pharmacoepidemiology and drug safety (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3648
ORIGINAL REPORT
An international comparison of spontaneous adverse event reports and potentially inappropriate medicine use associated with dabigatran Cameron J. McDonald, Lisa M. Kalisch Ellett, John D. Barratt and Gillian E. Caughey* Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
ABSTRACT Purpose The objective of this study was to analyse spontaneous adverse event (SAE) reports associated with the oral anticoagulant dabigatran from Australia, Canada and USA and to examine concomitant medicine use. Methods Spontaneous adverse event national databases from Australia, Canada and the USA were used to examine all reports of adverse events associated with dabigatran from 1st August 2005 to 31st March 2013. Disproportionality analysis was conducted for the quantitative detection of signals using the USA database. Concomitant medicine use was examined to identify potentially inappropriate medicines, which may place the patient at increased risk for adverse events. Results There were a total of 1039, 1333 and 13 788 SAE reports associated with dabigatran from Australia, Canada and USA, respectively. Gastrointestinal (GI) disorders were the most commonly reported adverse event, ranging from 27.5% for Australia and up to 40.5% for USA. Of these, GI haemorrhage accounted for 81.5% of Australian, 71.5% of Canadian and 42% of the USA adverse event reports for GI disorders. Positive signals were confirmed in the USA data (GI haemorrhage; PRR 18.18, χ2 40993.51 and ROR 19.55 95% CI 18.77–20.36). Use of concomitant medicines with the potential to increase bleeding risk across all three countries ranged from 34.1% for Australia to 51.1% for the USA. Conclusions A large proportion of adverse events were associated with concomitant therapies, which may have placed the patient at increased risk of harm. This highlights the need for pharmacovigilance by the prescribing clinician to minimise risk and ensure the safe and effective integration of dabigatran into routine clinical practice. Copyright © 2014 John Wiley & Sons, Ltd. key words—dabigatran; adverse event; haemorrhage; inappropriate prescribing; pharmacoepidemiology Received 18 December 2013; Revised 21 April 2014; Accepted 22 April 2014
INTRODUCTION Dabigatran is a direct thrombin inhibitor indicated for thromboembolic stroke prevention in atrial fibrillation and prophylaxis of deep vein thrombosis post hip and knee arthroplasty.1 Clinical trial data and subsequent meta-analyses have highlighted several safety concerns potentially associated with dabigatran. When compared with warfarin, a recent meta-analysis showed that dabigatran is associated with an increased risk of gastrointestinal haemorrhage (relative risk (RR) 1.41, 95% CI 1.28–1.55).2 Further, concerns have been raised of a trend towards an increased risk of
*Correspondence to: G. E. Caughey, Senior Research Fellow, Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA 5001, Australia. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
myocardial infarction (MI) with dabigatran (hazard ratio (HR) 1.30, 95% CI 0.93–1.81) by comparison with warfarin3 and increased drug discontinuation rates because of adverse events (RR 1.62, 95% CI 1.23–2.15).1 Currently, no antidote exists to reverse the anticoagulant effect of dabigatran in the event of haemorrhage.4 Further, dabigatran has potentially clinically significant interactions with potent inhibitors of P-glycoprotein and concomitant use of other antithrombotics or medicines associated with increased bleeding risk may increase the potential to develop adverse haemorrhagic events with dabigatran.5 There are a number of limitations associated with pre-marketing randomised clinical trials. Firstly, they often have a sample size that is too small to identify adverse events that have low incidence but are of clinical significance. The time of follow-up is relatively short (6–12 months on average), hence, they are unable
c. j. mcdonald et al.
to identify long-term adverse events potentially associated with a medicine.6 Finally, older patients, those with comorbidity, and those taking concomitant medicines, are generally excluded from these premarketing clinical trials. This means that when medicines reach the market, we have limited knowledge of their use in real-world patient populations. Postmarketing surveillance of medicines is important as it allows us to monitor the safety of medicines when they are used in clinical practice.6 Spontaneous adverse event (SAE) reporting involves the voluntary submission of adverse events experienced by patients to a centralised database by either the patient themselves or their health care provider.6 A series of SAE reports involving the same medicine, and the same adverse event can provide a signal of a potential adverse event associated with a medicine.6 The aim of this study was to analyse SAE reports from Australia, Canada and US in order to perform a cross-country comparison of adverse events reported for dabigatran, focusing specifically on haemorrhage and MI and to examine the reporting of concomitant medicine use that may potentiate bleeding risk. RESEARCH DESIGN AND METHODS Data source and study design Spontaneous adverse event reports from Australia, Canada and US were obtained for dabigatran from publically available online databases. Australian data was obtained from the Australian Therapeutic Goods Administration’s Database of Adverse Event Notifications for Medicines,7 Canadian data was obtained from Health Canada’s Vigilance Adverse Reaction Online Database8and USA data was obtained from the Food and Drug Administration Adverse Events Reporting System (FAERS) database.9 We included reports from the earliest available to the latest available date, ranging from the 1st August 2005 to 31st March 2013. The FAERS database contains reports from around the world, for the purposes of this study, only reports originating from the USA were included. Outcome definition Frequency of reporting of adverse events, grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC), were analysed for all datasets, to generate case report counts and reporting ratios. Patients who reported more than one adverse event classified under the same MedDRA SOC classification had these adverse events treated as Copyright © 2014 John Wiley & Sons, Ltd.
