ORIGINAL RESEARCH ARTICLE Evaluation of Dabigatran Bleeding Adverse Reaction Reports in the FDA Adverse Event Reporting System during the First Year of Approval Kevin W. McConeghy,1* Adam Bress,1 Dima M. Qato,1,2,3 Coady Wing,4 and Edith A. Nutescu,1,2,3 1
Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois; 2Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, Illinois; 3Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, Illinois; 4 Division of Health Policy and Administration, University of Illinois at Chicago, Chicago, Illinois
STUDY OBJECTIVE Evaluate dabigatran adverse event reports with a reported bleeding event and/or reported fatal outcome compared with warfarin. DESIGN Retrospective analysis of the FDA Adverse Event Reporting System (FAERS) database. MEASUREMENTS AND MAIN RESULTS We identified reports from October 1, 2010, through December 31, 2011, in the United States listing dabigatran or warfarin as the primary suspected agent. Bleeding events and related outcomes were determined. A bleeding-related mortality rate was calculated based on national dabigatran treatment data. RESULTS Dabigatran was the primary suspected agent in 9029 adverse reports. Of these, 2347 (26%) were bleeding events; a fatal outcome was reported in 348 (15%) of the bleeding events. In comparison, warfarin was the suspected agent in 2038 reports, of which 647 (32%) were reported as bleeding events. Among the warfarin bleeding reports, 46 (7.1%) reported a fatal outcome. Based on national dabigatran use and adverse bleed reports with fatal outcomes, we estimate a lower bound of 150 bleeding-related fatalities per 100,000 dabigatran patient-years. Because of underreporting bias, these estimates represent a lower bound on the population bleeding mortality rates. CONCLUSION Reports from FAERS are subject to significant bias but suggest that fatal outcomes among dabigatran reports are higher in clinical practice than they were in controlled clinical trials. KEY WORDS dabigatran, warfarin, atrial fibrillation, stroke prevention, bleeding. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1415
Disclosures: Edith A. Nutescu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL112908. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Edith A. Nutescu also receives research support from Janssen Health Economics and Outcomes Research and The Cranberry Institute. She serves on the board of regents for the American College of Clinical Pharmacy, board of directors of the Anticoagulation Forum, and the Medical and Scientific Advisory Board for the National Blood Clot Alliance. She serves as consultant for Janssen Health Economics and Outcomes Research, Daichii Sankyo, and CSL Behring. There are no other relevant disclosures for any of the other authors. Preliminary results of this study were presented at the American College of Cardiology 13th Annual Meeting, San Francisco, CA, March 9–11, 2013. J Am Coll Cardiol 2013;61:10S. *Author for correspondence: Kevin McConeghy, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
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Background Warfarin is the most widely prescribed oral anticoagulant for stroke prevention in nonvalvular atrial fibrillation (AF). However, the utility of warfarin is limited by variable dosing and a narrow therapeutic index that contribute to it being the leading cause of drug-related emergency hospitalizations among older adults in the United States.1 In October 2010, the Food and Drug Administration’s (FDA) approval of dabigatran for stroke prevention in nonvalvular AF offered the first alternative to warfarin. The FDA approval was based on the phase III clinical trial Evaluation of Long-Term Anticoagulant Therapy (RE-LY). In RE-LY, dabigatran 150 and 110 mg twice/day was tested against dose-adjusted warfarin in patients with AF and at least one stroke risk factor. Dabigatran 150 mg twice/day, the FDA-approved dosage, caused lower rates of stroke and systemic embolism (relative risk [RR] 0.66, 95% confidence interval [CI] 0.53–0.82]) with a similar risk of overall major bleeding (RR 0.93, 95% CI 0.81–1.07), lower risk of intracranial hemorrhage (RR 0.4, 95% CI 0.27–0.60), and higher rates of gastrointestinal hemorrhage (RR 1.5, 95% CI 1.19–1.89).2 From October 2010 to the end of 2011, the percentage of office visits for AF that were treated with dabigatran increased 4-fold, from 4–16.9%.3 Since the rapid expansion of dabigatran into clinical practice, both providers and patients have reported adverse bleeding events and poor clinical outcomes with dabigatran.4–8 Concerns have surfaced that these bleeding reports are driven by patients who are older, renally impaired, acutely injured, and have low body weight. These patients were not well-represented in RELY, and they may have higher risks of dabigatran-induced bleeding.5 In the RE-LY study, the average patient was 71 years of age; only one in three of the patients was 80 or older, and only one in five had a creatinine clearance less than 50 ml/minute.2, 5 A national cohort of Danish patients demonstrated 50% higher odds of dabigatran usage compared with warfarin in patients 75 years of age and older with AF.9 These patient-specific characteristics could increase risk of bleeding-related events with dabigatran compared with warfarin. Additionally, fatality rates among dabigatran-induced bleeding may be worse because bleeding from warfarin-induced coagulopathies can be reversed with vitamin K and fresh-frozen plasma, whereas dabigatran cannot be reversed with pharmacotherapy or transfu-
sion.10, 11 Therefore, the most likely factors contributing to these reports are either patient characteristics that increase the risk of bleeding or the acute consequences of dabigatran bleeds when they do occur. Recent evidence provides conflicting information that contradicts early reports of poorer than expected dabigatran outcomes. The FDA released an analysis of the Mini-Sentinel database that shows similar hospitalization rates due to bleeding among dabigatran and warfarin users.12 Those findings suggest that the gastrointestinal (GI) bleeding event rate per year among the elderly (75 years of age or older) is 0.9% with dabigatran and 1.7% with warfarin. This is different from the RE-LY study, in which GI bleeding in the elderly was the only subgroup where dabigatran had a higher risk than warfarin (2.8% vs 1.6%).13 This suggests that the Mini-Sentinel analysis may not be sufficiently sensitive to dabigatran-related bleeding events, and that further investigation is required before conclusions can be made about the safety of dabigatran in clinical practice. Additionally, a recent subanalysis of the RELY trial suggests a lower 30-day major bleeding mortality rate with dabigatran compared with warfarin (9.1 vs 13.0%, p=0.044),14 and a metaanalysis of clinical trial data suggests that bleeding