Reasons for Warfarin Discontinuation in ORBIT-AF
We used data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) to assess patterns of warfarin discontinuation over 1 year of follow-up. Details of the ORBIT-AF study design have been published. Briefly, ORBIT-AF is a US-based, prospective outpatient registry of AF conducted at 176 sites nationwide. The Duke Clinical Research Institute was responsible for ORBIT-AF site selection and study management. Eligible patients were ≥18 years old with electrocardiographically confirmed AF. Enrolling providers included cardiologists, electrophysiologists, and primary care providers. Site personnel entered information on demographics, medical history, cardiovascular risk factors, AF management strategy, and provider characteristics into a standardized, Web-based collection form. Following initial enrollment, longitudinal information was collected during clinic visits at approximately 6-month intervals up to 24 months and included information on hospitalizations, bleeding events, medication regimens, procedures, and quality of life.
Approximately 10,132 patients were enrolled in ORBIT-AF from June 2010 to August 2011. We excluded patients without follow-up data at the 6- and 12-month clinic visit (8.6%), patients who were not receiving warfarin at baseline entry into ORBIT-AF (25.7%), patients who switched to dabigatran during follow-up (5.3%), and patients who were missing information on warfarin discontinuation during follow-up (0.2%), for a final study population of 6,110 patients at 171 participating sites. Of these, 1,011 patients began warfarin therapy within 1 year prior to study enrollment.
The primary outcome of interest was the first reported discontinuation of warfarin therapy without resumption at either 6 or 12 months following enrollment. Additionally, patients who reported that they were not receiving warfarin at their 6- and/or 12-month follow-up were considered to be discontinued from warfarin therapy. For all who discontinued, providers were asked to identify one or more primary and secondary reasons for discontinuation from a prespecified list. Primary and secondary reasons were treated as equivalent. Reasons for discontinuation included dual antiplatelet therapy, pregnancy, frequent falls/frailty, high bleeding risk, gastrointestinal upset, prior intracranial hemorrhage, unable to adhere/monitor warfarin, bleeding event, allergy, physician preference, patient refusal/preference, comorbid illness, occupational risk, and other. The list of reasons for discontinuation collected was selected and approved by the ORBIT-AF executive committee based on clinical relevance during the study development phase.
Because the predefined set of reported reasons represents a wide variety of explanations for warfarin discontinuation, we conducted a set of analyses to examine factors associated with 2 secondary outcomes: event-related discontinuation and patient-related discontinuation. Event-related discontinuation was defined as any discontinuation of warfarin with one of the following reasons listed: allergy, pregnancy, comorbid illness, prior intracranial hemorrhage, and bleeding event. Patient-related discontinuation was defined as discontinuation with any non–event-related reason listed. Patients who discontinued and listed more than one reason for discontinuation could be classified as both patient related and event related.
We compared baseline characteristics between patients who discontinued warfarin over 1 year and patients who persisted using Pearson χ tests for categorical variables and Wilcoxon rank sum tests for continuous variables. We also examined warfarin discontinuation by estimated stroke risk using the CHADS2 score (C, congestive heart failure [1 point]; H, hypertension [1 point]; A, age >75 years [1 point]; D, diabetes [1 point]; S, prior stroke or transient ischemic attack [2 points]) and the CHA2DS2-VASc score (C, congestive heart failure [1 point]; H, hypertension [1 point]; A, age>75 years [2 points]; D, diabetes mellitus [1 point]; S, prior stroke or transient ischemic attack [2 points]; V, vascular disease [1 point]; A, age 65–74 years [1 point]; S, female sex [1 point]). To determine factors associated with warfarin discontinuation, we constructed a multivariable proportional odds model for discrete time because warfarin discontinuation was captured in discrete time intervals. This method fits a logistic regression for the binary occurrence of discontinuation at each discrete time point (6 or 12 months) and combines the results to provide a single odds ratio for the effect of covariates. Additionally, this model was fit using generalized estimating equations with exchangeable working correlation matrix to account for within-site clustering. Because warfarin discontinuation may directly result from a clinical event, we included cause-specific hospitalizations (bleeding, cardiovascular, noncardiovascular, nonbleeding) that occurred during follow-up (assumed the hospitalization preceded discontinuation) in a secondary analysis. Intervening events were included as time-dependent covariates. Candidate variables in the regression model included demographics, relevant clinical comorbidities, management strategy, prior procedures and interventions, laboratory values, and vital signs. Continuous variables were evaluated for nonlinearity with the outcome, and nonlinear relationships were addressed by using linear splines. Missing data were multiply-imputed, and final estimates and standard errors reflect the combined analysis over 5 imputed data sets (all the candidate variables had <2% missing except for the following variables: level of education [4.0%], serum creatinine [7%], hemoglobin [10%)] and hematocrit [10%]). Model selection using backward selection with a stay criterion of 0.05 using the first imputed data set was used to obtain a set of factors in which each factor was independently associated with warfarin discontinuation within 1 year. We repeated this strategy for the secondary outcomes of event-related discontinuation (vs no event-related discontinuation) and patient-related discontinuation (vs no patient-related discontinuation). In the study of event-related discontinuation, patient-related discontinuation resulted in censoring, and vice versa.
All P values presented are 2-sided. All statistical analyses for this study were performed using SAS software (version 9.3; SAS, Cary, NC). Written informed consent was obtained for all study participants. The Duke Institutional Review Board approved the ORBIT-AF Registry, and all participating sites obtained approval from local institutional review boards prior to entering patient data.
The ORBIT-AF registry is sponsored by Janssen Scientific Affairs, LLC, Raritan, NJ.
This project was supported (in part) by funding from the Agency of Healthcare Research and Quality through cooperative agreement number 1U19 HS021092 .