one adverse event. The outcomes of interest included those most commonly reported in clinical trials of dabigatran, namely haemorrhage and MI.1–3 Analyses were initially at the SOC level (including gastrointestinal disorders, nervous system disorders, vascular disorders and cardiac disorders), and then MedDRA preferred terms were used for the search strategy with a focus on haemorrhage and MI. All types of haemorrhage were also examined within any of the MedDRA SOC classification. Death was also examined but was only available in the Canadian and USA SAE reports. Concomitant medicines reported in adverse event reports were analysed to identify the prevalence of concomitant medicine use and specifically those with the potential to increase the risk of adverse events. These potentially inappropriate concomitant medicines were identified from Australian Therapeutic Guidelines10 and Australian Medicines Handbook11 and subsequently categorised into one of three groups; concomitant antithrombotics, concomitant bleeding risk medicines and medicines with potentially clinically significant interactions. Antithrombotic agents included warfarin, heparins, platelet aggregation inhibitors, direct thrombin inhibitors and direct Factor Xa inhibitors (ATC Codes B01A, excluding B01AE07—dabigatran). Bleeding risk medicines included non-steroidal anti-inflammatory drugs (NSAIDs, M01A), selective serotonin reuptake inhibitors (SSRIs, N06AB) and oral (systemic) corticosteroids (H02A). Medicines with potentially clinically significant interactions that would increase dabigatran exposure (p-glycoprotein inducers) included systemic azole antifungals (J02AB, JO2AC), macrolide antibiotics (J01FA), HIV protease inhibitors (J05AE), cyclosporine (L04AD01), dronedarone (C01BD07), tacrolimus (L04AD02), verapamil (C08DA01), amiodarone (C01BA01) and quinidine (C01BA01).10, 11 Statistical analysis The frequency of adverse events reported by MedDRA terms was calculated as a proportion of all adverse event reports for dabigatran within each of the datasets. The prevalence of concomitant therapies and those that were potentially inappropriate were calculated as a proportion of all SAE reports where concomitant therapies were reported for each of the datasets. Disproportionality analyses were conducted on the FAERS data only using the proportional reporting ratio (PRR) and the reporting odds ratio (ROR) to quantitate the strength of the association between observed adverse events and the suspected medicines from SAE reports.12, 13 These analyses were Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
adverse events associated with dabigatran
only able to be conducted using the FAERS data as both the Australian and Canadian SAE reporting databases do not have publicly available all the required data for this type of analyses, including total number of medicine adverse event reports in each dataset and the total number of individual types of adverse events reported by MedDRA terms. Using the PRR, a signal is detected if the count of co-occurrences ≥3 and the PRR ≥2.0 with an associated χ 2 value of ≥4.0.12 For the ROR, a signal is detected if the lower bound of the 95% two-sided confidence interval exceeds 1.13 Each adverse event report may contain multiple medicines and adverse events, the PRR and ROR calculated for all medicine/adverse event pairs. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS During the study period, there were 1039 SAE reports for dabigatran within the Australian database, 1333 in the Canadian database and 13 788 dabigatran SAE reports in the USA. The demographics of those who experienced the adverse event are described in Table 1, with the average age across all three databases of 76 years and the proportion of males ranged from 48.2% in USA to 58.3% in Australia. The frequency of the types of adverse events reported for dabigatran are shown in Table 1. For all three countries, gastrointestinal disorders were the most frequently reported adverse event, ranging from 27.5% of all reports for Australia, up to 40.5% for the USA (Table 1). Of these, gastrointestinal haemorrhage accounted for 81.5% of Australian, 71.5% of Canadian and 42% of USA gastrointestinal
adverse event reports. Nervous system disorders were the next most common reported adverse event, ranging from 16% for Australia to 31% for the Canadian adverse event reports. Nervous system haemorrhage ranged from 14% to 28% of all nervous system adverse event reports. Approximately 10% of all reports were for a vascular adverse event, and over half of these were a vascular haemorrhage for all countries. Cardiac adverse event disorders ranged from 7.1% for the USA to 9.6% for Canada of all adverse events reported. Whilst overall prevalence of myocardial infarction in SAE reports ranged from 0.7% to 3.2%, myocardial infarction accounted for almost a third of all reported cardiac adverse events for Australia and Canada, whereas it was only 10% in the USA. Death was not reported in the Australian dataset, but 7.2% of USA and 15.8% of Canadian reports associated with dabigatran use reported death as the outcome. Disproportionality analyses of the USA FAERS database found positive signals detected for all individual types of haemorrhage associated with dabigatran use, with GI haemorrhage resulting in the strongest signal (Table 2). In accord, all types of haemorrhage also generated positive signals. Signal strengths were similar for both types of disproportionality analyses. No signal was detected for an association of dabigatran use with cardiac disorders or specifically myocardial infarction using either method (Table 2). Concomitant medicines were reported in 41% of the adverse event reports associated with dabigatran in the Australian and Canadian databases and 44% of the USA FAERS. The average number of concomitant medicines reported in adverse event reports ranged from 4.5 ± 3.1 in the Australian dataset, 4.9 ± 3.8 in the Canadian dataset and 5.7 ± 4.2 in the USA dataset. The
Table 1. Demographics and type of spontaneous adverse events reported by Medical Dictionary for Regulatory Activities Classification for dabigatran* Australia n = 1039 Demographics Age (mean years ± SD, n) Gender (% male) Type of adverse event Gastrointestinal disorders - Gastrointestinal haemorrhage Nervous system disorders - Nervous system haemorrhage Vascular disorders - Vascular haemorrhage Cardiac disorders Myocardial infarction All haemorrhage Death
76.6 ± 10.4 (n = 372) 58.3% n % 286 27.5% 233 81.5% 167 16.1% 47 28.0% 88 8.5% 55 62.5% 88 8.5% 34 38.6% 367 35.3% N/A N/A
Canada
US
n = 1333
n = 13788
76.1 ± 11.3 (n = 886) 54.9% n % 495 37.1% 354 71.5% 413 31.0% 87 21.0% 181 13.6% 97 53.6% 128 9.6% 41 32.1% 582 43.7% 210 15.8%
75.2 ± 10.1 (n = 8225) 48.2% n % 5579 40.5% 2345 42.0% 2986 21.7% 422 14.1% 1478 10.7% 786 53.2% 983 7.1% 98 10% 3786 27.5% 991 7.2%
*Frequencies calculated as a proportion of all dabigatran spontaneous adverse event reports per country.
Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
c. j. mcdonald et al. Table 2. Signal detection for Dabigatran-associated adverse events in the USA Food and Drug Administration Adverse Events Reporting System database. Type of adverse event Gastrointestinal disorders - Gastrointestinal haemorrhage Nervous system disorders - Nervous system haemorrhage Vascular disorders - Vascular haemorrhage All haemorrhage Cardiac disorders - Myocardial Infarction
2
N
PRR (χ )
ROR (95% CI)
8864
3.19 (14399.60)*
3.94 (3.84–4.03)*
2566
18.18 (40993.51)*
19.55 (18.77–20.36)*
3684
1.51 (676.32)
1.57 (1.51–1.62)*
462
14.12 (5537.15)*
14.29 (13.02–15.68)*
1626 791
2.25 (114.55)* 15.47 (10529.54)*
2.31 (2.19–2.42)* 15.81 (14.73–16.98)*
4353 1227 115
12.75 (46917.73)* 0.84 (41.15) 0.50 (57.11)
14.43 (13.97–14.89)* 0.83 (0.78–0.88) 0.50 (0.42–0.60)
PRR, proportional reporting ratio; ROR, reporting odds ratio. N, number of occurrences of the medicine/adverse event pair reported. *Signal detected.
potentially inappropriate concomitant therapy most commonly reported in all three countries was concomitant administration of antithrombotic agents in combination with dabigatran, with prevalence ranging from 17.4% to 31.9%. Aspirin was the most commonly reported antithrombotic in all countries (Table 3). Bleeding risk medicines were the second most prevalent potentially inappropriate therapy in Australia and Canada and the third most prevalent in the US with prevalence ranging from 11.5% to 13.7% across all three countries (Table 3). Selective serotonin reuptake inhibitors were the most common concomitant bleeding-risk medicine in both Australia and US datasets, with overall prevalence ranging from 3.6% to 6.9% across all three countries. Non-steroidal antiinflammatory drugs were the most prevalent bleeding risk medicines in Canadian adverse event reports, with overall prevalence ranging from 2.1% to 5.3% across all three countries. Medicines with the potential for drug–drug interactions with dabigatran were the least prevalent of the potentially inappropriate concomitant therapies (with the exception of US), with amiodarone being the most prevalent in Australian and Canadian datasets (prevalence ranging from 4.9% to 7.0% across all three countries) and dronedarone being the most prevalent in the US dataset (present in 7.0% of US adverse event reports). Overall, across all three countries, between 34.1% and 51.1% of adverse event reports associated with dabigatran reported the concomitant use of at least Copyright © 2014 John Wiley & Sons, Ltd.
