Resuming anticoagulation after hemorrhage: A practical approach

WOULD A NEWER DRUG BE A BETTER CHOICE?

The emergence of target-specific oral anticoagulants, including factor Xa inhibitors such as rivaroxaban, apixaban, and edoxaban and the direct thrombin inhibitor dabigatran etexilate, presents further challenges in managing anticoagulation after hemorrhage. Table 4 summarizes the current FDA-approved indications.^64–67

These newer agents are attractive because, compared with warfarin, they have wider therapeutic windows, faster onset and offset of action, and fewer drug and food interactions.⁶⁸ A meta-analysis of data available to date suggests that the new drugs, compared with warfarin, show a favorable risk-benefit profile with reductions in stroke, intracranial hemorrhage, and mortality with similar overall major bleeding rates, except for a possible increase in gastrointestinal bleeding.⁶⁸

However, when managing anticoagulation after a bleeding event, the newer agents are challenging for two reasons: they may be associated with a higher incidence of gastrointestinal bleeding than warfarin, and they lack the typical reversal agents that can be used to manage an acute bleeding event.^68,69

In individual studies comparing warfarin with dabigatran,⁷⁰ rivaroxaban,⁷¹ apixaban,⁷² or edoxaban⁷³ for stroke prevention in patients with atrial fibrillation, there was no significant difference in the rate of major bleeding between dabigatran in its higher dose (150 mg twice a day) or rivaroxaban compared with warfarin.^70,71 The risk of major bleeding was actually lower with apixaban⁷² and edoxaban.⁷³

In regard to specific types of major bleeding, the rate of intracranial hemorrhage was significantly lower with dabigatran, rivaroxaban, apixaban, and edoxaban than with warfarin.^35,68–73 Some have proposed that since the brain is high in tissue factor, inhibition of tissue factor-factor VIIa complexes by vitamin K antagonists leaves the brain vulnerable to hemorrhage. Others suggest that the targeted mechanism of target-specific agents, as opposed to the multiple pathways in both the intrinsic and extrinsic coagulation cascade that vitamin K antagonists affect, may explain this difference.^35,74,75

However, some studies suggest that rivaroxaban and the higher doses of dabigatran and edoxaban are associated with higher rates of major gastrointestinal bleeding compared with warfarin.^69–71,76 But apixaban demonstrated no significant difference in gastrointestinal bleeding, and instead demonstrated rates of gastrointestinal bleeding comparable to that with aspirin for stroke prevention in atrial fibrillation.⁷²

The new oral anticoagulants lack antidotes or reversal agents such as phytonadione and fresh-frozen plasma that are available to manage warfarin-associated bleeding events. Other proposed reversal options for the new agents include activated charcoal (if the drugs were taken recently enough to remain in the gastrointestinal tract) and concentrated clotting factor product, though research is ongoing in regards to the most appropriate use in clinical practice.^37,69 Unlike rivaroxaban and apixaban, dabigatran has low plasma protein binding and is dialyzable, which provides another strategy in managing dabigatran-related bleeding.⁶⁹

We believe most patients should resume anticoagulation after 4 to 7 days of interruption after GI bleeding

Of note, the above bleeding risk calculations relate to the first anticoagulant-related bleeding event, though presumably the same risk comparison across agents may be applicable to rebleeding events. Given the data above, when anticoagulation is to be resumed after an intracranial hemorrhage, the risk of rebleeding, particularly in the form of recurrent intracranial hemorrhage, may be lower if a target-specific oral anticoagulant is used.⁷⁵ Similarly, when anticoagulation is to be resumed after a gastrointestinal bleeding event, reinitiation with warfarin or apixaban therapy may present the lowest risk of recurrent gastrointestinal rebleeding. In other sources of bleeding, such as retroperitoneal bleeding, we suggest consideration of transitioning to warfarin, given the availability of reversal agents in the event of recurrent bleeding.

Other important drug-specific factors that must be noted when selecting an agent with which to resume anticoagulation after a hemorrhage include the following:

• In patients with significant renal impairment, the choice of agent will be limited to a vitamin K antagonist.⁷⁷
• A meta-analysis of randomized clinical trials suggests that in the elderly (age 75 and older) target-specific oral anticoagulants did not cause excess bleeding and were associated with at least equal efficacy compared with vitamin K antagonists.⁷⁸
• Target-specific oral anticoagulants may be beneficial in patients who have challenges in achieving INR targets, as evidence suggests that switching to them is associated with a reduction in bleeding for patients who struggle to maintain an appropriately therapeutic INR.⁶⁸ On the other hand, if there is concern that a patient may occasionally miss doses of an anticoagulant, given the rapid onset and offset of action of target-specific agents compared with warfarin, a missed dose of a target-specific agent may result in faster dissolution of anticoagulant effect and increased risk of thrombotic events, and lapses in anticoagulation will not be identified by routine drug monitoring.^6–8,75 As such, it is vital to have a frank discussion with any patient who has difficulty maintaining therapeutic INRs on warfarin treatment to make sure that he or she is not missing doses.
• If there is no clear and compelling reason to select a particular agent, cost considerations should be taken into account. We have included estimated 30-day pricing for the various agents in Table 4.