Thrombosis Table 1: Guide to the discontinuation of dabigatran before elective surgery or invasive procedure [17]. Renal function When to stop dabigatran before surgery (CrCl mL/min) Standard risk of bleeding High risk of bleeding >80 >50 and ≤80 >30 and ≤50 24 hours before 1-2 days before 2-3 days before 2 days before 2-3 days before 4 days before When restarting dabigatran after surgery, clinicians should be aware of the rapid onset of its anticoagulant eﬀect. Dabigatran can be resumed 24 to 72 hours after surgery, depending on the bleeding risk of the patient and procedure, as recommended for therapeutic heparin in the ACCP Guidelines [36]. 2.10. Is a Patient Treated with Dabigatran Suitable for Neurax- ial Anesthesia? Neuraxial anesthesia comprises spinal (sub- dural space anesthesia) and epidural block (epidural space anesthesia) and is increasingly used in various types of surgery for pain relief, in the perioperative or postoperative periods [37]. The occurrence of spinal hematoma is a rare com- plication of neuraxial anesthesia, but may result in irre- versible neurological damage and its risk is increased with antithrombotic therapy [38, 39]. Therefore, neuraxial anes- thesia requires complete hemostatic function and dabigatran should be temporarily discontinued before the procedure. The timing of discontinuation should be adjusted in accor- dance to the patient’s renal function and the procedure’s risk of bleeding (Table 1). Dabigatran may be initiated as soon as clinically indi- cated and at least 6 hours after the removal of epidural catheter [40]. 2.11. Is Dialysis Eﬃcient in Removing Dabigatran from Circu- lation? Dabigatran is dialysable due to its relatively small molecular size and low plasma protein binding (∼35%) [23]. This concept is supported by small studies performed in patients with a renal function ranging from normal to severely depressed. One open-label study demonstrated that the mean fraction of dabigatran removed by hemodialysis was 62% at 2 hours and 68% at 4 hours [41]. Another open-label study performed in patients with end-stage renal disease showed that the mean fraction of dabigatran cleared from plasma by high ﬂow rate hemodialysis (400 mL/min) was 54 to 68% at 4 hours [32]. In emergency situations, hemodialysis can be employed to eliminate dabigatran and reduce its anticoagulant eﬀect [23]. 2.12. Can a Patient Treated with Dabigatran Receive Dual Antiplatelet Therapy (Aspirin Plus Clopidogrel)? Aspirin and/ or clopidogrel were used in 38.4% of patients during the RE- LY study and increased the relative risk of major bleeding by 60%, but the risk was lower with dabigatran 110 mg bid when compared to warfarin (HR 0.82, 95%CI: 0.67–1.00) [42]. 5 Almost 5% of patients received dual antiplatelet therapy with aspirin and clopidogrel [43]. In these patients, the relative eﬀects of both dabigatran 110 mg bid and 150 mg bid in comparison to warfarin in terms of major bleeding risk were consistent with the main trial results. Adding aspirin to oral anticoagulation in patients with stable vascular disease (coronary, carotid, or peripheral arterial disease) does not reduce the risk of vascular events, including myocardial infarction [14]. As such, concomitant use of antiplatelets and oral anticoagulants should be cautious and reserved to special indications such as acute coronary syndromes or revascularization procedures. Dual antiplatelet therapy should be restricted to patients receiving coronary stenting. Implantation of drug eluting stents, which require a period of 6 to 12 months of dual antiplatelet therapy, should be avoided whenever possible [14]. The more potent new P2Y12 inhibitors, prasugrel, and ticagrelor, which have a higher bleeding risk than clopidogrel [44, 45], set new challenges to the safety of combining OAC with antiplatelet therapy. In patients with nonvalvular atrial ﬁbrillation and a clear recommendation for oral anticoagulation (CHA2DS2- VASc Score >1) and antiplatelet therapy, dabigatran is an advantageous alternative to warfarin, particularly with the 110 mg bid dose [42, 43]. Whenever dual or triple antithrombotic therapy is used, strict blood pressure control is strongly recommended [46]. 2.13. How to Manage a Patient Treated with Dabigatran and Admitted for an Acute Coronary Syndrome? Which Antithrombotics Can Be Used If the Patient Is Referred for Primary Angioplasty? Can Dabigatran Be Administered Safely after an Acute Coronary Syndrome? In the RE-LY study, there were speciﬁc recommendations for the management of acute coronary syndromes (ACSs). This issue was also tackled in the protocol of the RELY-ABLE trial, an extension of the dabigatran treated patients that completed the RE-LY trial (Table 2) [47]. ESC and ACC/AHA Guidelines recommend the use of dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) in the setting of ACS [48–50] and this should also be applied to the patient treated with dabigatran. Since guidelines also recommend anticoagulation (heparin, fondaparinux, or bivalirudin) in the acute phase, it seems reasonable to temporarily discontinue dabigatran and start the recom- mended anticoagulants at least 12 hours after the last dose of dabigatran or as soon as the aPTT is <1.5 × baseline value. If the patient is suitable for reperfusion therapy (ST- segment elevation myocardial infarction and less than 12 hours of symptoms) primary percutaneous coronary inter- vention (PCI) is preferable to ﬁbrinolytic therapy. If primary PCI is not available, ﬁbrinolysis should only be administered if aPTT is <1.5 × baseline value and potential gains outweigh the bleeding risks (AR). Heparin should be administered during PCI according to the usual target of activated clotting time (ACT). There is a linear concentration-dependent increase in ACT with dabigatran plasma concentrations of up to 250 ng/mL [23].