Table 3. Prevalence of potentially inappropriate concomitant therapy in Dabigatran spontaneous adverse event reports*
Medication class Concomitant antithrombotic Aspirin Warfarin Clopidogrel Concomitant bleedingrisk medicines NSAIDs SSRIs Corticosteroids (systemic) Concomitant medicines with potential drug-drug interactions Amioderone Verapamil Dronedarone Overall proportion of potentially inappropriate therapy†
Australia
Canada
US
n = 425
n = 550
N = 6123
N (%)
N (%)
N (%)
74 (17.4%)
112 (20.4%)
1952 (31.9%)
46 (10.8%) 17 (4.0%) 14 (3.3%) 51 (12.0%)
50 (9.1%) 31 (5.6%) 28 (5.1%) 63 (11.5%)
1474 (24.1%) 341 (5.6%) 295 (4.8%) 841 (13.7%)
9 (2.1%) 26 (6.1%) 20 (4.7%)
27 (4.9%) 20 (3.6%) 21 (3.8%)
327 (5.3%) 420 (6.9%) 192 (3.1%)
45 (10.6%)
54 (9.8%)
1045 (17.1%)
25 (5.9%) 17 (4.0%) — 34.1%
27 (4.9%) — 17 (3.1%) 40.2%
431 (7.0%) 143 (2.3%) 473 (7.7%) 51.1%
*Only those concomitant medicines with a prevalence over 2% are shown. Expressed as proportion of adverse event reports where at least one potentially inappropriate bleeding-risk medicine was reported.
†
one medicine with the potential to increase patient’s risk of experiencing adverse events (Table 3). DISCUSSION This is the first study to examine the SAE reports from Australia, Canada and the USA, for the new oral anticoagulant, dabigatran. Analysis of adverse events reported from use of dabigatran in clinical practice are concordant with those seen in clinical trials; primarily, gastrointestinal adverse events and haemorrhage, specifically gastrointestinal haemorrhage. Gastrointestinal associated disorders were the most common type of adverse event reported for dabigatran, accounting for between 28% and 40% of all SAE reports, with the majority of these adverse events for a gastrointestinal haemorrhage. Overall, a third of all spontaneous adverse reports for dabigatran were for some type of haemorrhage, across all three countries studied. Disproportionality analysis of the USA FAERS database confirmed positive signals for these major adverse events, but not myocardial infarct associated with dabigatran. The use of concomitant medicines was high, with an average of five different medicines reported. Of concern, however, was the high prevalence of potentially inappropriate concomitant therapy use. Across countries between a third and half of all Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
adverse events associated with dabigatran
dabigatran adverse events reports were associated with a potentially inappropriate concomitant therapy, which may have placed the patient at increased risk of harm. The findings from our cross-country comparison that gastrointestinal disorders are the most common body system likely to be affected by an adverse event for dabigatran is in concordance with the results of the RE-LY clinical trial of dabigatran versus warfarin, where gastrointestinal disorders were the most common type of adverse event reported.14 Gastrointestinal haemorrhage was the most common of these in accord with the results from the RE-LY clinical trial, where dabigatran (at the highest dose 150 mg) was shown to have a 50% increased incidence of gastrointestinal haemorrhage (RR 1.50, 95% CI 1.19 - 1.89) by comparison with warfarin.14 In an analysis of the risk of MI from the RE-LY clinical trial, dabigatran (150 mg) was reported to have a trend towards increased risk of MI (HR 1.30, 95% CI 0.93–1.81) by comparison to warfarin.3 In our study, disproportionality analysis failed to find a positive signal for an association of dabigatran with MI. Concomitant antithrombotic medicines were the most prevalent potentially inappropriate medicine class across all countries, with aspirin the most common concomitant antithrombotic in all dataset adverse event reports across countries. A subgroup analysis of the RE-LY trial showed that concomitant administration of anti-platelet therapy with dabigatran (approximately 20% of patients who took dabigatran used aspirin continuously during the treatment period14), increased the risk of bleeding compared with dabigatran alone but did not improve primary prevention of stroke or systemic embolism by comparison with warfarin alone.15 Over one in ten adverse event reports reported concomitant use of medicines potentially associated with an increased risk of bleeding in our study. Although no current studies have assessed the clinical outcomes associated with concomitant administration of new oral anticoagulants with NSAIDs or SSRIs, a pharmacological basis for potential increased bleeding risk in these patients exists.16 Concomitant use of NSAIDs in combination with warfarin is associated with a 13-fold increase in haemorrhagic peptic ulcer disease in patients 65 years and older when compared with baseline.17 Use of SSRIs in monotherapy has been shown to increase risk of gastrointestinal bleeding by up to three-fold compared with baseline.18 Medicines with established or potential interactions that are clinically relevant were reported in 10% to Copyright © 2014 John Wiley & Sons, Ltd.
