Secondary Logo

Journal Logo

Prognostic Value of Clinical Variables at Presentation in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes

Results of the Proyecto de Estudio del Pronóstico de la Angina (PEPA)

DE SÁ, ESTEBAN LÓPEZ M.D.; LÓPEZ-SENDÓN, JOSÉ M.D.; ANGUERA, IGNASI M.D.; BETHENCOURT, ARMANDO M.D.; BOSCH, XAVIER M.D. PROYECTO DE ESTUDIO DEL PRONÓSTICO DE LA ANGINA (PEPA) INVESTIGATORS

Article
Free

Patients with suspected non-ST-segment elevation acute coronary syndromes (NSTEACS) constitute a heterogeneous population with variable outcomes. Risk stratification in this population of patients is difficult due to the complexity in patient risk profile. We conducted this study to characterize the value of clinical and electrocardiographic variables for risk stratification in an unselected population of consecutive patients with NSTEACS on admission. Thirty-five clinical and electrocardiographic variables at presentation in the emergency room of 18 hospitals were prospectively analyzed in 4,115 patients with NSTEACS and related with the outcomes at 90 days. We also developed a risk score using the variables found to be independent predictors of ischemic events to facilitate risk stratification.

Cardiovascular mortality was 4.3% and the rate for the outcome of either cardiovascular death or nonfatal myocardial infarction was 6.9%. The only independent predictors of mortality were age, diabetes, peripheral vascular disease, postinfarction angina, Killip class ≥2, ST-segment depression, and elevation of cardiac markers. A risk profile using the variables found to be independent predictors of events was calculated for cardiovascular mortality and for the combination of either death or nonfatal myocardial infarction. Event rates increased significantly in all subgroups of patients based on the number of independent risk factors as the risk score increased. Using these factors, 90-day mortality ranged from as low as 0.4% in patients with no risk factors to 21.1% for those with more than 4 risk factors.

In conclusion, simple clinical and electrocardiographic data obtained at hospital admission allow an accurate risk stratification of patients with NSTEACS. In the PEPA registry, simple variables easy to obtain at admission appear to be a valuable tool in discerning between patients at very low and very high risk according to the cluster of factors for each patient. The risk score developed was obtained from an unselected population, representative of the whole spectrum of patients with NSTEACS, allowing identification of patients at different risks for adverse outcomes, and, therefore, permitting optimization of therapy.

From Hospital General U. Gregorio Marañón (ELdS, JLS), Madrid; Cardiovascular Institute (IA, XB), Hospital Clinic, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona; and Hospital Son Dureta (AB), Palma de Mallorca, Spain.

This study was supported in part by an unrestricted grant from Pfizer.

Address reprint requests to: Xavier Bosch, MD, Cardiovascular Institute, Hospital Clinic, Villarroel 170, 08036 Barcelona, Spain. Fax: 34 91 451 86 66; e-mail: xbosch@medicina.ub.es.

Accessible online at “http://www.md-journal.com.” To search for Medicine articles in PubMed, use the journal name “Medicine Baltimore.”

Back to Top | Article Outline

Introduction

Abbreviations used in this article: ECG, electrocardiogram, NSTEACS, non-ST-segment elevation acute coronary syndromes.

Patients with non-ST-segment elevation acute coronary syndromes (NSTEACS) are a heterogeneous population, and early risk stratification is the first step for rational management (8). The final diagnosis and the risk of subsequent adverse events vary widely and are often discovered retrospectively based on complex and expensive complementary explorations. Clinical profiles and electrocardiogram (ECG) abnormalities at presentation provide simple and useful information for risk stratification and have been accepted empirically during the last decade (7). Risk scores have also been developed to predict prognosis (2,5,7,18,24). However, limited prospective information is available and most of the prognostic information has been obtained from small series (9,30), in selected groups of patients (10,27), or considering only a limited number of factors for multivariate analysis (14). Furthermore, in some prospective registries, as well as in some recent recommendations, many prognostic factors were empirically selected (18).

