A possible explanation of the conflicting results in the above trials is the fact that patients with unstable angina and non-ST-elevation wave MI present with a wide spectrum of clinical risk for death and cardiac ischemic events. Ideally, one ought to be able to identify high risk patients who might benefit mostly from an aggressive invasive approach, and those with lower risk where conservative management might be more appropriate.
Several analyses have been performed attempting to identify prognostic risk factors in patients with unstable angina and non-ST-elevation wave MI. Traditional risk factors associated with worse outcomes have included increased age, accelerated or rest angina, associated pulmonary edema, mitral regurgitation murmur or S3 sound, ischemic ECG changes, elevated creatinine kinase levels, and a positive stress test. More recently identified risk factors include elevated troponin (40-42), fibrinogen (43), and C-reactive protein levels (44,45). The most comprehensive risk assessment model to date is the TIMI risk score proposed by Antman at al. (46). In that analysis, the test cohort was the unfractionated heparin group in TIMI 11B trial and the 3 validation cohorts were the unfractionated heparin group from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events (ESSENCE) trial and both enoxaparin groups from the TIMI 11B and ESSENCE trials. The TIMI risk score was derived by selection of independent prognostic factors using multivariate logistic regression, and the numbers of factors present were added to categorize patients into risk strata. The seven TIMI risk score predictor variables were: age >65 yr, >3 risk factors for coronary artery disease, prior coronary stenosis >50%, ST-segment deviation on ECG on presentation, >2 anginal events in less than 24 h, use of aspirin in prior 7 d, and elevated serum markers (Table 5). Events rates increased significantly as the TIMI risk score increased, and ranged from 4.7%, when none or one risk factor is present, to 40.9%, when 6 or 7 risk factors are present (Fig. 8). The prognostic value of this model was confirmed in the unfractionated heparin group from the ESSENCE trial, both enoxaparin groups from the TIMI 11B and ESSENCE trials, and the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) and TACTICS-TIMI 18 trials (Figs. 9a,b).
Fig. 8. Risk of cardiac adverse events at 14 d in relation to number of TIMI risk factors. Reproduced with permission from Antman et al. The TIMI risk score for unstable angina/non-ST elevation MI: a method for prognostication and therapeutic decision making. JAMA 2000;284:835-842.
Having established those risk factors, investigators have attempted to identify those patients who would fail medical therapy, or conversely, those who would benefit most from an early invasive approach. Stone et al. (47) studied the 733 patients enrolled in the conservative arm in the TIMI IIIB database and found that baseline characteristics predictive of failure of medical therapy included rest angina with ST-segment depression, prior treatment with aspirin or heparin, history of prior angina, older age, and family history of premature coronary artery disease. The incidence of developing a clinical event ranged from 8% if none of the risk factors were present, to 63% if all are present. Using the TIMI risk score model in the TACTICS-TIMI 18 trial (Fig. 9b), an invasive approach was most beneficial when the TIMI risk score was 5-7 (OR = 0.55, 95% CI: 0.33-0.91). When the TIMI risk score is 0-2, on the other hand, early invasive or conservative approaches were similar.
Based on these studies, it seems that patients with unstable angina or non-ST-elevation MI who are at higher risk are likely to benefit the most from an early invasive approach. In lower risk patients, both approaches yield similar outcomes but a conservative approach might be more cost-effective. Further studies will help clarify these points.
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