17% of adverse event reports. The most prevalent drug–drug interaction reported was amiodarone in the Australian and Canadian adverse event reports and dronedarone the most common in US adverse event reports. An emergency information release by Boehringer Ingelheim, the manufacturer of dabigatran, during the RE-LY trial, highlighted the potential for increased bleeding risk with concomitant administration of moderate to strong P-glycoprotein inhibitors, such as verapamil and amiodarone with dabigatran.19 Simultaneous administration of dabigatran and dronedarone increases exposure to dabigatran by 70 to 140%,19 with the emergency release during the RE-LY trial stating that concomitant administration of dronedarone and dabigatran was not recommended.19 Given that these medicines are used for cardiac arrhythmias, and the likelihood of their concomitant use with dabigatran in atrial fibrillation is high, ascertaining the clinical relevance of these interactions and potential for serious adverse events is paramount to determining the risk/benefit profile of their concomitant use. The high frequency of overall concomitant use of medicines that have the potential to increase the risk of adverse events is of particular importance given the current inability to reverse the anticoagulant effect of dabigatran and the haemorrhagic adverse events being reported in clinical practice. The haemorrhage rates associated dabigatran have only been ascertained in randomised controlled trials; however, in comparison, the patients using these medicines in clinical practice are likely to be older, with potentially more comorbid conditions and therefore using more concomitant medicines than in the randomised controlled trials.20 Further, clinically relevant subgroups of patients with AF where the risk of both stroke and bleeding are increased include those 75 years or older, those with previous stroke or transient ischaemic attack and those with renal dysfunction. These subsets of patients are commonly underrepresented from clinical trials, limiting the overall safety and efficacy of results obtained from RCTs by comparison with these high risk groups. Increasing numbers of concomitant medicines taken in geriatric populations increases the risk of adverse events,21 a risk that is potentiated further by the high prevalence of potentially inappropriate concomitant therapies observed in this study. This study highlights the importance of awareness of patient’s concomitant therapies by both the prescriber and the pharmacist, and the potential for interactions and increased risk of harm. Limitations associated with the use of SAE reports include under-reporting, selective reporting Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
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and varying report quality. Although the adverse events reported in the current study are similar to those observed in clinical trial results, whether these reports are a true reflection of adverse events that are occurring in clinical practice or over-reporting of adverse events already associated with these therapies remains unclear. We were unable to determine from the adverse event reports if concomitant medicines were truly being co-administered with dabigatran. However, in defining the information required in the medicine list field of Australia’s Database of Adverse Event Notification, it is stated that reporters must provide information on any other medicines the patient was taking.7 Similarly, Health Canada defines that for its Vigilance Adverse Reaction Online Database that all health products listed in medicines list be classified as one of the following: concomitant, drug used to treat adverse event or suspected.22 Disproportionality analysis was only conducted in the USA FAERS database and it is possible that other signals may have been observed with the inclusion of other spontaneous report datasets if available. In Canada and Australia dabigatran is available in both 150 mg and 110 mg doses; whilst only 150 mg is available in USA. In the RE-LY trial only the 150 mg dose was associated with an increased risk of gastrointestinal haemorrhage,13 and the inclusion of adverse events by dose would be of interest in future post-marketing studies of dabigatran. These results highlight the ongoing need for continued post-marketing surveillance of dabigatran and the need for further validation and quantification of these results and risk of harm associated with dabigatran. In the Australian context, with the recent listing of these medicines on the Australian Government pharmaceutical benefits scheme for thromboembolic stroke prevention in atrial fibrillation, the use of dabigatran is set to increase. Given the lack of an antidote, coupled with the potential for haemorrhagic adverse events with dabigatran and the proportion of patients reporting concomitant therapy with potential to increase their likelihood of adverse events is of concern. This highlights the need for pharmacovigilance on the part of both the prescribing practitioner and the pharmacist alike to ensure the safe and effective integration of this new oral anticoagulant into routine clinical practice. CONFLICT OF INTEREST The authors declare no conflict of interest. Copyright © 2014 John Wiley & Sons, Ltd.
KEY POINTS
• • • • •
Clinical trial data and subsequent meta-analyses have highlighted several safety concerns potentially associated with the direct thrombin inhibitor dabigatran. When compared to warfarin, recent metaanalyses have shown that dabigatran is associated with an increased risk of gastrointestinal haemorrhage. Little is known about these safety issues associated with use of dabigatran in clinical practice that may be reported in SAE reports. Gastrointestinal disorders, namely gastrointestinal haemorrhage were the most common adverse event associated with dabigatran for Australia, Canada and USA SAE reports. Over a third of patients had at least one concomitant medicine reported that potentially may have placed the patient at increased risk of harm (namely haemorrhage).
ETHICS STATEMENT The authors state that no ethical approval was needed. ACKNOWLEDGEMENTS This work was supported by the Australian Government National Health and Medical Research Council Centre of Research Excellence in Post-Marketing Surveillance of Medicines and Medical Devices Grant (APP1040938). REFERENCES 1. Adam SS, McDuffie JR, Ortel TL, Williams JJW. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012; 157(11): 796–807. 2. Sipahi I, Celik S, Tozun N. A comparison of results of the US food and drug administration’s mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran. JAMA Intern Med 2013; 174(1): 150–151. 3. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 2012; 125(5): 669–676. 4. Legrand M, Mateo J, Aribaud A. The use of dabigatran in elderly patients. Arch Intern Med 2011; 171(14): 1285–1286. 5. Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as firstline agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012; 125(1): 159–164. 6. Strom BL, Kimmel SE, Hennessy S. Pharmacoepidemiology (5th edn). WileyBlackwell: West Sussex, UK, 2012. 7. Australian Therapeutic Goods Administration. Database of adverse event notifications (DAEN). Secondary Database of Adverse Event Notifications (DAEN) 2013. http://www.tga.gov.au/safety/daen.htm [25 June 2013]. 8. Health Canada. Canada vigilance adverse reaction online database. Secondary Canada Vigilance Adverse Reaction Online Database 2013. http://www.hc-sc. gc.ca/dhp-mps/medeff/databasdon/index-eng.php [1 July 2013].
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adverse events associated with dabigatran 9. U.S. Food and Drug Administration. FDA adverse event reporting system (FAERS). Secondary FDA Adverse Event Reporting System (FAERS) 2013. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseDrugEffects/default.htm [25 June 2013]. 10. Therapeutic Guidelines Limited. Therapeutic guidelines: cardiovascular. Version 6. 2012 http://www.tg.org.au/ [25 July 2013]. 11. Australian Medicines Handbook. Australian Medicines Handbook Pty. Ltd.: Adelaide, Australia, 2013. 12. Evans SJW, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 2001; 10(6): 483–486. 13. Egberts ACG, Meyboom RHB, Van Puijenbroek EP. Use of measures of disproportionality in pharmacovigilance: three Dutch examples. Drug Saf 2002; 25(6): 453–458. 14. Connolly S, Ezekowitz M, Phil D, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361(12): 1139–1151. 15. Dans A, Connolly S, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomised Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Circulation 2013; 127(5): 634–640.
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16. NPS Medicine Wise. Interactions with dabigatran, rivaroxaban and apixaban. Secondary Interactions with dabigatran, rivaroxaban and apixaban. 2013. http:// www.nps.org.au/medicines/heart-blood-and-blood-vessels/anti-clotting-medicines/for-individuals/anticoagulant-medicines/for-health-professionals/decision-tools/ newer-anticoagulant-drug-interactions [10 September 2013]. 17. Shorr R, Ray W, Daugherty J, Griffin M. Concurrent use of nonsteroidal antiinflammatory drugs and oral anticoagulants places elderly persons at high risk for haemorrhagic peptic ulcer disease. Arch Intern Med 1993; 153(14): 1665–1670. 18. Paton C, Ferrier N. SSRIs and gastrointestinal bleeding: gastroprotection may be justified in some patients. BMJ 2005; 331(7516): 529–530. 19. Boehringer Ingelheim Pharmaceuticals. RELY-ABLE trial emergency information. Secondary RELY-ABLE Trial Emergency Information 2013. http://www. rely-able-trial.com/Rely2Web/index.jsp [2 November 2013]. 20. Rawlins MD. A population approach to the rational use of therapeutic interventions. Clin Ther 2013; 35(10): 1634–1638. 21. Shah B, Hajjar E. Polypharmacy, adverse drug reactions, and geriatric syndromes. Clin Geriatr Med 2012; 28(2): 173–186. 22. Shah BR, Hux JE, Laupacis A, Zinman B, Booth GL. Use of vascular riskmodifying medications for diabetic patients differs between physician specialties. Diabet Med 2006; 23(10): 1117–1123.
