The thrombolysis in myocardial infarction risk score in unstable angina/non–ST-segment elevation myocardial infarction
Marc S. Sabatine, MD, MPH*,* and
Elliott M. Antman, MD, FACC*
* TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
Manuscript received May 7, 2002;
revised manuscript received October 7, 2002,
accepted December 18, 2002.
*
Reprint requests and correspondence: Dr. Marc S. Sabatine, Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA.
msabatine{at}partners.org
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Abstract
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Risk stratification in unstable angina (UA)/non–ST-segment elevation myocardial infarction (NSTEMI) can provide an estimate of a patient’s prognosis and optimize clinical choices. The Thrombolysis In Myocardial Infarction (TIMI) risk score for UA/NSTEMI is an integrated approach that uses baseline variables that are part of the routine medical evaluation to identify patients at high risk for death and other major cardiac ischemic events. Using multivariable logistic regression, seven independent predictor variables were identified: age  65 years, 3 risk factors for coronary artery disease (CAD), known CAD (stenosis 50%), severe anginal symptoms (2 anginal events in preceding 24 h), use of aspirin in the last seven days, ST-segment deviation 0.05 mV, and elevated serum cardiac markers of necrosis. Each predictor carried similar prognostic weight; therefore, a risk score was constructed as the simple arithmetic sum of the number of predictors. The rate of death, MI, or urgent revascularization significantly increased as the TIMI risk score increased, ranging from <5% for patients with a risk score of 0 or 1 to >40% for patients with a risk score of 6 or 7. The risk score has been validated in several other trials of UA/NSTEMI. In addition, using the risk score to categorize patients also effectively defines a gradient for benefit with specific treatments such as low-molecular-weight heparins, glycoprotein IIb/IIIa inhibitors, and an early invasive strategy.
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Abbreviations and Acronyms
| | ACC/AHA | = American College of Cardiology/American Heart Association | | CK-MB | = creatine kinase-MB isoenzyme | | cTn | = cardiac troponin | | ECG | = electrocardiogram/electrocardiographic | | GP | = glycoprotein | | LMWH | = low-molecular-weight heparin | | NSTEMI | = non–ST-segment elevation myocardial infarction | | RR | = relative risk | | UA | = unstable angina | | UFH | = unfractionated heparin |
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Unstable angina (UA) is classically defined as ischemic discomfort that either occurs at rest (or with minimal exertion), occurs in a crescendo pattern, or is severe and of new onset (1). If these symptoms are accompanied by a release of cardiac biomarkers of necrosis (e.g., creatine kinase-MB isoenzyme [CK-MB] or cardiac troponin), then a non–ST-segment elevation myocardial infarction (NSTEMI) is said to have occurred (2). Both entities share a common pathobiologic basis: development of a severe but non-occlusive coronary artery thrombus superimposed on a recently disrupted vulnerable plaque (3–5). Thus, treatments for UA and NSTEMI are identical and consist of a combination of anti-ischemic, antiplatelet, and antithrombotic therapies and, potentially, coronary revascularization (6). Nonetheless, among patients presenting with UA/NSTEMI, there is substantial heterogeneity in the risk of death and major cardiac ischemic events over the ensuing several weeks. In the Thrombolysis In Myocardial Infarction (TIMI) III registry, the rates of death and (re)infarction were 2.5% and 2.9%, respectively. In clinical trials, which tend to enroll higher-risk patients who manifest objective evidence of ischemia upon presentation, the rates are somewhat higher and range from 3.5% to 4.5% for death and 5% to 12% for (re)infarction (1).
Risk stratification, therefore, is useful in UA/NSTEMI in providing a more accurate assessment of a patient’s prognosis. Such information would be important to patients and their families and would also allow for more effective triage and clinical resource allocation. Recent trials have demonstrated the efficacy of new pharmacologic agents, such as low-molecular-weight heparins (LMWH) (7,8) and glycoprotein (GP) IIb/IIIa inhibitors (9,10), and of an early invasive management strategy (11,12). However, these treatment options are expensive and not without complications. Risk stratification can be used to identify patients who would derive particular benefit from these therapies.
