Best Evidence Analyses and Commentary

Pradaxa® (dabigatran) vs. Warfarin: Reported bleeding and adverse events
Adolfo Suarez, PharmD candidate; Marcus W. Campbell, PharmD, BC-ADM
September 2014

Warfarin is an oral anticoagulation drug which inhibits blood clotting by preventing the production of clotting factors II, VII, IX, X, as well as proteins C and S, all of which are synthesized by the liver. The assembly of these factors is dependent on vitamin K, which is antagonized by warfarin through the inhibition of vitamin K epoxide reductase. Warfarin is used in the prevention and treatment of deep vein thrombosis (DVT), pulmonary embolism (PE), as well as complications secondary to cardiovascular conditions arising from valve replacement, atrial fibrillation (Afib), myocardial infarction (MI), and stroke. The use of warfarin is limited by its narrow therapeutic index, as well as its requirement for frequent monitoring. Adverse drug reactions include bleeding, rash, abdominal pain, diarrhea, hepatitis, etc. Warfarin-induced bleeding can be reversed with the administration of vitamin K.1
Pradaxa® (dabigatran exilate) is a direct thrombin inhibitor approved by the FDA in October of 2010 as an alternative to warfarin in patients with nonvalvular Afib. Its approval was based on the results of the phase III Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial. Dabigatran specifically targets thrombin (factor IIa) in both, its free and fibrin-bound form. The mechanism of action of this medication inhibits clot formation by blocking thrombin-mediated functions, such as the conversion of fibrinogen to fibrin, thrombin-induced platelet aggregation, and activation of factors V, VIII, XI, and XIII. Dabigatran is used for the prevention and treatment of DVT, PE, and other embolic complications from Afib. It is also readily utilized to minimize recurrence of MI and strokes after a cardiovascular event. Unlike warfarin, dabigatran does not currently have an antidote on the market. The agent idarucizumab, a fully humanized agent has shown positive results in development research and has received FDA approval to be expedited.2,3
Alternative agents to warfarin have proven efficacy in the management of disease states requiring anticoagulation therapy. These new drugs offer ease in prescribing and monitoring, as well as a more favorable interaction profile. However, experts and prescribers alike have questioned the long-term adverse effects associated with these novel anticoagulants. A retrospective review of the FDA Adverse Event Reporting System (FAERS) database was conducted from October 2010 to December 2011, the year following the release of dabigatran. Information regarding reported bleeding adverse events and/or fatal outcomes associated with the use of dabigatran was gathered and compared to similar reported events involving warfarin.4
FAERS is a voluntary surveillance system made up of reports of adverse effects and related outcomes provided by manufacturers, healthcare providers, and consumers. Researchers conducted a query listing dabigatran or warfarin as primary suspecting agents. Drug information such as dose, indication, and duration of therapy were also included in the search. Bleeding events were classified as general hemorrhage, GI bleeds, or intracranial bleeds. Of note, numerous reported events for both dabigatran and warfarin were incomplete missing key covariates such as age, gender, and weight.4
The analysis outcomes were defined as number of bleeding events and number of bleeding cases that resulted in death. Investigators utilized a study found in the National Disease and Therapeutic Index to estimate treatment patterns for dabigatran in the US in the year following its release. This information provided a basis for comparison, as it estimated the population risk of bleeding fatalities in patients on dabigatran. Additionally, dabigatran-related fatality data was extracted from the RE-LY trial. Of the 966,536 initial case reports and follow-ups identified, 9,029 dabigatran cases and 2,038 warfarin cases were included in the analysis. In general, dabigatran adverse events were seen in older patients when compared to warfarin, 75.5 vs. 70.5 years, respectively. Dabigatran patients were less likely to be hospitalized (28% vs 46%) and included higher male population (56% vs. 47%) when compared to warfarin cases. The overall fatality rates from reports were similar for both dabigatran and warfarin (5.8% vs. 4.2%). In terms of classification of bleeds, a higher proportion of GI bleeds were seen with dabigatran (53% vs. 26%); conversely, a higher number of intracranial bleeds were reported in patients on warfarin (12.8% vs. 9.1%). While dosing information was often incomplete, in those reported, 51.6% of dabigatran bleeding reported cases were on the 150 mg twice daily dosing. Reported cases of bleeding, which resulted in death, predominated with dabigatran patients as compared to warfarin (14.8% vs. 7.1%), from October 2010 to December 2011, there were 348 deaths reported due to bleeding associated with dabigatran therapy.4,5
An additional stratified analysis was conducted comparing reporting odds ratio (ROR) of age, gender, and weight for dabigatran vs. warfarin. Dabigatran odds were higher in the age range 75-84 years of age compared to warfarin (ROR 1.4, 95% CI 1-1.9), as well as in patients weighing less than 100 kg (ROR 1.5, 95% CI 1.2-1.9), and women (ROR 2.7, 95% CI 1.9-3.6). Bleeding fatality RORs were higher with dabigatran across all stratification groups.4
While results of this retrospective analysis indicate higher incidents of adverse bleeding events resulting in fatalities with dabigatran, a number of limitations were identified. For instance, well-known underreporting associated with the FAERS. Since dabigatran is the newer agent, it is likely that bleeding events were reported more frequently as compared to warfarin. There is also a high possibility of duplicate cases, unavailable dosing information, and disproportionate distribution as it relates to patient demographics. The latter may have potentially had a profound impact on the results, as odds of adverse events are known to vary with age, gender, body weight and comorbidities. As a result, further studies of the bleeding events with dabigatran are merited. Furthermore, it will be interesting to see the impact of the antidote idarucizumab on the rate of dabigatran related fatalities.
1. Lexicomp Online. Lexi-Comp, Inc. (Lexi-Drugs). Lexi-Comp, Inc.; April 15, 2013. Accessed July 2014.
2. Houston, D. S., Zarychanski, R., Connolly, S. J., Ezekowitz, M. D., et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Eng J Med. 2009 Dec 31; 71(27): 2671.
3. Boehringer Ingelheim. Boehringer Ingelheim's investigational antidote for Pradaxa (dabigatran etexilate mesylate) receives FDA breakthrough therapy designation [press release]. 2014 Jun 26.
4. McConeghy, K. W., Bress, A., Qato, D. M., Wing, C., & Nutescu, E. A. Evaluation of dabigatran bleeding adverse reaction reports in the FDA adverse event reporting system during the first year of approval. Pharmacotherapy. 2014 June 1; 34(6): 561-9.
5. Kirley, K., Qato, D. M., Kornfield, R., Stafford, R. S., & Alexander, G. C. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012 Jan 1; 5(5): 615-21.

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