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
ORIGINAL REPORT
An international comparison of spontaneous adverse event reports and potentially inappropriate medicine use associated with dabigatran Cameron J. McDonald, Lisa M. Kalisch Ellett, John D. Barratt and Gillian E. Caughey* Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia
ABSTRACT Purpose The objective of this study was to analyse spontaneous adverse event (SAE) reports associated with the oral anticoagulant dabigatran from Australia, Canada and USA and to examine concomitant medicine use. Methods Spontaneous adverse event national databases from Australia, Canada and the USA were used to examine all reports of adverse events associated with dabigatran from 1st August 2005 to 31st March 2013. Disproportionality analysis was conducted for the quantitative detection of signals using the USA database. Concomitant medicine use was examined to identify potentially inappropriate medicines, which may place the patient at increased risk for adverse events. Results There were a total of 1039, 1333 and 13 788 SAE reports associated with dabigatran from Australia, Canada and USA, respectively. Gastrointestinal (GI) disorders were the most commonly reported adverse event, ranging from 27.5% for Australia and up to 40.5% for USA. Of these, GI haemorrhage accounted for 81.5% of Australian, 71.5% of Canadian and 42% of the USA adverse event reports for GI disorders. Positive signals were confirmed in the USA data (GI haemorrhage; PRR 18.18, χ2 40993.51 and ROR 19.55 95% CI 18.77–20.36). Use of concomitant medicines with the potential to increase bleeding risk across all three countries ranged from 34.1% for Australia to 51.1% for the USA. Conclusions A large proportion of adverse events were associated with concomitant therapies, which may have placed the patient at increased risk of harm. This highlights the need for pharmacovigilance by the prescribing clinician to minimise risk and ensure the safe and effective integration of dabigatran into routine clinical practice. Copyright © 2014 John Wiley & Sons, Ltd. key words—dabigatran; adverse event; haemorrhage; inappropriate prescribing; pharmacoepidemiology Received 18 December 2013; Revised 21 April 2014; Accepted 22 April 2014
INTRODUCTION Dabigatran is a direct thrombin inhibitor indicated for thromboembolic stroke prevention in atrial fibrillation and prophylaxis of deep vein thrombosis post hip and knee arthroplasty.1 Clinical trial data and subsequent meta-analyses have highlighted several safety concerns potentially associated with dabigatran. When compared with warfarin, a recent meta-analysis showed that dabigatran is associated with an increased risk of gastrointestinal haemorrhage (relative risk (RR) 1.41, 95% CI 1.28–1.55).2 Further, concerns have been raised of a trend towards an increased risk of
*Correspondence to: G. E. Caughey, Senior Research Fellow, Quality Use of Medicines and Pharmacy Research Centre, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide SA 5001, Australia. E-mail: [email protected]
Copyright © 2014 John Wiley & Sons, Ltd.
myocardial infarction (MI) with dabigatran (hazard ratio (HR) 1.30, 95% CI 0.93–1.81) by comparison with warfarin3 and increased drug discontinuation rates because of adverse events (RR 1.62, 95% CI 1.23–2.15).1 Currently, no antidote exists to reverse the anticoagulant effect of dabigatran in the event of haemorrhage.4 Further, dabigatran has potentially clinically significant interactions with potent inhibitors of P-glycoprotein and concomitant use of other antithrombotics or medicines associated with increased bleeding risk may increase the potential to develop adverse haemorrhagic events with dabigatran.5 There are a number of limitations associated with pre-marketing randomised clinical trials. Firstly, they often have a sample size that is too small to identify adverse events that have low incidence but are of clinical significance. The time of follow-up is relatively short (6–12 months on average), hence, they are unable
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to identify long-term adverse events potentially associated with a medicine.6 Finally, older patients, those with comorbidity, and those taking concomitant medicines, are generally excluded from these premarketing clinical trials. This means that when medicines reach the market, we have limited knowledge of their use in real-world patient populations. Postmarketing surveillance of medicines is important as it allows us to monitor the safety of medicines when they are used in clinical practice.6 Spontaneous adverse event (SAE) reporting involves the voluntary submission of adverse events experienced by patients to a centralised database by either the patient themselves or their health care provider.6 A series of SAE reports involving the same medicine, and the same adverse event can provide a signal of a potential adverse event associated with a medicine.6 The aim of this study was to analyse SAE reports from Australia, Canada and US in order to perform a cross-country comparison of adverse events reported for dabigatran, focusing specifically on haemorrhage and MI and to examine the reporting of concomitant medicine use that may potentiate bleeding risk. RESEARCH DESIGN AND METHODS Data source and study design Spontaneous adverse event reports from Australia, Canada and US were obtained for dabigatran from publically available online databases. Australian data was obtained from the Australian Therapeutic Goods Administration’s Database of Adverse Event Notifications for Medicines,7 Canadian data was obtained from Health Canada’s Vigilance Adverse Reaction Online Database8and USA data was obtained from the Food and Drug Administration Adverse Events Reporting System (FAERS) database.9 We included reports from the earliest available to the latest available date, ranging from the 1st August 2005 to 31st March 2013. The FAERS database contains reports from around the world, for the purposes of this study, only reports originating from the USA were included. Outcome definition Frequency of reporting of adverse events, grouped by Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC), were analysed for all datasets, to generate case report counts and reporting ratios. Patients who reported more than one adverse event classified under the same MedDRA SOC classification had these adverse events treated as Copyright © 2014 John Wiley & Sons, Ltd.
