201 – What is the optimal management of patients on antiplatelet and/or anticoagulation presenting with acute lower extremity trauma and needing surgery?

201 – What is the optimal management of patients on antiplatelet and/or anticoagulation presenting with acute lower extremity trauma and needing surgery?

Radoicic Dragan, Francisco Chana-Rodríguez, Antonio Benjumea-Carrasco, Jesús Gómez-Vallejo.

Response/Recommendation: Most of the studies recommend that in patients receiving acetylsalicylic acid (ASA), surgery can be performed without delay. In patients taking oral anticoagulants, coagulation tests need to be carried out. If anticoagulant activity is present and surgery can´t be delayed, anticoagulant reversal drugs or antidotes should be used. A shift away from routine use of bridging anticoagulation and delayed approach can be noted in recent literature with reports confirming that administration of reversal agents does not lead to adverse outcomes in lower extremity trauma surgery. In this context, earlier surgical care of hip fractures despite anticoagulant medication in some patients might be prudent.

The optimal management of patients on antiplatelet and/or anticoagulation presenting with acute lower extremity trauma and needing surgery should be a collaborative team effort, requiring an individualized assessment and balancing the risks of bleeding versus thrombosis. Depending on emergency, the extent of lower extremity trauma, and patients’ coagulation status the optimization approach can range from postponement of the procedure with coagulation monitoring, bridging therapy to active reversal measures.

Strength of Recommendation: Limited.

Rationale: Antithrombotics can be subdivided into two basic classes: anticoagulants and antiplatelet medications1,2.

When patients on antiplatelet/anticoagulation therapy undergo orthopaedic procedures, management should be a collaborative effort, requiring an individualized assessment and balancing the risks of bleeding versus thrombosis.

Currently, approximately 1 in 10 surgical patients is prescribed chronic anticoagulation, in some cases dual agent antiplatelet therapy can be present, and majority will require temporary antithrombotic interruption, bridging or reversal1,3-5.

Anticoagulation is not only becoming more prevalent; it is becoming more diverse6, leading to a wide variance in perioperative management of antiplatelet therapies. Several studies demonstrated a lack of consensus in orthopaedic community on this topic7.

Most of the recommendations regarding the interruption of anticoagulant or antiplatelet therapy in trauma with a moderate or high risk of bleeding are reflected in the clinical guidelines of specific societies8-10. These guidelines are based on expert opinions, consensus, non-randomized, and retrospective studies, so the level of evidence is limited. Most of the recommendations are based on safety of neuraxial anesthesia (spinal, epidural)8,10,11.

Treatment with antiplatelet drugs is considered to have little influence before urgent surgery. It is accepted that it is not justified to delay urgent, non-deferrable surgery in antiplatelet patients even with double antiplatelet therapy10,12.

Although understanding of best practices in perioperative anticoagulation management has advanced significantly, given the various indications for antithrombotics, medication diversity and patient heterogeneity, defining the optimal comprehensive management platform for patients presenting with acute lower extremity trauma and needing surgery turns out to be a momentous challenge.

Besides hip fractures, data on management of patients on antiplatelet and/or anticoagulation with other lower extremity fractures is almost non-existent.

In order to provide optimal anticoagulation adjustments, orthopaedic surgeons should always collaborate with their colleagues in cardiology, anesthesia, pulmonology, and other specialties during the preoperative and perioperative assessment of a patient on antithrombotics.

Periprocedural interruption and/or correction of anticoagulant therapy is often a complex risk-benefit intervention, requiring proper procedural bleed risk and patient-related bleed risk assessment. Attempts to cover various clinical scenarios have been made and detailed algorithms are available2,5.

The risk associated with delaying operative care in lower extremity trauma is surgery-specific. Depending on emergency, the extent of lower extremity trauma and patients’ coagulation status the optimization approach can range from postponement of the procedure and coagulation monitoring, bridging therapy to active reversal measures.

Any surgical procedure that can be safely delayed beyond 48 – 72 hr. without any impact on clinical outcome is considered non-urgent and allows for complete reversal of anticoagulation, similar to an elective procedure13. Reversal agents are now available for the direct oral anticoagulants (DOAC) but are not recommended for standard use pre-procedure. A shift away from routine use of bridging anticoagulation peri-procedure can be noted in recent literature13 with reports confirming that administration of reversal agents does not lead to  adverse outcomes in lower extremity trauma surgery14.

Numerous studies are focused on DOAC, in case of DOAC surgical delay to allow drug clearance was the longstanding mainstream option. Evidence-based guidelines regarding delay in patients on DOAC requiring urgent orthopaedic surgical care are lacking.

Recent data shows that hip fracture patients are prone to prolonged elimination half-lives of DOAC, with almost 50% having therapeutic levels at the time of surgery15. Patients on DOAC have increased delays to surgery compared to patients on no anticoagulation or on vitamin K antagonists. Average time to surgery for DOAC patients has been shown to vary from 35 hours to 66.9 hours16, 17. In light of this data King et al.18, conducted a study to evaluate DOAC relation to delay, and concluded that hip fracture patients taking DOAC on admission is not a reason to delay surgery. Bruckbauer et al.19, findings also suggest that earlier hip fracture surgery might be indicated in DOAC patients. Similarly, Schuetze et al.20, advocate early surgical care of proximal femur fractures as a safe procedure. They fix proximal femur fractures as soon as possible despite anticoagulant medication, patients are preoperatively prepared for possibly intraoperative transfusion, especially patients on DOAC.