The TIMI risk score for UA/NSTEMI was designed to provide clinicians with a prognostic tool that offers high discriminatory ability with the use of baseline variables that are part of the routine medical evaluation (13). The risk score was also developed to be applied easily at the bedside by any care provider. In this article, we review prognostic indicators in patients with UA/NSTEMI, the development and testing of the TIMI risk score for UA/NSTEMI, and several applications of the risk score.
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Individual prognostic indicators
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Studies have identified a number of individual variables as markers of higher risk for death and cardiac ischemic events (1,6). Elements of the medical history, including advanced age (>65 years) (14), diabetes mellitus (15), and extracardiac atherosclerotic disease (16), are associated with a higher risk of death or recurrent ischemic events. With regard to clinical presentation with acute symptoms, anginal pain at rest and post-infarction angina are both associated with worse outcomes (17). Patients with previous use of aspirin are also at increased risk (18). Whether this is due to the presence of aspirin-resistant platelet-rich thrombi or to the greater likelihood of severe coronary artery disease in patients who present with UA/NSTEMI despite taking aspirin remains unclear (19,20). The admission electrocardiogram (ECG) is one of the most useful and powerful predictors of adverse outcomes. An ST-segment deviation of as little as 0.05 mV is associated with an approximately twofold higher risk of death or MI at 30 days and at 1 year (21,22). Also, there appears to be a gradient of increasing risk with increasing degree of ST-segment depression (23). Unlike ST-segment depressions, T-wave inversions have not been shown to be associated with a worse prognosis.
Another powerful predictor of outcome is biochemical evidence of myocyte necrosis. Patients with elevations in either CK-MB or cardiac-specific troponin (cTn) have higher adverse event rates than patients without elevations (24). For both cTnI and cTnT, there is a quantitative relationship between the magnitude of elevation of the marker and the risk of death (25,26). However, despite the large amount of data supporting the prognostic utility of cTn, they should not be viewed in isolation. In their most recent UA/NSTEMI guidelines, the American College of Cardiology/American Heart Association (ACC/AHA) notes that "... troponins should not be relied on as the sole markers for risk, because patients without troponin elevations may still exhibit a substantial risk of an adverse outcome. Neither cTnI nor cTnT is totally sensitive and specific in this regard." (6).
Integrated approach.
Although the prognostic information associated with each of the above variables is useful, focusing on a single variable does not permit clinicians to use all of the information at their disposal, an observation echoed in the ACC/AHA statement on troponins quoted above. For example, an elderly patient presenting with severe angina, with ST-segment depressions despite medication with aspirin may have multiple cardiac risk factors, may have had a previous MI, and may yet have a negative troponin. Clearly, this patient is at high risk for death or cardiac ischemic events over the ensuing days and weeks, in spite of the absence of an elevated cardiac marker. Thus, reliance on one predictor to the exclusion of others may lead to misclassification of a patient’s risk.
The need for an integrated approach was recognized more than a decade ago with the Braunwald classification of unstable angina (27). Although it is typically used only to grade severity of the acute presentation, this classification system actually contains four axes: 1) severity of acute symptoms; 2) clinical circumstances; 3) intensity of medical treatment; and 4) ECG changes. Prospective validation of the Braunwald classification system confirmed the utility of such an approach (28,29). The completion of several recent clinical trials, in which a wealth of baseline clinical, ECG, and serum marker data was gathered, created the opportunity to develop a modern, integrated approach to prognostication in UA/NSTEMI.
Developing a model
Establishing a model for prediction of risk involves several key steps, including the selection of an end point to be predicted by the model, selection of potential predictor variables, testing of the individual predictor variables to create the final multivariable model, and statistical evaluation of the model. The TIMI risk score for UA/NSTEMI was developed in a derivation cohort consisting of 1,957 patients who were randomized to the unfractionated heparin (UFH) arm of the TIMI 11B trial. The TIMI 11B study was a phase III, international, randomized, double-blind UA/NSTEMI trial comparing UFH with the LMWH, enoxaparin (7). The primary end point was the composite of all-cause mortality, new or recurrent MI, or severe recurrent ischemia prompting urgent revascularization by day 14.
