Perioperative management of patients on new oral anticoagulants

Review Perioperative management of patients on new oral anticoagulants A. Lai 1, N. Davidson 2,S.W.Galloway 3 and J. Thachil 4 1 Department of General Surgery, Frenchay Hospital, North Bristol NHS Trust, Bristol, and Departments of 2 Cardiology and 3 Upper Gastrointestinal Surgery, University Hospital of South Manchester, and 4 Department of Haematology, Manchester Royal Infirmary, Manchester, UK Correspondence to: Miss A. Lai, Department of General Surgery, Frenchay Hospital, Frenchay Park Road, Bristol BS16 1JE, UK (e-mail: aida.lai@nbt.nhs.uk) Background: New oral anticoagulants (NOACs) offer an alternative to warfarin for preventing stroke in patients with atrial fibrillation. NOACs are expected to replace warfarin and other vitamin K antagonists for most of their indications in the future. Knowledge of the use of NOACs in the perioperative period is important for optimal care. Methods: Studies that reported on the use of NOACs were identified, focusing on evidence-based guidance relating to the perioperative period. PubMed was searched for relevant articles published between January 2000 and January 2014. Results: The anticipated expanded clinical use of NOACs such as rivaroxaban (Xarelto ), apixaban (Eliquis ) and dabigatran (Pradaxa ) has the potential to simplify perioperative anticoagulant management because of fewer drug drug interactions, rapid onset of action, predictable pharmacokinetics and relatively short half-lives. However, coagulation status cannot be monitored by international normalized ratio and no antidotes are currently available. In elective surgery, it is important to discontinue the use of NOACs, with special consideration of renal function as route of elimination. Guidelines for the management of bleeding complications in patients on NOACs are provided, and may be considered for trauma and emergency surgery. Haemodialysis could be considered for bleeding with use of dabigatran. Better options for reversal of the effects of NOACs when bleeding occurs may follow with novel drugs. Conclusion: Management of NOACs in elective and emergency conditions requires knowledge of time of last intake of drug, current renal function and the planned procedure in order to assess the overall risk of bleeding. Currently no antidote exists to reverse the effects of these drugs. Paper accepted 31 January 2014 Published online 29 April 2014 in Wiley Online Library (www.bjs.co.uk). DOI: 10.1002/bjs.9485 Introduction Anticoagulation is used widely in prevention of stroke, and in atrial fibrillation warfarin has been the drug of choice for several decades. However, the use of warfarin is limited by a narrow therapeutic index, the need for continuous monitoring and interactions with several drugs. Regular monitoring of the therapeutic effect by means of the international normalized ratio (INR) is required. The advent of new oral anticoagulants (NOACs) promises the delivery of equivalent benefit without the need for regular monitoring, and possibly a better safety profile by limiting the risks of overtreatment. NOACs are being used as an alternative to warfarin in patients who are intolerant of warfarin or in those who have poor INR control. The shorter half-life of these drugs also confers additional advantages in that temporary interruption required for haemorrhagic complications or surgical interventions can be easier than with warfarin. The European Society of Cardiology guidelines 1 recommend the use of NOACs in non-valvular atrial fibrillation, with a class IA level of evidence. However, potential drawbacks of NOACs include the lack of specific antidotes for these agents and the fact that coagulation status cannot be monitored by INR. This makes reversal of their effects during emergency surgery or bleeding particularly challenging. Moreover, an increasing number of elective surgical patients are on anticoagulation, including the new oral agents. Optimal management of these patients depends on the reason for the anticoagulation and the type of surgery being undertaken. This review presents updated information on the perioperative management of the NOACs. 2014 BJS Society Ltd BJS 2014; 101: 742 749