one adverse event. The outcomes of interest included those most commonly reported in clinical trials of dabigatran, namely haemorrhage and MI.1–3 Analyses were initially at the SOC level (including gastrointestinal disorders, nervous system disorders, vascular disorders and cardiac disorders), and then MedDRA preferred terms were used for the search strategy with a focus on haemorrhage and MI. All types of haemorrhage were also examined within any of the MedDRA SOC classification. Death was also examined but was only available in the Canadian and USA SAE reports. Concomitant medicines reported in adverse event reports were analysed to identify the prevalence of concomitant medicine use and specifically those with the potential to increase the risk of adverse events. These potentially inappropriate concomitant medicines were identified from Australian Therapeutic Guidelines10 and Australian Medicines Handbook11 and subsequently categorised into one of three groups; concomitant antithrombotics, concomitant bleeding risk medicines and medicines with potentially clinically significant interactions. Antithrombotic agents included warfarin, heparins, platelet aggregation inhibitors, direct thrombin inhibitors and direct Factor Xa inhibitors (ATC Codes B01A, excluding B01AE07—dabigatran). Bleeding risk medicines included non-steroidal anti-inflammatory drugs (NSAIDs, M01A), selective serotonin reuptake inhibitors (SSRIs, N06AB) and oral (systemic) corticosteroids (H02A). Medicines with potentially clinically significant interactions that would increase dabigatran exposure (p-glycoprotein inducers) included systemic azole antifungals (J02AB, JO2AC), macrolide antibiotics (J01FA), HIV protease inhibitors (J05AE), cyclosporine (L04AD01), dronedarone (C01BD07), tacrolimus (L04AD02), verapamil (C08DA01), amiodarone (C01BA01) and quinidine (C01BA01).10, 11 Statistical analysis The frequency of adverse events reported by MedDRA terms was calculated as a proportion of all adverse event reports for dabigatran within each of the datasets. The prevalence of concomitant therapies and those that were potentially inappropriate were calculated as a proportion of all SAE reports where concomitant therapies were reported for each of the datasets. Disproportionality analyses were conducted on the FAERS data only using the proportional reporting ratio (PRR) and the reporting odds ratio (ROR) to quantitate the strength of the association between observed adverse events and the suspected medicines from SAE reports.12, 13 These analyses were Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
adverse events associated with dabigatran
only able to be conducted using the FAERS data as both the Australian and Canadian SAE reporting databases do not have publicly available all the required data for this type of analyses, including total number of medicine adverse event reports in each dataset and the total number of individual types of adverse events reported by MedDRA terms. Using the PRR, a signal is detected if the count of co-occurrences ≥3 and the PRR ≥2.0 with an associated χ 2 value of ≥4.0.12 For the ROR, a signal is detected if the lower bound of the 95% two-sided confidence interval exceeds 1.13 Each adverse event report may contain multiple medicines and adverse events, the PRR and ROR calculated for all medicine/adverse event pairs. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS During the study period, there were 1039 SAE reports for dabigatran within the Australian database, 1333 in the Canadian database and 13 788 dabigatran SAE reports in the USA. The demographics of those who experienced the adverse event are described in Table 1, with the average age across all three databases of 76 years and the proportion of males ranged from 48.2% in USA to 58.3% in Australia. The frequency of the types of adverse events reported for dabigatran are shown in Table 1. For all three countries, gastrointestinal disorders were the most frequently reported adverse event, ranging from 27.5% of all reports for Australia, up to 40.5% for the USA (Table 1). Of these, gastrointestinal haemorrhage accounted for 81.5% of Australian, 71.5% of Canadian and 42% of USA gastrointestinal
adverse event reports. Nervous system disorders were the next most common reported adverse event, ranging from 16% for Australia to 31% for the Canadian adverse event reports. Nervous system haemorrhage ranged from 14% to 28% of all nervous system adverse event reports. Approximately 10% of all reports were for a vascular adverse event, and over half of these were a vascular haemorrhage for all countries. Cardiac adverse event disorders ranged from 7.1% for the USA to 9.6% for Canada of all adverse events reported. Whilst overall prevalence of myocardial infarction in SAE reports ranged from 0.7% to 3.2%, myocardial infarction accounted for almost a third of all reported cardiac adverse events for Australia and Canada, whereas it was only 10% in the USA. Death was not reported in the Australian dataset, but 7.2% of USA and 15.8% of Canadian reports associated with dabigatran use reported death as the outcome. Disproportionality analyses of the USA FAERS database found positive signals detected for all individual types of haemorrhage associated with dabigatran use, with GI haemorrhage resulting in the strongest signal (Table 2). In accord, all types of haemorrhage also generated positive signals. Signal strengths were similar for both types of disproportionality analyses. No signal was detected for an association of dabigatran use with cardiac disorders or specifically myocardial infarction using either method (Table 2). Concomitant medicines were reported in 41% of the adverse event reports associated with dabigatran in the Australian and Canadian databases and 44% of the USA FAERS. The average number of concomitant medicines reported in adverse event reports ranged from 4.5 ± 3.1 in the Australian dataset, 4.9 ± 3.8 in the Canadian dataset and 5.7 ± 4.2 in the USA dataset. The
Table 1. Demographics and type of spontaneous adverse events reported by Medical Dictionary for Regulatory Activities Classification for dabigatran* Australia n = 1039 Demographics Age (mean years ± SD, n) Gender (% male) Type of adverse event Gastrointestinal disorders - Gastrointestinal haemorrhage Nervous system disorders - Nervous system haemorrhage Vascular disorders - Vascular haemorrhage Cardiac disorders Myocardial infarction All haemorrhage Death
76.6 ± 10.4 (n = 372) 58.3% n % 286 27.5% 233 81.5% 167 16.1% 47 28.0% 88 8.5% 55 62.5% 88 8.5% 34 38.6% 367 35.3% N/A N/A
Canada
US
n = 1333
n = 13788
76.1 ± 11.3 (n = 886) 54.9% n % 495 37.1% 354 71.5% 413 31.0% 87 21.0% 181 13.6% 97 53.6% 128 9.6% 41 32.1% 582 43.7% 210 15.8%
75.2 ± 10.1 (n = 8225) 48.2% n % 5579 40.5% 2345 42.0% 2986 21.7% 422 14.1% 1478 10.7% 786 53.2% 983 7.1% 98 10% 3786 27.5% 991 7.2%
*Frequencies calculated as a proportion of all dabigatran spontaneous adverse event reports per country.
Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
c. j. mcdonald et al. Table 2. Signal detection for Dabigatran-associated adverse events in the USA Food and Drug Administration Adverse Events Reporting System database. Type of adverse event Gastrointestinal disorders - Gastrointestinal haemorrhage Nervous system disorders - Nervous system haemorrhage Vascular disorders - Vascular haemorrhage All haemorrhage Cardiac disorders - Myocardial Infarction
2
N
PRR (χ )
ROR (95% CI)
8864
3.19 (14399.60)*
3.94 (3.84–4.03)*
2566
18.18 (40993.51)*
19.55 (18.77–20.36)*
3684
1.51 (676.32)
1.57 (1.51–1.62)*
462
14.12 (5537.15)*
14.29 (13.02–15.68)*
1626 791
2.25 (114.55)* 15.47 (10529.54)*
2.31 (2.19–2.42)* 15.81 (14.73–16.98)*
4353 1227 115
12.75 (46917.73)* 0.84 (41.15) 0.50 (57.11)
14.43 (13.97–14.89)* 0.83 (0.78–0.88) 0.50 (0.42–0.60)
PRR, proportional reporting ratio; ROR, reporting odds ratio. N, number of occurrences of the medicine/adverse event pair reported. *Signal detected.
potentially inappropriate concomitant therapy most commonly reported in all three countries was concomitant administration of antithrombotic agents in combination with dabigatran, with prevalence ranging from 17.4% to 31.9%. Aspirin was the most commonly reported antithrombotic in all countries (Table 3). Bleeding risk medicines were the second most prevalent potentially inappropriate therapy in Australia and Canada and the third most prevalent in the US with prevalence ranging from 11.5% to 13.7% across all three countries (Table 3). Selective serotonin reuptake inhibitors were the most common concomitant bleeding-risk medicine in both Australia and US datasets, with overall prevalence ranging from 3.6% to 6.9% across all three countries. Non-steroidal antiinflammatory drugs were the most prevalent bleeding risk medicines in Canadian adverse event reports, with overall prevalence ranging from 2.1% to 5.3% across all three countries. Medicines with the potential for drug–drug interactions with dabigatran were the least prevalent of the potentially inappropriate concomitant therapies (with the exception of US), with amiodarone being the most prevalent in Australian and Canadian datasets (prevalence ranging from 4.9% to 7.0% across all three countries) and dronedarone being the most prevalent in the US dataset (present in 7.0% of US adverse event reports). Overall, across all three countries, between 34.1% and 51.1% of adverse event reports associated with dabigatran reported the concomitant use of at least Copyright © 2014 John Wiley & Sons, Ltd.
