REVIEW ARTICLE. Management of oral anticoagulation in the surgical patient. Introduction. ANZJSurg.com. Jilani Latona* and Atifur Rahman.

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1 REVIEW ARTICLE ANZJSurg.com Management of oral anticoagulation in the surgical patient Jilani Latona* and Atifur Rahman *Department of Cardiology, Gold Coast University Hospital, Gold Coast, Queensland, Australia and School of Medicine, Griffith University, Gold Coast, Queensland, Australia Key words anticoagulation, surgery. Correspondence Dr Jilani Latona, Department of Cardiology, Gold Coast University Hospital, Hospital Boulevard, Southport, Qld. 4215, Australia. J. Latona MBChB; A. Rahman MBBS, FRACP. Accepted for publication 23 February Abstract New oral anticoagulants (NOACs) have recently emerged as an alternative for vitamin K antagonists and are now widely available. Although there is good evidence for their roles in the appropriate clinical settings, so far no reversal agent is currently available. Likewise, there is no readily available laboratory test to quantify drug levels but coagulation assays may provide qualitative information about the presence of some NOACs. We aim to review the current literature regarding the optimal management of oral anticoagulation in the perioperative setting. doi: /ans Introduction New oral anticoagulants (NOACs) have recently emerged as an alternative for vitamin K antagonists (VKAs) and are now widely available. They are currently indicated in: (1) prevention of stroke in patients with non-valvular atrial fibrillation (AF); (2) prophylaxis of deep vein thrombosis/pulmonary embolism in patients undergoing knee or hip replacement surgery; and (3) treatment of deep vein thrombosis/pulmonary embolism. 1 With their increasing use, we often encounter situations where patients on NOACs have to undergo surgery and therefore are faced with the dilemma of when to stop anticoagulation and how to manage the risk of thromboembolism. We aim to review the literature regarding the perioperative management of NOACs. Non-valvular AF is associated with an increased risk of stroke. The loss of atrial systolic function results in sluggish blood flow in the atrium, whereas the distension of the atria cause disturbance of the endothelium and activates haemostatic factors leading to a hypercoagulable state. 2 Risk factors predisposing to stroke include increasing age, history of previous stroke or transient ischaemic attack (TIA), hypertension, diabetes and congestive cardiac failure. Other factors include female sex and vascular disease. Oral anticoagulation in the form of VKAs is a well-established treatment for stroke prevention in AF. The major positive aspects of NOACs include (i) no need for monitoring and (ii) reduced risk of adverse interactions with change in diet or concomitant drugs while being equally effective to VKAs for the prevention of strokes. We will aim to review three available NOACS and warfarin. The NOACs can be classified into the direct thrombin inhibitors (dabigatran) and factor Xa inhibitors: rivaroxaban and apixaban. Prophylaxis of thromboembolism in AF Decision making for prophylaxis of thromboembolism needs to balance the risk of stroke against the risk of major bleeding. In patients with AF, stroke risk stratification schemes have been developed to optimize antithrombotic treatment. The CHADS2 3 score is simple, frequently used but has limitations. It does not include many common potential stroke risk factors such as female sex, von Willebrand factor levels and left ventricular ejection fraction. 4 The new European Society of Cardiology guidelines instead recommend a risk factor-based approach with a new schema, the CHA2DS2-VASc score, 5 to complement the CHADS2 scheme. The CHA2DS2-VASc schema places greater emphasis on what it terms major risk factors, that is, age >75 years and previous stroke/tia, by allocating two points to each, with one point for the presence of each of the other clinically relevant non-major risk factors (Table 1). CHA2DS2-VASc score improves risk prediction and is better at identifying truly low-risk patients with AF. In patients with CHA2DS2-VASc score 2, all three NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk. 6 ANZ J Surg 85 (2015)

