Bleeding and outcome in acute coronary syndrome: Insights from continuous electrocardiogram monitoring in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial

Abstract

Bleeding is associated with adverse outcome in acute coronary syndromes. However, the precise pathophysiologic mechanisms have not been elucidated. We sought to determine the relationship between bleeding and myocardial ischemia detected by concurrent continuous electrocardiogram (ECG) monitoring and their independent long-term prognostic significance. The INTERACT trial was a randomized controlled trial of enoxaparin versus unfractionated heparin in patients with high-risk non-ST-elevation acute coronary syndromes. Continuous ECG monitoring, performed after enrollment up to 96 hours, was analyzed by an automated algorithm and reviewed by a blinded cardiologist. We centrally adjudicated all bleeding and clinical events in a blinded fashion and calculated the Global Registry of Acute Coronary Events risk score (a validated predictor of mortality) for each patient. Of the 746 patients enrolled, 34 (4.6%) developed major bleeding within 96 hours. After a median follow-up of 2.4 years, patients with bleeding had a higher risk of death (28.4% vs 7.3%, P < .001) and death/myocardial infarction (38.0% vs 12.9%, P < .001) compared with those without bleeding. Overall, 619 patients survived the first 96 hours with complete data on continuous ECG monitoring. Bleeding was associated with the simultaneous presence of ST-segment shifts on continuous ECG monitoring (P = .03). After adjusting for Global Registry of Acute Coronary Events risk score and myocardial ischemia detected by continuous ECG monitoring, major bleeding remained an independent predictor of death (adjusted hazard ratio = 3.48, 95% confidence interval 1.51-8.03, P = .003) and death/myocardial infarction (adjusted hazard ratio = 2.85, 95% confidence interval 1.40-5.78, P = .004). Bleeding is a powerful independent predictor of poor long-term outcome, even after adjusting for other associated prognostic factors such as advanced age and renal dysfunction. Although bleeding is associated with concurrent myocardial ischemia, its adverse prognostic impact may be mediated by complex pathophysiologic mechanisms rather than myocardial ischemia alone. Our findings suggest that future investigations should focus on other biologically plausible mechanisms.