Table 3. Prevalence of potentially inappropriate concomitant therapy in Dabigatran spontaneous adverse event reports*
Medication class Concomitant antithrombotic Aspirin Warfarin Clopidogrel Concomitant bleedingrisk medicines NSAIDs SSRIs Corticosteroids (systemic) Concomitant medicines with potential drug-drug interactions Amioderone Verapamil Dronedarone Overall proportion of potentially inappropriate therapy†
Australia
Canada
US
n = 425
n = 550
N = 6123
N (%)
N (%)
N (%)
74 (17.4%)
112 (20.4%)
1952 (31.9%)
46 (10.8%) 17 (4.0%) 14 (3.3%) 51 (12.0%)
50 (9.1%) 31 (5.6%) 28 (5.1%) 63 (11.5%)
1474 (24.1%) 341 (5.6%) 295 (4.8%) 841 (13.7%)
9 (2.1%) 26 (6.1%) 20 (4.7%)
27 (4.9%) 20 (3.6%) 21 (3.8%)
327 (5.3%) 420 (6.9%) 192 (3.1%)
45 (10.6%)
54 (9.8%)
1045 (17.1%)
25 (5.9%) 17 (4.0%) — 34.1%
27 (4.9%) — 17 (3.1%) 40.2%
431 (7.0%) 143 (2.3%) 473 (7.7%) 51.1%
*Only those concomitant medicines with a prevalence over 2% are shown. Expressed as proportion of adverse event reports where at least one potentially inappropriate bleeding-risk medicine was reported.
†
one medicine with the potential to increase patient’s risk of experiencing adverse events (Table 3). DISCUSSION This is the first study to examine the SAE reports from Australia, Canada and the USA, for the new oral anticoagulant, dabigatran. Analysis of adverse events reported from use of dabigatran in clinical practice are concordant with those seen in clinical trials; primarily, gastrointestinal adverse events and haemorrhage, specifically gastrointestinal haemorrhage. Gastrointestinal associated disorders were the most common type of adverse event reported for dabigatran, accounting for between 28% and 40% of all SAE reports, with the majority of these adverse events for a gastrointestinal haemorrhage. Overall, a third of all spontaneous adverse reports for dabigatran were for some type of haemorrhage, across all three countries studied. Disproportionality analysis of the USA FAERS database confirmed positive signals for these major adverse events, but not myocardial infarct associated with dabigatran. The use of concomitant medicines was high, with an average of five different medicines reported. Of concern, however, was the high prevalence of potentially inappropriate concomitant therapy use. Across countries between a third and half of all Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
adverse events associated with dabigatran
dabigatran adverse events reports were associated with a potentially inappropriate concomitant therapy, which may have placed the patient at increased risk of harm. The findings from our cross-country comparison that gastrointestinal disorders are the most common body system likely to be affected by an adverse event for dabigatran is in concordance with the results of the RE-LY clinical trial of dabigatran versus warfarin, where gastrointestinal disorders were the most common type of adverse event reported.14 Gastrointestinal haemorrhage was the most common of these in accord with the results from the RE-LY clinical trial, where dabigatran (at the highest dose 150 mg) was shown to have a 50% increased incidence of gastrointestinal haemorrhage (RR 1.50, 95% CI 1.19 - 1.89) by comparison with warfarin.14 In an analysis of the risk of MI from the RE-LY clinical trial, dabigatran (150 mg) was reported to have a trend towards increased risk of MI (HR 1.30, 95% CI 0.93–1.81) by comparison to warfarin.3 In our study, disproportionality analysis failed to find a positive signal for an association of dabigatran with MI. Concomitant antithrombotic medicines were the most prevalent potentially inappropriate medicine class across all countries, with aspirin the most common concomitant antithrombotic in all dataset adverse event reports across countries. A subgroup analysis of the RE-LY trial showed that concomitant administration of anti-platelet therapy with dabigatran (approximately 20% of patients who took dabigatran used aspirin continuously during the treatment period14), increased the risk of bleeding compared with dabigatran alone but did not improve primary prevention of stroke or systemic embolism by comparison with warfarin alone.15 Over one in ten adverse event reports reported concomitant use of medicines potentially associated with an increased risk of bleeding in our study. Although no current studies have assessed the clinical outcomes associated with concomitant administration of new oral anticoagulants with NSAIDs or SSRIs, a pharmacological basis for potential increased bleeding risk in these patients exists.16 Concomitant use of NSAIDs in combination with warfarin is associated with a 13-fold increase in haemorrhagic peptic ulcer disease in patients 65 years and older when compared with baseline.17 Use of SSRIs in monotherapy has been shown to increase risk of gastrointestinal bleeding by up to three-fold compared with baseline.18 Medicines with established or potential interactions that are clinically relevant were reported in 10% to Copyright © 2014 John Wiley & Sons, Ltd.
