocardial infarction | 175(30.3) | 99(37.8) | 52(28.3) | .050 |
| Prior coronary bypass grafting | 73(12.6) | 39(14.9) | 25(13.6) | .670 |
| Prior coronary angioplasty | 151(26.1) | 32(12.2) | 25(13.6) | <.001 |
| Risk factors | ||||
| Smoker | 111(19.2) | 67(25.6) | 60(32.6) | .001 |
| Hypercholesterolemia | 365(63.1) | 166(63.4) | 112(60.9) | .836 |
| Arterial hypertension | 359(62.1) | 168(64.1) | 112(60.9) | .765 |
| Diabetes mellitus | 96(16.6) | 59(22.5) | 40(21.7) | .076 |
| Obesity (BMI >30) | 89(15.8) | 58(20.1) | 38(21.1) | .145 |
| Impaired renal function⁎ | 38(6.6) | 48(18.6) | 18(9.8) | <.001 |
| Laboratory values on admission: | ||||
| White blood cell count (× 109/L) | 7.9(6.7-9.7) | 8.5(7.1-10.9) | 9.7(7.8-11.2) | <.001 |
| C-reactive protein (mg/L) | 3.4(3.0-7.2) | 6.9(3.0-14.3) | 6.4(3.0-17.2) | <.001 |
| Creatinine kinase (U/L) | 30(21-45) | 40(26-61) | 101(43-195) | -† |
| Creatinine kinase MB (U/L) | 5(4-7) | 6(4-9) | 11(6-23) | -† |
| Troponin T (μg/L) | 0.00(0.00-0.01) | 0.16(0.06-0.40) | 0.22(0.04-0.85) | -† |
| Cardiopulmonary resuscitation | 6(1.0) | 5(1.9) | 5(2.7) | .243 |
| Cardiogenic shock | 4(0.7) | 6(2.3) | 3(1.6) | .142 |
| Ischemic ECG changes‡ | 205(35.5) | 119(45.4) | 99(53.8) | <.001 |
| Impaired left ventricular function§ | 243(43.1) | 149(58.4) | 119(65.7) | <.001 |
| Multi-vessel disease | 328(56.7) | 202(77.1) | 118(64.1) | <.001 |
| Procedural characteristics | ||||
| Definite treatment | ||||
| Percutaneous coronary intervention | 283(49.0) | 176(67.2) | 124(67.3) | <.001 |
| Coronary stent implantation | 202(76.8) | 142(86.1) | 103(88.0) | .008 |
| Coronary artery bypass grafting | 74(12.8) | 51(19.4) | 22(12.0) | .023 |
| Medical therapy | 221(38.2) | 35(13.4) | 38(20.7) | <.001 |
| Time to percutaneous intervention (h) | 4.7(1.7-20.2) | 3.5(1.6-17.7) | 2.8(1.3-6.7) | .118 |
| Time to bypass grafting (days) | 3(1-7) | 3(1-9) | 4(1-13) | .822 |
| Medication at discharge | ||||
| Aspirin | 475(85.9) | 212(91.0) | 159(90.3) | .075 |
| Thienopyridines | 240(43.3) | 151(64.8) | 115(65.3) | <.001 |
| Beta-blockers | 420(75.9) | 185(79.4) | 147(83.5) | .093 |
| ACE inhibitors | 268(48.5) | 146(62.7) | 104(59.1) | <.001 |
| Diuretics | 116(21.0) | 58(24.9) | 43(24.4) | .392 |
| Statins | 347(62.7) | 129(55.4) | 113(64.2) | .102 |
⁎Glomerular filtration rate <60 mL/min/1.73m2 using the “Modification of Diet in Renal Disease” study formula. |
†No comparison between groups because differences between groups are due to their definition. |
‡Typical ST-segment depression >0.1 mV or T-wave inversion or both. |
§Left ventricular ejection fraction <50%. |
After coronary angiography (median time to catheterization between 2.4 and 3.1 hours among groups), about 70% of patients underwent revascularization (median of 5.3 hours after admission). Percutaneous coronary intervention was the predominant revascularization strategy among all 3 groups, and the overall percutaneous coronary intervention to coronary artery bypass grafting ratio was 4 to 1. Patients undergoing surgical treatment received 3.2±0.9 distal bypass graft anastomoses including left internal mammary artery grafts in 89%.
