Trauma Risk in Oral Anticoagulant Users Prompt Search for Antidotes

LAKE BUENA VISTA, FLA. – Patients on one of the powerful new oral anticoagulants are left without a good antidote for bleeding if they experience a traumatic injury.

The use of these agents is climbing as baby boomers age and the number of patients with atrial fibrillation continues its steady rise from 2.0 million in 1995 to a projected 4.34 million by 2030.

"If you think it’s an epidemic now, it will become even more so in the coming years," Dr. Mark Cipolle, medical director of trauma and neurocritical care at Christiana Care Health System in Wilmington, Del., said at the annual meeting of the Eastern Association for the Surgery of Trauma.

Currently, no specific antidote is available for dabigatran (Pradaxa) or the factor Xa inhibitor rivaroxaban (Xarelto), both of which are approved for stroke prevention in nonvalvular atrial fibrillation and for deep vein thrombosis following hip or knee replacement surgery.

The oral Xa inhibitor apixaban (Eliquis) is under priority review for stroke and DVT prevention in atrial fibrillation and will likely move, sans antidote, into the marketplace later this year based on robust results from the recent ARISTOTLE trial.

Vitamin K and protamine sulfate are not expected to affect the anticoagulant activity of the new oral anticoagulants. Some centers have had anectodal success in reversing dabigatran with activated prothrombin complex concentrates (aPCCs), but this has not been widely adopted, according to Dr. Cipolle.

"Some of my colleagues in pharmacy think this may be the drug to help us reverse dabigatran ... but our blood bank hematologists aren’t thrilled about going to this because of the development of antibodies for the new agents," he said.

The two aPCCs available in the United States are factor eight inhibitor binding activity (FEIBA) and anti-inhibitor coagulant complex, heat treated (Autoplex T); both are indicated for bypass therapy in patients with acquired inhibitors and contain the coagulation factors II, VII, IX, and X.

One of the first randomized trials to look at a specific PCC (Cofact) showed that a single bolus immediately and completely reversed the anticoagulation effect of rivaroxaban in 12 healthy volunteers who were taking 20 mg twice daily, but the PCC had no influence on the effect of dabigatran 150 mg twice daily (Circulation 2011;124:1573-9), said copanelist John Gallagher, clinical nurse specialist for the surgical/trauma ICU at the Hospital of the University of Pennsylvania in Philadelphia.

Recombinant activated factor VIIa has been widely studied in trauma, but not for this specific indication. Early research on antibody monoclonal development is showing promise, Dr. Cipolle said. A recent study described a monoclonal mouse antibody with a high and specific affinity to inhibit dabigatran in both human plasma and whole blood and in a rat in vivo model (J. Am. Coll. Cardiol. 2011;57:E1130).

The package insert for dabigatran recommends emergency dialysis as a reversal strategy, stating that about 60% of dabigatran is removed over 2-3 hours. "This [strategy] may work," said Dr. Cipolle, observing that about 80% of dabigatran is renally excreted, compared with 66% of rivaroxaban and only 25% of apixaban.

Although not trivial, the half-lives of dabigatran (14-17 hours), rivaroxaban (9 hours), and apixaban (9-14 hours) are shorter than that of warfarin (40 hours), which means that "if you can wait and just not give them the drug, you are probably going to be okay," he said.

Dr. Cipolle cautioned, however, that reversal of labs may not indicate loss of anticoagulant effects. Also, clotting factors and continued prolongation of anticoagulation assays do not indicate lack of effect.

"The drug industry has spent years developing a drug that we could take orally that you don’t have to measure, and all we want to do is measure it," he said. "We would like to know just how much anticoagulant effect is present, and if our reversal strategies are working.

"A normal PTT [partial thromboplastin time] is very helpful, but other than that, the classic anticoagulation studies aren’t terribly helpful."

This point was also referenced in a recent letter to the New England Journal of Medicine penned by two trauma surgeons and an emergency physician who treated several injured patients on dabigatran, all of whom had poor outcomes (N. Engl. J. Med. 2011;365:2039-40). Although their values for activated clotting time on rapid thromboelastography (rTEG) were grossly abnormal at the time of admission, all of the patients had normal results on conventional anticoagulation studies.

"Unfortunately, even with the aid of rTEG, supportive care is all that is available in the emergency setting," wrote the authors, who strongly urged that hemorrhagic complications and death resulting from trauma be included as part of routine surveillance of all newly approved oral anticoagulants. The authors also argued that "the ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level 1 trauma centers."