Perioperative management of patients on new oral anticoagulants 743 Damaged surface XII XIIa VIIa VII XI XIa Tissue factor Trauma IX IXa VIlla Direct inhibition of factor Xa by rivaroxaban or apixaban X Xa X Va Prothrombin Direct inhibition of thrombin by dabigatran Fibrin formation Thrombin Clot formation Fibrin Fibrinogen Fig. 1 Site of effects of new oral anticoagulants in the coagulation cascade Description of new oral anticoagulants The NOACs discussed in this article are rivaroxaban (Xarelto ; Bayer Healthcare, Leverkusen, Germany), apixaban (Eliquis ; Bristol-Myers Squibb, New York, USA) and dabigatran (Pradaxa ; Boehringer Ingelheim Pharmaceuticals, Ingelheim am Rhein, Germany). All have completed phase III clinical trials for stroke prevention in atrial fibrillation. National Institute for Health and Care Excellence guidelines 2 4 have recommended all three NOACs as options for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Rivaroxaban and apixaban are both inhibitors of activated factor Xa, whereas dabigatran is a direct thrombin inhibitor (Fig. 1). Another factor Xa inhibitor currently undergoing phase III trials is edoxaban. NOACs should be considered for stroke prevention in patients with atrial fibrillation who have failed to achieve target INR despite adherence to treatment with warfarin, in those who have contraindications or are allergic to warfarin therapy, and in patients with poor adherence to monitoring requirements. The anticoagulant effect of NOACs decreases rapidly 12 24 h after intake, so patient compliance is essential. Compliance should be emphasized during patient followup appointments. All NOACs require dose reductions depending on renal function. Renal function needs to be assessed on a 6-monthly basis if creatinine clearance (CrCl) is 30 60 ml/min or for patients on dabigatran 5.Thereare currently no data on the effect of NOACs in patients with advanced chronic kidney disease (CrCl below 30 ml/min) and the European Society of Cardiology guidelines 1 advise against their use in this group and in patients on dialysis. NOACs are not recommended in patients with severe liver dysfunction. The bioavailability of dabigatran is significantly lower than that of rivaroxaban and apixaban. Therefore, slight fluctuations in absorption will have a much greater impact on the plasma levels 6. Key pharmacokinetic properties of rivaroxaban, apixaban and dabigatran are summarized in Table 1. Rivaroxaban Rivaroxaban is an oral direct factor Xa inhibitor (Fig. 1). Its efficacy is equivalent to that of warfarin in stroke prevention and bleeding risk, with no significant difference

744 A. Lai, N. Davidson, S. W. Galloway and J. Thachil Table 1 Summary of characteristics of rivaroxaban, apixaban and dabigatran Rivaroxaban Apixaban Dabigatran Mechanism of action Factor Xa inhibitor Factor Xa inhibitor Direct thrombin inhibitor Dosing frequency Once daily Twice daily Twice daily Half-life (h) 5 13 12 8 15 Bioavailability (%) 80 66 6 5 Renal clearance (%) 66 25 80 Plasma protein binding (%) > 90 87 35 in major bleeding events but an increased risk of major gastrointestinal bleeding 7. Owing to high plasma protein binding, rivaroxaban cannot be eliminated during haemodialysis. The recommended dose for prevention of stroke is 20 mg once daily. It is contraindicated in patients with an estimated glomerular filtration rate below 15 ml per min per 1 73 m 2. Rivaroxaban is also used in the treatment of deep vein thrombosis (DVT), and prevention of recurrent pulmonary embolism and DVT. The recommended dosage for treatment of acute DVT is 15 mg twice daily for the initial 21 days followed by 20 mg once daily for continued treatment and prevention of recurrence. Rivaroxaban is metabolized through the CYP3A4 pathway and is also a substrate for P-glycoprotein. For this reason, it interacts with certain drugs including quinidine, ketaconazole, fluconazole, ciclosporin and erythromycin, which can increase the risk of bleeding with concomitant use of rivaroxaban. Its effect is reduced with the use of CYP3A4 