Primary End Point
In-hospital mortality was 1.0% (6/578) in patients with “unstable angina,” 2.2% (4/184) in patients according to “WHO criteria,” and 4.6% (12/262) in patients according to “additional criteria” (P=.005; comparison of both myocardial infarction groups: P=.179). During total follow-up (median 16 months, interquartile range 6-29 months), 67 deaths and 45 nonfatal myocardial infarctions occurred (Table 2). Kaplan-Meier analysis (Figure 2) showed cumulative 3-year mortality rates of 5.6% in patients with “unstable angina,” 9.1% in patients according to “WHO criteria,” and 17.5% in patients according to “additional criteria” (P <.001). Most of the early deaths seen in the “additional criteria” group occurred in the patients requiring urgent coronary artery bypass grafting. Periprocedural 30-day mortality was 11.2% in this group. Univariate Cox regression analysis confirmed “additional criteria” as a significant predictor of long-term mortality (hazard ratio 3.1; 95% confidence interval 1.9-5.0; P <.001).
Table 2. Cumulative Incidence of Death and Myocardial Infarction at 36 Months
| Unstable Angina n=578 | Additional Criteria n=262 | WHO Criteria n=184 | P Value | |
|---|---|---|---|---|
| Death | 5.6% | 17.5% | 9.1% | <.001 |
| Non-fatal myocardial infarction | 8.1% | 19.0% | 7.0% | .023 |
| Death or myocardial infarction | 11.6% | 28.5% | 15.4% | <.001 |
Figure 2.
Mortality within 36 months in the study groups. P-value by log-rank test.
Multivariable analysis for the prediction of death showed that the high mortality seen in the “additional criteria” cohort seemed largely explained by their unfavorable baseline characteristics, including age, C-reactive protein, and impaired left ventricular function (Table 3).
Table 3. Predictors of Long Term Mortality in Multivariate Regression Analysis
| Hazard Ratio | 95% Confidence Interval | P Value | |
|---|---|---|---|
| “Additional criteria”-cohort | 1.076 | 0.523-2.211 | .843 |
| Age (years) | 1.072 | 1.031-1.114 | <.001 |
| Prior myocardial infarction | 1.177 | 0.588-2.355 | .645 |
| Diabetes mellitus | 0.744 | 0.321-1.728 | .492 |
| Impaired renal function⁎ | 1.050 | 0.427-2.583 | .916 |
| White blood cell count (× 109/L) | 1.014 | 0.971-1.059 | .540 |
| C-reactive protein (mg/L) | 1.127 | 1.044-1.217 | .002 |
| Troponin T (μg/L) | 1.010 | 0.569-1.792 | .973 |
| Cardiogenic shock | 2.281 | 0.510-10.205 | .281 |
| Impaired left ventricular function† | 2.601 | 1.034-6.547 | .042 |
| Multivessel disease | 2.443 | 0.974-6.126 | .057 |
| Coronary artery bypass grafting | 1.016 | 0.439-2.349 | .970 |
| Diuretics at discarge | 1.507 | 0.769-2.952 | .232 |
⁎Glomerular filtration rate <60 mL/min/1.73m2 using the “Modification of Diet in Renal Disease” study formula. |
†Left ventricular ejection fraction <50%. |
Secondary End Point
The incidence of nonfatal myocardial infarction and the composite of death or nonfatal myocardial infarction are shown in Table 2. Kaplan-Meier analysis demonstrated a cumulative 3-year incidence of nonfatal myocardial infarction of 8.1% in patients with “unstable angina,” 7.0% in patients according to “WHO criteria,” and 19.0% in patients according to “additional criteria” (P=.023). Comparable results were obtained using the combined end point of death or myocardial infarction.
Discussion
This large cohort study evaluated the prognosis of patients who are additionally classified as non-ST-segment elevation myocardial infarction in the newer definitions (cardiac troponin), but not detected by the WHO definition of myocardial infarction (creatine phosphokinase and creatine phosphokinase MB). We report as our major finding that, despite contemporary early invasive therapy, these “additional criteria” patients demonstrate a higher long-term mortality than patients defined according to only the “WHO criteria.” This observation has important clinical implications as it strongly supports the label myocardial infarction in these high-risk patients. Multivariable analysis suggested that higher age, systemic inflammation, and impaired left ventricular function contribute significantly to the unfavorable outcome in “additional criteria.”
This analysis has 3 particular strengths. First, it is derived from an evaluation of consecutive unselected patients rather than a randomized trial. This limits selection bias and facilitates the extrapolation of findings into clinical practice. Second, the study included long-term follow-up. Third, as currently recommended by European and American cardiac societies, a uniform and early revascularization strategy was used in all patients.
