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.
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.
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.
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.
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.
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.
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.
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