inducers such as phenytoin, St John s wort and rifampicin 5. Apixaban Apixaban is also an oral direct factor Xa inhibitor (Fig. 1). Comparison of apixaban versus warfarin in patients with atrial fibrillation showed a reduction of stroke with apixaban along with a significant reduction in major bleeding 8. Patients treated with apixaban also had significantly lower rates of haemorrhagic stroke and intracranial haemorrhage. As a result of drug drug interactions similar to those with rivaroxaban, there is an increased risk of bleeding in patients taking ketoconazole and kiltiazem 5. The effect is reduced with the use of CYP3A4 inducers 5. Dabigatran Dabigatran is a reversible direct thrombin inhibitor. In a study 9 of patients with atrial fibrillation, dabigatran had lower rates of stroke and systemic embolism than warfarin. Major bleeding was also reduced with dabigatran at 150 mg compared with warfarin (relative risk (RR) 0 80, 95 per cent confidence interval (c.i.) 0 69 to 0 93), but a higher incidence of major gastrointestinal bleeding (RR 1 1, 0 86 to 1 41). The incidence of intracranial haemorrhage was lower with dabigatran at doses of both 110 and 150 mg. Dabigatran is excreted predominantly renally and renal function should be monitored regularly. The relatively low protein binding of dabigatran allows elimination of the drug to a large extent by haemodialysis 10. The intestinal absorption of dabigatran is dependent on ph and is therefore reduced in patients taking proton pump inhibitors. As a result of drug drug interaction, there is also an increased risk of bleeding in patients taking ketoconazole, amiodarone, quinidine and verapamil 1.Its effect is reduced with the use of CYP3A4 inducers 5. Edoxaban Edoxaban is an oral direct factor Xa inhibitor. A randomized, double-dummy trial compared two once-daily regimens of edoxaban with warfarin in 21 105 patients with moderate-to-high-risk atrial fibrillation 11. The annual rate of major bleeding was 3 4 per cent with warfarin versus 2 8 per cent with high-dose edoxaban (hazard ratio (HR) 0 80, 95 per cent c.i. 0 71 to 0 91; P < 0 001) and 1 6 per cent with low-dose edoxaban (HR 0 47, 0 41 to 0 55; P < 0 001). Annual rates of death from cardiovascular causes were 3 2 versus 2 7 per cent (HR 0 86, 0 77 to 0 97; P = 0 01) and 2 7 per cent (HR 0 85, 0 76 to 0 96; P = 0 008). Monitoring anticoagulant effect of new oral anticoagulants Routine coagulation monitoring is not required in patients on NOACs as these drugs have predictable pharmacokinetics. However, there are tests that could be used to estimate the anticoagulation effect. These assessments may be useful in situations such as acute bleed, requirement for emergency surgery and suspected overdose. For accurate assessment of the anticoagulation effect, it is important to know exactly the interval between NOAC administration and blood sampling, and the dose 5. NOACs reach their maximal effect at their maximum concentration, which is approximately 3 h after intake 5. Thrombin clotting time and ecarin clotting time can be used to test the anticoagulation effect of dabigatran 12.Prothrombin time (PT) is relatively insensitive to dabigatran 12. The activated partial thromboplastin time (APTT) assay shows a curvilinear dose response relationship with

Perioperative management of patients on new oral anticoagulants 745 dabigatran, but results need to be interpreted with caution as sensitivity is variable 13. The diluted thrombin time (dtt), available as the Hemoclot assay (Boehringer Ingelheim Pharmaceuticals) provides direct assessment of thrombin activity. When plotted on a graph, it displays a linear relationship with plasma levels of dabigatran. Therefore, it is used for reliable quantitative assessment of dabigatran concentrations 5. A dtt of more than 65 s is associated with an increased risk of bleeding but the assay may be available only in specialized laboratories 14. PT has higher sensitivity than APTT in assessing the anticoagulation effect of rivaroxaban but there is marked variability between PT reagents 15,16.Theanti-Xa chromogenic assay can be used to estimate the anticoagulation