Potential predictor variables were selected from baseline characteristics that could be readily identified at presentation. The candidate list was further restricted to include only those characteristics previously reported to be important variables in predicting outcome. This process yielded a total of 12 baseline characteristics arranged in a dichotomous fashion (Table 1).
Of these 12 variables, those that achieved a significance level of p < 0.20 on univariate testing were entered into a multivariable logistic regression model. Variables associated with a significance level of p < 0.05 in a backward elimination process were retained in the final model. This process yielded seven independent, statistically significant predictors of the composite end point at 14 days: age 65 years, 3 risk factors for CAD, previous coronary artery stenosis 50%, severe anginal symptoms (2 anginal events in the previous 24 h), use of aspirin in last 7 days, ST-segment deviation 0.05 mV, and an elevated serum cardiac marker (CK-MB or cardiac-specific troponin).
After the predictor variables in the regression model had been finalized, two statistical tests were performed to assess the model’s performance: the Hosmer-Lemeshow statistic and the C-statistic. The Hosmer-Lemeshow statistic is a measure of "goodness-of-fit" or calibration of the model (30). Essentially, it stratifies test cohort subjects into groups by the predicted probability of outcome and measures the difference between the predicted and observed number of outcomes across all groups. Small chi-squared test statistics (and large associated p values) for the Hosmer-Lemeshow test imply a well-calibrated model. For the TIMI risk score for UA/NSTEMI, the Hosmer-Lemeshow statistic was 3.56 with 8 df, with a corresponding p = 0.89, demonstrating excellent goodness-of-fit.
The C-statistic is a measure of discriminative ability or of how well the model classifies patients into varying degrees of risk. It represents the frequency with which the model, when given a pair of subjects (one of whom experienced an outcome and one of whom did not), assigns a higher outcome probability to the subject who actually experienced the outcome. It is also equivalent to the area under a receiver operating characteristic curve for dichotomous outcomes. For the TIMI risk score for UA/NSTEMI, the C-statistic in the derivation cohort was 0.65. There is an inherent trade-off between calibration and discrimination in prediction algorithms. Diamond (31) has presented theoretical evidence that a perfectly calibrated prediction rule would have a maximal C-statistic of 0.83. C-statistics higher than that are possible, but at a cost of poorer calibration and, with more complex prediction rules, erosion of the concept of ease of use at the bedside. In contrast, for example, to laboratory or radiographic tests, one can argue that for clinical prediction rules used to estimate prognosis and guide triage, calibration rather than discrimination should be the priority. Moreover, the capacity of a prediction rule to identify high-risk subsets of patients that enjoy particularly large benefits from certain therapeutic strategies may be more clinically important than the results of any individual test statistic.
Development of the risk score
Using a multivariable logistic regression model, one can calculate the probability of the outcome of interest for any given patient using a complex equation that supplies a weight to each of the individual predictors. Such an approach, however, requires computational support and, thus, typically precludes rapid point-of-care bedside application.
Fortunately, because the magnitudes of prognostic significance (i.e., the odds ratios) for each independent predictor variable were similar, the TIMI risk score for UA/NSTEMI was constructed as the simple arithmetic sum of the number of predictors. Thus, the risk score is calculated by assigning 1 point for each variable that is present (Table 2).
