Research
Original Investigation
Risk of Bleeding With Dabigatran in Atrial Fibrillation Inmaculada Hernandez, PharmD; Seo Hyon Baik, PhD; Antonio Piñera, MD; Yuting Zhang, PhD Editor's Note page 25 IMPORTANCE It remains unclear whether dabigatran etexilate mesylate is associated with
higher risk of bleeding than warfarin sodium in real-world clinical practice. OBJECTIVE To compare the risk of bleeding associated with dabigatran and warfarin using
Medicare data.
Supplemental content at jamainternalmedicine.com CME Quiz at jamanetworkcme.com and CME Questions page 152
DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011. EXPOSURES Dabigatran users (n = 1302) and warfarin users (n = 8102). MAIN OUTCOMES AND MEASURES We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities. RESULTS Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. CONCLUSIONS AND RELEVANCE Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.
Author Affiliations: Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Hernandez, Baik, Zhang); Department of Obstetrics and Gynecology, La Paz University Hospital, Madrid, Spain (Piñera).
JAMA Intern Med. 2015;175(1):18-24. doi:10.1001/jamainternmed.2014.5398 Published online November 3, 2014. 18
Corresponding Author: Yuting Zhang, PhD, Department of Health Policy and Management, University of Pittsburgh, 130 De Soto St, Crabtree Hall, Room A664, Pittsburgh, PA 15261 ([email protected]). jamainternalmedicine.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
Dabigatran Bleeding Risk
Original Investigation Research
T
he Food and Drug Administration (FDA) approved dabigatran etexilate mesylate for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) in October 20101 based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.2 The RE-LY trial did not find differences in the rates of major bleeding between treatments; however, dabigatran was superior to warfarin sodium in the prevention of stroke. In addition, dabigatran etexilate mesylate, 150 mg, was associated with a higher risk of gastrointestinal bleeding but a lower rate of intracranial hemorrhage compared with warfarin. Several months after the approval of dabigatran, the FDA received a large number of reports of severe dabigatranrelated bleeding reports through its Adverse Event Reporting System. Concurrently, several case reports of dabigatraninduced bleeding were published in medical journals3-6 and discussed in the mainstream media.7 The incidence of serious bleeding was especially high among elderly users and users with renal impairment.5,6,8 On the basis of a study9 that did not adjust for patient characteristics, the FDA concluded that the incidence of gastrointestinal and intracranial bleeding was not higher for dabigatran compared with warfarin. In contrast, a meta-analysis10 found that dabigatran was associated with a significantly higher risk of gastrointestinal bleeding. In addition, a 2013 study11 using data from Danish National Registries found that the rates of major and gastrointestinal bleeding for warfarin and dabigatran were similar. It is still unclear whether the use of dabigatran leads to more bleeding compared with warfarin, especially in the realworld clinical practice. Using 2010 to 2011 Medicare Part D data, we examine this question among patients with AF.
Methods Data Source and Study Population The study was approved by the institutional review board at the University of Pittsburgh as exempt because existing deidentified data were used. We obtained a 5% random sample of Medicare beneficiaries in 2010 and 2011 (most recent data available) from the Centers for Medicare & Medicaid Services (CMS). We identified patients who were newly diagnosed as having AF from October 1, 2010, through October 31, 2011, by using the CMS Chronic Condition Warehouse indicator that traced the first diagnosis date back to January 1, 1999. The diagnosis of AF was defined as having 1 inpatient or 2 outpatient claims with primary or secondary International Classification of Diseases, Ninth Revision (ICD-9), code 427.31.12 We also required that individuals in our study sample had filled an outpatient prescription for either dabigatran or warfarin within 2 months of the first diagnosis (N = 9562). Those who filled prescriptions for dabigatran and warfarin during the first 2 months after diagnosis were excluded (N = 158). We followed up each individual from the first prescription of dabigatran or warfarin until discontinuation of use for more than 60 days, switch of anticoagulants, death, or December 31, 2011. Our final overall study sample included 1302 dabigatran users and 8102 warfarin users.