rates and outcomes are similar or even better with dabigatran.15 These findings should be interpreted with caution. Clinical trials, such as RE-LY, followed strict inclusion/exclusion criteria, strict monitoring protocols, and were designed to limit inclusion of patients with a high-bleeding risk. For example, patients treated with both dabigatran and warfarin in the first year of RE-LY had follow-up visits at 14 days, 1 month, 3 months, and then every 3 months thereafter and then every 4 months until the study ended.2 It is quite possible that observational studies have found a higher risk of hemorrhage and hospitalization simply because in clinical settings, dabigatran and warfarin users have additional comorbidities and bleeding risk factors. But it is also possible that the relative efficacy of dabigatran is different in some of these new subpopulations or that levels of dabigatran monitoring are much lower in practice than in the trial setting and that the reduction in monitoring is a risk factor.16 If the existing clinical trials lack generalizability to clinical practice, surveillance in a practice setting is important for characterizing differential risks. Our objectives in this study were to describe the population of dabigatran users experiencing
BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al adverse events in clinical practice, estimate the fatality rate among bleeding reports for dabigatran and warfarin patients, and determine a lower bound estimate of dabigatran-related bleeding fatalities in the United States. Methods Data The FDA Adverse Event Reporting System Database (FAERS) is a voluntary surveillance system comprising reports of adverse events due to medications and related outcomes. These reports are sometimes received by manufacturers and forwarded to the FDA or are directly submitted from health care providers or consumers.17 The system has a number of well-known limitations as a tool for pharmacoepidemiologic research. Substantial underreporting is possible because reporting is voluntary for health care professionals, patients, or patient advocates who are aware of an adverse event. However, manufacturers are required to report any adverse events of which they are made aware. The raw data from FAERS may also contain duplicate cases and follow-up reports of the same event, which can lead to some degree of overreporting of specific cases. Additionally, the link between stated adverse reaction and reported outcome is subject to the reporter’s assessment and therefore limits causal inference. Identification of Dabigatran and Warfarin Adverse Event Reports The FAERS database was queried for U.S.based reports from October 1, 2010, through December 31, 2011, listing dabigatran or warfarin as the primary suspected agent. Drugs are entered as free-text strings into FAERS and were identified by searching for “dabigatran,” “Pradaxa,” “warfarin,” “Coumadin,” “Jantoven,” and possible misspellings (i.e., “dabigatron,” “dabigitran”). Drug information—including dose, indication, and duration of therapy—was included when available. Cases with the same ID case number (duplicates cases including follow-up reports) were consolidated by including only the report with the most recent FDA submission date. Identification of Bleeding Cases Our evaluation focused on outcomes associated with major or minor bleeding. The FAERS database does not differentiate major or minor
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bleeding by clinical criteria.18 Adverse events are described by the Medical Dictionary for Regulatory Activities (MedDRA) v.15.1 terminology.19 We identified “bleeding cases” as adverse events described with the terms “haemorrhage,” “haemorrhagic,” “haemotoma,” “hematoma,” “bleed,” “haemoptysis,” and “exsanguination.” To identify GI bleeding, we cross-referenced bleeding cases with the terms “gastrointestinal,” “oesophageal,” “intestinal,” “diarrhoea,” and “rectal.” And to identify intracranial bleeding, reports were cross-referenced using the terms “intracranial, “cerebral,” and “subdural.” Covariates Reports are required to have a primary suspected drug, adverse reaction, and outcome. Therefore, although reports of bleeding and outcomes are generally complete, the submission of covariate information is optional in FAERS, and only 15.4% of included cases reported age, gender, and weight. Age information was missing for 44% of dabigatran reports and 26% of warfarin reports. Gender information was missing for 13% of dabigatran and 4.6% of warfarin reports. Weight information was missing for 90% of dabigatran and 57% of warfarin reports. Only 18% of directly submitted reports had any missing data; 95% of manufacturer submitted reports had at least one missing covariate. When it was available in the report, we retained information on patient age, gender, weight, and the source of the report. Our stratified analysis was performed on cases with complete covariate information. Outcomes The goal of our analysis was to estimate the reported fatality rate among bleeding cases for warfarin and dabigatran. We defined the fatality rate as the number of bleeding cases where the reported outcome was death, divided by the total number of reported bleeding cases. We also examined the proportion of hospitalization events among bleeding events. The bleed-fatality rates do not provide a direct measure of the population-level risk of a bleed fatality. One study used data from the National Disease and Therapeutic Index (NDTI) to estimate medication treatment patterns for dabigatran from 2010 through the end of 2011 in the United States (the time frame of our study).3 There were 232,000 patient-years of dabigatran exposure estimated during this time period,
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which provided the denominator for our estimate of the population risk of bleeding fatalities among dabigatran users. Assuming that the bleeding fatalities are underreported to FAERS, our estimates represent a lower bound on the true bleeding fatality rate. An estimate of expected bleeding fatalities based on the RE-LY fatality rate was also determined for comparison (28 deaths among 486 major bleeds with 10,261 subject-years at risk).20 Statistical Analysis We compared outcomes of bleeding reports between warfarin reports and dabigatran reports using counts and proportions. We calculated reporting odds ratios with 95% CIs, stratifying reports by age and gender. Mantel-Haenszel tests for homogeneity were performed, with significant heterogeneity defined as a p value 100% because more than one indication and outcome is possible per case report (i.e., hospitalized and died). c Expedited and periodic reports are submitted by manufacturers. Reports must be submitted within 15 days for serious adverse reactions (expedited), or quarterly if designated less serious (periodic reports).