On the other side Gosch et al.21, have found that hip fracture patients on oral anticoagulation had worse outcomes in regard of in-hospital mortality, 3 or more packed red cells, revision surgery, major bleeding, loss of hemoglobin of 6 g per deciliter or more, myocardial infarction, stroke, and thromboembolic events, compared to controls without.

In conclusion, the need to immediately reverse the effect of the anticoagulant or antiplatelet drug will be determined by the need to perform surgery urgently. If it is impossible to delay surgery, it will be necessary to apply reversing drugs or different therapies to control the bleeding. In cases where it is possible to delay surgery without prejudice to the patient, one must wait until the effect of the antithrombotic drug has worn off.

Reversal strategies for patients receiving oral anticoagulants needing emergency orthopaedic surgery have largely been developed from studies addressing various other emergencies typically in the general surgical and neurosurgical fields22.

The following recommendations are brief excerpts of the current guidelines and recent literature meant to provide an update on most common antithrombotics reversal strategies. Chronic anticoagulation therapy corrections as well as implementation of reversal agents, prior to orthopaedic surgical procedure, should be preferably carried out in collaboration with cardiology, anesthesiology, and other specialties.

Warfarin – Coumadin: There is everlasting debate regarding warfarin and fractures, with two possibilities either watch-and-wait or reverse. It is well known that fracture surgery can be accelerated and planned earlier by reversing the effect of warfarin with vitamin K23,24.

The National Institute for Health and Care Excellence (NICE) guidelines underline the importance of the prompt surgical management of elderly patients with hip fractures within the first 36 hr., and it has been highlighted that delays related to anticoagulation are unjustified25. Gulati et al.26, and Moores et al.27, advise that action of warfarin should be reversed to expedite hip fracture surgery.

In watch–and-wait approach the 2017 American College of Cardiology (ACC) guidelines recommend checking a baseline international normalized ratio (INR) 5 to 7 days before surgery. The patient’s INR should then be rechecked within 24 hours of surgery to ensure normalization, a baseline INR 1 week before surgery is recommended.

Given this prolonged interruption of warfarin before most procedures, bridging anticoagulation, typically with low-molecular-weight heparin (LMWH) is undertaken in patients at high thrombotic risk, defined as a: Congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, stroke or transient ischemic attack (TIA), vascular disease, age 65 to 74 years, sex category (CHA2DS2-VASc) score of seven or more (greater than 10% annual risk of stroke or embolism) or with a thrombotic event within the past 3 months2.

Reversal can be achieved with vitamin K, prothrombin complex concentrate, fresh frozen plasma (FFP), Beriplex, or recombinant factor VIIa4,28.

Dabigatran – Pradaxa: For high bleed risk procedures, the ACC guidelines recommend an antithrombotic interruption (ATI) period of 2 days before surgery; there is no need for bridging anticoagulation therapy. In patients with impaired renal function (creatinine clearance < 50 mL/min), a longer ATI duration of 4 days is recommended2. The fourth edition of the American Society of Regional Anesthesia (ASRA) guidelines suggest only a 34-hour discontinuation interval before neuraxial block (72 to 90 in renal impairment); therefore, we do not recommend a prolonged ATI period if concurrent neuraxial block is performed29

In the event of overdose, its effect can be reversed by hemodialysis and pradaxa antidote idarucizumab (Praxbind)30. The approved dose is two 2.5 – g intravenous (IV) bolus infusions administered within 15 min1. In life-threatening bleeding, it can be used combined with tranexamic acid (TXA) (1 g. IV).

Procoagulant agents also can be used, such as the prothrombin complex concentrate (PCC), which facilitates the activation of thrombin but does not act directly against anticoagulants. PCC promotes hemostasis but increases the risk of thrombotic complications. Although it has been shown to be effective in reversing the effects of vitamin K antagonists, there is little experience with its use with DOAC. Another option is FFP, although currently its use is relegated to rescue therapy if other alternatives are not available11,31.

Low-molecular-weight heparin (LMWH): For patients under treatment doses of low LMWH surgery based on neuraxial anesthesia should be delayed 24 hours. With prophylactic doses of LMWH the delay should be 12 hours8.

Treatment with oral anticoagulants should be withdrawn in surgery with a moderate or high risk of bleeding, including long bone and hip fractures10. In case of deferred emergency surgery with low or moderate thrombotic risk, it is not necessary to associate bridging therapy. However, for patients with high thromboembolic risk, bridging therapy with LMWH at prophylactic doses can be performed. In case of urgent surgery, use of reversing drugs should be considered10,31.

