Dealing with Dabigatran-Associated Life-Threatening Bleeding: One Center's Perspective

April 16, 2014

PITTSBURGH, PA — How does a physician manage life-threatening bleeding in patients taking dabigatran (Pradaxa, Boehringer Ingelheim), given that there is no specific antidote for the new anticoagulant?

While the overall bleeding rates are low and the rates of serious life-threatening bleeding even lower, "when something does happen, you can be in a real bind in terms of how best to deal with these complications," according to one expert.

With such uncertainty, Dr Brian Henry (University of Pittsburgh Medical Center, PA), along with Drs Rohit Kumar and Roy Smith (University of Pittsburgh Medical Center), published a series of case vignettes in the Journal of Intensive Care Medicine along with their recommendations for managing dabigatran-associated bleeding[1]. The goal, said Henry, is to provide some rational strategies for physicians who might not be as familiar with managing bleeding complications in these patients.

Given how long warfarin and heparin have been around, doctors are more comfortable with these agents because there are established protocols when there is a life-threatening bleeding event. With dabigatran, however, a new anticoagulant that does not have a specific reversal agent, there is a fair amount of uncertainty over how to best manage serious bleeding events when they occur.

Some Initial Testing and Then Hemodialysis

At their university medical center, the severity of bleeding is first assessed, and patients undergo initial laboratory testing that will include a full metabolic panel, complete blood count (CBC), activated partial thromboplastin time (aPTT), thrombin time (TT), and assessment of dabigatran levels.

While actually measuring the dabigatran levels is most effective for determining the degree of anticoagulation, this can take up to 24 hours, said Henry. On the other hand, aPTT can provide a "qualitative measure" of the degree of anticoagulation, and TT is also very sensitive to the presence of any direct thrombin inhibitor. Neither the aPTT nor TT measurements are truly effective for determining how much dabigatran is present, however.

"What I encourage people to do is examine the patient clinically," he told heartwire . "If you think you have a significant hemorrhage caused by dabigatran, and you think this is dangerous, and you want to reverse this person's coagulopathy now or as quickly as possible, this is when we start to recommend proceeding with options like dialysis and things like that. The coagulation studies are actually best for measuring response to your reversal strategy. The aPTT and TT will be prolonged, but as you remove dabigatran from the system, those numbers will improve."

In terms of recommendations for treating patients with hemorrhage caused by the novel anticoagulant, Henry said his center has good follow-up data showing that hemodialysis is effective for reducing dabigatran levels. In addition, they frequently treat patients with recombinant human activated factor VII (rhFVIIa), and others have claimed success with prothrombin complex concentrates (PCCs). Henry said that rhFVIIa and PCCs work by generating thrombin and might be effective in hemorrhage patients with normal dabigatran levels.

"But in situations where you have a patient who has very high levels of dabigatran, usually in the setting of acute renal failure, like a lot of our patients, you're not going to be able to generate enough thrombin to overcome the drug levels," said Henry. "This is where dialysis comes into play. It's the only therapy that actually removes it from the system."

If the last dose of dabigatran was less than two hours ago, the group says that activated charcoal is an option. They also provide some scenarios and recommendations on when to consider using cryoprecipitate and desmopressin. The use of fresh frozen plasma and vitamin K is not recommended.

Other Drugs and Underestimating Risk

Regarding other anticoagulants, including rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), which are direct factor Xa inhibitors and have a different mechanism of action from that of dabigatran, hemodialysis is not as effective, said Henry. Rivaroxaban and apixaban have a higher affinity for plasma proteins and as such are unable to be removed in this way. For these drugs, others are focusing on PCCs as a potential reversal agent.

Boehringer Ingelheim has recently come under fire and is facing more than 2000 lawsuits in the US over claims that dabigatran, approved in 2010, caused fatal and severe bleeding. In addition, recent media reports suggested that the company failed to provide regulators with data suggesting higher risks of bleeding with dabigatran than in the pivotal Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) trial. The US Food and Drug Administration is planning a study to assess safety outcomes in adults with atrial fibrillation who recently started taking dabigatran or warfarin.

On the whole, Henry stressed that bleeding with dabigatran is a legitimate concern, although he thinks the problem might be overstated. In the clinical trials, bleeding rates are low for those treated with warfarin and dabigatran. In RE-LY, there was less intracerebral and fatal bleeding with dabigatran compared with warfarin, although gastrointestinal bleeding was increased. Henry believes that physicians might be underanticoagulating patients by overestimating the bleeding risk and underestimating the risk of stroke.

"People with atrial fibrillation are at an increased risk for stroke, so we know they benefit from being anticoagulated," said Henry. "However, any patient that gets put on a blood thinner, any blood thinner, is going to be at an increased risk of bleeding, even though we know that the risk/benefit profile ultimately favors putting these patients on anticoagulation."

The authors report no conflicts of interest.


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