outcome. Reported adverse events among other dabigatran deaths varied but included reports of “death” (i.e., adverse event was reported as death, and outcome was death), “renal failure,” and cardiovascular events (“stroke,” “myocardial infarction,” and “arrhythmia”). Reported adverse events among other warfarin deaths included “completed suicide,” “death,” “medication error,” and “toxicity.” Dabigatran had significantly more deaths directly reported to the FDA than warfarin (84 vs 17) and more expedited reports from manufacturers (178 vs 27). Because missing data are a significant limitation of manufacturing reports, we performed a subgroup analysis limited to direct reports where data are more complete. Patient characteristics and indications were similar between warfarin and dabigatran reports in this subgroup. However, the case-fatality rate difference was more pronounced between dabigatran and warfarin (17% vs 4.1%, respectively) in this subgroup. This is
likely due to a large number (73%) of dabigatran reports submitted by manufacturers that reflected less serious reactions. Stratified Analysis of Age, Gender, and Weight among Reports We restricted reports to the 1702 with complete information on age, gender, and weight. Within these subgroups, we performed a stratified analysis of the reporting odds ratio (ROR) for dabigatran versus warfarin. An ROR greater than 1 suggests higher odds of an adverse report being bleed-related or resulting in fatal outcome for dabigatran versus warfarin (Table 2). The odds of a dabigatran report being bleed-related were higher in age group 75-84 years of age versus warfarin (ROR 1.4, 95% CI 1.0–1.9). Patients who weighed less than 100 kg on dabigatran versus warfarin had an ROR of 1.5 (95% CI 1.2–1.9) versus 0.5 (95% CI 0.3–0.8)
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Table 2. Stratified Analysis of Reporting Odds Ratios with Dabigatran versus Warfarin by Age, Gender, and Weight (n=1702) No. of cases Age ≤ 64 yrs 65–74 yrs 75–84 yrs ≥ 85 yrs Gender Male Female Weight < 100 kg ≥ 100 kg
a
Bleed report RORb
95% CI
No. of cases
c
Fatal outcome ROR
95% CI
141 214 316 174
0.9 1.0 1.4 1.2
0.6–1.5 0.7–1.5 1.0–1.9 0.4–1.9
11 30 34 18
8.5 3.7 7.2 5.3
1.9–52 1.4–10 2.2–37 1.2–48
497 348
0.7 2.7*
0.6–0.9 1.9–3.6
48 45
5.6 4.9
1.9–22 2.4–11
681 164
1.5 0.5*
1.2–1.9 0.3–0.8
15 79
4.7 7.3
2.4–9.7 1.8–41
No. of Reported Deaths 50 100
20 12 Q1
20 11 Q4
Q3
20 11
20 11 Q2
20 11 Q1
20 10
0
Q4
Fatalities were plotted by yearly quarter and adjusted for the number of dabigatran users. From 2010 to 2011, dabigatran treatment visits have increased from 63,000 to 363,000 per quarter, with an estimated 232,000 patient-years of exposure.3 Using these estimates of quarterly dabigatran use, we adjusted the counts of quarterly reports by drug volume per quarter to generate an estimated number of bleed fatalities per 100,000 dabigatran users. Figure 1 demonstrates bleeding-related fatalities by quarter adjusted and unadjusted for the number of users of dabigatran. Although the unadjusted number of case-fatalities has increased rapidly over time, it is stable when taking into account increasing use of the drug. If the underlying risk of the bleeding-fatality rate in clinical practice is the same as estimated in the RE-LY trial (272 deaths per 100,000 patient years), we would expect about 631 bleeding-related fatalities to have occurred in 2011 given published utilization estimates.3 Our analysis shows that 348 bleeding-related fatalities were reported to FAERS in 2011 (150 bleeding-related fatalities per 100,000 patient-years).
20 10
Death and Bleeding Reports over Time
Q3
for those 100 kg or greater. Dabigatran had a bleed report ROR of 2.7 (95% CI 1.9–3.6) among women and ROR of 0.7 (95% 0.6–0.9) among men versus warfarin. The RORs for a bleeding fatality were higher with dabigatran versus warfarin across age groups, weight, and gender.
150
CI = confidence interval. a Total number of bleed reports for each strata. b The reporting odds ratio (ROR) for dabigatran versus warfarin relates the odds of a report being a bleed-related adverse reaction versus another type of adverse reaction. c Total number of bleed reports with an outcome of death for each strata. *p value < 0.05 for test of homogeneity within strata.
Quarter of Year Deaths
Deaths adjusted for no. of users
Figure 1. Number of reported deaths among dabigatran adverse bleeding case reports from October 1, 2010, to December 31, 2011. ○ = Adverse bleeding reports with dabigatran where reported outcome was death. x = Reported deaths adjusted per 100,000 users.
Discussion Our review of the FAERS database shows that 25% of dabigatran adverse event reports are related to bleeding. Furthermore, significantly more reported deaths were due to bleeding with dabigatran (348) than warfarin (46); the proportion of bleed cases with a reported fatal outcome was twice as high with dabigatran compared with warfarin (14.8% vs 7.1%). This reported bleed-fatality rate significantly exceeds the observed rates from the phase III clinical trials (9.1% vs 13%). Consistent with the RE-LY trial results, dabigatran reports are less likely to reflect bleeding adverse reactions compared with warfarin but more likely to reflect GI bleeding.2
BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al The increased bleed-fatality rate observed in FAERS may represent a signal of increased risk of poor bleeding outcomes in certain subpopulations. The higher rates could be related to a combination of risk factors known to increase exposure and decrease elimination of dabigatran. For example, women on average have 10% higher drug exposure than men,20 and there was a higher proportion of women among dabigatran bleeding reports submitted to FAERS (54%) than what was reported in RE-LY (36%).2 Also, dabigatran is renally eliminated unchanged (80–85%) through glomerular filtration—and is therefore subject to accumulation with abrupt changes in renal function—whereas warfarin is hepatically metabolized.11 In healthy volunteers, the terminal half-life is 13.4 hours. In comparison, patients with moderate (30–59 ml/min) and severe renal impairment (15–29 ml/min) have terminal half-lives of 18.4 and 27.2 hours, respectively. Older age is highly correlated with decreasing renal function, but even after adjusting for renal function, each additional year of age past 72 years decreases clearance of the drug by 0.4%.20 Individuals weighing 50–100 kg also have decreased volumes of distribution and higher trough concentrations compared with those weighing 100 kg or more.20 Drug–drug interactions with inhibitors of P-glycoprotein transport of dabigatran (verapamil and amiodarone) can also increase dabigatran exposure by as much as 50%. However, despite these subgroups identified with increased drug exposure, the only significant interaction between treatment and bleeding in the RE-LY trial was age. Those 80 years of age and older and taking dabigatran had a 1% absolute increased risk of a major bleed annually compared with warfarin.13 Ultimately, an increased bleeding risk with dabigatran may be due to a confluence of these risk factors in the older population including decreased renal function, higher numbers of female users, low body weights, and more drug– drug interactions that together increase the drug exposure threshold to an unsafe margin—thus increasing bleed risk. This hypothesis is supported by a subgroup analysis of clinical trials. For example, compared with the clinical trials where 40% were at least 75 years old and a third of participants were women, the FDA reports cite a higher proportion of older patients and women. Other estimates confirm this trend in clinical practice, with U.S. claims data reporting that ~48% of patients using dabigatran are 75 years or older.3