Our findings extend and corroborate previous data on the outcome of patients additionally identified by the newer definitions of myocardial infarction.11, 12, 13, 14 We confirm earlier studies indicating that the adoption of the novel criteria increases the number of myocardial infarction patients by 50% to 140%.11, 12, 13, 14 The inclusion of these patients with very small infarctions compared with those identified by older criteria raised the question of how important the smaller myocardial infarctions, labeled under the revised definition, are.17, 24 Further on, it wasn't clear if microscopic muscle necrosis, sufficient to produce a measurable blood troponin “blip,” should automatically attract the label of myocardial infarction.20 Our data are supported by 2 studies showing a higher mortality after 1 year in patients with “additional” myocardial infarction not addressed by WHO criteria compared with patients with “WHO” myocardial infarction.13, 14 Pell et al13 conducted a retrospective analysis of over 2600 patients admitted to the hospital with myocardial infarction. The use of the newer definition led to an increase of 58% of patients with myocardial infarction. The additional patients were significantly older, more often female, and received thrombolysis in only 1%, compared with 40% in patients with myocardial infarction according to WHO criteria. Coronary revascularization also was less often performed in the additional patients. One-year mortality was 45% in the additional patients, compared with 27% in patients with myocardial infarction according to old criteria. Salomaa et al analyzed 6104 patients with acute coronary syndromes in a population-based myocardial infarction register study.14 Application of the troponin definition identified 83% more myocardial infarctions. The additional patients were older, more often had diabetes, and less often received revascularization or thrombolysis. One-year mortality in the additional patients was almost twice as high (21.4%) compared with patients with myocardial infarction according to both definitions. However, it remained uncertain whether these results in outcome had been biased by revascularization and thrombolysis rates, which were substantially lower in patients additionally identified by the newer definition. Therefore, it is of major importance to note that in our study, “additional criteria” patients demonstrated increased mortality despite application of an early invasive strategy in all patients.
Kaplan-Meier curves suggested that in our study, both early and late mortality was significantly higher in patients classified additionally as non ST-segment elevation myocardial infarction. Although the initial leap primarily reflects the substantial periprocedural mortality in “additional criteria” patients requiring coronary artery bypass grafting, the persistently higher slope suggests the influence of persistent factors. These seem to include higher age, systemic inflammation, coronary multivessel disease, impaired left ventricular function, and impaired renal function. As indicated by the results of the multivariable Cox regression analysis, most of these factors seem to be the independent contributors leading to the observed excess mortality.
With the advent of highly specific and sensitive cardiac troponin assays, a chance for reassessing the definition of myocardial infarction had come. The new consensus document redefined the diagnostic criteria for myocardial infarction and upgraded cardiac troponins as the new gold standard for the diagnosis of myocardial injury.8, 9 When compared with conventional creatine phosphokinase and creatine phosphokinase MB assays, cardiac troponins have several advantages,25 including both higher sensitivity and higher specificity for myocardial necrosis, as well as stronger prognostic value, as highlighted by our results.
Limitations
Several study limitations have to be acknowledged. First, we can only hypothesize the reasons behind the higher mortality rate seen in “additional criteria” as compared with “WHO criteria” patients. Multivariate analysis suggested that age, inflammation, and impaired left ventricular function may have been the most important independent predictors of mortality in “additional criteria” patients. However, other unknown or undetected variables also might have played a role. Second, given the observational nature of this study, timing and treatment of patients were left to the discretion of the attending physician. Although minor remaining bias cannot be completely excluded, the main findings of our study seem robust, as all patients were treated uniformly with an early invasive strategy and definite treatment was comparable among groups. Third, our study clearly demonstrates that patients according to “additional criteria” have a higher mortality rate as compared with patients defined according to the “WHO criteria.” However, our data do not allow the quantification of the risk added by the new “additional criteria” event versus the risk already present in the individual patient before the event. This quantification would be possible only in experimental medicine models and does seem secondary for the primary aim of the newer definition of myocardial infarction: the easy and rapid identification of patients at high risk of death.
Summary
Current definitions of myocardial infarction assign more patients to the diagnosis of non-ST-segment elevation myocardial infarction compared with WHO criteria of myocardial infarction. The additional cohort of patients with non-ST-segment elevation myocardial infarction not meeting the older WHO criteria are appropriately labeled as myocardial infarction by the new definition, as they have a significantly increased risk of death despite most contemporary early invasive therapy. In fact, long-term mortality in “additional criteria” patients is higher than in “WHO criteria” patients.
Acknowledgments
The authors thank Peter Betz, MD and Anita Abels for help in data acquisition.
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The authors declare that there are no conflicts of interest. Dr. Mueller was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the Novartis Foundation. Design and conduct of the study as well as the preparation of the manuscript were not influenced by any of the sponsors.
PII: S0002-9343(08)00108-3
doi:10.1016/j.amjmed.2008.01.033
© 2008 Elsevier Inc. All rights reserved.
