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Dabigatran

Dabigatran Etexilate (Pradaxa®) is an oral direct thrombin (factor IIa) inhibitor approved by the FDA to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Dabigatran etexilate is a prodrug that is rapidly absorbed from the GI tract and then converted to its active form, dabigatran. Dosing for patients with normal renal function is 150 mg by mouth twice daily. Therapeutic levels are reached within 30 minutes to two hours following oral administration. Steady state is reached within 2 to 3 days. The drug is excreted unchanged via the kidneys (~80%) with the remainder excreted via bile. Circulating half life is 12-17 hours.

Supra-therapeutic concentrations of dabigatran result in modest elevations of INR (~2.0). However the effect on INR is variable and unpredictable. INR should not be used as a measure of the anticoagulant effect of dabigatran.

There is a reasonable, non-linear correlation between dabigatran plasma concentration and the activated plasma thromboplastin time (aPTT). Dabigatran prolongs the aPTT to 1.5 – 2.5 times the control. At a dose of 150 mg bid, less than 10% of patients have aPTTs greater than 65 sec (or 2 times control) when measured 12 hours after dosing. An aPTT >2.5 x control may indicate over-anticoagulation.

Thrombin Time exhibits a linear correlation with plasma concentrations of dabigatran up to 400 ng/mL. Thrombin time may be elevated as much as 10 to 20 times control in patients with therapeutic plasma concentrations of dabigatran. Thrombin time may be too sensitive for routinely monitorin of dabigatran because in many instances an endpoint is never reached. Dabigatran affects the activated clotting time (ACT) as do other direct thrombin inhibitors but no systematic investigation of their efficacy has been undertaken.

Ecarin clotting time (ECT) is a specific test that shows a close linear correlation with the plasma concentrations of direct thrombin inhibitors, including dabigatran. However, this test is not generally available in hospital laboratories. ECT ratios of 2-4 have been observed for plasma concentrations of dabigatran after 150 mg bid.

The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial demonstrated lower bleeding and hemorrhagic stroke rates with dabigatran than with heparin. However, the incidence of dyspepsia and major GI bleeding were higher with dabigatran than warfarin. Bleeding risk is increased with concomitant use of antiplatelet medications.

Patients with therapeutic levels of dabigatran are at increased risk of bleeding during invasive procedures or surgery. Dabigatran should be discontinued at least 24 hours prior to elective surgery depending on the degree of renal impairment and risk of bleeding. In patients with normal renal function and a standard bleeding risk, discontinuation of dabigatran 24 hours before surgery will decrease plasma levels to approximatrely 12-25% of steady state trough levels. Plasma levels are decreased to 15% at 36 hours and 5-10% at 48 hours before surgery. Dabigatran should probably be discontinued for 2-4 days prior to surgery for patients at higher risk of bleeding or for major surgery. For patients at high risk of bleeding, a thrombin time can be performed 6-12 hours before surgery. An elevated thrombin time, in the absence of heparin or other direct thrombin inhibitors, is an indication of the continued presence of dabigatran.

Data from many phase III clinical trials of dabigatran indicated that the bleeding rate was approximately 3%. Unfortunately, if bleeding does occur, no specific antidote is available. Fresh frozen plasma will not be very effective in reversing the anticoagulant effect of these drugs because of its relatively low concentration of coagulation factor II (thrombin) and factor X. Most articles written on this topic have suggested that nonactivated Prothrombin Complex Concentrate (PCC, Proplex T®, Beriplex® or Octaplex® ) and activated prothrombin complex concentrate (Feiba VH®) would be useful in reversing the anticoagulant effect of these drugs because they contain large doses of coagulation factors II, VII, IX and X. However, a recent publication demonstrated that PCC did not correct the anticoagulant effect of dabigatran (Circulation 2011; 124:1573-79). The authors concluded that PCC but has no role in the reversal of dabigatran.

The only remaining option for treating the bleeding associated with dabigatran is off label use of recombinant activated factor VII (rFVIIa, NovoSeven®), which achieves hemostasis by directly activating thrombin on the surface of platelets. However, the use of rFVIIa has had inconsistent results with other direct thrombin inhibitors. Other options include activated charcoal to absorb recently ingested drug and dialysis. Clearly, more research is needed in this area.

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