2 Anticoagulants in surgery 621 Table 1 CHA2DS2-VASc scoring A. Ref 2,3 CHADS2 score C Congestive heart failure 1 point H Hypertension 1 point A Age >75 years 1 point D Diabetes 1 point S2 Stroke 2 points CHA2DS2-VASc score C Congestive heart failure 1 point H Hypertension 1 point A2 Age >75 years 2 points D Diabetes 1 point S2 Stroke 2 points V Vascular disease 1 point A Age >65 years 1 point Sc Sex category, female 1 point B. Adjusted risk of stroke for CHADS2 and CHA2DS2-VASc scores Score CHADS2 (%/year) CHA2DS2-VASc (%/year) On the other hand, many risk factors for stroke are also risk factors for bleeding. Therefore, integral to the decision of anticoagulation in AF patients is the assessment of bleeding risk. This should be undertaken on an individual basis. To assist with identifying which patients are at increased risk of bleeding, different bleeding risk tools have been proposed. One of the most widely used and accepted ones is the HAS-BLED score. HAS-BLED represents each of the bleeding risk factors and assigns one point for the presence of each of the following: (1) Hypertension (uncontrolled systolic blood pressure >160 mmhg) (2) Abnormal renal and/or liver function (3) Previous stroke (4) Bleeding history or predisposition (5) Labile international normalized ratios (6) Elderly, and concomitant drugs and/or alcohol excess The HAS-BLED scores range from 0 to 9, with scores of 3 indicating high risk of bleeding, for which caution and regular review of the patient are recommended. 7 NOACS in venous thromboembolic disease Dabigatran, rivaroxaban and apixaban are available in Australia for primary venous thromboembolism (VTE) prophylaxis, but approval is currently limited to the context of elective hip and knee replacement surgery where they have been studied. 8 With regard to treatment of deep vein thrombosis and pulmonary embolus, only rivaroxaban is approved for use in Australia. There is no role for the use of NOAC in patients with artificial valves. The RE-ALIGN investigators found that the use of dabigatran in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications as compared with warfarin, thus showing no benefit and an excess risk. 9 Pharmacokinetics Dabigatran etexilate is an orally administered prodrug, which is rapidly absorbed over a P-glycoprotein (P-gp) receptor and converted to the active form, dabigatran. Excretion is predominantly via the renal route as unchanged drug. Dabigatran is not metabolized by cytochrome P450 isoenzymes. It has a bioavailability of 3 7%, and 80% of the absorbed drug is renally cleared. An important interaction mechanism consists of significant resecretion over a P-gp transporter after absorption in the gut. 10 The elimination half-life is around h. 11 Because of its high renal excretion, dabigatran is to be used with caution in patients with renal impairment and are best avoided in patients with a creatinine clearance (CrCl) of <30 ml/min. Rivaroxaban is also absorbed through the gut with a bioavailability of 66% without food and 100% with food. Unlike dabigatran and apixaban, it is not resecreted over the P-gp receptor. Sixty-five per cent of the absorbed drug is cleared non-renally whereas 35% is cleared renally. Importantly, CYP3A4 type cytochrome P450 is involved in elimination of the drug in the liver. Its elimination half-life is around 5 9 h in the young as compared with h in the old. 10 Therefore, rivaroxaban is best avoided in patients with liver disease with an ALT more than two times the upper limit of normal or Childs Pugh B or C and in patients with CrCl <30 ml/min. 12 Apixaban, another Xa inhibitor, has a bioavailability of 50%. Seventy-three per cent of the absorbed drug is non-renally cleared whereas 27% is cleared renally. 13 It should be avoided in patients with CrCl <25 ml/min. CYP3A4 has minor contribution in its elimination as most of the hepatic clearance of the drug is an unchanged molecule. The elimination half-life is around 12 h and may be used with caution in patients with Child Pugh grade B hepatic impairment. Warfarin is a VKA that inactivates vitamin K in the liver. This interferes with the formation of vitamin K-dependent clotting factors. Following rapid and complete absorption, it is bound to albumin with a half-life of 37 h. It is metabolized by the enzyme cytochrome P450 and vitamin K epoxide reductase. Drug interactions Based on the above, it is now clear that drugs that act as P-gp substrates or that inhibit or induce CYP3A4 will affect the plasma levels of the NOACS. Drugs used in AF such as verapamil and amiodarone are P-gp substrates. For instance verapamil can cause % increase in plasma levels of dabigatran while amiodarone can increase plasma levels by up to 60%. 14 Verapamil (immediate release) should therefore be taken more than 2 h after dabigatran ingestion. The dose of dabigatran should be reduced when taken with verapamil-sustained release.