Both Dr. Cipolle and Mr. Gallagher emphasized that institutions should have a protocol in place for anticoagulant reversal. The protocol should be based on evidence and practice guidelines, be transparent and modifiable, and identify specific anticoagulant agents, triggers for reversal such as intracranial hemorrhage or solid organ injury, and reversal strategies and methods for monitoring both the use of anticoagulants and reversal strategies, Mr. Gallagher said.

During a discussion of the study, attendees asked how to address anticoagulation at discharge in, for example, a 72-year-old man with early Alzheimer’s disease and a fourth admission for a fall. Dr. Cipolle replied that a recommendation would be placed in his chart based on his initial risk and that a hospitalist or cardiologist would also be called in. He observed that trauma surgeons typically overestimate the fall risk, compared with the stroke risk, and often feel that making such a recommendation may be out of their purview.

Audience member Dr. Ronald Gross, chief of trauma and emergency surgery at Baystate Medical Center in Springfield, Mass., said trauma surgeons need to play a more active role in anticoagulation. He added that physicians at his center have a conversation prior to discharge with every single fall patient about the risks and benefits of anticoagulation, and also contact their prescribing physicians.

Session moderator Dr. Lewis Kaplan, a trauma and critical care surgeon at Yale University, New Haven, Conn., said the nurse practitioners at his center call primary care physicians when trauma patients are admitted and make a follow-up call upon discharge. The trauma surgeon makes an anticoagulation recommendation at discharge, although half the time, despite the conversation, patients are back on their anticoagulants in a matter of weeks, Dr. Kaplan said.

Dr. Cipolle and Mr. Gallagher reported no conflicts of interest. Dr. Lewis serves as a consultant to Pfizer.

LAKE BUENA VISTA, FLA. – Patients on one of the powerful new oral anticoagulants are left without a good antidote for bleeding if they experience a traumatic injury.

The use of these agents is climbing as baby boomers age and the number of patients with atrial fibrillation continues its steady rise from 2.0 million in 1995 to a projected 4.34 million by 2030.

"If you think it’s an epidemic now, it will become even more so in the coming years," Dr. Mark Cipolle, medical director of trauma and neurocritical care at Christiana Care Health System in Wilmington, Del., said at the annual meeting of the Eastern Association for the Surgery of Trauma.

Currently, no specific antidote is available for dabigatran (Pradaxa) or the factor Xa inhibitor rivaroxaban (Xarelto), both of which are approved for stroke prevention in nonvalvular atrial fibrillation and for deep vein thrombosis following hip or knee replacement surgery.

The oral Xa inhibitor apixaban (Eliquis) is under priority review for stroke and DVT prevention in atrial fibrillation and will likely move, sans antidote, into the marketplace later this year based on robust results from the recent ARISTOTLE trial.

Vitamin K and protamine sulfate are not expected to affect the anticoagulant activity of the new oral anticoagulants. Some centers have had anectodal success in reversing dabigatran with activated prothrombin complex concentrates (aPCCs), but this has not been widely adopted, according to Dr. Cipolle.

"Some of my colleagues in pharmacy think this may be the drug to help us reverse dabigatran ... but our blood bank hematologists aren’t thrilled about going to this because of the development of antibodies for the new agents," he said.

The two aPCCs available in the United States are factor eight inhibitor binding activity (FEIBA) and anti-inhibitor coagulant complex, heat treated (Autoplex T); both are indicated for bypass therapy in patients with acquired inhibitors and contain the coagulation factors II, VII, IX, and X.

One of the first randomized trials to look at a specific PCC (Cofact) showed that a single bolus immediately and completely reversed the anticoagulation effect of rivaroxaban in 12 healthy volunteers who were taking 20 mg twice daily, but the PCC had no influence on the effect of dabigatran 150 mg twice daily (Circulation 2011;124:1573-9), said copanelist John Gallagher, clinical nurse specialist for the surgical/trauma ICU at the Hospital of the University of Pennsylvania in Philadelphia.

Recombinant activated factor VIIa has been widely studied in trauma, but not for this specific indication. Early research on antibody monoclonal development is showing promise, Dr. Cipolle said. A recent study described a monoclonal mouse antibody with a high and specific affinity to inhibit dabigatran in both human plasma and whole blood and in a rat in vivo model (J. Am. Coll. Cardiol. 2011;57:E1130).

The package insert for dabigatran recommends emergency dialysis as a reversal strategy, stating that about 60% of dabigatran is removed over 2-3 hours. "This [strategy] may work," said Dr. Cipolle, observing that about 80% of dabigatran is renally excreted, compared with 66% of rivaroxaban and only 25% of apixaban.