effect of the factor Xa inhibitors rivaroxaban and apixaban, but this would require calibration with drug-specific reagents as different assays have different dynamic ranges 17,18. The assays are used to estimate the plasma concentrations of the factor Xa inhibitors, but there are currently no data associating a concentration with risk of bleeding. New oral anticoagulants versus warfarin Bleeding complications The most feared bleeding complication of warfarin is intracranial haemorrhage. In this respect, NOACs are appealing as they are associated with a lower risk of intracranial bleeding, but at the cost of slightly increased risk of gastrointestinal bleeding. A meta-analysis 19 of phase II and phase III randomized clinical trials comparing NOACs with vitamin K antagonists in patients with atrial fibrillation showed that use of NOACs was associated with a significant reduction in the composite outcome of stroke (RR 0 77, 95 per cent c.i. 0 70 to 0 86). NOACs also reduced major bleeding (RR 0 86, 0 72 to 1 02) and significantly decreased the risk of intracranial haemorrhage (RR 0 46, 0 39 to 0 56). Reversibility The effects of warfarin can be reversed easily with the use of prothrombin complex concentrates (PCCs) and vitamin K. One of the major concerns regarding NOACs is the lack of a specific antidote. NOACs have short half-lives, and drug concentrations will decline rapidly in patients with normal renal function. In the setting of an overdose, activated charcoal may be used to decrease absorption of dabigatran 20. Monoclonal antibodies to neutralize the effect of dabigatran are currently in development, reaching the stage of early-phase clinical trials in humans 21.Other new compounds being researched to reverse the effects of NOACs are agents with antifibrinolytic activity 22. PCC has been shown to reverse the anticoagulant effect of rivaroxaban completely and immediately in healthy subjects, but has no influence on the anticoagulant action of dabigatran 23. Discontinuation of new oral anticoagulants before surgery Bridging is recommended in patients with atrial fibrillation who have high thromboembolic risk treated with vitamin K antagonists. However, this is not necessary for patients on NOACs as the diminution of effect is predictable, and enables the relatively short-term cessation and restarting of NOAC before and after surgery 5,24. Elective surgery In surgical procedures with no clinically important bleeding risk, such as ophthalmological and superficial dermatological procedures, the European Heart Rhythm Association (EHRA) 5 recommends the NOACs be discontinued 18 24 h before the procedure and then restarted 6 h later. In procedures with minor bleeding risk, such as biopsy of the prostate or bladder and endoscopy with biopsy, abdominal hysterectomy and hernia repair, the EHRA recommends discontinuing NOACs at least 24 h before elective procedures in patients with normal renal function. For procedures with a high risk of bleeding, such as major abdominal, cardiovascular, thoracic, orthopaedic, intracranial or spinal operations and liver and kidney biopsy, the EHRA recommends discontinuation of NOACs 48 h before intervention. The management of NOACs before surgery is summarized in Fig. 2. The Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis 24 provide different recommendations. For procedures with a low haemorrhagic risk, the recommendation is to stop NOACs 24 h before surgery and restart them 24 h afterwards. For procedures with a medium or high haemorrhagic risk, the suggestion is to stop NOACs 5 days before surgery and restart according to the bleeding risk. In managing patients with an increased likelihood of bleeding complications, the risk of bleeding should be assessed against the urgency of the intervention. A haematologist should be involved in the discussion. Recommendations for periprocedural interruption of dabigatran are based primarily on its pharmacokinetic