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A recent analysis of an Italian cohort also demonstrated a mean age of 76 years, a higher use of amiodarone (20.2%) versus RE-LY (10.7%) and a population that was 57% female.21 At least one study has demonstrated that women and the elderly (75 years and older) have increased drug exposure with dabigatran, and that increased plasma concentrations are associated with major bleeding compared with no bleeding in RE-LY.20 A post hoc analysis of the RE-LY trial demonstrated a significant interaction between increasing age and increasing risk of major bleeding on dabigatran compared with warfarin.13 In the subgroup of 7258 patients 75 years and older in the RE-LY trial, the relative risk of major bleeding was 17% higher with dabigatran compared with warfarin. In that same subgroup, they observed an 80% higher relative risk of GI hemorrhage compared with warfarin.13 Our stratified analysis is consistent with this hypothesis, with increasing odds of dabigatran adverse reports being bleed related as age increases, among women versus men, and in patients with lower body weight (less than 100 kg). However, our analysis is subject to significant bias due to missing data and selective reporting. A Danish patient registry found a higher risk of bleeding among a cohort of elderly patients taking dabigatran compared with warfarin, although the availability of 110mg dosing in Europe makes comparison of their results challenging.9 This may have been due to the selection bias of high-risk patients because the difference was not significant (hazard ratio 1.13, 95% CI 0.69–1.85) when only comparing warfarin-naive patients. The estimated bleeding incidence for warfarin-naive patients on 150 mg twice/day in the Danish study was similar to RE-LY (3.6 vs 3.3 per 100 years), but they did not evaluate mortality. This selection bias of high-risk elderly patients for dabigatran may be a potential explanation for the signal of increased bleed fatalities in our data and in other reports. Another explanation may be offlabel use. A recent clinical trial of dabigatran versus warfarin for mechanical heart valve anticoagulation was terminated due to an increased risk of stroke (9 vs 0 stroke events) and bleeding (7 vs 2 bleeding events) in the dabigatran arm.22 A few reports stated a mechanical heart valve indication, but there was substantial missing data on therapeutic indication (~40% of reports). Our estimate of U.S. bleed fatalities is lower than expected compared with the clinical trial
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data (348 vs 631). However, our estimate is likely to be a lower bound on the bleed-fatality rate because of substantial underreporting in FAERS. An underreporting rate of 45% (i.e., one in two bleeds reported to the FDA) would equalize the two rates, but the true reporting bias is unknown and reporting rates may be substantially lower (1–10%). Post hoc analyses of the clinical trials, trial registry data, and the FDA Mini-Sentinel analysis all suggest lower or equivalent bleeding risk with dabigatran.12–14 Our analysis demonstrates a lower or similar proportion of bleedingrelated adverse reports with dabigatran compared with warfarin, with heterogeneity by age, weight, and gender. However, the number of case fatalities among these bleeds greatly exceeds warfarin, which was not directly evaluated by the FDA Mini-Sentinel analysis or previous reports. This represents an important signal for further evaluation. Therefore, FDA reports of increased bleeding-related morbidity and mortality with dabigatran remain important evidence of risk. Our analysis has limitations, and the FAERS data are subject to substantial biases. These include the possibility of duplicate entries, missing data on reports, misclassification of events and outcomes, misspelling of drug names, underreporting (for instance, 46 bleeding fatalities due to warfarin over 2 years is almost certainly a small fraction of the true number of fatalities), overreporting of serious adverse events (as in dabigatran bleed fatalities), and the Weber effect (dependence of reporting rate by time on the market of each drug).23 It is possible that despite a similar number of direct reports, and even more bleeding reports submitted for warfarin compared with dabigatran, that clinicians selectively report deaths due to dabigatran versus warfarin. This would falsely elevate the case-fatality rate. If present, however, this bias would have to account for a 2-fold increased risk of death among dabigatran reports compared with warfarin. Estimates of deaths and bleeding from the FAERS system performed by different researchers may also differ to some degree because of inclusion criteria for reporting, exclusion of duplicate reports and definitions of adverse events, outcomes, and drug identification. However, our estimates and overall conclusion of a signal for bleeding risk and fatalities are similar to reports by both the Institute for Safe Medication Practices and the FDA.4, 24
Conclusion Our analysis of the FAERS reports suggests increased odds of bleed-related mortality in clinical practice with dabigatran compared with the clinical trials. Further pharmacoepidemiologic analysis is required to uncover the “true” population case-fatality rate with dabigatran. Bleeding-related fatalities represent a critical end result of care that is important for patients and providers when choosing among various oral antithrombotic strategies. Although our estimates of the true population case-fatality rate from the FAERS data may be subject to significant bias, the research serves as an important step. Making inferences using estimates from highly controlled clinical trial data (e.g., RE-LY) may be problematic due to poor generalizability. Although we acknowledge our estimates from the FAERS data are provisional, they do support continued surveillance and investigation into this matter. Acknowledgments We would like to recognize Keith A. Rodvold, Janet Engle, and Larisa Cavallari for providing editorial, financial, and travel support to Kevin McConeghy and Adam Bress.
References 1. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Eng J Med 2011;365:2002–12. 2. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Eng J Med 2009;361:1139–51. 3. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes 2012;5:615–21. 4. The United States Food and Drug Administration. FDA drug safety communication: update on the risk for serious bleeding events with the anticoagulant Pradaxa. Available from http:// www.fda.gov/Drugs/DrugSafety/ucm326580.htm#data. Accessed November 6, 2012. 5. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Eng J Med 2012;366:864–6. 6. Cotton BA, McCarthy JJ, Holcomb JB. Acutely injured patients on dabigatran. N Eng J Med 2011;365:2040. 7. Starke RM, Dumont AS. Neurosurgical implications of dabigatran associated intracerebral hemorrhage. World Neurosurg 2012;79(1):75–7. 8. Thomas K. A promising drug with a flaw. The New York Times. , November 3, 2012:B1. 9. Sørensen R, Gislason G, Torp-Pedersen C, et al. Dabigatran use in Danish atrial fibrillation patients in 2011: a nationwide study. BMJ Open 2013;3(5):e002758. 10. Aiyagari V, Testai FD. Correction of coagulopathy in warfarin associated cerebral hemorrhage. Curr Opin Crit Care 2009;15:87–92. 11. Boehringer Ingelheim Pharmaceuticals, Inc. PRADAXA (dabigatran etexilate mesylate) package insert. Ridgefield, CT; 2012.
BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al 12. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Eng J Med 2013;368:1272–4. 13. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123:2363–72. 14. Majeed A, Hwang HG, Brueckmann M, et al. Management and outcomes of major bleeding on dabigatran or warfarin. Atlanta, GA: American Society of Hematology, Oral and Poster Abstract; 2012. 15. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110:453–60. 16. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689–96. 17. The United States Food and Drug Administration. FDA Adverse Event Reporting (FAERS). Available from http:// www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm. Accessed October 24, 2012. 18. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
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Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. Medical Dictionary for Regulatory Activities. MedDRA. Available from http://www.meddra.org/. Accessed October 10, 2013. Boehringer Ingelheim Pharmaceuticals Inc. FDA Advisory Committee briefing document, drug substance: dabigatran etexilate (DE). Drafted August 27, 2010. Meeting: September 20, 2010. Washington, DC. Available from http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM226009.pdf. Accessed November 12, 2013. Joppi R, Cinconze E, Mezzalira L, et al. Hospitalized patients with atrial fibrillation compared to those included in recent trials on novel oral anticoagulants: a population-based study. Eur J Intern Med 2013;24(4):318–23. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Eng J Med 2013;369:1206–2014. Hartnell NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy 2004;24:743–9. Furberg CD, Cohen MR. QuarterWatch monitoring FDA MedWatch Reports: anticoagulants the leading reported drug risk in 2011. Institute for Safe Medication Practices. Available from http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf. Accessed March 23, 2013.
