When patients on target-specific oral anticoagulants need surgery

Laboratory monitoring

Inevitably, some patients on TSOACs require urgent or emergency surgery. In certain situations, such as before an orthopedic spine procedure, in which the complications of bleeding could be devastating, it may be necessary to know if any residual anticoagulant effect is present.

Monitoring dabigatran. As one might expect, direct thrombin inhibitors such as dabigatran can prolong the prothrombin time and activated partial thromboplastin time (aPTT).^44–47 However, the prothrombin time is not recommended for assessing the level of anticoagulation from dabigatran. Many institutions may be using a normal aPTT to rule out therapeutic concentrations of dabigatran, based on results from early in vitro and ex vivo studies.⁴⁶ While appealing from a practical standpoint, practitioners should exercise caution when relying on the aPTT to assess the risk of perioperative bleeding. A more recent investigation in patients treated with dabigatran found that up to 35% of patients with a normal aPTT still had a plasma concentration in the therapeutic range.⁴⁸

The thrombin time and ecarin clotting time are more sensitive tests for dabigatran. A normal thrombin time or ecarin clotting time indicates that no or only minimal dabigatran is present.⁴⁸ Unfortunately, these two tests often are either unavailable or are associated with long turnaround times, which limits their usefulness in the perioperative setting.

Monitoring rivaroxaban and apixaban. Factor Xa inhibitors such as rivaroxaban and apixaban can also influence the prothrombin time and aPTT (Figure 1).^{44–47,49,50} The aPTT is relatively insensitive to these drugs at low concentrations. It has been suggested that a normal prothrombin time can reasonably exclude therapeutic concentrations of rivaroxaban.^45,46 However, the effects on the prothrombin time are highly variable, changing with the reagent used.^49,50 In addition, apixaban appears to have less impact on the prothrombin time overall. The INR is not recommended for monitoring the effect of factor Xa inhibitors.

Anti-factor Xa assays likely represent the best option to provide true quantitative information on the level of anticoagulation with either rivaroxaban or apixaban. However, the assays must be specifically calibrated for each drug for results to be useful. (Anti-factor Xa assays cannot be used for heparin or low-molecular-weight heparin.) Further, most institutions do not yet have this capability. When appropriately calibrated, normal anti-factor Xa levels would exclude any effect of rivaroxaban or apixaban.

Reversal of anticoagulation

If patients on TSOACs require emergency surgery or present with significant bleeding in the setting of persistent anticoagulation, it may be necessary to try to reverse the anticoagulation.

Unlike warfarin or heparin, TSOACS do not have specific reversal agents, though specific antidotes are being developed. For example, researchers are evaluating antibodies capable of neutralizing dabigatran, as well as recombinant thrombin and factor Xa molecules that could antagonize dabigatran and rivaroxaban, respectively.^51–53

Reversal can be attempted by neutralizing or removing the offending drug. Activated charcoal may be able to reduce absorption of TSOACs that were recently ingested,⁴⁴ and dabigatran can be removed by hemodialysis.

However, certain practical considerations may limit the use of dialysis in the perioperative period. Insertion of a temporary dialysis line in an anticoagulated patient poses additional bleeding risks. A standard 4-hour hemodialysis session may remove only about 70% of dabigatran from the plasma, which may not be enough to prevent perioperative bleeding.⁵⁴ Dabigatran also tends to redistribute from adipose tissue back into plasma after each dialysis session.⁵⁵ Serial sessions of high-flux intermittent hemodialysis or continuous renal replacement therapy may therefore be needed to counteract rebound elevations in the dabigatran concentration.

Reversal can also be attempted through activation of the coagulation cascade via other mechanisms. Fresh-frozen plasma is unlikely to be a practical solution for reversal.⁴⁴ Although it can readily replace the clotting factors depleted by vitamin K antagonists, large volumes of fresh-frozen plasma would be needed to overwhelm thrombin or factor Xa inhibition by TSOACs.

There are limited data on the use of prothrombin complex concentrates or recombinant activated factor VIIa in patients on TSOACs, though their use can be considered.⁵⁶ In a trial in 12 healthy participants, a nonactivated four-factor prothrombin complex concentrate containing factors II, VII, IX, and X immediately and completely reversed the anticoagulant effect of rivaroxaban but had no effect on dabigatran.⁵⁷ Before 2013, there were no nonactivated four-factor prothrombin complex concentrates available in the United States. The FDA has since approved Kcentra for the urgent reversal of vitamin K antagonists, meaning that the reversal of TSOACs in major bleeding events would still be off-label.⁵⁸ Giving any of the clotting factors carries a risk of thromboembolism.

Resumption of anticoagulation

TSOACs have a rapid onset of action, and therapeutic levels are reached within a few hours of administration.

Extrapolating from the ACCP guidelines, TSOACs can generally be restarted at therapeutic doses 24 hours after low-bleeding-risk procedures.² Therapeutic dosing should be delayed 48 to 72 hours after a procedure with a high bleeding risk, assuming adequate hemostasis has been achieved. Prophylactic unfractionated heparin or low-molecular-weight heparin therapy can be given in the interim if deemed safe. Alternatively, for orthopedic patients ultimately transitioning back to therapeutic rivaroxaban after hip or knee arthroplasty, prophylactic rivaroxaban doses can be started 6 to 10 hours after surgery.¹⁴

There are numerous reasons why the resumption of TSOACs may have to be delayed after surgery, including nothing-by-mouth status, postoperative nausea and vomiting, ileus, gastric or bowel resection, and the anticipated need for future procedures. Since dabigatran capsules cannot be crushed, they cannot be given via nasogastric tube in patients with postoperative dysphagia. Parenteral anticoagulants should be used until these issues resolve.

Unfractionated heparin is still the preferred anticoagulant in unstable or potentially unstable patients, given its ease of monitoring, quick offset of action, and reversibility. When patients have stabilized, TSOACs can be resumed when the next dose of low-molecular-weight heparin would have been due or when the unfractionated heparin drip is discontinued.^3,14,23

UNTIL EVIDENCE-BASED GUIDELINES ARE DEVELOPED

The development of TSOACs has ushered in an exciting new era for anticoagulant therapy. Providers involved in perioperative medicine will increasingly encounter patients on dabigatran, rivaroxaban, and apixaban. However, until evidence-based guidelines are developed for these new anticoagulants, clinicians will have to apply their knowledge of pharmacology and critically evaluate expert recommendations in order to manage patients safely throughout the perioperative period.