Methods
Study Population
We used data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) to assess patterns of warfarin discontinuation over 1 year of follow-up. Details of the ORBIT-AF study design have been published. Briefly, ORBIT-AF is a US-based, prospective outpatient registry of AF conducted at 176 sites nationwide. The Duke Clinical Research Institute was responsible for ORBIT-AF site selection and study management. Eligible patients were ≥18 years old with electrocardiographically confirmed AF. Enrolling providers included cardiologists, electrophysiologists, and primary care providers. Site personnel entered information on demographics, medical history, cardiovascular risk factors, AF management strategy, and provider characteristics into a standardized, Web-based collection form. Following initial enrollment, longitudinal information was collected during clinic visits at approximately 6-month intervals up to 24 months and included information on hospitalizations, bleeding events, medication regimens, procedures, and quality of life.
Approximately 10,132 patients were enrolled in ORBIT-AF from June 2010 to August 2011. We excluded patients without follow-up data at the 6- and 12-month clinic visit (8.6%), patients who were not receiving warfarin at baseline entry into ORBIT-AF (25.7%), patients who switched to dabigatran during follow-up (5.3%), and patients who were missing information on warfarin discontinuation during follow-up (0.2%), for a final study population of 6,110 patients at 171 participating sites. Of these, 1,011 patients began warfarin therapy within 1 year prior to study enrollment.
Warfarin Discontinuation
The primary outcome of interest was the first reported discontinuation of warfarin therapy without resumption at either 6 or 12 months following enrollment. Additionally, patients who reported that they were not receiving warfarin at their 6- and/or 12-month follow-up were considered to be discontinued from warfarin therapy. For all who discontinued, providers were asked to identify one or more primary and secondary reasons for discontinuation from a prespecified list. Primary and secondary reasons were treated as equivalent. Reasons for discontinuation included dual antiplatelet therapy, pregnancy, frequent falls/frailty, high bleeding risk, gastrointestinal upset, prior intracranial hemorrhage, unable to adhere/monitor warfarin, bleeding event, allergy, physician preference, patient refusal/preference, comorbid illness, occupational risk, and other. The list of reasons for discontinuation collected was selected and approved by the ORBIT-AF executive committee based on clinical relevance during the study development phase.
Event-related and Patient-related Discontinuation
Because the predefined set of reported reasons represents a wide variety of explanations for warfarin discontinuation, we conducted a set of analyses to examine factors associated with 2 secondary outcomes: event-related discontinuation and patient-related discontinuation. Event-related discontinuation was defined as any discontinuation of warfarin with one of the following reasons listed: allergy, pregnancy, comorbid illness, prior intracranial hemorrhage, and bleeding event. Patient-related discontinuation was defined as discontinuation with any non–event-related reason listed. Patients who discontinued and listed more than one reason for discontinuation could be classified as both patient related and event related.
Statistical Analysis
We compared baseline characteristics between patients who discontinued warfarin over 1 year and patients who persisted using Pearson χ tests for categorical variables and Wilcoxon rank sum tests for continuous variables. We also examined warfarin discontinuation by estimated stroke risk using the CHADS2 score (C, congestive heart failure [1 point]; H, hypertension [1 point]; A, age >75 years [1 point]; D, diabetes [1 point]; S, prior stroke or transient ischemic attack [2 points]) and the CHA2DS2-VASc score (C, congestive heart failure [1 point]; H, hypertension [1 point]; A, age>75 years [2 points]; D, diabetes mellitus [1 point]; S, prior stroke or transient ischemic attack [2 points]; V, vascular disease [1 point]; A, age 65–74 years [1 point]; S, female sex [1 point]). To determine factors associated with warfarin discontinuation, we constructed a multivariable proportional odds model for discrete time because warfarin discontinuation was captured in discrete time intervals. This method fits a logistic regression for the binary occurrence of discontinuation at each discrete time point (6 or 12 months) and combines the results to provide a single odds ratio for the effect of covariates. Additionally, this model was fit using generalized estimating equations with exchangeable working correlation matrix to account for within-site clustering. Because warfarin discontinuation may directly result from a clinical event, we included cause-specific hospitalizations (bleeding, cardiovascular, noncardiovascular, nonbleeding) that occurred during follow-up (assumed the hospitalization preceded discontinuation) in a secondary analysis. Intervening events were included as time-dependent covariates. Candidate variables in the regression model included demographics, relevant clinical comorbidities, management strategy, prior procedures and interventions, laboratory values, and vital signs. Continuous variables were evaluated for nonlinearity with the outcome, and nonlinear relationships were addressed by using linear splines. Missing data were multiply-imputed, and final estimates and standard errors reflect the combined analysis over 5 imputed data sets (all the candidate variables had <2% missing except for the following variables: level of education [4.0%], serum creatinine [7%], hemoglobin [10%)] and hematocrit [10%]). Model selection using backward selection with a stay criterion of 0.05 using the first imputed data set was used to obtain a set of factors in which each factor was independently associated with warfarin discontinuation within 1 year. We repeated this strategy for the secondary outcomes of event-related discontinuation (vs no event-related discontinuation) and patient-related discontinuation (vs no patient-related discontinuation). In the study of event-related discontinuation, patient-related discontinuation resulted in censoring, and vice versa.
All P values presented are 2-sided. All statistical analyses for this study were performed using SAS software (version 9.3; SAS, Cary, NC). Written informed consent was obtained for all study participants. The Duke Institutional Review Board approved the ORBIT-AF Registry, and all participating sites obtained approval from local institutional review boards prior to entering patient data.
Funding Sources
The ORBIT-AF registry is sponsored by Janssen Scientific Affairs, LLC, Raritan, NJ.
This project was supported (in part) by funding from the Agency of Healthcare Research and Quality through cooperative agreement number 1U19 HS021092 .
Source...