Quantifying risk factors for ischemic events in patients evaluated for NSTEACS serves to identify patients at higher risk with the aim of providing the best therapeutic management. The Proyecto de Estudio del Pronóstico de la Angina (PEPA) was a prospective observational study designed to evaluate the prognosis in patients with suspected unstable angina and non-ST-segment elevation myocardial infarction using the clinical and electrocardiographic data available at presentation. The primary objective of this study was to determine the weight of each clinical and electrocardiographic variable obtained at admission to characterize the outcome.

Back to Top | Article Outline

Methods

Study population

Between October 1997 and October 1998 a total of 4,115 consecutive patients with NSTEACS admitted to the emergency department at 18 clinical centers in Spain (see Appendix) were enrolled in the study. During the study period, all patients with chest pain admitted to the participating hospitals within 12 hours from the onset of symptoms were evaluated and classified as having or not having a NSTEACS. Only patients with chest pain suspected to be ischemic in nature by a cardiologist participating in the study were included. Patients with suspected nonischemic chest pain, patients with chest pain with persistent ST-segment elevation, and patients referred from other centers were excluded from the study. All patients provided unwritten consent to participate in the study.

Back to Top | Article Outline

Clinical and electrocardiographic data

All clinical and ECG definitions were prospectively stated in a protocol available to all physicians in every emergency department participating in the study. The baseline clinical characteristics were recorded at the emergency department within 12 hours after admission on standardized forms. Baseline characteristics included were those previously reported to be important variables predicting outcomes in patients with NSTEACS (8,15,19,32). All patients were characterized at enrollment according to the Braunwald classification (7) of unstable angina, considering the following:

  • Severity of symptoms
    • I. New onset of severe angina or accelerated angina
    • II. Subacute angina at rest within the past month but not within the preceding 48 hours
    • III. Acute angina at rest within 48 hours
  • Clinical circumstances
    • A. Secondary angina that develops in presence of extracardiac condition that intensifies myocardial ischemia
    • B. Primary angina that develops in absence of extracardiac condition
    • C. Postinfarction angina that develops within 2 weeks after myocardial infarction
  • Intensity of prior medical treatment
    1. None
    2. Standard treatment for chronic stable angina
    3. Maximal anti-ischemic drug therapy

A family history of coronary artery disease was defined as present when disease occurred in relatives less than 50 years old. At least 1 ECG was obtained for each patient. When several ECGs were available at enrollment, the ECG with more severe alterations was selected for correlation with prognosis. Data from the qualifying ECG were locally analyzed and categorized according to the presence or absence of transient ST-segment elevation ≥0.1 mV, defined as ST-segment elevation that resolved after the administration of sublingual nitroglycerin, ST-segment depression ≥0.1 mV or T-wave inversion ≥0.1 mV in 2 or more contiguous leads, or nondiagnostic ECG (bundle branch block, paced rhythm or W-P-W syndrome). Patients were grouped into 5 mutually exclusive categories: 1) transient ST-segment elevation, 2) STsegment depression, 3) T-wave inversion, 4) nondiagnostic, and 5) normal. Myocardial infarction was diagnosed in the presence of creatine kinase and/or MB-creatine kinase levels exceeding twice the upper limit of normality at each institution.

Back to Top | Article Outline

Follow-up

The main end point was cardiovascular mortality. Deaths that occurred during follow-up were considered of cardiovascular origin when a medical record conclusively yielded this diagnosis or when the death occurred suddenly (within 1 hour of symptoms) or without hospitalization and no cause other than cardiovascular disease was stated in the death certificate. The secondary end point included both cardiovascular death and nonfatal myocardial infarction. For 1- and 3-month follow-up, patients were contacted by the investigators to determine the vital status and development of events. Vital status information was completed in 94% of patients. Data recorded on case report forms were audited and validated by an independent contract research organization (Verum Itempharma).

