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Risk for blood clots caused by dabigatran requires more data
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Can dabigatran cause clots? On the surface, such a question seems illogical. One may wonder how a drug can cause the problem that it is supposed to treat or prevent.
However, such an occurrence is neither unique nor unknown. For example, most antiarrhythmic agents, including amiodarone, are considered proarrhythmic. Also, all antibiotics, even when used appropriately, can cause overgrowth of nonsusceptible organisms, including other bacteria and fungi. Among the anticoagulants, unfractionated heparin may cause thrombosis in patients who develop heparin-induced thrombocytopenia (HIT). Warfarin may do the same in patients who develop skin necrosis early in therapy because of rapid inhibition of the protein C, a natural anticoagulant, before its effect on other clotting factors are realized.
Examination of recent studies
The possible association of dabigatran (Pradaxa, Boehringer Ingelheim) with thrombotic events comes from a recent examination and re-examination of adverse events reported in the RE-LY trial. RE-LY was the key study for FDA approval of dabigatran in October 2010 for its labeled indication, the prevention of stroke and systemic embolism in patients with nonvalvular AF.
Larry Lopez
In RE-LY, two blinded doses of dabigatran (110 mg and 150 mg twice daily) were prospectively compared with open-label warfarin (dose adjusted to achieve INR value between 2 and 3). Final results were reported on 18,113 patients with AF and at least one risk factor for stroke. After a median follow-up of 2 years, the frequency of stroke or systemic embolism in patients assigned warfarin was 1.7% compared with 1.54% and 1.11% in the low-dose and high-dose dabigatran groups, respectively. Frequency of major bleeding in patients assigned warfarin was greater than that observed in those assigned low-dose dabigatran (3.57% vs. 2.87%), but comparable to that observed in patients assigned high-dose dabigatran (3.57% vs. 3.31%). Intracranial bleeding was observed less often in both dabigatran groups (0.23% and 0.3%, respectively) compared with the warfarin group (0.74%). Hemorrhagic stroke was similar (0.1% for both dabigatran groups vs. 0.38% for warfarin group). Notably, new-onset MI in the original report was noted less frequently in those taking warfarin (0.53%) than in those taking either dose of dabigatran (low-dose, 0.72%; high-dose, 0.74%). Subsequently, numerous additional safety outcome events were identified that changed these numbers dramatically. Specifically, frequency of new-onset MI in the study groups changed to 0.82%, 0.81% and 0.64%, respectively.
There was enough concern about these potentially prothrombotic effects of dabigatran that another group of investigators combined data from the RE-LY trial and six other trials involving dabigatran, warfarin, enoxaparin and placebo for a meta-analysis. The purpose of this analysis was to determine whether dabigatran use was associated with an increase in risk for occurrence of ACS or MI. The seven trials included 30,514 patients. Patients were studied in three short-term deep venous thrombosis trials; two stroke prophylaxis trials in patients with AF; one trial of anticoagulation in patients with acute thromboembolism; and one trial of anticoagulation in patients with ACS. These data revealed that dabigatran use was associated with higher risk for MI or ACS compared with the other agents (1.19% vs. 0.79%). These differences persisted when revised RE-LY trial results were used or when short-term trials were excluded from the data analyses. Researchers of this meta-analysis concluded, “Clinicians should consider the potential of these serious harmful cardiovascular effects …” when using dabigatran.
Although these data are disturbing, it should be noted that this analysis has limitations. First, 57% of patients included in the meta-analysis and 74% of events reported originated in the RE-LY trial, which was the largest of the trials and larger than all of the other studies combined. Second, in the RE-LY trial, MI was a secondary endpoint, a finding that has a greater likelihood to be associated with chance as compared with a primary endpoint. Lastly, when data from RE-LY were excluded in a separate analysis, MI or ACS occurred with dabigatran no more frequently that with the other anticoagulants.
Lack of data to confirm association
It appears there probably is not an association between the use of dabigatran and MI or ACS. These observations suggest that use of dabigatran is associated with new clots no more often than either warfarin or enoxaparin.
Nevertheless, although data from the RE-LY trial regarding occurrence of MI were considered nonsignificant, the clinical relevance of these differences remains debatable. Additionally, dabigatran has been available for clinical use for less than 2 years, although clinical experience with the drug continues to accumulate. It is prudent for clinicians to be vigilant for the possible occurrence of new clots in patients receiving dabigatran until more definitive data become available.
Editor’s Note: This article was originally published in the Shands at the University of Florida Drugs and Therapy Bulletin and has been reprinted with permission.
Disclosure: Lopez reports no relevant financial disclosures.