Department of Pharmacy Practice, University of Illinois at Chicago, Chicago, Illinois; 2Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, Chicago, Illinois; 3Center for Pharmacoepidemiology and Pharmacoeconomic Research, University of Illinois at Chicago, Chicago, Illinois; 4 Division of Health Policy and Administration, University of Illinois at Chicago, Chicago, Illinois
STUDY OBJECTIVE Evaluate dabigatran adverse event reports with a reported bleeding event and/or reported fatal outcome compared with warfarin. DESIGN Retrospective analysis of the FDA Adverse Event Reporting System (FAERS) database. MEASUREMENTS AND MAIN RESULTS We identified reports from October 1, 2010, through December 31, 2011, in the United States listing dabigatran or warfarin as the primary suspected agent. Bleeding events and related outcomes were determined. A bleeding-related mortality rate was calculated based on national dabigatran treatment data. RESULTS Dabigatran was the primary suspected agent in 9029 adverse reports. Of these, 2347 (26%) were bleeding events; a fatal outcome was reported in 348 (15%) of the bleeding events. In comparison, warfarin was the suspected agent in 2038 reports, of which 647 (32%) were reported as bleeding events. Among the warfarin bleeding reports, 46 (7.1%) reported a fatal outcome. Based on national dabigatran use and adverse bleed reports with fatal outcomes, we estimate a lower bound of 150 bleeding-related fatalities per 100,000 dabigatran patient-years. Because of underreporting bias, these estimates represent a lower bound on the population bleeding mortality rates. CONCLUSION Reports from FAERS are subject to significant bias but suggest that fatal outcomes among dabigatran reports are higher in clinical practice than they were in controlled clinical trials. KEY WORDS dabigatran, warfarin, atrial fibrillation, stroke prevention, bleeding. (Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1415
Disclosures: Edith A. Nutescu is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K23HL112908. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Edith A. Nutescu also receives research support from Janssen Health Economics and Outcomes Research and The Cranberry Institute. She serves on the board of regents for the American College of Clinical Pharmacy, board of directors of the Anticoagulation Forum, and the Medical and Scientific Advisory Board for the National Blood Clot Alliance. She serves as consultant for Janssen Health Economics and Outcomes Research, Daichii Sankyo, and CSL Behring. There are no other relevant disclosures for any of the other authors. Preliminary results of this study were presented at the American College of Cardiology 13th Annual Meeting, San Francisco, CA, March 9–11, 2013. J Am Coll Cardiol 2013;61:10S. *Author for correspondence: Kevin McConeghy, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 833 S. Wood Street, Chicago, IL 60612; e-mail: [email protected]. Ó 2014 Pharmacotherapy Publications, Inc.
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Background Warfarin is the most widely prescribed oral anticoagulant for stroke prevention in nonvalvular atrial fibrillation (AF). However, the utility of warfarin is limited by variable dosing and a narrow therapeutic index that contribute to it being the leading cause of drug-related emergency hospitalizations among older adults in the United States.1 In October 2010, the Food and Drug Administration’s (FDA) approval of dabigatran for stroke prevention in nonvalvular AF offered the first alternative to warfarin. The FDA approval was based on the phase III clinical trial Evaluation of Long-Term Anticoagulant Therapy (RE-LY). In RE-LY, dabigatran 150 and 110 mg twice/day was tested against dose-adjusted warfarin in patients with AF and at least one stroke risk factor. Dabigatran 150 mg twice/day, the FDA-approved dosage, caused lower rates of stroke and systemic embolism (relative risk [RR] 0.66, 95% confidence interval [CI] 0.53–0.82]) with a similar risk of overall major bleeding (RR 0.93, 95% CI 0.81–1.07), lower risk of intracranial hemorrhage (RR 0.4, 95% CI 0.27–0.60), and higher rates of gastrointestinal hemorrhage (RR 1.5, 95% CI 1.19–1.89).2 From October 2010 to the end of 2011, the percentage of office visits for AF that were treated with dabigatran increased 4-fold, from 4–16.9%.3 Since the rapid expansion of dabigatran into clinical practice, both providers and patients have reported adverse bleeding events and poor clinical outcomes with dabigatran.4–8 Concerns have surfaced that these bleeding reports are driven by patients who are older, renally impaired, acutely injured, and have low body weight. These patients were not well-represented in RELY, and they may have higher risks of dabigatran-induced bleeding.5 In the RE-LY study, the average patient was 71 years of age; only one in three of the patients was 80 or older, and only one in five had a creatinine clearance less than 50 ml/minute.2, 5 A national cohort of Danish patients demonstrated 50% higher odds of dabigatran usage compared with warfarin in patients 75 years of age and older with AF.9 These patient-specific characteristics could increase risk of bleeding-related events with dabigatran compared with warfarin. Additionally, fatality rates among dabigatran-induced bleeding may be worse because bleeding from warfarin-induced coagulopathies can be reversed with vitamin K and fresh-frozen plasma, whereas dabigatran cannot be reversed with pharmacotherapy or transfu-
sion.10, 11 Therefore, the most likely factors contributing to these reports are either patient characteristics that increase the risk of bleeding or the acute consequences of dabigatran bleeds when they do occur. Recent evidence provides conflicting information that contradicts early reports of poorer than expected dabigatran outcomes. The FDA released an analysis of the Mini-Sentinel database that shows similar hospitalization rates due to bleeding among dabigatran and warfarin users.12 Those findings suggest that the gastrointestinal (GI) bleeding event rate per year among the elderly (75 years of age or older) is 0.9% with dabigatran and 1.7% with warfarin. This is different from the RE-LY study, in which GI bleeding in the elderly was the only subgroup where dabigatran had a higher risk than warfarin (2.8% vs 1.6%).13 This suggests that the Mini-Sentinel analysis may not be sufficiently sensitive to dabigatran-related bleeding events, and that further investigation is required before conclusions can be made about the safety of dabigatran in clinical practice. Additionally, a recent subanalysis of the RELY trial suggests a lower 30-day major bleeding mortality rate with dabigatran compared with warfarin (9.1 vs 13.0%, p=0.044),14 and a metaanalysis of clinical trial data suggests that bleeding rates and outcomes are