746 A. Lai, N. Davidson, S. W. Galloway and J. Thachil Minimized risk Risk of bleeding associated with procedure Minor risk High risk risk of bleeding, it is recommended that discontinuation starts at least 36 h before surgery. For those taking rivaroxaban with CrCl of 15 30 ml/min undergoing procedures with a high risk of bleeding, discontinuation should be started at least 48 h before surgery. Stop 18 24 h before surgery Stop 24 h before surgery Stop 48 h before surgery Fig. 2 Algorithm for management with new oral anticoagulants around the time of surgery, for patients on rivaroxaban or apixaban with a creatinine clearance (CrCl) of more than 30 ml/min undergoing elective surgery. *Surgery in a place where bleeding is accepted as minimal (for example superficial dermatological procedures); surgery in a place where bleeding can be controlled easily with local haemostatic measures and will not compromise organ function (for example joint aspirations). Discontinuation instructions for patients taking dabigatran and those with CrCl lower than 30 ml/min are shown in Table 2 Table 2 Suggested interruption of new oral anticoagulants before surgical intervention according to risk of bleeding and renal function Creatinine clearance (ml/min) Suggested interruption (h) Risk of bleeding Rivaroxaban Apixaban Dabigatran 80 Low 24 24 24 High 48 48 48 50 79 Low 24 24 36 High 48 48 72 30 49 Low 24 24 48 High 48 48 96 15 29 Low 36 36 Not indicated High 48 48 Not indicated < 15 No indication for any agent Adapted from Heidbuchel and colleagues 5. properties. As dabigatran is eliminated primarily by renal mechanisms, the regimen for discontinuation is based on the bleeding risk of the procedure and the patient s CrCl (Table 2). A recent study of a subgroup of patients in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial 25 showed no significant differences in rates of major bleeding among patients undergoing urgent surgery between warfarin and dabigatran 150 mg (4 6 versus 5 1 per cent respectively; RR 0 82, 95 per cent c.i. 0 50 to 1 35) when the last dose of dabigatran was given a mean of 49 h before surgery. In patients taking rivaroxaban with CrCl of 15 30 ml/min undergoing procedures with a low Emergency and trauma surgery Perioperative management for emergency and trauma surgery can be of particular concern as no specific antidote exists for NOACs. As NOACs have relatively short halflives, supportive care and withholding further doses is likely to be sufficient for most patients. If possible, surgery should be deferred until at least 12 h, ideally 24 h, after the last dose. Expert opinion suggests the use of oral activated charcoal in the setting of recent ingestion (within 2 h). Haemodialysis should be considered in patients on dabigatran with impaired renal function who will require more time for drug clearance. Use of dialysis is not likely to be effective for clearance of rivaroxaban and apixaban as these drugs are highly protein bound 26. Prophylactic administration of a haemostatic product as PCC or fresh frozen plasma is not recommended routinely unless there is severe haemorrhage related to the use of NOACs, such as intracranial bleeding. In the presence of major bleeding, such as ruptured aneurysm and bleeding peptic ulcer, haemodynamic support should be provided as in usual circumstances. Massively transfused patients may require replacement of plasma or platelets in addition to red blood cells. Activated PCC or factor VIIa should be considered as a last resort in instances of life-threatening bleeding when conventional treatment methods have failed 27. Restarting new oral anticoagulants after surgery NOACs may be restarted at a therapeutic dose 24 h after procedures with a low bleeding risk and 48 72 h after operations with a high bleeding risk, as long as adequate haemostasis has been achieved 28. For procedures associated with immobilization, it is recommended to start low molecular weight heparins (LMWHs) 6 8 h after surgery once haemostasis has been achieved. NOACs are then restarted 48 72 h after the procedure (Fig. 3). Overall, if the NOACS are stopped 48 h before surgery and restarted 48 h after operation, given their rapid onset of action, the patient will be without therapeutic anticoagulation for less than 5 days, which is significantly less than with warfarin.