Clinical utility of the model
Application of the TIMI risk score for UA/NSTEMI to patients in the UFH derivation cohort revealed that the score has several features desirable in risk stratification. First, the pattern of TIMI risk scores within that population followed a normal distribution (see bottom row of Fig. 1). Second, there was a progressive, significant pattern of increasing event rates for the composite end point of death, MI, and urgent revascularization (p < 0.001 by chi-squared for trend; Fig. 1) with increasing TIMI risk score. Third, this pattern was also seen for each individual component of the composite end point (p < 0.001 by chi-squared for trend for each component; data not shown) (13). Fourth, the TIMI risk score categorized patients into a wide range of risk. Patients with a score of 0 or 1 had a <5% rate of death, MI, or urgent revascularization, while patients with a score of 6 or 7 had a >40% rate of these events.
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Figure 1 Rates of all-cause mortality (D), myocardial infarction (MI) , and severe recurrent ischemia leading to urgent revascularization (UR) through 14 days among patients randomized to unfractionated heparin in Thrombolysis In Myocardial Infarction (TIMI) 11B trial, with patients stratified by the TIMI risk score. NSTEMI = non–ST-segment elevation myocardial infarction; % Popl’n = percent of overall trial population with that TIMI risk score; UA = unstable angina. Adapted from 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;284:835–42.
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Validation of the model
Although a well-constructed prediction model may perform adequately within its own derivation cohort, this is no guarantee that it will perform well in other cohorts. Therefore, prospective validation is required to ensure generalizability to other patient populations. The TIMI risk score for UA/NSTEMI was validated in three separate cohorts of patients: 1) the enoxaparin group from TIMI 11B (n = 1953); 2) the UFH group from the Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) trial (n = 1564); and 3) the enoxaparin group from ESSENCE (n = 1564) (8). For all three validation cohorts, there was a significant increase in the rate of events as the TIMI risk score increased (p < 0.001 by chi-squared for trend), and the C-statistics ranged from 0.59 to 0.65, confirming the generalizability of the risk score. Moreover, the slope of the increase in event rates was not statistically different between the UFH arms of TIMI 11B and ESSENCE (p = 0.18), demonstrating a homogeneous risk pattern among patients receiving similar treatments across different trials (13).
The TIMI risk score has also been tested retrospectively in another UA/NSTEMI clinical trial population: Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited to very Unstable Signs and Symptoms (PRISM-PLUS) (9). The pattern of TIMI risk scores within that population followed a normal distribution. As it did in TIMI 11B and ESSENCE, stratification by the TIMI risk score in PRISM-PLUS revealed an increasing gradient of risk for the prespecified composite end point of death, MI, and refractory ischemia by 14 days (p < 0.001 by chi-squared for trend; Fig. 2A) (32). The C-statistic (0.64) was similar to what was observed in the derivation cohort, and the Hosmer-Lemeshow goodness-of-fit test statistic was 3.85 with 3 df, yielding a p = 0.28 and demonstrating good calibration.
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Figure 2 (A) Rates of all-cause mortality (D), myocardial infarction (MI), or severe recurrent ischemia leading to urgent revascularization (UR) through 14 days among all patients in Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited to very Unstable Signs and Symptoms (PRISM-PLUS) trial, with patients stratified by Thrombolysis In Myocardial Infarction (TIMI) risk score. Adapted from Morrow DA, Antman EM, Snapinn SM, McCabe CH, Theroux P, Braunwald E. An integrated clinical approach to predicting the benefit of tirofiban in non–ST-elevation acute coronary syndromes: application of the TIMI risk score for UA/NSTEMI in PRISM-PLUS. Eur Heart J 2002;23:223–9. (B) Rates of D, MI, or re-admission for acute coronary syndrome (ACS) through 6 months among all patients in Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS) TIMI-18, with patients stratified by TIMI risk score. NSTEMI = non–ST-segment elevation myocardial infarction; % Popl’n = percent of overall trial population with that TIMI Risk Score; UA = unstable angina.
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The risk score was prospectively applied in the TACTICS TIMI-18 UA/NSTEMI clinical trial (11), using the prespecified composite end point of death, MI, or readmission for an acute coronary syndrome by six months. Once again the pattern of TIMI risk scores within that population followed a normal distribution, and there was a statistically significant increasing gradient of risk with an increasing risk score (p < 0.001 by chi-squared for trend; Fig. 2B). The C-statistic was 0.58, and the Hosmer-Lemeshow goodness-of-fit test statistic was 4.01 with 6 df, yielding a p = 0.67 and demonstrating excellent calibration.