similar or even better with dabigatran.15 These findings should be interpreted with caution. Clinical trials, such as RE-LY, followed strict inclusion/exclusion criteria, strict monitoring protocols, and were designed to limit inclusion of patients with a high-bleeding risk. For example, patients treated with both dabigatran and warfarin in the first year of RE-LY had follow-up visits at 14 days, 1 month, 3 months, and then every 3 months thereafter and then every 4 months until the study ended.2 It is quite possible that observational studies have found a higher risk of hemorrhage and hospitalization simply because in clinical settings, dabigatran and warfarin users have additional comorbidities and bleeding risk factors. But it is also possible that the relative efficacy of dabigatran is different in some of these new subpopulations or that levels of dabigatran monitoring are much lower in practice than in the trial setting and that the reduction in monitoring is a risk factor.16 If the existing clinical trials lack generalizability to clinical practice, surveillance in a practice setting is important for characterizing differential risks. Our objectives in this study were to describe the population of dabigatran users experiencing
BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al adverse events in clinical practice, estimate the fatality rate among bleeding reports for dabigatran and warfarin patients, and determine a lower bound estimate of dabigatran-related bleeding fatalities in the United States. Methods Data The FDA Adverse Event Reporting System Database (FAERS) is a voluntary surveillance system comprising reports of adverse events due to medications and related outcomes. These reports are sometimes received by manufacturers and forwarded to the FDA or are directly submitted from health care providers or consumers.17 The system has a number of well-known limitations as a tool for pharmacoepidemiologic research. Substantial underreporting is possible because reporting is voluntary for health care professionals, patients, or patient advocates who are aware of an adverse event. However, manufacturers are required to report any adverse events of which they are made aware. The raw data from FAERS may also contain duplicate cases and follow-up reports of the same event, which can lead to some degree of overreporting of specific cases. Additionally, the link between stated adverse reaction and reported outcome is subject to the reporter’s assessment and therefore limits causal inference. Identification of Dabigatran and Warfarin Adverse Event Reports The FAERS database was queried for U.S.based reports from October 1, 2010, through December 31, 2011, listing dabigatran or warfarin as the primary suspected agent. Drugs are entered as free-text strings into FAERS and were identified by searching for “dabigatran,” “Pradaxa,” “warfarin,” “Coumadin,” “Jantoven,” and possible misspellings (i.e., “dabigatron,” “dabigitran”). Drug information—including dose, indication, and duration of therapy—was included when available. Cases with the same ID case number (duplicates cases including follow-up reports) were consolidated by including only the report with the most recent FDA submission date. Identification of Bleeding Cases Our evaluation focused on outcomes associated with major or minor bleeding. The FAERS database does not differentiate major or minor
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bleeding by clinical criteria.18 Adverse events are described by the Medical Dictionary for Regulatory Activities (MedDRA) v.15.1 terminology.19 We identified “bleeding cases” as adverse events described with the terms “haemorrhage,” “haemorrhagic,” “haemotoma,” “hematoma,” “bleed,” “haemoptysis,” and “exsanguination.” To identify GI bleeding, we cross-referenced bleeding cases with the terms “gastrointestinal,” “oesophageal,” “intestinal,” “diarrhoea,” and “rectal.” And to identify intracranial bleeding, reports were cross-referenced using the terms “intracranial, “cerebral,” and “subdural.” Covariates Reports are required to have a primary suspected drug, adverse reaction, and outcome. Therefore, although reports of bleeding and outcomes are generally complete, the submission of covariate information is optional in FAERS, and only 15.4% of included cases reported age, gender, and weight. Age information was missing for 44% of dabigatran reports and 26% of warfarin reports. Gender information was missing for 13% of dabigatran and 4.6% of warfarin reports. Weight information was missing for 90% of dabigatran and 57% of warfarin reports. Only 18% of directly submitted reports had any missing data; 95% of manufacturer submitted reports had at least one missing covariate. When it was available in the report, we retained information on patient age, gender, weight, and the source of the report. Our stratified analysis was performed on cases with complete covariate information. Outcomes The goal of our analysis was to estimate the reported fatality rate among bleeding cases for warfarin and dabigatran. We defined the fatality rate as the number of bleeding cases where the reported outcome was death, divided by the total number of reported bleeding cases. We also examined the proportion of hospitalization events among bleeding events. The bleed-fatality rates do not provide a direct measure of the population-level risk of a bleed fatality. One study used data from the National Disease and Therapeutic Index (NDTI) to estimate medication treatment patterns for dabigatran from 2010 through the end of 2011 in the United States (the time frame of our study).3 There were 232,000 patient-years of dabigatran exposure estimated during this time period,
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which provided the denominator for our estimate of the population risk of bleeding fatalities among dabigatran users. Assuming that the bleeding fatalities are underreported to FAERS, our estimates represent a lower bound on the true bleeding fatality rate. An estimate of expected bleeding fatalities based on the RE-LY fatality rate was also determined for comparison (28 deaths among 486 major bleeds with 10,261 subject-years at risk).20 Statistical Analysis We compared outcomes of bleeding reports between warfarin reports and dabigatran reports using counts and proportions. We calculated reporting odds ratios with 95% CIs, stratifying reports by age and gender. Mantel-Haenszel tests for homogeneity were performed, with significant heterogeneity defined as a p value 100% because more than one indication and outcome is possible per case report (i.e., hospitalized and died). c Expedited and periodic reports are submitted by manufacturers. Reports must be submitted within 15 days for serious adverse reactions (expedited), or quarterly if designated less serious (periodic reports).