Perioperative management of patients on new oral anticoagulants 747 Bleeding risk Low High Start 24 h postop. Immobilization No immobilization Start prophylactic dose of LMWH 6 8 h postop. Restart NOAC 48 72 h postop. Restart NOAC 48 72 h postop. Fig. 3 Restarting new oral anticoagulants (NOACs) after surgery. Mechanical thromboprophylaxis measures should be considered if there are no contraindications. LMWH, low molecular weight heparin The rapid onset and offset of action of NOACs should preclude the need for bridging anticoagulation in most patients. However, in patients with postoperative ileus in whom NOAC bioavailability may be affected over a prolonged period or patients undergoing gastric resection, use of a therapeutic dose of LMWHs (such as enoxaparin 1 mg/kg twice daily) may be warranted. In patients who are unable to take oral medications after surgery, 2 3 days of a low-dose LMWH bridging regimen of enoxaparin 40 mg once daily may be needed until oral intake is resumed 28. Management of bleeding complications of new oral anticoagulants In all events of bleeding complications associated with NOACs, it is important to enquire about the exact time of last intake and dosing regimen. For bleeding that is not life-threatening, withholding the NOAC and standard supportive measurements, such as fluid resuscitation and haemostatic measures, should be initiated. As NOACs have short elimination half-lives, time is the most important antidote. Normalization of haemostasis may occur by approximately 12 24 h. Red cell and platelet transfusions may be given if necessary. Fresh frozen plasma can be administered as a plasma expander, but not as a reversal agent as it is unlikely to be effective 5. In the event of severe or life-threatening bleeding, the same initial approach is adopted. In addition, the anticoagulant effects could be reversed by PCC (25 units/kg) if immediate haemostatic support is needed 5. Activated PCC (50 units/kg) can be considered before PCC, if available 5. Haemodialysis is another potential option for emergency removal of dabigatran, as discussed above. Use of new oral anticoagulants for thromboprophylaxis after orthopaedic surgery Large randomized clinical trials have evaluated the safety and efficacy of the use of apixaban, rivaroxaban and dabigatran in the prevention of venous thromboembolism (VTE). The drugs have been approved in many countries for prevention of VTE in patients undergoing elective hip or knee arthroplasty. A meta-analysis 29 of the data from four phase III trials showed that dabigatran 200 mg versus the standard treatment dose of enoxaparin 40 mg once daily was associated with similar efficacy in preventing VTE (RR 1 03, 95 per cent c.i. 0 93 to 1 15) and a similar risk of clinically relevant bleeding (RR 1 13, 0 92 to 1 39). Meta-analysis 29,30 of four phase III trials showed significant improvement in prevention of VTE with rivaroxaban 10 mg versus enoxaparin 40 mg once daily (RR 0 46, 0 39 to 0 54). It was, however, associated with a higher risk of clinically relevant bleeding (RR 1 25, 1 02 to 1 54; P = 0 03). Apixaban 2 5 mg twice daily was compared with enoxaparin 40 mg once daily in prevention of VTE after total knee arthroplasty in the large phase III trial, ADVANCE-2 31. The results showed a significant reduction in VTE with apixaban compared with enoxaparin (15 1 versus 24 4 per cent; P < 0 001) and a similar risk of major bleeding (0 6 versus 0 9 per cent; P = 0 30). The ADVANCE-3 trial 32, comparing treatment with apixaban 2 5 mg twice daily and enoxaparin 40 mg once daily after hip arthroplasty, showed significantly reduced VTE with apixaban (1 4 versus 3 9 per cent; P < 0 001) with a similar risk of major bleeding (0 8 versus 0 7 per cent; P = 0 54). The recommended time for initiation of anticoagulant after surgery is 6 10 h for rivaroxaban, 12 24 h for apixaban and 1 4 h for dabigatran, with a starting dose of 50 per cent (110 mg instead of 220 mg) 33. The

748 A. Lai, N. Davidson, S. W. Galloway and J. Thachil recommended duration of treatment is 35 days following hip arthroplasty and 10 days following knee arthroplasty 30. Conclusion NOACs have demonstrated non-inferior efficacy to warfarin for stroke prevention in atrial fibrillation. Major and non-major clinically relevant bleeding rates with NOACs are acceptable compared with those of vitamin K antagonist, and significant reductions in intracranial bleeds have also been shown for all NOACs. With these results, the avoidance of anticoagulation monitoring and a lower risk of significant interactions, it is anticipated that their clinical use will increase rapidly in future. However, there is an important issue regarding the lack of antidote for the reversal of effects of these drugs. Disclosure J.T. has received honoraria from Bristol Myers Squibb, Bayer and Boehringer Ingelheim pharmaceuticals, whose products are described in this article. 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