3 622 Latona and Rahman Because of its metabolism by the enzyme cytochrome P450, warfarin can interact with any drugs that inhibit or induce CYP450. Up to 80% of drugs may interact with warfarin. 15 Current Pharmaceutical Benefits Scheme indication for using NOAC (A) Prevention of stroke or systemic embolism in a patient with non-valvular AF who is at moderate to high risk of developing stroke or systemic embolism as evidenced by one or more of the following risk factors: (1) Age 75 years or older (2) Hypertension (3) Diabetes mellitus (4) Heart failure or left ventricular dysfunction (ejection fraction less than 40%) (5) Previous stroke or transient ischaemic attack or systemic embolism The term valvular AF is used to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves. Rheumatic mitral valve disease with AF carries a 17-fold increased risk of stroke and requires anticoagulation with warfarin. 16 AF in patients with prosthetic valves also requires anticoagulation, usually with a higher international normalised ratio (INR) target dependent on type of valve. (B) Prophylaxis of deep vein thrombosis/pulmonary embolism in patients undergoing knee or hip replacement surgery. (C) Treatment of deep vein thrombosis/pulmonary embolism. 1 NOAC trials Rivaroxaban was non-inferior to warfarin for the prevention of stroke and thromboembolism in the ROCKET AF trial in which patients were randomized to either rivaroxaban or warfarin. The risk of major bleeding in the rivaroxaban group was no different compared with the warfarin group while intracranial haemorrhage (0.5 versus 0.7%, P = 0.02) and fatal bleeding (0.2 versus 0.5%, P = 0.003) were reduced. 17 Apixaban was evaluated against warfarin in the ARISTOTLE trial in which patients were enrolled. Apixaban was superior to warfarin in preventing stroke or systemic embolization while causing less bleeding and mortality. 18 Dabigatran was compared with warfarin in the RELY trial in which patients were enrolled. Dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin (1.53 versus 1.69%, P < 0.001), as well as lower rates of major haemorrhage (2.71% per year in the group receiving 110 mg dabigatran as compared with 3.36% per year in the group receiving warfarin; P = 0.003). 19 Anticoagulation management in the perioperative setting Trials have previously shown that about one in four patients who need anticoagulation therapy requires temporary cessation of their anticoagulants within 2 years. 20 When the anticoagulants are discontinued in high-risk patients, the interval without anticoagulation should be as short as possible with the risk of thromboembolism balanced against the risk of bleeding. Patients with mechanical heart valves are also at increased risk of systemic embolization and occlusive thrombus of the orifice of the prosthetic valve during sub-therapeutic levels of warfarin. 21 Older, caged-ball valves are the most thrombogenic followed by tilting disc valves. Bileaflet valves are the least thrombogenic. 22 In the absence of anticoagulant therapy, mitral position valves have an annualized risk of thrombosis of 22% compared with aortic position valves, with an annualized risk of approximately 10 12%. 23 The anticoagulation strategy selected depends on an evaluation of the thromboembolic risk and the haemorrhagic risk of the surgical procedure. The American College of Chest Physician guidelines on antithrombotic therapy suggest a clinically useful thromboembolic risk stratification in the peri-procedural period as shown in Table Table 2 Risk of thromboembolism in patients on VKAs Risk stratum High Moderate Low Any mitral valve prosthesis Any caged ball or tilting disc aortic valve prosthesis Recent (within 6 months) stroke or transient ischaemic attack Bileaflet aortic valve prosthesis and one or more of the of following risk factors: atrial fibrillation, prior stroke or transient ischaemic attack, hypertension, diabetes, congestive heart failure, age >75 years Indication for VKA therapy Mechanical heart valve Atrial fibrillation VTE CHADS2 score of 5 or 6 Recent (within 3 months) stroke or transient ischaemic attack Rheumatic valvular heart disease Bileaflet aortic valve prosthesis without atrial fibrillation and no other risk factors for stroke CHADS2 score of 3 or 4 CHADS2 score of 0 2 (assuming no prior stroke or transient ischaemic attack) Recent (within 3 months) VTE Severe thrombophilia (e.g. deficiency of protein C, protein S or antithrombin; antiphospholipid antibodies; multiple abnormalities) VTE within the past 3 12 months Non-severe thrombophilia (e.g. heterozygous factor V Leiden or prothrombin gene mutation) Recurrent VTE Active cancer (treated within 6 months or palliative) VTE >12 months previous and no other risk factors VKA, vitamin K antagonist; VTE, venous thromboembolism.

