More then 2.5 million patients in the United States are on long-term anticoagulation therapy for atrial fibrillation, venous thromboembolic disease, or mechanical heart valves,1 and the number is expected to rise as the population ages. Each year, about 10% of these patients undergo an invasive procedure or surgery that requires temporary interruption of anticoagulation.2
Most physicians are familiar with the perioperative management of warfarin, a vitamin K antagonist, since for decades it has been the sole oral anticoagulant available. However, many physicians lack experience with the three target-specific oral anticoagulants (TSOACs; also known as “novel” oral anticoagulants) approved so far: the direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitors rivaroxaban (Xarelto) and apixaban (Eliquis).
With their rapid onset of action, predictable pharmacokinetics, relatively short half-lives, and fewer drug-drug interactions than warfarin, TSOACs overcome many of the limitations of the older oral anticoagulant warfarin. In many ways, these qualities simplify the perioperative management of anticoagulation. At the same time, these new drugs also bring new challenges: caution is needed in patients with renal impairment; the level of anticoagulation is difficult to assess; and there is no specific antidote or standardized procedure to reverse their anticoagulant effect. While various periprocedural protocols for TSOAC therapy have been proposed, evidence-based guidelines are still to come.
This article first discusses the pharmacology of dabigatran, rivaroxaban, and apixaban that is pertinent to the perioperative period. It then briefly reviews the general principles of perioperative management of anticoagulation. The final section provides specific recommendations for the perioperative management of TSOACs.
PHARMACOLOGY OF TARGET-SPECIFIC ORAL ANTICOAGULANTS
Dabigatran, a factor IIa inhibitor
Dabigatran is an oral direct thrombin (factor IIa) inhibitor. It exerts its anticoagulant effect by blocking the generation of fibrin, inhibiting platelet aggregation, and dampening the activity of factors V, VIII, and XI (Figure 1).3,4 From its introduction in October 2010 through August 2012, nearly 3.7 million prescriptions were dispensed to 725,000 patients in the United States.5
Indications for dabigatran. Dabigatran is approved in the United States and Canada for preventing stroke in nonvalvular atrial fibrillation (Table 1).6 More recently, it received US approval for treating deep vein thrombosis or pulmonary embolism after 5 to 10 days of a parenteral anticoagulant.7,8 It is also approved in Europe and Canada for preventing venous thromboembolism (VTE) after total hip replacement and knee arthroplasty.9,10
Dabigatran is contraindicated in patients with a mechanical heart valve, based on a phase 2 study in which it conferred a higher risk of thromboembolism and bleeding than warfarin.3,11
Pharmacokinetics of dabigatran. Dabigatran is formulated as a prodrug, dabigatran etexilate, in a capsule containing multiple small pellets.12 The capsules should not be crushed, as this significantly increases oral bioavailability. The prodrug is absorbed across the gastric mucosa and is then rapidly converted to the active form (Table 2).
Plasma concentrations peak within 2 hours of ingestion, which means that therapeutic anticoagulation is achieved shortly after taking the drug.
Only 35% of dabigatran is protein-bound, which allows it to be removed by hemodialysis. Nearly 85% of the drug is eliminated in the urine. It has a half-life of 13 to 15 hours in patients with normal renal function.3 However, its half-life increases to about 27 hours in patients whose creatinine clearance is less than 30 mL/min. As a result, the dose must be reduced in patients with renal impairment (Table 1).
Dabigatran is not metabolized by the cytochrome P450 enzymes, but it is a substrate for P-glycoprotein, so it still has the potential for drug-drug interactions.3 Practitioners should be familiar with these potential interactions (Table 3), as they can result in higher- or lower-than-expected plasma concentrations of dabigatran in the perioperative period.13