Milwaukee VA Develops Reversal Protocol for Novel Oral Anticoagulants

By Annette M. Boyle

Jennifer Koch, PharmD

Jennifer Koch, PharmD

MILWAUKEE – Many patients prefer the devil they know. When asked whether they want to go on or switch to a novel oral anticoagulant (NOAC) that requires little monitoring, has few drug-drug or food interactions, appears to reduce all-cause mortality and reduces the risk of a life-threatening bleeding event but has no certain antidote if hemorrhaging occurs, many patients at the Clement J. Zablocki Veterans Administration Medical Center in Milwaukee opt to start or stay with warfarin.

“We really restrict the novel oral anticoagulants to patients who don’t do well on warfarin. They have trouble getting to a stable INR, have adverse effects or can’t readily get to a warfarin clinic,” said Jennifer Koch, PharmD, an internal medicine clinical pharmacy specialist at the Milwaukee VAMC.

“When we discuss the advantages and disadvantages of switching with those patients, a lot of them choose not to go on a novel anticoagulant because there is currently no specific antidote for these agents,” added Daisy Peterson, PharmD, a primary care clinical pharmacy specialist at the Zablocki VAMC.

Daisy Peterson 0547 E

Daisy Peterson, PharmD

The Milwaukee VAMC has used the novel or target specific oral anticogaulants (TSOAs) — dabigatran etexilate, rivaroxaban and apixaban — since they were first approved, starting in 2009 with dabigatran. The advantages were clear, but the lack of a specific antidote was troubling, not only for patients, but also for the pharmacists and physicians involved in the anticoagulation clinics.

In 2012, James Sebastian, MD, the physician champion for anticoagulation, convened a group to tackle the problem and develop a protocol for treating a bleeding event in a patient on dabigatran or rivaroxaban. Review of research and appeals to an anticoagulation listserv had turned up few previously developed protocols.

The group revised its protocol last fall to include apixaban. Another update is in review now that adjusts the recommendations for concentrated clotting factor products. And, given the pace of change in the field, another revision likely will be needed shortly.

Trials for specific antidotes are in process for dabigatran and for agents that reverse Factor Xa inhibition, the mechanism of action for apixaban, rivaroxaban and edoxaban, a new anticoagulant in the same class that is currently in trials.

Dabigatran Associated Bleeding

In the meantime, the protocol provides some direction for clinicians. For life-threatening bleeding, the protocol instructs clinicians to first evaluate coagulation parameters.

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“We test thrombin time for dabigatran and prothrombin for the other two TSOAs, mainly to detect presence or absence, rather than the level of drug in the system. There are no readily accessible tests that allow us to predict the concentration in the blood,” Peterson noted.

The next priority is to control the site of bleeding, mechanically or surgically, and provide supportive treatment including fluid replacement, hemodynamic support and blood product transfusions, as necessary and in ratios specified. The protocol recommends use of fresh frozen plasma, not to reverse the anticoagulation effect of dabigatran, but to avoid dilutional coagulopathy. Activated charcoal may be administered at standard doses if dabigatran has been taken within two hours and hemodialysis should be considered.

“Dialysis is the only known intervention that reduces plasma concentrations of dabigatran. It’s not useful for other TSOAs because they have high plasma protein binding, where dabigatran doesn’t. Dialysis may be effective in removing 60% of dabigatran in two to four hours,” Peterson explained.

“A single session of dialysis may not be adequate, however,” she added. “Dabigatran can be redistributed through the body following initial dialysis. There is also the concern that a patient may not tolerate the volume removed through dialysis.”

As a last resort, clinicians may consider using recombinant activated Factor VII (rFVIIa) or three-factor prothrombin complex concentrate (PCC) to help with clot formation at the site of bleeding. The protocols note that “the strength of the evidence for these interventions is weak and limited.”

Managing Other NOACs

The protocols for apixaban and rivaroxaban are similar to those for dabigatran but have a few differences. Activated charcoal administration is recommended if the last dose of rivaroxaban was ingested within eight hours or if apixaban was taken within the last six hours. As a last resort, the current protocol recommends using three-factor PCC.

The next update will recommend use of four-factor PCC.

“The main reason is that CHEST guidelines specifically say to use four-factor PCC for warfarin reversal,” Koch said, referring to the official journal of the American College of Chest Physicians. “When we started, three factor was the only one available in the U.S., but four factor had been in use in Europe longer, so there was larger body of evidence for it.”

The team also will recommend a small amount of rFVIIa be administered concurrently with three-factor PCC in the upcoming revision.

Both PCC and rFVIIa pose a risk of thrombosis. “The order set that accompanies the protocol takes a provider through the process, but it’s the physician’s responsibility to weigh the risk of using those agents. When we looked at studies for PCC in healthy individuals or in warfarin patients, the risk of thrombosis wasn’t that high,” Koch told U.S. Medicine.

In part, the analysis rests on the risk of possible thrombosis vs. an actual, life-threatening hemorrhage. “In a life-threatening bleed situation, the risk of not using one of these is higher than the risk of thrombosis and a physician will generally do everything possible to stop the bleeding,” Koch added.

At least two other VAMCs have requested the protocols through the listserv for anticoagulation clinics, they pointed out.


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