Whatís New in the Patient Safety World

July 2011

First Thoughts on Dabigatran



For years we have waited for safer anticoagulants to help us manage problems like atrial fibrillation. Warfarin has always been on our Top 10 list of high alert medications. Though the efficacy of warfarin in preventing stroke in patients with atrial fibrillation has been well documented, there is still tremendous underutilization when clearcut indications are present. The reason(s): the hassle for both the patient and physician and the dangers of bleeding complications. So the introduction of newer agents to address those concerns has been widely heralded.


One of the first such drugs to achieve FDA approval has been dabigatran. The FDA approved dabigatran in 2010 for prevention of stroke in patients with atrial fibrillation. The approval was based on results of the RE-LY trial (Connolly 2009), which showed that dabigatran reduced the risk of stroke compared to warfarin and had no higher risk of major bleeding.


But like all newly introduced drugs, there typically follows a number of reports of side effects and other untoward consequences that appear when the drug is used in real world settings as opposed to the relatively controlled environment of clinical trials.


Already some reports are coming in about unexpected consequences. A look-alike/sound-alike (LASA) issue has arisen between the brand name of dabigatran (PRADAXA) and brand name clopidogrel (PLAVIX) (ISMP Canada 2011). In that case report, the patient received Pradax 150 mg. daily instead of the intended Plavix 150 mg. daily. The similarity was further confounded by the fact that the dose prescribed was 150 mg., a dose that could apply to either drug. Fortunately, the error was picked up before any harm came to the patient. But you can bet that this particular LASA error is likely to be repeated many times over. We would certainly anticipate that a TALLman lettering convention will be developed for this LASA pair of drugs but wonít make our own suggestion. Typically, an organization like ISMP will mock up a few potential TALLman solutions and make sure they donít conflict with other existing ones, then do a survey to see which solution works best.


In RE-LY, the rates of major bleeding overall were similar for dabigatran and warfarin. However, for patients aged 75 and older the rate of intracranial bleeding was lower with dabigatran but the rate of extracranial bleeding was higher (Eikelboom 2011). Since many of the patients at highest risk for stroke from atrial fibrillation are in this age group, we may well see more frequent extracranial hemorrhages (primarily GI bleeds) in the elderly. The major concern is that there is currently no known antidote for reversing the effect of dabigatran (unlike warfarin which can be reversed with vitaimin K).


Also, the dabigatran dose must be adjusted in patients with renal dysfunction. ISMP reported a case in which a patient with stage IV CKD received a standard dose of 150 mg twice daily rather than the recommended 75 mg twice daily and developed a serious GI bleed (ISMP 2011). Having rules-based alerts for renal dosing during CPOE obviously would help avoid this sort of incident.


So we donít know what the bleeding rates are likely to be in a real-world setting. Also, as pointed out in an editorial (Avorn 2011) on a cost-effectiveness study of dabigatran (Shah 2011), we use the INR to assess whether patients on warfarin are in the therapeutic range or not but with dabigatran we have no test to tell us whether the patient is over- or under-anticoagulated. Avorn also notes it is likely that patient adherence to dabigatran is likely to be lower because of its twice daily dosing and its cost, so the stroke rate is likely to be higher than in RE-LY.


Also, we know that warfarin has always been underutilized for patients with atrial fibrillation. We predict that many physicians previously reluctant to use it (for the reasons noted earlier) may now be less reluctant to prescribe the newer agents. The direct-to-consumer advertising that has already hit the media will also likely increase the number of patients being treated with dabigatran. So you can expect to see complications of treatment more often.







Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151




ISMP Canada. Drug Name Alert: Potential for Confusion between Pradax and Plavix.

ISMP Canada Safety Bulletin 2011; 11(4): 1-2 May 27, 2011




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;123:2363-2372; published online ahead of print May 16, 2011 and again May 31, 2011




ISMP. Adjust Pradaxa dose for renal impairment. ISMP Medication Safety Alert. Community/Ambulatory Care Edition. February 2011 issue




Avorn J. The relative cost-effectiveness of anticoagulants: Obvious, except for the cost and the effectiveness. Circulation 2011; 123:2519-2521




Shah SV, Gage BF. Cost-effectiveness of dabigatran for stroke prophylaxis in atrial fibrillation. Circulation 2011; 123:2562-2570.
















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