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• W2895583402 abstract "Direct oral anticoagulants (DOAC) have a number of advantages over warfarin, such as: fixed dosing; no requirement for routine monitoring; predictable pharmacokinetics; fewer interactions; and a rapid onset/offset of clinical effect. Despite much enthusiasm for their use, there remain many challenges, such as: optimal drug and dose selection; their use in patients with a history of gastro-intestinal bleeding; their reversal in the acute setting; and dosing at extremes of body weight 1. Although research on the management of DOACs in the peri-operative period is increasing, knowledge among clinicians and formal guidance seems to be variable 2. This month in Anaesthesia, Erdoes et al. report their consensus statement on DOACs for cardiac surgical patients 3. Their work provides an evidence-based synthesis of available pharmacokinetic and clinical data; delivers recommendations for cessation, monitoring and reversal, and suggests management strategies for DOAC-associated bleeding. The aim of this editorial is to give clinical context to this new consensus statement and discuss the peri-operative implications of the increasing number of patients prescribed a DOAC. Direct oral anticoagulants are commonly prescribed in the cardiac surgical population, as comorbid diseases such as atrial fibrillation and venous thromboembolism are common. Furthermore, DOACs are increasingly prescribed for ‘off label’ indications such as valvular heart disease and mural thrombus. That said, they are contraindicated in patients with mechanical heart valve prostheses. Peri-procedural cardiac surgical bleeding is common and management strategies are complex 4. Given that urgent or emergency cardiac surgery is also common and adequate cessation of medication before surgery is not always possible, peri-procedural bleeding, whether surgical or coagulopathic, may be exacerbated by DOAC-associated bleeding. Restarting a DOAC following surgery is likewise complex due to the use of large bore chest drains, pacing wires and the occasional requirement for subsequent procedures, such as permanent pacemaker implantation. Finally, other haemostatic agents, such as high-dose heparin, tranexamic acid, aprotinin and protamine are used in the peri-operative period and our understanding of how their interaction with DOACs may affect point of care coagulation tests or laboratory assays is limited 5. For these reasons, the need for specific guidance for cardiac surgical patients is warranted. There are, however, additional scenarios to which this guidance does not allude, such as: thoracic surgery; the patient with inherited or acquired coagulopathy; and anaesthesia for procedures, e.g. emergency coronary stenting, transcatheter aortic valve implantation and heart and/or lung transplantation. Published guidance on the timing of DOAC cessation before surgery varies according to patient, anaesthetic and surgical factors 6. For example, a generally accepted cessation period before neuraxial anaesthesia in a patient with normal renal function is 4 days for dabigatran and 3 days for rivaroxaban, apixaban and edoxaban 7. Further comprehensive guidance is also available for patients undergoing regional anaesthesia 8. The recommendations from Erdoes et al. are in broad agreement with published literature for patients presenting for elective major surgery. In a patient with no renal impairment, they recommend a minimum cessation period of 2 days for dabigatran, apixaban and edoxaban. Rivoroxaban should be stopped for a minimum of 3 days 3. Unlike warfarin, bridging therapy is not recommended during this period, as it significantly increases the risk of peri-procedural bleeding 9, 10. Furthermore, a recent systematic review and meta-analysis concluded that peri-operative interruption of DOACs in patients with atrial fibrillation was associated with a 0.4% risk of thromboembolic and 1.8% risk of major bleeding events 30 days after surgery 11, which seems reassuring. Cardiac surgery carries a high peri-procedural bleeding risk. A recent classification system grades bleeding from insignificant (Class 0) to massive (Class 4) as a function of sternal closure, postoperative chest drain blood loss, transfusion requirements and re-exploration or tamponade 12. Erdoes et al. similarly grade DOAC-associated bleeding tendency as mild, moderate or severe with stepwise, graded management strategies including: laboratory investigations; the use of tranexamic acid, reversal agents, prothrombin complex concentrate and fibrinogen concentrate; and allogeneic blood product transfusion 3. Although this seems more relevant to emergency surgery, where there may be inadequate pre-operative cessation, some argue current cessation times fail to completely negate the risk of DOAC-associated bleeding 13. Atrial fibrillation is common following cardiac surgery and the postoperative use of anticoagulant or antiplatelet therapies alongside DOACs increase the risk of bleeding. Many patients undergoing emergency or elective interventional procedures for coronary artery disease are also in atrial fibrillation and the use of triple therapy in the form of a DOAC together with aspirin and clopidogrel or ticragelor may be required. Current guidance tries to limit the duration of triple or dual therapy and recommends the use of the lowest approved dose of DOAC 14. Just as there are several guidelines, recommendations and consensus statements on the use of DOACs in the peri-operative period, so too there are for their measurement. In 2014, the British Committee for Standards in Haematology (BCSH) issued their guidance on the measurement of anticoagulants and their effects on tests of haemostasis 15. Quantitative tests include dilute thrombin time (dTT), ecarin-based assays and chromogenic anti-IIa assays for dabigatran, and chromogenic anti-Xa assays for direct FXa inhibitors. Irrespective of the test used, the end user should receive laboratory results in terms of plasma drug concentration (ng.ml−1). Prothrombin time (PT) and activated partial thromboplastin time (APTT) should only be used as crude estimates of DOAC activity in certain circumstances. For example, for patients taking dabigatran, a normal APTT likely excludes significant plasma drug