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Background Bleeding and hospital death have an independent association in observational records of acute coronary syndromes (ACS), leading to interpretation of this relationship as causal. However, association does not guarantee causality, and better exploitation of this phenomenon is necessary. Purpose To describe the association between bleeding and death of patients with ACS, exploring causality through the cascade of events that separate these two phenomena. Methods Patients consecutively admitted to Coronary Unit by objective criteria of ACS were included prospectively. Major bleeding during hospitalization was defined according to types 3 and 5 of the Universal Bleeding Classification. Logistic regression and sequence analysis of events were used to evaluate the association between bleeding and death. Results A total of 1104 patients were studied, age 65±14 years, 58% male, 23% with ST elevation. The incidence of major bleeding was 4.7% (52 cases). Bleeding patients presented mortality of 31% (16 deaths), compared to 4.7% death in the non-bleeding group (RR=6.6, 95% CI: 4.0–11). Those who bled had a GRACE score significantly higher than those free of bleeding (157±39 versus 121±38, P&amp;lt;0.001). After adjustment for this score, bleeding remained strongly associated with death (OR=4.5, 95% CI: 2.1–9.7, P&amp;lt;0.001). However, among the 16 deaths that occurred after bleeding, in 56% of the patients the death was due to hemorrhage, while the remainder was a consequence of the myocardial injury of the infarct or natural evolution of noncardiac morbidities. Conclusion The independent association between major bleeding and death in acute coronary syndromes is only partially mediated by causality. In the same proportion, deaths coexist with bleeding without a causal relationship. Funding Acknowledgement Type of funding source: None

Strong independent association between hospital bleeding and death in acute coronary syndromes: causal relationship or coexistence of two phenomena?