4 Anticoagulants in surgery 623 Management of warfarin in the perioperative setting Low-bleeding risk procedures VKAs may be continued with relatively low INR for minor procedures with a low risk of bleeding. 8 These include excision of skin lesions, cataract surgery and procedures in which the bleeding can be controlled readily by local measures. This approach is not recommended for laparoscopic surgery and ultrasound or computed tomography-guided biopsies. High-bleeding risk procedures The strategy for perioperative anticoagulation in patients undergoing major, high-bleeding risk surgery is based on the assessment of the risk of thromboembolism versus the risk of haemorrhage. In the low thromboembolism risk group, warfarin can be withheld for 5 days before surgery without any bridging anti-coagulation with unfractionated or low molecular weight heparin. Generally, high thromboembolism risk patients should be considered for more aggressive perioperative management strategy with bridging therapy. With regard to warfarin, a relatively normal zone of haemostasis exists when the INR is Although the INR value at which the risk of bleeding increases is not known, the risk is assumed not to be elevated when the INR <1.5 and is elevated when the INR is more than When bridging therapy is needed for patients at high risk, unfractionated heparin is preferred when the CrCl <30 ml/min. In procedures when bridging therapy is required, the usual protocol is to stop warfarin 5 days before the procedure and start low molecular weight heparin at a therapeutic dose once the INR <2. 25 The INR is usually checked on the morning of the procedure while enoxaparin should be last given 24 h prior to the procedure. Unfractionated heparin on the other hand is usually stopped 4 6 h before high-risk procedures. 23 Management of NOACS in the perioperative setting Patients on NOACs are less likely to require bridging therapy. 10 This is explained by the short half-life that allows for properly timed short-term cessation and early re-initiation after surgery. Non-emergency surgery can be deferred to a later date in patients with transient risk factor while in the case of emergency, surgery should ideally be deferred for h (since the last dose) if possible. If not, then a multidisciplinary team approach including surgeon, haematologist and cardiologist should be considered and the risk of bleeding carefully assessed and discussed with the patient and relatives. These should be assessed on a case-to-case basis. These novel drugs do not have specific antidotes and management of bleeding is thus largely supportive. For dabigatran, haemodialysis may be considered to increase drug elimination. 26 Evidence for administration of pre-homeostatic agents is limited. Activated prothrombic complex concentrate and fourfactor PCC have been shown to reduce bleeding in animal models with variable effect on coagulation parameters. 27 Activated charcoal can also be considered in patients presenting within 2 h of NOAC ingestion with moderate-to-severe bleeding. Packed red cell transfusion can be considered based on haemoglobin and for patients with a platelet count of <50 109/L or on antiplatelet therapy. Table 3 summarizes the perioperative management of anticoagulants as described earlier. In neuraxial anaesthesia for patients with adequate renal function and receiving rivaroxaban for VTE prophylaxis, the drug can be stopped 24 h before catheter insertion or removal. The first dose of rivaroxaban is best deferred 22 h post-traumatic puncture while its first dose should be given at least 6 h after catheter removal. There is currently no data on the safety of neuraxial anaesthesia in patients therapeutically anticoagulated with NOAC. 12 Restarting NOACS after surgery The timing to restart the NOACS after surgery will depend on multiple factors. These include the factors mentioned earlier along with the type of surgery and the ability to achieve immediate haemostasis. A close working relationship between the surgeons and the primary physician is therefore of paramount importance. Again the risk of bleeding should be weighed against the risk of thromboembolism. For procedures with immediate and complete haemostasis, NOAC can be resumed 6 8 h after intervention. In many surgical interventions, the resumption of anticoagulation within may carry a bleeding risk and therefore are better off Table 3 Summary of perioperative management of anticoagulation Drugs Mechanism of action Dosage Stopping medication before surgery Warfarin Vitamin K antagonist Widely varies Withheld for approximately 5 days Dabigatran (Pradaxa) Direct thrombin inhibitors 150 mg BD for most patients. 