17% of adverse event reports. The most prevalent drug–drug interaction reported was amiodarone in the Australian and Canadian adverse event reports and dronedarone the most common in US adverse event reports. An emergency information release by Boehringer Ingelheim, the manufacturer of dabigatran, during the RE-LY trial, highlighted the potential for increased bleeding risk with concomitant administration of moderate to strong P-glycoprotein inhibitors, such as verapamil and amiodarone with dabigatran.19 Simultaneous administration of dabigatran and dronedarone increases exposure to dabigatran by 70 to 140%,19 with the emergency release during the RE-LY trial stating that concomitant administration of dronedarone and dabigatran was not recommended.19 Given that these medicines are used for cardiac arrhythmias, and the likelihood of their concomitant use with dabigatran in atrial fibrillation is high, ascertaining the clinical relevance of these interactions and potential for serious adverse events is paramount to determining the risk/benefit profile of their concomitant use. The high frequency of overall concomitant use of medicines that have the potential to increase the risk of adverse events is of particular importance given the current inability to reverse the anticoagulant effect of dabigatran and the haemorrhagic adverse events being reported in clinical practice. The haemorrhage rates associated dabigatran have only been ascertained in randomised controlled trials; however, in comparison, the patients using these medicines in clinical practice are likely to be older, with potentially more comorbid conditions and therefore using more concomitant medicines than in the randomised controlled trials.20 Further, clinically relevant subgroups of patients with AF where the risk of both stroke and bleeding are increased include those 75 years or older, those with previous stroke or transient ischaemic attack and those with renal dysfunction. These subsets of patients are commonly underrepresented from clinical trials, limiting the overall safety and efficacy of results obtained from RCTs by comparison with these high risk groups. Increasing numbers of concomitant medicines taken in geriatric populations increases the risk of adverse events,21 a risk that is potentiated further by the high prevalence of potentially inappropriate concomitant therapies observed in this study. This study highlights the importance of awareness of patient’s concomitant therapies by both the prescriber and the pharmacist, and the potential for interactions and increased risk of harm. Limitations associated with the use of SAE reports include under-reporting, selective reporting Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
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and varying report quality. Although the adverse events reported in the current study are similar to those observed in clinical trial results, whether these reports are a true reflection of adverse events that are occurring in clinical practice or over-reporting of adverse events already associated with these therapies remains unclear. We were unable to determine from the adverse event reports if concomitant medicines were truly being co-administered with dabigatran. However, in defining the information required in the medicine list field of Australia’s Database of Adverse Event Notification, it is stated that reporters must provide information on any other medicines the patient was taking.7 Similarly, Health Canada defines that for its Vigilance Adverse Reaction Online Database that all health products listed in medicines list be classified as one of the following: concomitant, drug used to treat adverse event or suspected.22 Disproportionality analysis was only conducted in the USA FAERS database and it is possible that other signals may have been observed with the inclusion of other spontaneous report datasets if available. In Canada and Australia dabigatran is available in both 150 mg and 110 mg doses; whilst only 150 mg is available in USA. In the RE-LY trial only the 150 mg dose was associated with an increased risk of gastrointestinal haemorrhage,13 and the inclusion of adverse events by dose would be of interest in future post-marketing studies of dabigatran. These results highlight the ongoing need for continued post-marketing surveillance of dabigatran and the need for further validation and quantification of these results and risk of harm associated with dabigatran. In the Australian context, with the recent listing of these medicines on the Australian Government pharmaceutical benefits scheme for thromboembolic stroke prevention in atrial fibrillation, the use of dabigatran is set to increase. Given the lack of an antidote, coupled with the potential for haemorrhagic adverse events with dabigatran and the proportion of patients reporting concomitant therapy with potential to increase their likelihood of adverse events is of concern. This highlights the need for pharmacovigilance on the part of both the prescribing practitioner and the pharmacist alike to ensure the safe and effective integration of this new oral anticoagulant into routine clinical practice. CONFLICT OF INTEREST The authors declare no conflict of interest. Copyright © 2014 John Wiley & Sons, Ltd.
KEY POINTS
• • • • •
Clinical trial data and subsequent meta-analyses have highlighted several safety concerns potentially associated with the direct thrombin inhibitor dabigatran. When compared to warfarin, recent metaanalyses have shown that dabigatran is associated with an increased risk of gastrointestinal haemorrhage. Little is known about these safety issues associated with use of dabigatran in clinical practice that may be reported in SAE reports. Gastrointestinal disorders, namely gastrointestinal haemorrhage were the most common adverse event associated with dabigatran for Australia, Canada and USA SAE reports. Over a third of patients had at least one concomitant medicine reported that potentially may have placed the patient at increased risk of harm (namely haemorrhage).
ETHICS STATEMENT The authors state that no ethical approval was needed. ACKNOWLEDGEMENTS This work was supported by the Australian Government National Health and Medical Research Council Centre of Research Excellence in Post-Marketing Surveillance of Medicines and Medical Devices Grant (APP1040938). REFERENCES 1. Adam SS, McDuffie JR, Ortel TL, Williams JJW. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med 2012; 157(11): 796–807. 2. Sipahi I, Celik S, Tozun N. A comparison of results of the US food and drug administration’s mini-sentinel program with randomized clinical trials: the case of gastrointestinal tract bleeding with dabigatran. JAMA Intern Med 2013; 174(1): 150–151. 3. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (randomized evaluation of long-term anticoagulation therapy) trial. Circulation 2012; 125(5): 669–676. 4. Legrand M, Mateo J, Aribaud A. The use of dabigatran in elderly patients. Arch Intern Med 2011; 171(14): 1285–1286. 5. Granger CB, Armaganijan LV. Newer oral anticoagulants should be used as firstline agents to prevent thromboembolism in patients with atrial fibrillation and risk factors for stroke or thromboembolism. Circulation 2012; 125(1): 159–164. 6. Strom BL, Kimmel SE, Hennessy S. Pharmacoepidemiology (5th edn). WileyBlackwell: West Sussex, UK, 2012. 7. Australian Therapeutic Goods Administration. Database of adverse event notifications (DAEN). Secondary Database of Adverse Event Notifications (DAEN) 2013. http://www.tga.gov.au/safety/daen.htm [25 June 2013]. 8. Health Canada. Canada vigilance adverse reaction online database. Secondary Canada Vigilance Adverse Reaction Online Database 2013. http://www.hc-sc. gc.ca/dhp-mps/medeff/databasdon/index-eng.php [1 July 2013].
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16. NPS Medicine Wise. Interactions with dabigatran, rivaroxaban and apixaban. Secondary Interactions with dabigatran, rivaroxaban and apixaban. 2013. http:// www.nps.org.au/medicines/heart-blood-and-blood-vessels/anti-clotting-medicines/for-individuals/anticoagulant-medicines/for-health-professionals/decision-tools/ newer-anticoagulant-drug-interactions [10 September 2013]. 17. Shorr R, Ray W, Daugherty J, Griffin M. Concurrent use of nonsteroidal antiinflammatory drugs and oral anticoagulants places elderly persons at high risk for haemorrhagic peptic ulcer disease. Arch Intern Med 1993; 153(14): 1665–1670. 18. Paton C, Ferrier N. SSRIs and gastrointestinal bleeding: gastroprotection may be justified in some patients. BMJ 2005; 331(7516): 529–530. 19. Boehringer Ingelheim Pharmaceuticals. RELY-ABLE trial emergency information. Secondary RELY-ABLE Trial Emergency Information 2013. http://www. rely-able-trial.com/Rely2Web/index.jsp [2 November 2013]. 20. Rawlins MD. A population approach to the rational use of therapeutic interventions. Clin Ther 2013; 35(10): 1634–1638. 21. Shah B, Hajjar E. Polypharmacy, adverse drug reactions, and geriatric syndromes. Clin Geriatr Med 2012; 28(2): 173–186. 22. Shah BR, Hux JE, Laupacis A, Zinman B, Booth GL. Use of vascular riskmodifying medications for diabetic patients differs between physician specialties. Diabet Med 2006; 23(10): 1117–1123.
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