Of note, the TIMI risk score was designed to facilitate risk stratification in patients with UA/NSTEMI. It was not designed to aid in the diagnosis of UA/NSTEMI, which remains a clinical diagnosis that may be supported by appropriate ECG changes and, in the case of NSTEMI, requires elevated myonecrosis biomarkers. Nonetheless, the TIMI risk score has been applied in a study of 237 unselected patients suspected of having an acute coronary syndrome when presenting to an emergency department with chest pain. Patient information was collected 30 days after the initial presentation, and the TIMI risk scores were prospectively calculated. Major cardiac events (death, MI, or severe ischemia requiring revascularization) were then evaluated. Event rates and risk score results were as follows: 0% among patients with a score of 0; 12% with a score of 1; 17% with a score of 2; 24% with a score of 3; 42% with a score of 4; 52% with a score of 5; and 68% among patients with a risk score of 6 or 7 (p < 0.0001) (33).
Application of the model
The TIMI risk score for UA/NSTEMI serves as a simple bedside tool for predicting death and cardiac ischemic events. Clinicians can use the prognostic information from the risk score to guide their decisions regarding triage and clinical resource allocation during the patient’s index hospitalization. Moreover, the risk score appears to predict not only which patients will have acute events, but also which patients are at risk of dying or suffering cardiac ischemic events after discharge (34).
Another area in which the TIMI risk score for UA/NSTEMI has proven useful is in guiding the use of specific therapies. In particular, whether to use an LMWH, a GP IIb/IIIa inhibitor, or an early invasive strategy represents three treatment decisions that clinicians continue to debate (6). All of these treatments have been shown to be beneficial in large randomized trials. Nonetheless, the cost and potential complications associated with each suggest a need to identify patients who would derive particular benefit from these therapies.
Using the TIMI risk score for UA/NSTEMI to categorize patients, one can demonstrate a gradient of benefit for all three treatments. In TIMI 11B and ESSENCE, treatment with the LMWH, enoxaparin, had an effect similar to treatment with UFH in patients with a risk score of 0 to 2. Enoxaparin conferred a 17% relative risk (RR) reduction (p = 0.016) in patients with a risk score of 3 or 4 and conferred a 25% RR reduction (p = 0.0025) in patients with a risk score of 5 to 7 (pinteraction = 0.02) (Fig. 3) (13). As the TIMI risk score increases, the absolute and relative risk reductions in the composite end point seen with enoxaparin increase, and consequently, the number that need to be treated to prevent one event decreases.
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Figure 3 Rates of all-cause mortality (D), myocardial infarction (MI), or severe recurrent ischemia leading to urgent revascularization (UR) through 14 days in the unfractionated heparin (UFH) and enoxaparin (ENOX) treatment groups in the pooled Thrombolysis In Myocardial Infarction (TIMI) 11B and Efficacy and Safety of Subcutaneous Enoxaparin in Non–Q-wave Coronary Events (ESSENCE) trial populations, with patients stratified by TIMI risk score. NSTEMI = non–ST-segment elevation myocardial infarction; % Popl’n = percent of overall trial population with that TIMI risk score; UA = unstable angina.
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In PRISM-PLUS, treatment with the combination of the GP IIb/IIIa inhibitor, tirofiban, and UFH had an effect similar to treatment with UFH alone in patients with a risk score of <4, but it conferred a 34% RR reduction (p = 0.016) in patients with a risk score of 4 (pinteraction = 0.05) (Fig. 4) (32). Subgroup analyses from the GP IIb/IIIa inhibitor trials in UA/NSTEMI suggested that the benefit of GP IIb/IIIa inhibition occurs primarily in patients who undergo percutaneous coronary intervention. However, not only are these analyses potentially confounded by the fact that patients who underwent revascularization during their index hospitalization tended to be a sicker group, but also the implications are less than practical because the decision to undergo revascularization may have occurred relatively late in the patient’s hospital course. Instead, when patients were stratified by their baseline TIMI risk score, those with a risk score 4 who received tirofiban had 25% to 30% RR reductions in death, MI, or refractory ischemia, regardless of whether or not they underwent percutaneous coronary intervention (35).