Back to Top | Article Outline

Statistical analysis

Kaplan-Meier estimates were calculated for 90-day survival and time to cardiac events for each categorical variable. Differences between the curves were tested for significance with the log-rank test (22). For the purpose of the analyses, age was categorized at a cutoff point of 65 years, based on previous studies (2,5,8,9). The independent effects of selected clinical and electrocardiographic variables on outcomes were assessed by Cox proportional-hazards model applied to the patients’ survival times and estimated as risk ratios with corresponding 95% confidence intervals (12). The variables included in the multivariate model were age, diabetes, gender, heart failure, elevation of creatine kinase or MB-creatine kinase fraction, atrial fibrillation, renal failure, previous stroke, previous myocardial infarction, previous percutaneous coronary angioplasty/stent, previous coronary artery bypass graft, Braunwald classification, and ECG categories. The statistical significance of these variables in the multivariate models was evaluated by Breslow likelihood estimation. All tests of significance were 2-tailed, and a p value < 0.05 was considered to indicate statistical significance. We developed a risk score to describe each patient’s probability of mortality or of having a cardiac event (death or nonfatal myocardial infarction) using the beta-coefficients of the independent variables found in the multivariate model, and the population of patients was divided in quartiles of risk for comparison of each risk profile. Because the beta-coefficients for the independent risk factors were similar, a simplified score consisted of assigning 1 point for each risk factor observed. Data analysis was performed with SAS Institute, Inc., statistical software.

Back to Top | Article Outline

Results

Patient characteristics

The mean age of patients was 64.9 ± 11.4 years. (range, 25–97 yr), and 33% were female. Twenty-six percent of patients had diabetes and 33% had a previous myocardial infarction (Table 1). More than 50% of patients had prolonged chest pain and 80% had had rest angina within the previous 48 hours (Braunwald class III). Ischemic ST-T changes were present at admission in 58% of patients (Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

A total of 1,086 (26.4%) patients were admitted to the coronary care unit, 2,163 (52.6%) to an intermediate or cardiology ward, 419 (10.2%) to other hospital areas, and 447 (10.9%) were discharged from the emergency room. The median hospital stay was 8 days (range, 4–12 d). Patients were treated with beta-blockers (41.8%), calcium channel blockers (45.7%), nitrates (67.4%), antiplatelet agents (93.3%), and anticoagulants (44.8%). Coronary angiography was performed before discharge in 1,544 (37.5%) patients, percutaneous revascularization in 536 (13.0%), and coronary artery bypass grafting in 355 (8.6%) patients.

Back to Top | Article Outline

Outcome

At 90 days, cardiovascular mortality was 4.3%. The composite outcome of cardiovascular death or nonfatal myocardial infarction occurred in 6.9% of patients. Tables 1 and 2 show the outcomes in the different groups according to clinical variables.

Back to Top | Article Outline

Univariate analysis:

Predictors of mortality and of death or nonfatal myocardial infarction related to patient history were age ≥65 years, gender, diabetes, peripheral vascular disease, renal failure, and previous myocardial infarction. History of previous stroke was also significantly associated with mortality (see Table 1).

Table 2 shows the outcomes in the different groups according to the characteristics of angina at presentation. Mortality and the combined end point of death or nonfatal myocardial infarction were significantly higher in patients with post-myocardial infarction angina, Killip class ≥2, and elevated cardiac markers. Maximal antianginal treatment before hospital admission and atrial fibrillation were also associated with mortality. Acute rest angina and recurrent chest pain within 24 hours before admission were associated with death or myocardial infarction. Mortality and cardiac events were significantly different in each of the electrocardiographic categories, being maximal in patients with ST-segment depression and minimal in patients with normal ECG at presentation.

Back to Top | Article Outline

Independent prognostic variables:

Independent predictors of 90-day mortality were age (≥65 years), diabetes, peripheral vascular disease, post-myocardial infarction angina, Killip class ≥2 at admission, STsegment depression, and elevation of cardiac markers. The secondary end point of death or myocardial infarction was best predicted by age, diabetes, postmyocardial infarction angina, recurring chest pain within the previous 24 hours, Killip class ≥2, STsegment depression, and elevation of cardiac markers (Table 3).