outcome. Reported adverse events among other dabigatran deaths varied but included reports of “death” (i.e., adverse event was reported as death, and outcome was death), “renal failure,” and cardiovascular events (“stroke,” “myocardial infarction,” and “arrhythmia”). Reported adverse events among other warfarin deaths included “completed suicide,” “death,” “medication error,” and “toxicity.” Dabigatran had significantly more deaths directly reported to the FDA than warfarin (84 vs 17) and more expedited reports from manufacturers (178 vs 27). Because missing data are a significant limitation of manufacturing reports, we performed a subgroup analysis limited to direct reports where data are more complete. Patient characteristics and indications were similar between warfarin and dabigatran reports in this subgroup. However, the case-fatality rate difference was more pronounced between dabigatran and warfarin (17% vs 4.1%, respectively) in this subgroup. This is
likely due to a large number (73%) of dabigatran reports submitted by manufacturers that reflected less serious reactions. Stratified Analysis of Age, Gender, and Weight among Reports We restricted reports to the 1702 with complete information on age, gender, and weight. Within these subgroups, we performed a stratified analysis of the reporting odds ratio (ROR) for dabigatran versus warfarin. An ROR greater than 1 suggests higher odds of an adverse report being bleed-related or resulting in fatal outcome for dabigatran versus warfarin (Table 2). The odds of a dabigatran report being bleed-related were higher in age group 75-84 years of age versus warfarin (ROR 1.4, 95% CI 1.0–1.9). Patients who weighed less than 100 kg on dabigatran versus warfarin had an ROR of 1.5 (95% CI 1.2–1.9) versus 0.5 (95% CI 0.3–0.8)
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Table 2. Stratified Analysis of Reporting Odds Ratios with Dabigatran versus Warfarin by Age, Gender, and Weight (n=1702) No. of cases Age ≤ 64 yrs 65–74 yrs 75–84 yrs ≥ 85 yrs Gender Male Female Weight < 100 kg ≥ 100 kg
a
Bleed report RORb
95% CI
No. of cases
c
Fatal outcome ROR
95% CI
141 214 316 174
0.9 1.0 1.4 1.2
0.6–1.5 0.7–1.5 1.0–1.9 0.4–1.9
11 30 34 18
8.5 3.7 7.2 5.3
1.9–52 1.4–10 2.2–37 1.2–48
497 348
0.7 2.7*
0.6–0.9 1.9–3.6
48 45
5.6 4.9
1.9–22 2.4–11
681 164
1.5 0.5*
1.2–1.9 0.3–0.8
15 79
4.7 7.3
2.4–9.7 1.8–41
No. of Reported Deaths 50 100
20 12 Q1
20 11 Q4
Q3
20 11
20 11 Q2
20 11 Q1
20 10
0
Q4
Fatalities were plotted by yearly quarter and adjusted for the number of dabigatran users. From 2010 to 2011, dabigatran treatment visits have increased from 63,000 to 363,000 per quarter, with an estimated 232,000 patient-years of exposure.3 Using these estimates of quarterly dabigatran use, we adjusted the counts of quarterly reports by drug volume per quarter to generate an estimated number of bleed fatalities per 100,000 dabigatran users. Figure 1 demonstrates bleeding-related fatalities by quarter adjusted and unadjusted for the number of users of dabigatran. Although the unadjusted number of case-fatalities has increased rapidly over time, it is stable when taking into account increasing use of the drug. If the underlying risk of the bleeding-fatality rate in clinical practice is the same as estimated in the RE-LY trial (272 deaths per 100,000 patient years), we would expect about 631 bleeding-related fatalities to have occurred in 2011 given published utilization estimates.3 Our analysis shows that 348 bleeding-related fatalities were reported to FAERS in 2011 (150 bleeding-related fatalities per 100,000 patient-years).
20 10
Death and Bleeding Reports over Time
Q3
for those 100 kg or greater. Dabigatran had a bleed report ROR of 2.7 (95% CI 1.9–3.6) among women and ROR of 0.7 (95% 0.6–0.9) among men versus warfarin. The RORs for a bleeding fatality were higher with dabigatran versus warfarin across age groups, weight, and gender.
150
CI = confidence interval. a Total number of bleed reports for each strata. b The reporting odds ratio (ROR) for dabigatran versus warfarin relates the odds of a report being a bleed-related adverse reaction versus another type of adverse reaction. c Total number of bleed reports with an outcome of death for each strata. *p value < 0.05 for test of homogeneity within strata.
Quarter of Year Deaths
Deaths adjusted for no. of users
Figure 1. Number of reported deaths among dabigatran adverse bleeding case reports from October 1, 2010, to December 31, 2011. ○ = Adverse bleeding reports with dabigatran where reported outcome was death. x = Reported deaths adjusted per 100,000 users.
Discussion Our review of the FAERS database shows that 25% of dabigatran adverse event reports are related to bleeding. Furthermore, significantly more reported deaths were due to bleeding with dabigatran (348) than warfarin (46); the proportion of bleed cases with a reported fatal outcome was twice as high with dabigatran compared with warfarin (14.8% vs 7.1%). This reported bleed-fatality rate significantly exceeds the observed rates from the phase III clinical trials (9.1% vs 13%). Consistent with the RE-LY trial results, dabigatran reports are less likely to reflect bleeding adverse reactions compared with warfarin but more likely to reflect GI bleeding.2
BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al The increased bleed-fatality rate observed in FAERS may represent a signal of increased risk of poor bleeding outcomes in certain subpopulations. The higher rates could be related to a combination of risk factors known to increase exposure and decrease elimination of dabigatran. For example, women on average have 10% higher drug exposure than men,20 and there was a higher proportion of women among dabigatran bleeding reports submitted to FAERS (54%) than what was reported in RE-LY (36%).2 Also, dabigatran is renally eliminated unchanged (80–85%) through glomerular filtration—and is therefore subject to accumulation with abrupt changes in renal function—whereas warfarin is hepatically metabolized.11 In healthy volunteers, the terminal half-life is 13.4 hours. In comparison, patients with moderate (30–59 ml/min) and severe renal impairment (15–29 ml/min) have terminal half-lives of 18.4 and 27.2 hours, respectively. Older age is highly correlated with decreasing renal function, but even after adjusting for renal function, each additional year of age past 72 years decreases clearance of the drug by 0.4%.20 Individuals weighing 50–100 kg also have decreased volumes of distribution and higher trough concentrations compared with those weighing 100 kg or more.20 Drug–drug interactions with inhibitors of P-glycoprotein transport of dabigatran (verapamil and amiodarone) can also increase dabigatran exposure by as much as 50%. However, despite these subgroups identified with increased drug exposure, the only significant interaction between treatment and bleeding in the RE-LY trial was age. Those 80 years of age and older and taking dabigatran had a 1% absolute increased risk of a major bleed annually compared with warfarin.13 Ultimately, an increased bleeding risk with dabigatran may be due to a confluence of these risk factors in the older population including decreased renal function, higher numbers of female users, low body weights, and more drug– drug interactions that together increase the drug exposure threshold to an unsafe margin—thus increasing bleed risk. This hypothesis is supported by a subgroup analysis of clinical trials. For example, compared with the clinical trials where 40% were at least 75 years old and a third of participants were women, the FDA reports cite a higher proportion of older patients and women. Other estimates confirm this trend in clinical practice, with U.S. claims data reporting that ~48% of patients using dabigatran are 75 years or older.3