Rivaroxaban – Xarelto: The ACC guidelines recommend a discontinuation period of 2 days before high bleed risk procedures, with a longer ATI of 3 days in the setting of renal impairment. The ASRA guidelines recommend discontinuing rivaroxaban 22 to 26 hours before neuraxial block except in the setting of renal impairment, in which case 44 to 65 hours is recommended29.

Xarelto is not removed by hemodialysis, regarding reversal agents, the FDA approved Andexanet alfa (AndexXa) on May 3, 2018. It’s the first and only antidote to reverse bleeding in patients taking rivaroxaban (Xarelto), apixaban (Eliquis) or edoxaban (Savaysa)32.

Activated charcoal may reduce absorption in cases of acute over ingestion of all non-vitamin K antagonist oral anticoagulants (NOAC), it can be administered within 1-2 hours of intake to prevent NOAC absorption, but there is no evidence on its efficacy beyond 2 hours of the last NOAC dose33.

Apixaban – Eliquis: The ACC recommends an apixaban ATI of 2 days; approximately 27% of the drug is renally cleared; therefore, a longer ATI of 3 days is recommended in the setting of renal impairment2. The ASRA guidelines recommend discontinuing apixaban 26 to 30 hours before neuraxial procedures (40 to 75 hours in patients with a serum creatinine of 1.5 or more)29.

Eliquis antidote: andexanet alfa (AndexXa).

Edoxaban – Savaysa: No published studies exist that directly investigate periprocedural safety of continued use or ATI of edoxaban in the setting of orthopaedic surgery. The ACC recommends a discontinuation period of 48 hours before surgery in patients with normal renal function and 72 hours in the setting of renal impairment2. ASRA guidelines have been updated to include edoxaban and recommend a 20- to 28-hour interruption period before neuraxial procedures (40 to 70 hours in renal impairment)29.

Acetylsalicylic acid – Aspirin (ASA): Bleeding risk while taking ASA in the perioperative period has been extensively studied, but contradictory results have been found, several studies have demonstrated the safety of continuing ASA during elective hip and knee surgery.

Recent guidelines recommend continuing ASA perioperatively in patients at moderate to high risk for cardiovascular events and discontinuing aspirin 7 to 10 days before surgery in patients at low risk for cardiovascular events, acknowledging that discontinuation may carry an increased risk of thrombotic events in patients with strong cardiovascular risk factors in the perioperative period5, 4.

In patients receiving antiplatelet therapy with ASA, surgery should not be postponed, as it does not significantly increase the risk of bleeding. The use of a dose of 300 mg/d does not justify the surgical delay12,35,36.

The ASRA guidelines recommend continuation of ASA without consideration for dosage or indication before neuraxial procedures, citing multiple studies demonstrating that ASA does not present a notable additional risk in the development of spinal hematomas in neuraxial blocks29.

There is a risk of significant bleeding if ASA is taken in combination with other thromboprophylactic medication, may be withheld during inpatient stay unless indicated for unstable angina or recent/frequent transient ischemic attacks23.

Clopidogrel – Plavix: The 2012 American College of Chest Physicians (ACCP) guidelines recommend stopping clopidogrel or prasugrel 5 days before surgery34. The ASRA guidelines recommend discontinuing clopidogrel 5 days before neuraxial procedures.

Bridging is not required during temporary clopidogrel discontinuation in the perioperative setting, but aspirin should be continued in patients on Dual antiplatelet therapy (DAPT) after stent placement37.

The recent Scottish Intercollegiate Guidelines Network (SIGN) guidelines recommend that operation should not be delayed, nor should platelets be administered prophylactically, but marginally greater blood loss should be expected. Although this is associated with an increased risk of intra-operative bleeding and also an increased risk of spinal hematoma where regional anaesthesia is employed23.

The only way to overcome the antiplatelet effect of clopidogrel is with platelet transfusions because clopidogrel irreversibly inhibits platelet function for the life of the platelet, and there is no known antidote.

Platelet concentrates may be administered if platelet dysfunction is documented in a patient treated with antiplatelet agents (APA) who requires urgent surgery, suffers continued bleeding, or sustains an intracranial hemorrhage. Desmopressin (0.3 μg/kg) may be administered in patients treated with platelet-inhibiting drugs or von Willebrand disease (Grade 2C)9.

Prasugrel – Effient: No published data exist describing the safety of continuing prasugrel in the setting of orthopaedic surgery.

Guidelines: The AACP recommends stopping clopidogrel or prasugrel 5 days before cardiac surgery34; the ASRA guidelines recommend discontinuing prasugrel 7 days before neuraxial block29.

No available reversal agent exists.

Ticagrelor – Brilinta: No data exist regarding continuing ticagrelor before orthopaedic surgery. Platelet aggregation returns to normal within 5 days of discontinuation of ticagrelor38. The ASRA guidelines recommend discontinuing ticagrelor 5 days before any procedure29.

No registered specific reversal agent exists. PB2452, a monoclonal antibody fragment that binds ticagrelor is being developed as an antidote for ticagrelor patients requiring urgent surgery or experiencing major or life-threatening bleeding where ticagrelor reversal may be desirable39,40.

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