Outcomes We identified 9 types of bleeding according to anatomical position: intracranial hemorrhage, hemoperitoneum, gastrointestinal bleeding, hematuria, epistaxis, hemoptysis, vaginal hemorrhage, hemarthrosis, and not otherwise specified (NOS) hemorrhage (the ICD-9 codes for these bleeding events are listed in eTable 1 in the Supplement).13 We categorized bleeding events as major and minor events. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for gastrointestinal, hematuria, or NOS hemorrhage; minor bleeding events included epistaxis, hemoptysis, vaginal hemorrhage, hemarthrosis and any outpatient claim for hematuria, gastrointestinal, and NOS hemorrhage. Any bleeding included major and minor bleeding events. Several claims for the same type of bleeding made within 1 week were considered as the same event to avoid double counting.14 We defined time to bleeding as days between the first warfarin or dabigatran prescription and the date of the bleeding event. We analyzed the time to the first bleeding event, as well as the time to the first major hemorrhage, intracranial hemorrhage, gastrointestinal bleeding, hematuria, vaginal bleeding, hemarthrosis, hemoptysis, epistaxis, and NOS hemorrhage.
Covariates We adjusted for 2 main categories of covariates: demographic variables and clinical characteristics. Demographic variables included age, sex, race, and Medicaid eligibility. Clinical characteristics included CHADS2 (congestive heart failure, hypertension, age of 75 years or older, diabetes mellitus, and stroke) score, chronic kidney disease, hypertension, history of stroke or transient ischemic attack, history of acute myocardial infarction, diabetes mellitus, congestive heart failure, acquired hypothyroidism, the number of other CMS priority comorbidities (Table 1), history of bleeding in the year before treatment initiation, history of hospitalization in the year before treatment initiation, use of nonsteroidal inflammatory drugs (NSAIDs), use of antiplatelet agents, and the CMS prescription drug hierarchical condition category (CMS-RxHCC) score. The CHADS2 score predicts the risk of stroke in patients with AF; in calculating CHADS2, a history of previous stroke or transient ischemic attack is assigned 2 points; congestive heart failure, hypertension, age of 75 years or older, and diabetes are each assigned 1 point. The score is calculated as the sum of all points.15 The ICD-9 codes used to identify the conditions mentioned are listed in eTable 2 in the Supplement. History of bleeding was defined as having one medical claim with ICD-9 codes for any bleeding in the year before treatment initiation, and history of any hospitalization was defined as having at least one inpatient admission related to any condition in the year before treatment initiation. We defined the use of NSAIDs as having at least one prescription for diclofenac, ibuprofen, naproxen, ketoprofen, fenoprofen calcium, flurbiprofen, piroxicam, meloxicam, mefenamic acid, or indomethacin after treatment initiation. Use of antiplatelet agents was defined as having at least one pharmacy claim for aspirin, clopidogrel bisulfate, prasugrel, dipyridamol, ticlopidine hydrochloride, and ticagrelor after treatment initiation. The CMS-RxHCC score was
jamainternalmedicine.com
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
19
Research Original Investigation
Dabigatran Bleeding Risk
Table 1. Baseline Characteristics of the Cohorts, Before and After Propensity Score Weighting, by Treatment Group Propensity Score Weighting, % Before Characteristic Age, mean (SD), y
Warfarin (n = 8102)
P Value
Warfarin (n = 8102)
Dabigatran (n = 1302)
75.7 (8.5)
.02
75.6 (9.5)
40.9
42.3
.34
41.0
42.1
White
82.1
88.71
83.0
84.4
Black
8.7
3.6
8.1
6.4
Asian
2.0
1.8
1.9
2.4
Male sex
75.0 (10.4)
After
Dabigatran (n = 1302)
75.1 (10.2)
P Value .15 .49
Race
Hispanic
5.9
4.5
5.7
5.1
Native American
0.4
0.3
0.4
0.4
Other
0.6
0.6
0.6
0.9
Unknown
0.3
0.4
0.3
0.4
35.8
23.2
32.1
34.2
1
18.5
23.7
18.9
19.1
2-3
50.4
52.7
≥4
31.1
23.6
Medicaid eligibility
Original Investigation
Risk of Bleeding With Dabigatran in Atrial Fibrillation Inmaculada Hernandez, PharmD; Seo Hyon Baik, PhD; Antonio Piñera, MD; Yuting Zhang, PhD Editor's Note page 25 IMPORTANCE It remains unclear whether dabigatran etexilate mesylate is associated with
higher risk of bleeding than warfarin sodium in real-world clinical practice. OBJECTIVE To compare the risk of bleeding associated with dabigatran and warfarin using
Medicare data.
