Radoicic Dragan, Francisco Chana-Rodríguez, Antonio Benjumea-Carrasco, Jesús Gómez-Vallejo.
Response/Recommendation: The optimal management of patients on antiplatelets and/or anticoagulants presenting with acute lower extremity trauma and needing surgery should involve a risk-benefit assessment weighing the risk of bleeding against the risk of thrombosis. Depending on the degree of urgency, extent of trauma and patient’s coagulation status, the optimal approach may involve postponing the procedure and monitoring the coagulation status, perioperative bridging therapy, or acute reversal of anticoagulation.
Most studies recommend that patients receiving aspirin (ASA) can undergo surgery safely without delay. In patients taking oral anticoagulants, coagulation tests should be performed. If surgery cannot be delayed, anticoagulant reversal agents should be administered. Recent literature has suggested that the use of reversal agents does not lead to adverse outcomes following lower extremity trauma surgery. In addition, early surgical treatment of hip fractures despite anticoagulation may be prudent in a subgroup of patients.
Strength of Recommendation: Limited.
Rationale: Antithrombotic agents can be broadly subdivided into two classes: anticoagulants and antiplatelet medications1,2. When patients on these agents undergo orthopaedic procedures, management should entail an individualized assessment of the risk of bleeding as well as the risk of thrombosis. Approximately 1 in 10 surgical patients are prescribed chronic anticoagulation or antiplatelet therapy, and majority will require temporary antithrombotic interruption, bridging, or reversal1,3–5. It is widely established that urgent, non-deferrable surgery should not be delayed in patients on antiplatelets, even in those receiving dual antiplatelet therapy6,7. In contrast, given the wide variety of anticoagulation agents available8, there is substantial heterogeneity with regards to the perioperative management of these patients. Not surprisingly, there is still a lack of consensus on this topic within the orthopaedic community9.
The majority of recommendations regarding the interruption of anticoagulant or antiplatelet therapy in trauma patients with a moderate to high risk of bleeding are reflected in the latest clinical guidelines of various professional societies6,10,11. These strategies have largely been developed from general surgical and neurosurgical literature12. As existing guidelines are based on expert opinion, consensus, and retrospective studies, the level of evidence is extremely limited. In addition, most recommendations have been restricted to the safety of neuraxial anesthesia rather than trauma surgery per se6,10,13.
Recent data has shown that hip fracture patients are prone to prolonged elimination half-lives of direct oral anticoagulants (DOAC), with almost 50% of patients still having therapeutic levels at the time of surgery14. Patients on DOAC have increased delays to surgery compared to patients who are not on anticoagulation or those on vitamin K antagonists. The average time to surgery for DOAC patients may range from 35.0 hours to 66.9 hours15,16. King et al.17, concluded that taking DOAC on admission was not a reason to delay hip fracture surgery. Similarly, Bruckbauer et al.18, suggested that early hip fracture surgery should be indicated in DOAC patients. Consistent with these findings, Schuetze et al.19, noted that early surgical care of proximal femur fractures was safe in patients on anticoagulants, as long as preparations for possible intraoperative transfusions were made. In contrast, Gosch et al.20, found that hip fracture patients on oral anticoagulation had higher rates of in-hospital mortality, transfusion (requiring 3 or more packed red cells), major bleeding, hemoglobin drop of 6 g/dL or more, myocardial infarction, stroke, and thromboembolic events, compared to controls who were not on anticoagulation.
Besides hip fractures, data on the management of other lower extremity fractures in patients on antiplatelet or anticoagulation remains scarce. Recent literature has demonstrated a trend away from the routine use of bridging anticoagulation21, with several reports suggesting that the administration of reversal agents may not lead to adverse outcomes in lower extremity trauma surgery22. Ultimately, the risks associated with delaying operative care in lower extremity trauma is fracture- and patient-specific. Depending on the degree of urgency, extent of trauma, and patient’s coagulation status, the optimal approach may involve postponing the procedure and monitoring the coagulation status, perioperative bridging therapy, or acute reversal of anticoagulation.
The following recommendations are brief excerpts from current guidelines and recent literature, which provide an update on the most common antithrombotic reversal strategies or corrective measures. These strategies should be carried out in collaboration with cardiology, anesthesiology, and other specialties.