110 mg BD for age >75, ClCr ml/min Between 24 h in low-bleeding risk patients with normal renal function to >96 h in high-risk individual with impaired renal function 11 Rivaroxaban (Xarelto) Factor Xa inhibitor 20 mg daily for most patients. 15 mg daily if ClCr ml/min. Avoid if ClCr <30 ml/min Between 24 and 48 h 11 Apixaban (Eliquis) Factor Xa inhibitor 5 mg BD for most patients. For age >80 years, WT <60 kg, S creat >133 μm/l may require 2.5 mg BD Between 24 and 48 h Some variation exists in the recommended time to cease dabigatran between the European Society of Cardiology guidelines 11 and Queensland Health guidelines. 20 The Queensland Health guidelines recommend stopping dabigatran for 5 days in patients with creatinine clearance (CrCl) of ml/min and greater than 5 days (and not to restart) in patients with CrCl <30.

5 624 Latona and Rahman deferred. Low molecular weight heparin in a prophylactic dose may be considered to prevent deep vein thrombosis in these cases. Once NOACs are restarted, maximal anticoagulation will be obtained within 2 h. Switching from warfarin to NOAC The decision of switching from warfarin to a NOAC should always be performed in consultation with the patient. Ultimately, the decision rests on the patient to decide whether they would consider switching from one to the other. Risks and benefits of both types of drugs should be discussed at length and an informed decision made. NOACs should not be used as a bridging therapy for patients who were previously on warfarin and who are initiated back on VKAs. Renal function Before switching from warfarin to NOAC, one of the most important considerations should be renal function. In the presence of significant renal impairment (estimated glomerular filtration rate <30 ml/ min), most of the NOAC are contraindicated. In the presence of moderate renal impairment, NOAC should be used with caution and in most cases dosages need to be reduced. Compliance Compliance and adherence to treatment is crucial, especially as these drugs have a relatively short half-life, such that patients would be left without any anticoagulation protection if more than one dose were missed. INR When switching from a VKA to a NOAC, the INR should be allowed to fall to about 2.0. Antidote These novel drugs do not have specific antidotes and management of bleeding is thus largely supportive, given that these drugs have a relatively short (5 17 h) half-life. The lack of antidote is compounded by the fact that the activity of these drugs cannot be readily monitored as discussed below. Measurement of anticoagulant effect Dabigatran The aptt may provide a qualitative assessment of dabigatran level and activity and if the aptt level at trough (12 24 h) is double than the upper limit of normal; this may be associated with a higher risk of bleeding. 28 Dabigatran has also little effect on INR and prothrombin time (PT). Rivaroxaban and apixaban PT and aptt are affected to a varying extent by the Xa inhibitors. aptt cannot be used for any meaningful evaluation of Xa inhibitory effect. 29 Importantly, INR is completely unreliable in monitoring the anticoagulant effect of the factor Xa inhibitors. If INR is elevated, it may be a marker of vitamin K deficiency that needs to be separately corrected. Certain laboratories may also have access to specific assays. A drug-specific antifactor Xa chromogenic assay is sensitive for quantitative measurement of rivaroxaban 30 while a dilute thrombin clotting time assay such as the HEMOCLOT thrombin inhibitor assay is the recommended assay to determine dabigatran drug level. Conclusion The NOACs are currently approved for clinical use in different settings. These are at least as effective as warfarin in preventing embolic stroke and are safer with less intracranial haemorrhage. The strategy of management of anticoagulation in the perioperative period is based on the assessment of each patient s thromboembolic and bleeding risks. Most patients having minor procedures can continue to take anticoagulants, provided that they are closely monitored. High-risk patients should be considered for more aggressive perioperative management. Early, effective and ongoing communication between physicians and surgeons is required to maximize patient safety during perioperative transitions of anticoagulation. 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