Major Bleeding in AF With Apixaban or Warfarin
Major Bleeding in AF With Apixaban or Warfarin
The ARISTOTLE trial design has been reported previously. Patients with AF and at least 1 risk factor for stroke were randomized to receive either dose-adjusted warfarin or apixaban, 5 mg twice daily. A reduced dose of apixaban, 2.5 mg twice daily, was designated for participants with 2 or more of the following criteria: age ≥80 years, weight ≤60 kg, or serum creatinine concentration ≥1.5 mg/dl (133 μmol/l). The reduced dose of apixaban was administered to 428 patients (4.7%). To enhance the quality of warfarin management, a dosage algorithm was provided, and a program implemented to provide regular feedback to sites regarding their level of international normalized ratio (INR) control.
The analyses of bleeding events included all patients who received at least 1 dose of a study drug and included all events from the time of the first dose until 2 days after the last dose was received. Major bleeding was defined according to International Society on Thrombosis and Haemostasis (ISTH) criteria as clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2 g/dl or transfusion of at least 2 units of packed red cells, occurring at a critical site (intracranial, intraocular, intraspinal, intra-articular, intramuscular with compartment syndrome, pericardial, retroperitoneal), or resulting in death. No time restrictions were applied to this definition. Laboratory and transfusion data coupled with clinical event details were used to identify and adjudicate potential bleeding events. Routine collection of hemoglobin occurred every 3 months. Location of bleeding was extracted from the case report form. Additional source documents were collected when necessary. The primary safety outcomes were adjudicated on the basis of pre-specified criteria by a clinical events committee whose members were not aware of study group assignments.
Parameters to assess the severity of major hemorrhage, in addition to anatomic location, for apixaban and warfarin were determined and compared. Metrics relevant for major extracranial hemorrhage included decrease of hemoglobin of at least 2 g/dl, hospitalization because of bleeding, transfusion of packed red cells, number of units transfused, medical or surgical consultation or evaluation, medical or surgical intervention to stop the bleeding, hemodynamic compromise, and change in antithrombotic therapy. Thirty-day mortality rates following first ISTH major hemorrhage were evaluated and compared between warfarin- and apixaban-treated patients.
Categorical variables were summarized as frequencies and percentages and continuous variables as medians and 25th and 75th percentiles. p Values representing comparisons between patients with and without major bleeding were based on Cox regression models with ISTH criteria first major hemorrhage as a dependent variable. p Values for the interactions between randomized treatment and each covariate were derived using Cox models. Factors associated with the first ISTH major hemorrhage were identified using a multivariable Cox model. Candidate variables included demographics and clinical characteristics, medications, and laboratory values at baseline. Randomized treatment and region of enrollment were also included as candidate variables. Missing values in predictors were imputed using multiple imputations. Missing values were uncommon (<3%) for all predictors, except for history of fall (9%). Twenty-five imputed datasets were generated, and a stepwise selection method was used in each dataset. Predictors selected in more than 80% of the imputed datasets were included in the final model. We tested for interactions between variables in the final model and randomized treatment.
Four additional endpoints were defined according to the consequences of hemorrhage, including major extracranial hemorrhage, followed by hospitalization, medical or surgical intervention, transfusion, and change in antithrombotic therapy. These endpoints were summarized overall and by randomized treatment as rates (except for the number of units of packed cells transfused), number of events, and hazard ratios (HR) comparing all patients randomized to apixaban versus those to warfarin. All statistical analyses were performed using SAS version 9.2 software (SAS Institute, Inc., Cary, North Carolina).
Methods
The ARISTOTLE trial design has been reported previously. Patients with AF and at least 1 risk factor for stroke were randomized to receive either dose-adjusted warfarin or apixaban, 5 mg twice daily. A reduced dose of apixaban, 2.5 mg twice daily, was designated for participants with 2 or more of the following criteria: age ≥80 years, weight ≤60 kg, or serum creatinine concentration ≥1.5 mg/dl (133 μmol/l). The reduced dose of apixaban was administered to 428 patients (4.7%). To enhance the quality of warfarin management, a dosage algorithm was provided, and a program implemented to provide regular feedback to sites regarding their level of international normalized ratio (INR) control.
The analyses of bleeding events included all patients who received at least 1 dose of a study drug and included all events from the time of the first dose until 2 days after the last dose was received. Major bleeding was defined according to International Society on Thrombosis and Haemostasis (ISTH) criteria as clinically overt bleeding accompanied by a decrease in the hemoglobin level of at least 2 g/dl or transfusion of at least 2 units of packed red cells, occurring at a critical site (intracranial, intraocular, intraspinal, intra-articular, intramuscular with compartment syndrome, pericardial, retroperitoneal), or resulting in death. No time restrictions were applied to this definition. Laboratory and transfusion data coupled with clinical event details were used to identify and adjudicate potential bleeding events. Routine collection of hemoglobin occurred every 3 months. Location of bleeding was extracted from the case report form. Additional source documents were collected when necessary. The primary safety outcomes were adjudicated on the basis of pre-specified criteria by a clinical events committee whose members were not aware of study group assignments.
Severity of Hemorrhage and 30-day Mortality Following First ISTH Major Hemorrhage
Parameters to assess the severity of major hemorrhage, in addition to anatomic location, for apixaban and warfarin were determined and compared. Metrics relevant for major extracranial hemorrhage included decrease of hemoglobin of at least 2 g/dl, hospitalization because of bleeding, transfusion of packed red cells, number of units transfused, medical or surgical consultation or evaluation, medical or surgical intervention to stop the bleeding, hemodynamic compromise, and change in antithrombotic therapy. Thirty-day mortality rates following first ISTH major hemorrhage were evaluated and compared between warfarin- and apixaban-treated patients.
Statistical Analyses
Categorical variables were summarized as frequencies and percentages and continuous variables as medians and 25th and 75th percentiles. p Values representing comparisons between patients with and without major bleeding were based on Cox regression models with ISTH criteria first major hemorrhage as a dependent variable. p Values for the interactions between randomized treatment and each covariate were derived using Cox models. Factors associated with the first ISTH major hemorrhage were identified using a multivariable Cox model. Candidate variables included demographics and clinical characteristics, medications, and laboratory values at baseline. Randomized treatment and region of enrollment were also included as candidate variables. Missing values in predictors were imputed using multiple imputations. Missing values were uncommon (<3%) for all predictors, except for history of fall (9%). Twenty-five imputed datasets were generated, and a stepwise selection method was used in each dataset. Predictors selected in more than 80% of the imputed datasets were included in the final model. We tested for interactions between variables in the final model and randomized treatment.
Four additional endpoints were defined according to the consequences of hemorrhage, including major extracranial hemorrhage, followed by hospitalization, medical or surgical intervention, transfusion, and change in antithrombotic therapy. These endpoints were summarized overall and by randomized treatment as rates (except for the number of units of packed cells transfused), number of events, and hazard ratios (HR) comparing all patients randomized to apixaban versus those to warfarin. All statistical analyses were performed using SAS version 9.2 software (SAS Institute, Inc., Cary, North Carolina).
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