TABLE 3

TABLE 3

Back to Top | Article Outline

Risk profile:

The Kaplan-Meier curves at 90 days for the different quartiles of risk are shown in Figure 1. A more practical, simplified individual risk profile could be achieved considering the number of independent predictors present in each patient. Figure 2 shows the outcomes of patients with 0, 1, 2, 3, 4, or more than 4 independent risk factors for mortality and for death or nonfatal myocardial infarction. Risk score rates for 1) mortality and 2) death or nonfatal myocardial infarction through 90 days of follow-up were calculated. Event rates increased significantly in all subgroups of patients based on the number of independent risk factors as the risk score increased (p < 0.00001).

Fig. 1

Fig. 1

Fig. 2

Fig. 2

Back to Top | Article Outline

Discussion

We found that simple, bedside clinical and ECG parameters obtained at the time of hospital admission allow an accurate early risk stratification in patients with suspected NSTEACS. Age ≥65 years, diabetes, peripheral vascular disease, postinfarction angina, Killip class ≥2, ST-segment depression, and elevated cardiac markers were identified as variables independently associated with cardiovascular mortality. Using these factors, 90-day mortality ranged from the low of 0.4% in patients with no risk factors, to 4.4% for those with ≤2 risk factors, and to the high of 21.1% for those with more than 4 risk factors—more than a 50-fold difference. Almost the same variables predicted death or nonfatal myocardial infarction: the incidence of death or nonfatal myocardial infarction was 2.2%, 8.7%, and 28.4%, respectively.

Back to Top | Article Outline

Predictors of prognosis

The outcome of patients with acute coronary syndromes other than ST-segment elevation myocardial infarction varies in different studies according to the characteristics of the selected population. In-hospital mortality ranges from 1% to 5% (3,16,17,26,27,31). Other parameters such as infarction, recurrent ischemia, or urgent revascularization present a greater variability, as the definition of these parameters may be arbitrary or subjective. Accordingly, a recommendation to use a definite end point and time for follow-up has not been established. In the PEPA registry, only cardiovascular mortality and the combination of patients with death or nonfatal myocardial infarction were selected as end points because they are more objective. In this unselected population, mortality was similar to previous studies (2,5,18,24) and to the recently reported PRAIS-UK and GRACE registries (11,13), and varied greatly in different subgroups, demonstrating the heterogeneity of the spectrum of patients with this syndrome.

Several factors have been related to prognosis in patients with NSTEACS. Some clinical, electrocardiographic, and analytical parameters may be obtained early after presentation. Others, such as reinfarction, recurrent angina, or the need for revascularization, are derived from the observation of patient evolution during the first days. Still others are obtained using special diagnostic techniques not available at presentation or not desirable to be obtained in all patients. That is the case of ECG, Holter monitoring, stress-test, echocardiography, or coronary angiography (9,10,20,25,30).

In the PEPA study, risk stratification was focused at hospital presentation and ensured that the whole spectrum of NSTEACS was included. In other studies the selection of patients was restricted by age, absence of previous myocardial infarction or revascularization, duration of chest pain episodes, presence of ischemia on ECG, or absence of secondary angina (14,28,30). Older age and ECG changes, specifically ST-segment depression, were the only variables consistently found in most studies (9,10,14,18,26–28,30). The variability in the identification of independent predictors may be attributed to the small number of patients in some studies (9,10,30) and selection bias in others. Patients with chest pain at rest and chest pain lasting more than 20 minutes have been considered to be at particularly high risk (7). In the present study, the only subgroup of the Braunwald classification of unstable angina that appeared independently related with worse prognosis was the post-myocardial infarction angina subgroup. Patients with progressive and rest acute angina presented a similar prognosis. Although the subgroup of patients with rest subacute angina was small, it is important to note that the combination of death or myocardial infarction at 90 days was 0% in that subgroup. Several studies failed to identify differences in prognosis between primary and secondary angina, as well as between the different subgroups of intensity of treatment (9,30). The present study showed no differences in outcome between secondary and primary angina, but a trend toward worse prognosis was observed in patients with intense antianginal treatment before admission.