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A recent analysis of an Italian cohort also demonstrated a mean age of 76 years, a higher use of amiodarone (20.2%) versus RE-LY (10.7%) and a population that was 57% female.21 At least one study has demonstrated that women and the elderly (75 years and older) have increased drug exposure with dabigatran, and that increased plasma concentrations are associated with major bleeding compared with no bleeding in RE-LY.20 A post hoc analysis of the RE-LY trial demonstrated a significant interaction between increasing age and increasing risk of major bleeding on dabigatran compared with warfarin.13 In the subgroup of 7258 patients 75 years and older in the RE-LY trial, the relative risk of major bleeding was 17% higher with dabigatran compared with warfarin. In that same subgroup, they observed an 80% higher relative risk of GI hemorrhage compared with warfarin.13 Our stratified analysis is consistent with this hypothesis, with increasing odds of dabigatran adverse reports being bleed related as age increases, among women versus men, and in patients with lower body weight (less than 100 kg). However, our analysis is subject to significant bias due to missing data and selective reporting. A Danish patient registry found a higher risk of bleeding among a cohort of elderly patients taking dabigatran compared with warfarin, although the availability of 110mg dosing in Europe makes comparison of their results challenging.9 This may have been due to the selection bias of high-risk patients because the difference was not significant (hazard ratio 1.13, 95% CI 0.69–1.85) when only comparing warfarin-naive patients. The estimated bleeding incidence for warfarin-naive patients on 150 mg twice/day in the Danish study was similar to RE-LY (3.6 vs 3.3 per 100 years), but they did not evaluate mortality. This selection bias of high-risk elderly patients for dabigatran may be a potential explanation for the signal of increased bleed fatalities in our data and in other reports. Another explanation may be offlabel use. A recent clinical trial of dabigatran versus warfarin for mechanical heart valve anticoagulation was terminated due to an increased risk of stroke (9 vs 0 stroke events) and bleeding (7 vs 2 bleeding events) in the dabigatran arm.22 A few reports stated a mechanical heart valve indication, but there was substantial missing data on therapeutic indication (~40% of reports). Our estimate of U.S. bleed fatalities is lower than expected compared with the clinical trial
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data (348 vs 631). However, our estimate is likely to be a lower bound on the bleed-fatality rate because of substantial underreporting in FAERS. An underreporting rate of 45% (i.e., one in two bleeds reported to the FDA) would equalize the two rates, but the true reporting bias is unknown and reporting rates may be substantially lower (1–10%). Post hoc analyses of the clinical trials, trial registry data, and the FDA Mini-Sentinel analysis all suggest lower or equivalent bleeding risk with dabigatran.12–14 Our analysis demonstrates a lower or similar proportion of bleedingrelated adverse reports with dabigatran compared with warfarin, with heterogeneity by age, weight, and gender. However, the number of case fatalities among these bleeds greatly exceeds warfarin, which was not directly evaluated by the FDA Mini-Sentinel analysis or previous reports. This represents an important signal for further evaluation. Therefore, FDA reports of increased bleeding-related morbidity and mortality with dabigatran remain important evidence of risk. Our analysis has limitations, and the FAERS data are subject to substantial biases. These include the possibility of duplicate entries, missing data on reports, misclassification of events and outcomes, misspelling of drug names, underreporting (for instance, 46 bleeding fatalities due to warfarin over 2 years is almost certainly a small fraction of the true number of fatalities), overreporting of serious adverse events (as in dabigatran bleed fatalities), and the Weber effect (dependence of reporting rate by time on the market of each drug).23 It is possible that despite a similar number of direct reports, and even more bleeding reports submitted for warfarin compared with dabigatran, that clinicians selectively report deaths due to dabigatran versus warfarin. This would falsely elevate the case-fatality rate. If present, however, this bias would have to account for a 2-fold increased risk of death among dabigatran reports compared with warfarin. Estimates of deaths and bleeding from the FAERS system performed by different researchers may also differ to some degree because of inclusion criteria for reporting, exclusion of duplicate reports and definitions of adverse events, outcomes, and drug identification. However, our estimates and overall conclusion of a signal for bleeding risk and fatalities are similar to reports by both the Institute for Safe Medication Practices and the FDA.4, 24
Conclusion Our analysis of the FAERS reports suggests increased odds of bleed-related mortality in clinical practice with dabigatran compared with the clinical trials. Further pharmacoepidemiologic analysis is required to uncover the “true” population case-fatality rate with dabigatran. Bleeding-related fatalities represent a critical end result of care that is important for patients and providers when choosing among various oral antithrombotic strategies. Although our estimates of the true population case-fatality rate from the FAERS data may be subject to significant bias, the research serves as an important step. Making inferences using estimates from highly controlled clinical trial data (e.g., RE-LY) may be problematic due to poor generalizability. Although we acknowledge our estimates from the FAERS data are provisional, they do support continued surveillance and investigation into this matter. Acknowledgments We would like to recognize Keith A. Rodvold, Janet Engle, and Larisa Cavallari for providing editorial, financial, and travel support to Kevin McConeghy and Adam Bress.
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BLEEDING ADVERSE REACTION REPORTS WITH DABIGATRAN McConeghy et al 12. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Eng J Med 2013;368:1272–4. 13. Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123:2363–72. 14. Majeed A, Hwang HG, Brueckmann M, et al. Management and outcomes of major bleeding on dabigatran or warfarin. Atlanta, GA: American Society of Hematology, Oral and Poster Abstract; 2012. 15. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol 2012;110:453–60. 16. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 2007;115:2689–96. 17. The United States Food and Drug Administration. FDA Adverse Event Reporting (FAERS). Available from http:// www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm. Accessed October 24, 2012. 18. Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis.
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Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005;3:692–4. Medical Dictionary for Regulatory Activities. MedDRA. Available from http://www.meddra.org/. Accessed October 10, 2013. Boehringer Ingelheim Pharmaceuticals Inc. FDA Advisory Committee briefing document, drug substance: dabigatran etexilate (DE). Drafted August 27, 2010. Meeting: September 20, 2010. Washington, DC. Available from http://www.fda.gov/ downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ UCM226009.pdf. Accessed November 12, 2013. Joppi R, Cinconze E, Mezzalira L, et al. Hospitalized patients with atrial fibrillation compared to those included in recent trials on novel oral anticoagulants: a population-based study. Eur J Intern Med 2013;24(4):318–23. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Eng J Med 2013;369:1206–2014. Hartnell NR, Wilson JP. Replication of the Weber effect using postmarketing adverse event reports voluntarily submitted to the United States Food and Drug Administration. Pharmacotherapy 2004;24:743–9. Furberg CD, Cohen MR. QuarterWatch monitoring FDA MedWatch Reports: anticoagulants the leading reported drug risk in 2011. Institute for Safe Medication Practices. Available from http://www.ismp.org/quarterwatch/pdfs/2011Q4.pdf. Accessed March 23, 2013.