Supplemental content at jamainternalmedicine.com CME Quiz at jamanetworkcme.com and CME Questions page 152
DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study, we used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare beneficiaries. We identified participants as those newly diagnosed as having atrial fibrillation from October 1, 2010, through October 31, 2011, and who initiated dabigatran or warfarin treatment within 60 days of initial diagnosis. We followed up patients until discontinued use or switch of anticoagulants, death, or December 31, 2011. EXPOSURES Dabigatran users (n = 1302) and warfarin users (n = 8102). MAIN OUTCOMES AND MEASURES We identified any bleeding events and categorized them as major and minor bleeding by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria, gastrointestinal, or other hemorrhage. We used a propensity score weighting mechanism to balance patient characteristics between 2 groups and Cox proportional hazards regression models to evaluate the risk of bleeding. We further examined the risk of bleeding for 4 subgroups of high-risk patients: those 75 years or older, African Americans, those with chronic kidney disease, and those with more than 7 concomitant comorbidities. RESULTS Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 (95% CI, 1.20-1.41) for any bleeding event, 1.58 (95% CI, 1.36-1.83) for major bleeding, and 1.85 (95% CI, 1.64-2.07) for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 (95% CI, 0.20-0.50) for dabigatran compared with warfarin. Dabigatran was consistently associated with an increased risk of major bleeding and gastrointestinal hemorrhage for all subgroups analyzed. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. CONCLUSIONS AND RELEVANCE Dabigatran was associated with a higher incidence of major bleeding (regardless of the anatomical site), a higher risk of gastrointestinal bleeding, but a lower risk of intracranial hemorrhage. Thus, dabigatran should be prescribed with caution, especially among high-risk patients.
Author Affiliations: Department of Health Policy and Management, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania (Hernandez, Baik, Zhang); Department of Obstetrics and Gynecology, La Paz University Hospital, Madrid, Spain (Piñera).
JAMA Intern Med. 2015;175(1):18-24. doi:10.1001/jamainternmed.2014.5398 Published online November 3, 2014. 18
Corresponding Author: Yuting Zhang, PhD, Department of Health Policy and Management, University of Pittsburgh, 130 De Soto St, Crabtree Hall, Room A664, Pittsburgh, PA 15261 ([email protected]). jamainternalmedicine.com
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
Dabigatran Bleeding Risk
Original Investigation Research
T
he Food and Drug Administration (FDA) approved dabigatran etexilate mesylate for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) in October 20101 based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial.2 The RE-LY trial did not find differences in the rates of major bleeding between treatments; however, dabigatran was superior to warfarin sodium in the prevention of stroke. In addition, dabigatran etexilate mesylate, 150 mg, was associated with a higher risk of gastrointestinal bleeding but a lower rate of intracranial hemorrhage compared with warfarin. Several months after the approval of dabigatran, the FDA received a large number of reports of severe dabigatranrelated bleeding reports through its Adverse Event Reporting System. Concurrently, several case reports of dabigatraninduced bleeding were published in medical journals3-6 and discussed in the mainstream media.7 The incidence of serious bleeding was especially high among elderly users and users with renal impairment.5,6,8 On the basis of a study9 that did not adjust for patient characteristics, the FDA concluded that the incidence of gastrointestinal and intracranial bleeding was not higher for dabigatran compared with warfarin. In contrast, a meta-analysis10 found that dabigatran was associated with a significantly higher risk of gastrointestinal bleeding. In addition, a 2013 study11 using data from Danish National Registries found that the rates of major and gastrointestinal bleeding for warfarin and dabigatran were similar. It is still unclear whether the use of dabigatran leads to more bleeding compared with warfarin, especially in the realworld clinical practice. Using 2010 to 2011 Medicare Part D data, we examine this question among patients with AF.
Methods Data Source and Study Population The study was approved by the institutional review board at the University of Pittsburgh as exempt because existing deidentified data were used. We obtained a 5% random sample of Medicare beneficiaries in 2010 and 2011 (most recent data available) from the Centers for Medicare & Medicaid Services (CMS). We identified patients who were newly diagnosed as having AF from October 1, 2010, through October 31, 2011, by using the CMS Chronic Condition Warehouse indicator that traced the first diagnosis date back to January 1, 1999. The diagnosis of AF was defined as having 1 inpatient or 2 outpatient claims with primary or secondary International Classification of Diseases, Ninth Revision (ICD-9), code 427.31.12 We also required that individuals in our study sample had filled an outpatient prescription for either dabigatran or warfarin within 2 months of the first diagnosis (N = 9562). Those who filled prescriptions for dabigatran and warfarin during the first 2 months after diagnosis were excluded (N = 158). We followed up each individual from the first prescription of dabigatran or warfarin until discontinuation of use for more than 60 days, switch of anticoagulants, death, or December 31, 2011. Our final overall study sample included 1302 dabigatran users and 8102 warfarin users.