Different prospective registries designed to study the outcome of patients with NSTEACS have been reported (10,27,28,31). In these, prognostic variables were identified but a risk score for clinical severity and outcome was not implemented. In the TIMI III registry (28), 6-week mortality was 2.3% and elderly patients experienced the more adverse outcomes. In the TIMI III registry ECG ancillary study (10), 6 variables were identified as multivariate predictors of 1-year death or nonfatal myocardial infarction: older age, the use of nitrates or thrombolytics in the previous week, left bundle branch block, ST-segment depression ≥0.5 mm, and exclusion from the TIMI IIIB study because of the impossibility of complying with the follow-up. In the OASIS registry (31), independent predictors were age, heart rate, systolic blood pressure, abnormal ECG, diabetes, and history of heart failure. Using these variables, the database was divided into tertiles of risk, predicting probabilities of cardiovascular death or myocardial infarction at 6 months of 6.2%, 9.5%, and 15.5%. In the RESCATE registry (27), age, peripheral vascular disease, and ECG changes at admission independently predicted 6-month cardiac mortality. The importance of other variables such as diabetes, heart failure, and postinfarction angina has been also reported in other studies, although not in a comprehensive prospective registry environment or in association with the above-mentioned factors.

Back to Top | Article Outline

Risk scores

To help stratify risk at hospital admission, different risk scores have been constructed (2,5,18,24). In the PEPA registry, simple variables easy to obtain at admission appear to be a valuable tool in discerning between patients at very low and very high risk according to the cluster of factors for each patient. The independent risk factors for adverse outcome that emerged in this study could be divided into 2 groups. The first constitutes general baseline characteristics including age ≥65 years, diabetes mellitus, and peripheral vascular disease. The second group of factors corresponds to the clinical presentation of the chest pain; it also relates independently to prognosis and includes post-myocardial infarction angina, Killip class ≥2 at admission, ST-segment depression, elevation of cardiac markers, and occurrence of more than 2 episodes of angina in the 24 hours preceding admission.

In the Minnesota Heart Survey, an empirical score (PREDICT) derived from factors previously shown to be predictive in other settings was used (18). A total of 24 clinical, ECG, analytical, and radiologic components obtained during admission and assigned different weights were included. Although complex, the score performed well to predict long-term outcome at 6 years. The relation between baseline characteristics and the occurrence of 1) death and 2) death or nonfatal myocardial infarction at 30 days was investigated in a large group of patients with NSTEACS derived from the PURSUIT trial (5). A simple risk-evaluation scheme based on the most important prognostic factors was reported. Age, gender, worst angina class, heart rate, systolic blood pressure, signs of heart failure, and ST-depression on presenting ECG were the predictive factors in the multivariate analyses. Event rates (30-day mortality and 30-day mortality or nonfatal myocardial infarction) increased significantly with different points assigned to each predictive factor.

The results of the present investigation are in some way similar to those reported by the TIMI investigators (2). In both studies a score has been constructed by the simple arithmetic sum of the simple independent variables recorded at admission. There are, however, some differences with our study. The cohort of patients from whom the TIMI risk score was derived came from clinical trials on fractionated heparin; patients presented with high-risk clinical characteristics of unstable angina and non-ST elevation myocardial infarction; and a composite end point of death, myocardial infarction, or need for urgent revascularization at 14 days follow-up was used. In contrast, the PEPA registry included an unselected population of patients with variable degrees of clinical severity; focused on mortality; and the follow-up was extended to 90 days from initial hospitalization.

Back to Top | Article Outline

Clinical implications

The risk score derived from the PEPA registry serves as an easily and readily applicable prognostication scheme. The prospective nature of our study, performed in unselected patients and in a variety of hospitals of different sizes and serving different populations, has permitted us to identify all relevant factors independently related to 3-month prognosis. All parameters included in the score are routinely available at bedside during the initial medical evaluation of patients with NSTEACS. The ease of use may be of practical value for a quick evaluation of the risk for death and ischemic events in an individual and may help to establish different diagnostic and therapeutic strategies. Another use could be for better selection of candidates for clinical trials. In addition, the balance between groups in clinical trials is generally analyzed by comparing the percentages of each individual risk factor. A more accurate assessment of risk could be made using the percentage of cluster of risk factors present in each group.