Although not trivial, the half-lives of dabigatran (14-17 hours), rivaroxaban (9 hours), and apixaban (9-14 hours) are shorter than that of warfarin (40 hours), which means that "if you can wait and just not give them the drug, you are probably going to be okay," he said.

Dr. Cipolle cautioned, however, that reversal of labs may not indicate loss of anticoagulant effects. Also, clotting factors and continued prolongation of anticoagulation assays do not indicate lack of effect.

"The drug industry has spent years developing a drug that we could take orally that you don’t have to measure, and all we want to do is measure it," he said. "We would like to know just how much anticoagulant effect is present, and if our reversal strategies are working.

"A normal PTT [partial thromboplastin time] is very helpful, but other than that, the classic anticoagulation studies aren’t terribly helpful."

This point was also referenced in a recent letter to the New England Journal of Medicine penned by two trauma surgeons and an emergency physician who treated several injured patients on dabigatran, all of whom had poor outcomes (N. Engl. J. Med. 2011;365:2039-40). Although their values for activated clotting time on rapid thromboelastography (rTEG) were grossly abnormal at the time of admission, all of the patients had normal results on conventional anticoagulation studies.

"Unfortunately, even with the aid of rTEG, supportive care is all that is available in the emergency setting," wrote the authors, who strongly urged that hemorrhagic complications and death resulting from trauma be included as part of routine surveillance of all newly approved oral anticoagulants. The authors also argued that "the ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level 1 trauma centers."

Both Dr. Cipolle and Mr. Gallagher emphasized that institutions should have a protocol in place for anticoagulant reversal. The protocol should be based on evidence and practice guidelines, be transparent and modifiable, and identify specific anticoagulant agents, triggers for reversal such as intracranial hemorrhage or solid organ injury, and reversal strategies and methods for monitoring both the use of anticoagulants and reversal strategies, Mr. Gallagher said.

During a discussion of the study, attendees asked how to address anticoagulation at discharge in, for example, a 72-year-old man with early Alzheimer’s disease and a fourth admission for a fall. Dr. Cipolle replied that a recommendation would be placed in his chart based on his initial risk and that a hospitalist or cardiologist would also be called in. He observed that trauma surgeons typically overestimate the fall risk, compared with the stroke risk, and often feel that making such a recommendation may be out of their purview.

Audience member Dr. Ronald Gross, chief of trauma and emergency surgery at Baystate Medical Center in Springfield, Mass., said trauma surgeons need to play a more active role in anticoagulation. He added that physicians at his center have a conversation prior to discharge with every single fall patient about the risks and benefits of anticoagulation, and also contact their prescribing physicians.

Session moderator Dr. Lewis Kaplan, a trauma and critical care surgeon at Yale University, New Haven, Conn., said the nurse practitioners at his center call primary care physicians when trauma patients are admitted and make a follow-up call upon discharge. The trauma surgeon makes an anticoagulation recommendation at discharge, although half the time, despite the conversation, patients are back on their anticoagulants in a matter of weeks, Dr. Kaplan said.

Dr. Cipolle and Mr. Gallagher reported no conflicts of interest. Dr. Lewis serves as a consultant to Pfizer.

LAKE BUENA VISTA, FLA. – Patients on one of the powerful new oral anticoagulants are left without a good antidote for bleeding if they experience a traumatic injury.

The use of these agents is climbing as baby boomers age and the number of patients with atrial fibrillation continues its steady rise from 2.0 million in 1995 to a projected 4.34 million by 2030.

"If you think it’s an epidemic now, it will become even more so in the coming years," Dr. Mark Cipolle, medical director of trauma and neurocritical care at Christiana Care Health System in Wilmington, Del., said at the annual meeting of the Eastern Association for the Surgery of Trauma.

Currently, no specific antidote is available for dabigatran (Pradaxa) or the factor Xa inhibitor rivaroxaban (Xarelto), both of which are approved for stroke prevention in nonvalvular atrial fibrillation and for deep vein thrombosis following hip or knee replacement surgery.

The oral Xa inhibitor apixaban (Eliquis) is under priority review for stroke and DVT prevention in atrial fibrillation and will likely move, sans antidote, into the marketplace later this year based on robust results from the recent ARISTOTLE trial.

Vitamin K and protamine sulfate are not expected to affect the anticoagulant activity of the new oral anticoagulants. Some centers have had anectodal success in reversing dabigatran with activated prothrombin complex concentrates (aPCCs), but this has not been widely adopted, according to Dr. Cipolle.

"Some of my colleagues in pharmacy think this may be the drug to help us reverse dabigatran ... but our blood bank hematologists aren’t thrilled about going to this because of the development of antibodies for the new agents," he said.

