4 sample taken 10 to 16 hours (trough level) after ingestion of the same dose [25]. The following coagulation tests may be used to assess the risk of bleeding. (i) aPTT: this test may be useful in determining an excess of anticoagulant activity, despite aPTT being less sensitive to the activity of dabigatran above therapeutic levels [23]. An aPTT >80 seconds (2 to 3 × baseline value) at trough is associated with a higher risk of bleeding [26]. A normal aPTT (not exceeding the upper limit of normal) indicates no clinically relevant anticoagulant eﬀect of dabigatran. Most patients with therapeutic dabigatran plasma concentrations will have an aPTT ratio of about 1.5 to 2.0 (45 s to 65 s), at trough [23, 24]. However, as previously stated, aPTT should not be used as a quantitative measurement of dabigatran plasma concentrations. (ii) TT: the actual test measure will depend on the coagulometer and the thrombin lot used for measurement. (iii) Calibrated Hemoclot thrombin inhibitor assay (a diluted TT): an assay calibrated with dabigatran standards, to calculate dabigatran concentration [23]. In patients taking dabigatran for stroke prevention in nonvalvular AF, a diluted TT measure of >200 ng/mL of dabigatran plasma concen- tration (approximately >65 seconds) prior to the next drug intake (trough measure) is associated with a higher risk of bleeding [24]. A normal diluted TT measurement indicates no clinically relevant anticoagulant eﬀect of dabigatran [26]. (iv) Prothrombin time and INR are unreliable in patients on dabigatran and false positive INR elevations have been reported [23, 27]. These tests should not be used (AR). 2.8. How Should Patients on Dabigatran with Major or Life- Threatening Bleeding Events Be Managed? Even though life- threatening bleeding events are expected to be lower with dabigatran compared to VKA, it is advisable that hospitals develop speciﬁc protocols for emergency situations. Presently, there is no speciﬁc antidote for dabigatran. However, it has recently been demonstrated that a speciﬁc humanized antibody fragment may provide a selective and rapid reversal of dabigatran activity. This antibody fragment is currently under clinical development for human use [28]. In the event of hemorrhagic complications, dabigatran must be discontinued and the source of bleeding investi- gated. As dabigatran is primarily excreted in the urine, ade- quate diuresis is needed and ﬂuids should be administered as tolerated (AR). Transfusions with fresh frozen plasma, red blood cells, and fresh platelet concentrates may be consid- ered, especially in cases where long-acting antiplatelet drugs have been used. Reversal agents like recombinant factor VIIa (rFVIIa) and activated or nonactivated prothrombin complex concentrates (PCCs) may also be considered, as suggested by experimental data [23, 29, 30]. Nevertheless, their eﬃcacy remains unproven in the clinical setting. In a study with 12 healthy young volunteers who received dabigatran 150 mg bid for two and a half days, a single 50 IU/Kg bolus of PCC did not reverse the aPTT, ECT, and TT. However, no assessment of bleeding time or correlation with bleeding was performed [31]. Thrombosis When considering a surgical resolution for the life- threatening hemorrhagic complication, the risks of this procedure must be very carefully considered. If all of the above measures fail to control the bleeding, hemodialysis may be useful for dabigatran removal, especially in patients with renal impairment (see Section 2.11) [23, 32]. Hemop- erfusion over a charcoal ﬁlter may also have some beneﬁts [33]. As an example of an oﬃcial emergency room protocol, the Pharmaceutical Management Agency of New Zealand recently issued the following guidelines for management of bleeding in patients treated with dabigatran [34]. (i) Mild bleeding: local hemostatic measures; delay next dose of dabigatran or discontinue treatment, as appropriate. (ii) Moderate-to-severe bleeding: local measures; ﬂuid replacement; blood product transfusion; admin- istration of antiﬁbrinolytic agent for example, tranexamic acid IV (15–30 mg/kg)±continuous infu- sion (1 mg/kg/hr); consider Prothrombinex-VF 25– 50 IU/kg, and repeat if necessary with hematology guidance. (iii) Life-threatening bleeding: previous measures; rFVIIa (100 mcg/kg by IV bolus), repeat if necessary with hematology guidance; hemodialysis, especially if renal failure is present. 2.9. How to Manage a Patient Treated with Dabigatran and Referred for Urgent Surgery? Patients receiving antithrom- botic therapy who undergo elective surgery or invasive procedures are at increased risk of bleeding. Therefore, these interventions may require temporary discontinuation of antithrombotic agents, and dabigatran is not an exception. Dabigatran should be discontinued 1 to 4 days prior to elec- tive surgery, depending on the degree of renal impairment and risk of bleeding (Table 1) [17]. If the surgery or invasive procedure cannot be delayed to allow renal elimination of dabigatran and reversal of its anticoagulant eﬀect, the degree of anticoagulation should be checked with the diluted TT assay (Hemoclot thrombin inhibitor assay) or aPTT [20, 26]. In the event of a normal diluted TT or aPTT (not exceeding the upper limit of normal) then no clinically relevant anticoagulant eﬀect of dabigatran is present and surgery or invasive procedure can proceed without delay. If plasma concentration of dabigatran is >200 ng/mL or aPTT >80 seconds (2 to 3 × baseline value) and an urgent procedure with a high risk of bleeding is necessary, reversal of the anticoagulant eﬀect of dabigatran with PCC or rFVIIa should be considered. If the blood sample is not collected at trough, reference values for coagulation tests are not currently available. In the RE-LY study, patients receiving dabigatran were more likely to have a surgery or invasive procedure within 24 hours of withholding OAC and did so with a substantially lower risk of major bleeding than patients on warfarin (relative risk reduction of 82% for dabigatran 110 mg bid and 56% for 150 mg bid) [35].