Back to Top | Article Outline

Study limitations

The management of patients with NSTEACS has changed since patients were enrolled in the present registry, with increasing use of low-molecular weight heparins and glycoprotein IIb/IIIa-receptor blockers (3,15,16). However, it is difficult to assume that the use of these drugs has had a significant impact on mortality in unselected populations of patients with NSTEACS. There is increasing evidence that the clinical benefit of these therapies is limited to preventing refractory angina and myocardial infarction in high-risk patients, especially when coronary revascularization is performed (6,8). Biochemical markers of necrosis were used differently in each institution, preventing the analysis of the relative value of different markers when considered along with the other studied factors. Although troponins have proved to be useful in risk stratification (8,14,20,21,23), the clinical impact of these new markers has not been studied in prospective registries of patients with NSTEACS in relation to other prognostic factors. The results of serum cardiac markers were used as dichotomous variables for predicting risk. Given the quantitative relationship between serum levels of cardiac markers and prognosis, it is possible that the risk score could be improved by incorporating quantitative data of biomarkers determined at hospital admission. Finally, other important markers of prognosis, such as fibrinogen (29) or inflammatory markers such as interleukin-6 (4), interleukin-10 (1), or C-reactive protein, were not studied (21,29). Their determination may have improved the predictive value of the final risk score but was precluded by the aim of our study, which was to evaluate the predictive value of clinical variables that can be easily and rapidly recorded at presentation in any hospital, allowing for an immediate risk stratification of patients with NSTEACS.

Back to Top | Article Outline

Appendix

PEPA Registry Study Group

PEPA Registry Chairmen: José L. López-Sendón, Esteban López de Sá. Advisory Board: Juan L. Delcán, Alfonso Castro Beiras, José Espejo, Jenaro Froufe. Clinical Endpoint Committee: José Eizaguirre, Javier Ortigosa, Jesús Palomo. Coordinating Centre: Hospital General U. Gregorio Marañón. Contract Research Organization: Verum Itempharma.

Back to Top | Article Outline

PEPA Registry ECG Clinical Centers

Hospital Gregorio Marañón (Madrid): Esteban López de Sá, José López-Sendón, Rafael Rubio, Raul Moreno, Jaime F. Bobadilla. Hospital Son Dureta (Palma de Mallorca): Armando Bethencourt, Bartolomé Vallbona, Tomas Ripoll. Hospital Clinic (Barcelona): Xavier Bosch, Faustino Miranda-Guardiola, Ignasi Anguera. Hospital La Paz (Madrid): Luís Martín Jadraque, Inmaculada Roldán. Hospital Juan Canalejo (Coruña): Ramón Calviño. Hospital Germans Trias i Pujol (Barcelona): Vicente Valle, Damian Pereferrer, Román Freixa. Hospital Carlos Haya (Malaga): Félix Malpartida. Hospital Clínico (Valladolid): Francisco Fernández Avilés, José Bermejo. Hospital Virgen Macarena (Sevilla): José M. Cruz. Hospital de la Victoria (Malaga): Eduardo de Teresa, Angel Montiel. Instituto de Cardiología (Madrid): Manuel de los Reyes. Hospital Xeral de Galicia (Santiago): Miguel Gil de la Peña, Milagros Pedreira. Hospital Virgen de las Nieves (Granada): José Azpitarte. Hospital Sant Pau (Barcelona): Modesto García Moll. Clínica Puerta de Hierro (Madrid): Manuel de Artaza, Angeles Alonso. Hospital Clinico (Salamanca): Pedro Pabón. Hospital General (Valencia): José A. Velasco. Hospital Miguel Servet (Zaragoza): Enrique Navarro.

