Dr. Chang is a senior resident in the Ronald Reagan UCLA/Olive View-UCLA emergency medicine residency program. Dr. Lovato is an associate professor at the David Geffen School of Medicine at UCLA, the ED director of clinical practice at Olive View-UCLA Medical Center, and the co-chair for the Emergency Medicine Best Practices Committee for the Los Angeles County Department of Health Services.
A new group of medications known as novel oral anticoagulants is forcing us to reconsider our approach to the hemorrhaging patient. Dabigatran (marketed as Pradaxa) was the first novel oral anticoagulant approved by the FDA, and is most likely to find itself on a patient's med reconciliation form.
Like warfarin, dabigatran is approved for long-term anticoagulation for atrial fibrillation. Dabigatran, a direct thrombin inhibitor, has a distinct advantage over warfarin with few dietary interactions. Its few medication interactions occur mainly with P-glycoprotein inducers such as carbamazepine, rifampin, phenytoin, and St. John's wort. Dabigatran is primarily metabolized by the kidney, and similar to low-molecular-weight heparins, it has a relatively predictable therapeutic effect, obviating the need for routine plasma monitoring.
Now, the bad news. Dabigatran has no accepted reversal agent. Fresh frozen plasma and vitamin K have no effect in treating dabigatran-related hemorrhage. Prothrombin complex concentrates, recombinant activated factor VII (rFVIIa), and hemodialysis with special filters are all recommended for life-threatening bleeding related to dabigatran, but these remain unproven rescue therapies for reversing the effect of direct thrombin inhibition.
A recent study in Annals of Emergency Medicine compares and contrasts the presentation, patterns of bleeding, and treatment course for ED patients admitted to the hospital with hemorrhagic complications of dabigatran and warfarin.
Hemorrhagic Complications in Emergency Department Patients who Are Receiving Dabigatran Compared with Warfarin
Berger R, Salhanick SD, et al
Ann Emerg Med
This study is a prospective chart review conducted from June to December 2011 at a tertiary academic ED in Boston. Fifteen patients on dabigatran and 123 on warfarin were admitted for bleeding. The authors randomly sampled 20 percent of all study dates, and used 25 bleeding warfarin patients for statistical analysis to make the warfarin cohort more comparable with the dabigatran group. This study did not compare bleeding rates between dabigatran and warfarin, but instead only characterized those bleeding events in the ED and the inpatient setting.
The majority (80%) of the 15 patients who had dabigatran-related bleeding had gastrointestinal bleeding; none had intracranial bleeding. Two patients died. Compared with randomly selected patients with warfarin-related bleeds, dabigatran patients had a shorter length of hospital stay, received fewer units of fresh frozen plasma and fewer packed RBC transfusions, and experienced fewer major and life-threatening bleeding complications.
None of the patients in the dabigatran group received prothrombin complex concentrates, rVIIa, or hemodialysis. Acute kidney injury was present in 53 percent of hemorrhaging dabigatran patients, leading the authors to conclude that acute kidney injury is a risk factor in these patients. Patients in the dabigatran group also tended to be older than the warfarin group (77 vs. 70) so advanced age also appeared to be a risk. The authors also concluded that bleeding into a closed space such as the pericardium is potentially fatal because no established reversal agent exists.
Though from a small sample, these results are somewhat consistent with those of previous reports such as the RE-LY trial (N Engl J Med 2009;361:1139) and the RE-COVER trial (N Engl J Med 2009;361:2342), both sponsored by dabigatran's manufacturer. The studies are randomized clinical trials that compared dabigatran and warfarin side-by-side, but enrolled relatively younger patients with higher BMIs and mild renal impairment. These trials reported comparatively less major and intracranial bleeding events compared with warfarin, and they touted the relative ease of administering dabigatran. Another study from New Zealand, an audit of all bleeding events related to dabigatran since its debut there, also inferred that bleeding may be related to patient selection. (N Engl J Med 2012;366:864.)
Unfortunately, we emergency physicians are not able to choose what we would like our atrial fibrillation patients to take for anticoagulation. Because dabigatran is relatively new to the market, well-meaning prescribers may not be familiar with its FDA precautions, such as the need to be extra vigilant with frail, elderly patients and those with impaired renal function, precautions this study seems to support. Of course, bleeding can occur even when precautions are followed. Whatever the case, we receive these patients in the ED when they hemorrhage. We are right to be concerned about not having an effective antidote.
Hopefully, reversal agents will become available in the near future. This study should offer some cautious reassurance for now that many patients with dabigatran-related bleeding do well merely with supportive measures and discontinuing the agent. But the best treatment plan is to have planned ahead when hemorrhage related to novel oral anticoagulants is severe. Consider developing multidisciplinary guidelines within your institution to standardize the approach to hemorrhage to limit your liability, speed your decision-making, and make it easier to recruit appropriate assistance, however limited these options may be.
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* Read an abstract of the Annals of Emergency Medicine article, “Hemorrhagic Complications in Emergency Department Patients who Are Receiving Dabigatran Compared with Warfarin,” at http://bit.ly/XJ1qyB.
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