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Figure 4 Rates of all-cause mortality (D) or myocardial infarction (MI) through 30 days in the heparin alone and tirofiban plus heparin treatment groups in Platelet Receptor inhibition for Ischemic Syndrome Management in Patients Limited to very Unstable Signs and Symptoms (PRISM-PLUS), with patients stratified by Thrombolysis In Myocardial Infarction (TIMI) trial risk score.
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Finally, in TACTICS TIMI-18, the TIMI risk score again defines a gradient of benefit: treatment using an early invasive strategy had an effect similar to treatment with a conservative strategy in patients with a risk score of 0 to 2, and it conferred a 21% RR reduction (p = 0.048) in patients with a risk score of 3 or 4, and a 36% RR reduction (p = 0.018) in patients with a risk score of 5 to 7 (Fig. 5) (11).
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Figure 5 Rates of all-cause mortality (D), myocardial infarction (MI), or readmission for acute coronary syndrome (ACS) through six months in the invasive (INV) and conservative (CONS) treatment strategy arms in Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction (TACTICS TIMI)-18 trial, with patients stratified by TIMI risk score.
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Conclusions
The TIMI risk score for UA/NSTEMI is a simple yet effective clinical tool for risk stratification. Using seven baseline variables, clinicians can rapidly acquire prognostic information regarding their patients with UA/NSTEMI. The TIMI risk score performs well both for short-term (14-day) and long-term (6-month) end points and in a variety of patient populations, including UA/NSTEMI clinical trials and cohorts of patients presenting with chest pain. Furthermore, the risk score can be used to define a gradient of benefit associated with various treatments, thereby facilitating decision-making regarding who should be considered for more aggressive antiplatelet and antithrombotic therapies as well as early invasive strategies.
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Footnotes
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Please refer to the Trial Appendix at the back of this supplement for the complete list of clinical trials.
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References
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P. Jeetley, L. Burden, and R. Senior
Stress echocardiography is superior to exercise ECG in the risk stratification of patients presenting with acute chest pain with negative Troponin
Eur J Echocardiogr,
March 1, 2006;
7(2):
155 - 164.
[Abstract]
[Full Text]
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T. J. Gluckman, M. Sachdev, S. P. Schulman, and R. S. Blumenthal
A Simplified Approach to the Management of Non-ST-Segment Elevation Acute Coronary Syndromes
JAMA,
January 19, 2005;
293(3):
349 - 357.
[Abstract]
[Full Text]
[PDF]
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B. S. Wiggins and S. Spinler
Antiplatelet and Antithrombin Therapy for Early Management of Acute Coronary Syndromes
Journal of Pharmacy Practice,
October 1, 2004;
17(5):
347 - 369.
[Abstract]
[PDF]
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J. J. Popma, P. Berger, E. M. Ohman, R. A. Harrington, C. Grines, and J. I. Weitz
Antithrombotic Therapy During Percutaneous Coronary Intervention: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy
Chest,
September 1, 2004;
126(3_suppl):
576S - 599S.
[Abstract]
[Full Text]
[PDF]
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G. Montalescot, J.P. Collet, M.L. Tanguy, A. Ankri, L. Payot, R. Dumaine, R. Choussat, F. Beygui, V. Gallois, and D. Thomas
Anti-Xa Activity Relates to Survival and Efficacy in Unselected Acute Coronary Syndrome Patients Treated With Enoxaparin
Circulation,
July 27, 2004;
110(4):
392 - 398.
[Abstract]
[Full Text]
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Top
Abstract
Individual prognostic indicators