Back to Top | Article Outline

References

1. Anguera I, Miranda-Guardiola F, Bosch X, Filella X, Sitges M, Marin JL, Betriu A, Sanz G. Elevation of serum levels of the anti-inflammatory cytokine interleukin-10 and decreased risk of coronary events in patients with unstable angina. Am Heart J (in press), 2002.
2. Antman EM, Cohen M, Bernink PJL, McCabe CH, Horacek T, Papuchis G, Mautner B, Corbalan R, Radley D, Braunwald E. The TIMI risk score for unstable angina/non-ST elevation MI. A method for prognostication and therapeutic decision-making. JAMA 284: 835–42, 2000.
3. Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein D, Bayes de Luna A, Fox K, Lablanche JM, Radley D, Premmereur J, Braunwald E. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 100: 1593–601, 1999.
4. Biasucci LM, Liuzzo G, Fantuzzi G, Caliguri G, Rebuzzi AG, Ginnetti F, Dinarello CA. Increasing levels of interleukin (IL)-1Ra and IL-6 during the first 2 days of hospitalization in unstable angina are associated with increased risk of in-hospital coronary events. Circulation 99: 2079–84, 1999.
5. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, Lincoff AM, Califf RM, Topol EJ, Simoons ML. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 101: 2557–67, 2000.
6. Bosch X, Marrugat J. Platelet glycoprotein IIb/IIIa blockers for percutaneous coronary revascularization, and unstable angina and non-ST-segment elevation myocardial infarction. Cochrane Database Syst Rev 4: CD002130, 2001.
7. Braunwald E. Unstable angina. A classification. Circulation 80: 410–4, 1989.
8. Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer JW, Smith III, EE Steward DE, Theroux P, Alpert JS, Eagle KA, Faxon DP, Fuster V, Gardner TJ, Gregoratos G, Russell RO, Smith Jr. SC ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 36: 970–1062, 2000.
9. Calvin JE, Klein LW, VandenBerg BJ, Meyer P, Condon JV, Snell RJ, Ramirez-Morgen LM, Parrillo JE. Risk stratification in unstable angina. Prospective validation of the Braunwald classification. JAMA 273: 136–41, 1995.
10. Cannon CP, McCabe CH, Stone PH, Rogers WJ, Schactman M, Thompson BW, Pearce DJ, Diver DJ, Kells C, Feldman T, Williams M, Gibson RS, Kronenberg MW, Ganz LI, Anderson HV, Braunwald E. The Electrocardiogram predicts one-year outcome of patients with unstable angina and non-Q wave myocardial infarction: Results of the TIMI III registry ECG ancillary study. J Am Coll Cardiol 30: 133–40, 1997.
11. Collinson J, Flather MD, Fox KAA, Findlay I, Rodrigues E, Dooley P, Ludman P, Adgey J, Bowker TJ, Mattu R, for the PRAIS-UK Investigators. Clinical outcomes, risk stratification and practice patterns of unstable angina and myocardial infarction without ST elevation: Prospective registry of acute ischaemic syndromes in the UK (PRAIS-UK). Eur Heart J 21: 1450–7, 2000.
12. Cox DR. Regression models and life-tables. J R Stat Soc [B] 34: 187–220, 1972.
13. Goldberg RJ, Spencer F, Gore JM, Sadiq I, Sullivan C, Fox K, Steg G, Eagle K, Granger C, Avezum A. Six month prognosis after hospital discharge in patients with acute coronary syndromes: The GRACE Project. J Am Coll Cardiol 37(Suppl A): 315A, 2001.
14. Hamm CW, Goldmann BU, Heeschen C, Kreymann G, Berger J, Meinertz T. Emergency room triage of patients with acute chest pain by means of rapid testing for cardiac troponin T or troponin I. N Engl J Med 337: 1648–53, 1997.
15. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein Iib/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 339: 436–43, 1998.
16. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) study investigators. N Engl J Med 338: 1488–97, 1998.
17. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 354: 708–15, 1999.