levels. For patients taking apixaban, normal APTT and PT values may be found despite therapeutic plasma drug levels. For patients taking rivaroxaban and edoxaban, a normal PT likely excludes significant plasma drug levels. Each laboratory should know the sensitivity of their PT and APTT tests to DOACs and be able to advise on their interpretation. Near-patient viscoelastic tests are often available in the cardiac surgical setting 16-18 and may detect DOAC activity 19, though further work is required to better define their utility. More recently, the International Council for Standardization in Haematology (ICSH) published their guidance 20. Reassuringly, the message in these and others is the same, and the authors of this new consensus statement for cardiac surgical patients have incorporated all these points in a clear manner 3. There is, nevertheless, much variation on the availability of quantitative tests among cardiac surgical centres, as the need to measure plasma drug levels for those prescribed a DOAC is only beginning to emerge. That said, the number of patients prescribed a DOAC presenting to hospital in the context of major trauma 21, acute haemorrhage, for other forms of emergency surgery, for urgent surgery requiring neuraxial anaesthesia, following accidental or intentional overdose, or for thrombolysis in the context of acute stroke, may dramatically increase over the coming years. We argue there will inevitably be a future requirement for more widespread availability of quantitative tests of DOAC activity to allow for the safe management of these and other patients. There are currently three agents manufactured for the reversal of DOACs in the acute setting. Idarucizumab (Praxbind®, Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA), which specifically binds dabigatran and its metabolites, is the first such agent to be licensed in the UK and has been approved in many countries since 2015 22. It acts immediately and lasts for 24 h, though there is a risk of postoperative bleeding thereafter and another dose may be required. It costs £2,400 ($3050, €2680) per 5 g dose 23. Andexanet alfa (AdnexXa, Portola Pharmaceuticals, San Francisco, CA, USA), a specific reversal agent for direct FXa inhibitors, obtained FDA approval in 2018 24. The cost of one reversal dose for Andexanet alfa is thought to be in the region of 10–20 times the cost of Idarucizumab. Finally, Ciraparantag is under investigation for the reversal of all DOACs and heparins but is currently unavailable outside clinical trials. Although prothrombin complex concentrate (PCC) and activated PCC have been suggested as effective non-specific reversal agents, the evidence to justify this recommendation is of low quality and difficult to apply to surgical patients 25. Moreover, reversal agents, whether specific or non-specific, are not without adverse effects such as thrombosis, which is especially relevant in the cardiac surgery setting. Finally, ultrafiltration effectively clears dabigatran in a matter of hours, and Erdoes et al. rightly highlight the role of ultrafiltration during cardiopulmonary bypass to this end for cardiac surgical patients 3. The ‘cost’ of a new intervention, drug or piece of equipment can be difficult to judge 26. Direct oral anticoagulants were introduced due to, among other factors, a favourable cost profile as compared with warfarin. A recent evidence-based cost effectiveness analysis adds weight to this suggestion 27. Unfortunately, all such analyses have, thus far, failed to account for peri-operative costs, both to the hospital and the patient. The National Institute for Health and Care Excellence (NICE) in the UK estimates around 600,000 patients in England are eligible for DOAC therapy 28. Although there are no data for the proportion presenting for emergency surgery, up to 6.5% of all patients per year receiving oral anticoagulants present to hospital with major bleeding. If only 1% require emergency surgery each year, there may be up to 6000 patients a year in England alone for which it is not possible to measure drug levels or normalise coagulation. Given the potential costs of uncontrollable peri-procedural bleeding, the consequences will likely be significant. Working out where the balance lies has no easy answer, though it could be argued the peri-operative costs resulting from the introduction of DOACs should have been envisaged at the beginning of the process rather than later. The recent widespread introduction of DOACs has and will continue to generate peri-operative confusion and controversy. In the context of major trauma, haemorrhage, urgent/emergency surgery or elective surgery in those with chronic kidney disease, DOAC-associated bleeding may indeed emerge as a clinically significant problem, for which management strategies are limited. The other possibility is that, in the future, access to quantitative assays and reversal agents may reduce the incidence of DOAC associated-bleeding and/or limit its severity, thereby providing simplicity for clinicians and patients. The scale of the problem will hopefully become clear as our experience of DOACs in the peri-operative period increases, which it no doubt will. For now, while the costs and benefits of introducing quantitative laboratory tests and reversal agents are debated, we advise clinicians to work with their local institutions to develop pragmatic guidance based on the available literature and their available resources. For cardiac surgical patients, we wholeheartedly support the need for and the quality of this new consensus statement, which advises on the peri-operative management of DOACs and DOAC-associated bleeding. It is essential reading for all cardiac anaesthetists and we hope its publication improves outcomes for a population of patients that will dramatically increase over the coming years. MC is the previous Anaesthesia Trainee Fellow and the current Social Media Editor. RA has received investigator-initiated research funding from Bayer Healthcare and Covidien and honoraria from Bayer Healthcare, Boehringer-Ingelheim, Pfizer and Sanofi." @default.
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• W2895583402 title "Direct oral anticoagulants: peri-operative considerations and controversies" @default.
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