The two aPCCs available in the United States are factor eight inhibitor binding activity (FEIBA) and anti-inhibitor coagulant complex, heat treated (Autoplex T); both are indicated for bypass therapy in patients with acquired inhibitors and contain the coagulation factors II, VII, IX, and X.

One of the first randomized trials to look at a specific PCC (Cofact) showed that a single bolus immediately and completely reversed the anticoagulation effect of rivaroxaban in 12 healthy volunteers who were taking 20 mg twice daily, but the PCC had no influence on the effect of dabigatran 150 mg twice daily (Circulation 2011;124:1573-9), said copanelist John Gallagher, clinical nurse specialist for the surgical/trauma ICU at the Hospital of the University of Pennsylvania in Philadelphia.

Recombinant activated factor VIIa has been widely studied in trauma, but not for this specific indication. Early research on antibody monoclonal development is showing promise, Dr. Cipolle said. A recent study described a monoclonal mouse antibody with a high and specific affinity to inhibit dabigatran in both human plasma and whole blood and in a rat in vivo model (J. Am. Coll. Cardiol. 2011;57:E1130).

The package insert for dabigatran recommends emergency dialysis as a reversal strategy, stating that about 60% of dabigatran is removed over 2-3 hours. "This [strategy] may work," said Dr. Cipolle, observing that about 80% of dabigatran is renally excreted, compared with 66% of rivaroxaban and only 25% of apixaban.

Although not trivial, the half-lives of dabigatran (14-17 hours), rivaroxaban (9 hours), and apixaban (9-14 hours) are shorter than that of warfarin (40 hours), which means that "if you can wait and just not give them the drug, you are probably going to be okay," he said.

Dr. Cipolle cautioned, however, that reversal of labs may not indicate loss of anticoagulant effects. Also, clotting factors and continued prolongation of anticoagulation assays do not indicate lack of effect.

"The drug industry has spent years developing a drug that we could take orally that you don’t have to measure, and all we want to do is measure it," he said. "We would like to know just how much anticoagulant effect is present, and if our reversal strategies are working.

"A normal PTT [partial thromboplastin time] is very helpful, but other than that, the classic anticoagulation studies aren’t terribly helpful."

This point was also referenced in a recent letter to the New England Journal of Medicine penned by two trauma surgeons and an emergency physician who treated several injured patients on dabigatran, all of whom had poor outcomes (N. Engl. J. Med. 2011;365:2039-40). Although their values for activated clotting time on rapid thromboelastography (rTEG) were grossly abnormal at the time of admission, all of the patients had normal results on conventional anticoagulation studies.

"Unfortunately, even with the aid of rTEG, supportive care is all that is available in the emergency setting," wrote the authors, who strongly urged that hemorrhagic complications and death resulting from trauma be included as part of routine surveillance of all newly approved oral anticoagulants. The authors also argued that "the ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level 1 trauma centers."

Both Dr. Cipolle and Mr. Gallagher emphasized that institutions should have a protocol in place for anticoagulant reversal. The protocol should be based on evidence and practice guidelines, be transparent and modifiable, and identify specific anticoagulant agents, triggers for reversal such as intracranial hemorrhage or solid organ injury, and reversal strategies and methods for monitoring both the use of anticoagulants and reversal strategies, Mr. Gallagher said.

During a discussion of the study, attendees asked how to address anticoagulation at discharge in, for example, a 72-year-old man with early Alzheimer’s disease and a fourth admission for a fall. Dr. Cipolle replied that a recommendation would be placed in his chart based on his initial risk and that a hospitalist or cardiologist would also be called in. He observed that trauma surgeons typically overestimate the fall risk, compared with the stroke risk, and often feel that making such a recommendation may be out of their purview.

Audience member Dr. Ronald Gross, chief of trauma and emergency surgery at Baystate Medical Center in Springfield, Mass., said trauma surgeons need to play a more active role in anticoagulation. He added that physicians at his center have a conversation prior to discharge with every single fall patient about the risks and benefits of anticoagulation, and also contact their prescribing physicians.

Session moderator Dr. Lewis Kaplan, a trauma and critical care surgeon at Yale University, New Haven, Conn., said the nurse practitioners at his center call primary care physicians when trauma patients are admitted and make a follow-up call upon discharge. The trauma surgeon makes an anticoagulation recommendation at discharge, although half the time, despite the conversation, patients are back on their anticoagulants in a matter of weeks, Dr. Kaplan said.

Dr. Cipolle and Mr. Gallagher reported no conflicts of interest. Dr. Lewis serves as a consultant to Pfizer.