18. Jacobs Jr, DR Kroenke C, Crow R, Deshpande M, Gu DF, Gatewood L, Blackburn H. PREDICT: a simple risk score for clinical severity and long-term prognosis after hospitalization for acute myocardial infarction or unstable angina. The Minnesota Heart Survey. Circulation 100: 599–607, 1999.
19. Lee KL, Woodlief LH, Topol EJ, Weaver WD, Betriu A, Col J, Simoons M, Aylward P, Van de Werf F, Califf RM. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction: results from an international trial of 41.021 patients. Circulation 91: 1659–68, 1995.
20. Lindahl B, Andren B, Ohlsson J, Venge P, Wallentin L. Risk stratification in unstable coronary artery disease. Additive value of troponin T determinations and pre-discharge exercise tests. FRISK Study Group. Eur Heart J 18: 762–70, 1997.
21. Lindahl B, Toss H, Siegbahn A, Vengel P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 343: 1139–47, 2000.
22. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50: 163–70, 1966.
23. Norgaard BL, Andersen K, Dellborg M, Abrahamson P, Ravkilde J, Thygesen K. Admission risk assessment by cardiac Troponin T in unstable coronary artery disease: Additional prognostic information from continuous ST segment monitoring. TRIM Study Group. Thrombin Inhibition in Myocardial Ischemia. J Am Coll Cardiol 33: 1519–27, 1999.
24. Rizik DG, Healy S, Margulis A, Vandam D, Bakalyar D, Timmis G, Grines C, O’Neill WW, Schreiber TL. A new clinical classification for hospital prognosis of unstable angina pectoris. Am J Cardiol 75: 993–7, 1995.
25. Sabia P, Afrookteh A, Touchstone DA, Keller MW, Esquivel L, Kaul S. Value of regional wall motion abnormality in the emergency room diagnosis of acute myocardial infarction: A prospective study using two-dimensional echocardiography. Circulation 84(Suppl I): 85–92, 1991.
26. Scirica BM, Moliterno DJ, Every NR, Anderson HV, Aguirre FV, Granger CB, Lambrew CT, Rabbani LE, Arnold A, Sapp SK, Booth JE, Ferguson JJ, Cannon CP. Differences between men and women in the management of unstable angina pectoris (The GUARANTEE Registry). The GUARANTEE Investigators. Am J Cardiol 84: 1145–50, 1999.
27. Seres L, Valle V, Marrugat J, Sanz G, Masia R, Lupon J, Curos A, Sala J, Molina L, Pavesi M. Usefulness of hospital admission risk stratification for predicting nonfatal acute myocardial infarction or death six months later in unstable angina pectoris. RESCATE Study Group. Resources Used in Acute Coronary Syndromes and Delays in Treatment. Am J Cardiol 84: 963–9, 1999.
28. Stone PH, Thompson B, Anderson HV, Kronenberg MW, Gibson RS, Rogers WJ, Diver DJ, Theroux P, Warnica JW, Nasmith JB, Kells C, Kleiman N, McCabe CH, Schactman M, Knatterud GL, Braunwald E. Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: The TIMI III registry. JAMA 275: 1104–12, 1996.
29. Toss H, Lindahl B, Siegbahn A, Wallentin L. Prognostic influence of increased fibrinogen and C-reactive protein levels in unstable coronary artery disease. FRISC Study Group. Fragmin during instability in coronary artery disease. Circulation 96: 4204–10, 1997.
30. Van Miltenburg-van Zijl AJ, Simoons ML, Veerhoek RJ, Bossuyt PM. Incidence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol 25: 1286–92, 1995.
31. Yusuf S, Flather M, Pogue J, Hunt D, Varigos J, Piegas L, Avezum A, Anderson J, Keltai M, Budaj A, Fox K, Ceremuzynski L. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators. Lancet 352: 507–14, 1998.
32. Zaachs SM, Liebson PR, Calvin JE, Parrillo JE, Klein LW. Unstable angina and non-Q-wave myocardial infarction: Does the clinical diagnosis have therapeutic implications? J Am Coll Cardiol 33: 107–18, 1999.
© 2002 Lippincott Williams & Wilkins, Inc.