Outcomes We identified 9 types of bleeding according to anatomical position: intracranial hemorrhage, hemoperitoneum, gastrointestinal bleeding, hematuria, epistaxis, hemoptysis, vaginal hemorrhage, hemarthrosis, and not otherwise specified (NOS) hemorrhage (the ICD-9 codes for these bleeding events are listed in eTable 1 in the Supplement).13 We categorized bleeding events as major and minor events. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for gastrointestinal, hematuria, or NOS hemorrhage; minor bleeding events included epistaxis, hemoptysis, vaginal hemorrhage, hemarthrosis and any outpatient claim for hematuria, gastrointestinal, and NOS hemorrhage. Any bleeding included major and minor bleeding events. Several claims for the same type of bleeding made within 1 week were considered as the same event to avoid double counting.14 We defined time to bleeding as days between the first warfarin or dabigatran prescription and the date of the bleeding event. We analyzed the time to the first bleeding event, as well as the time to the first major hemorrhage, intracranial hemorrhage, gastrointestinal bleeding, hematuria, vaginal bleeding, hemarthrosis, hemoptysis, epistaxis, and NOS hemorrhage.
Covariates We adjusted for 2 main categories of covariates: demographic variables and clinical characteristics. Demographic variables included age, sex, race, and Medicaid eligibility. Clinical characteristics included CHADS2 (congestive heart failure, hypertension, age of 75 years or older, diabetes mellitus, and stroke) score, chronic kidney disease, hypertension, history of stroke or transient ischemic attack, history of acute myocardial infarction, diabetes mellitus, congestive heart failure, acquired hypothyroidism, the number of other CMS priority comorbidities (Table 1), history of bleeding in the year before treatment initiation, history of hospitalization in the year before treatment initiation, use of nonsteroidal inflammatory drugs (NSAIDs), use of antiplatelet agents, and the CMS prescription drug hierarchical condition category (CMS-RxHCC) score. The CHADS2 score predicts the risk of stroke in patients with AF; in calculating CHADS2, a history of previous stroke or transient ischemic attack is assigned 2 points; congestive heart failure, hypertension, age of 75 years or older, and diabetes are each assigned 1 point. The score is calculated as the sum of all points.15 The ICD-9 codes used to identify the conditions mentioned are listed in eTable 2 in the Supplement. History of bleeding was defined as having one medical claim with ICD-9 codes for any bleeding in the year before treatment initiation, and history of any hospitalization was defined as having at least one inpatient admission related to any condition in the year before treatment initiation. We defined the use of NSAIDs as having at least one prescription for diclofenac, ibuprofen, naproxen, ketoprofen, fenoprofen calcium, flurbiprofen, piroxicam, meloxicam, mefenamic acid, or indomethacin after treatment initiation. Use of antiplatelet agents was defined as having at least one pharmacy claim for aspirin, clopidogrel bisulfate, prasugrel, dipyridamol, ticlopidine hydrochloride, and ticagrelor after treatment initiation. The CMS-RxHCC score was
jamainternalmedicine.com
JAMA Internal Medicine January 2015 Volume 175, Number 1
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ by a New York University User on 05/19/2015
19
Research Original Investigation
Dabigatran Bleeding Risk
Table 1. Baseline Characteristics of the Cohorts, Before and After Propensity Score Weighting, by Treatment Group Propensity Score Weighting, % Before Characteristic Age, mean (SD), y
Warfarin (n = 8102)
P Value
Warfarin (n = 8102)
Dabigatran (n = 1302)
75.7 (8.5)
.02
75.6 (9.5)
40.9
42.3
.34
41.0
42.1
White
82.1
88.71
83.0
84.4
Black
8.7
3.6
8.1
6.4
Asian
2.0
1.8
1.9
2.4
Male sex
75.0 (10.4)
After
Dabigatran (n = 1302)
75.1 (10.2)
P Value .15 .49
Race
Hispanic
5.9
4.5
5.7
5.1
Native American
0.4
0.3
0.4
0.4
Other
0.6
0.6
0.6
0.9
Unknown
0.3
0.4
0.3
0.4
35.8
23.2
32.1
34.2
1
18.5
23.7
18.9
19.1
2-3
50.4
52.7
≥4
31.1
23.6
Medicaid eligibility
