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Major bleeding is a frequent complication for patients with acute myocardial infarction (AMI) and is associated with significant morbidity and mortality.To develop a contemporary model for inhospital major bleeding that can both support clinical decision-making and serve as a foundation for assessing hospital quality.An inhospital major bleeding model was developed using the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines (ACTION Registry–GWTG) database. Patients hospitalized with AMI between January 1, 2012 and December 31, 2013 across 657 hospitals were used to create a derivation cohort (n=144,800) and a validation cohort (n=96,684). Multivariable hierarchal logistic regression was used to identify significant predictors of major bleeding. A simplified risk score was created to enable prospective risk stratification for clinical care.The rate of major bleeding in the overall population was 7.53%. There were 8 significant, independent factors associated with major bleeding: presentation after cardiac arrest (OR 2.99 [2.77–3.22]); presentation in cardiogenic shock (OR 2.22 [2.05–2.40]); STEMI (OR 1.72 [1.65–1.80]); presentation in heart failure (OR 1.55 [1.47–1.63]); baseline hemoglobin less than 12 g/dL (1.55 [1.48–1.63]); heart rate (per 10 beat per minute increase) (OR 1.13 [1.12–1.14]); weight (per 10 kilogram decrease) (OR 1.12 [1.11–1.14]); creatinine clearance (per 5-mL decrease) (OR 1.07 [1.07–1.08]). The model discriminated well in the derivation (C-statistic = 0.74) and validation (C-statistic = 0.74) cohorts. In the validation cohort, a risk score for major bleeding corresponded well with observed bleeding: very low risk (2.2%), low risk (5.1%), moderate risk (10.1%), high risk (16.3%), and very high risk (25.2%).The new ACTION Registry–GWTG inhospital major bleeding risk model and risk score offer a robust, parsimonious, and contemporary risk-adjustment method to support clinical decision-making and enable hospital quality assessment. Strategies to mitigate risk should be developed and tested as a means to lower costs and improve outcomes in an era of alternative payment models.