Warfarin: There is an ongoing debate regarding the perioperative management of trauma patients on warfarin. Some authors advocate a watch-and-wait approach, while others recommend urgent reversal. It is well established that fracture surgery can be expedited by reversing the anticoagulation effect of warfarin with vitamin K23,24. The National Institute for Health and Care Excellence (NICE) guidelines have underscored the importance of prompt surgical management of elderly patients with hip fractures within the first 36 hours, reiterating that delays related to anticoagulation are often unjustified25. Gulati et al.26, and Moores et al.27, advised that the action of warfarin should be reversed in order to expedite hip fracture surgery. This reversal can be achieved with vitamin K, prothrombin complex concentrate ([PCC] Beriplex), fresh frozen plasma (FFP), or recombinant factor VIIa4,28.
For surgeons adopting a watch-and-wait approach, the 2017 American College of Cardiology (ACC) guidelines recommended checking the international normalized ratio (INR) 5 to 7 days before surgery. The INR should then be rechecked within 24 hours of surgery to ensure normalization. Bridging anticoagulation, typically with low-molecular-weight heparin (LMWH), is undertaken in patients at high thrombotic risk, which has been defined as patients with a Congestive heart failure, Hypertension,
Age ≥ 75 years, Diabetes mellitus, prior Stroke or transitory ischemic attack (TIA) or thromboembolism – Vascular disease, Age 65 – 74 years, female Sex category (CHA2DS2-VASc) score of ≥ 7 (greater than 10% annual risk of stroke or embolism) or patients with a thrombotic event within the past 3 months2.
Dabigatran: For procedures with high bleeding risk, ACC guidelines recommend an antithrombotic interruption (ATI) period of 2 days before surgery without the need for bridging anticoagulation. 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 ATI interval before neuraxial block, and 72 to 90 hours in patients with renal impairment29.
In the event of overdose, its effect can be reversed with hemodialysis and antidote administration using idarucizumab (Praxbind)30. The approved dose is two 2.5 g IV bolus infusions administered within 15 min1. In life-threatening bleeding, this can be combined with tranexamic acid (TXA) (1 g. IV). PCC is another option, although there is limited evidence regarding its use in patients on DOAC. The use of FFP is currently restricted to rescue therapy if other alternatives are not available13,31.
Low-molecular-weight heparin (LMWH): For patients on treatment doses of LMWH, surgery under neuraxial anesthesia should be delayed for at least 24 hours. For patients on prophylactic doses of LMWH, this delay can be reduced to 12 hours10.
Oral anticoagulants should be discontinued prior to procedures with a moderate to high risk of bleeding including long bone fractures and hip fractures6. In patients with a low to moderate thrombotic risk, perioperative bridging therapy may not be necessary. However, for patients with a high thromboembolic risk, bridging therapy with LMWH at prophylactic doses can be administered. If urgent surgery is indicated, the use of reversal agents should be considered6,31.
Rivaroxaban: The ACC guidelines recommend a discontinuation period of 2 days before high-risk procedures, with a longer ATI period 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.
Rivaroxaban is not removed by hemodialysis. Andexanet alfa (AndexXa) is the first and only antidote for patients taking rivaroxaban (Xarelto), apixaban (Eliquis) or edoxaban (Savaysa)32. Activated charcoal may help to reduce absorption in cases of acute over-ingestion of DOAC and should be administered within 1 – 2 hours of novel oral anticoagulants (NOAC) intake33.
Apixaban: The ACC recommends an ATI period of 2 days. As 27% of the drug is renally cleared, 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, and 40 to 75 hours in patients with a serum creatinine of 1.5 mg/dL or more29.
Edoxaban: No published studies have investigated the periprocedural safety of continued use of edoxaban, nor the appropriate ATI period for this anticoagulant in the setting of orthopaedic surgery. The ACC recommends an ATI period of 48 hours before surgery in patients with normal renal function and 72 hours in patients with renal impairment2. The ASRA guidelines recommend a 20- to 28-hour interruption period before neuraxial procedures, and 40 to 70 hours for patients with renal impairment29.
Acetyl salicylic acid – Aspirin (ASA): Bleeding risk while taking ASA in the perioperative period has been extensively studied, but conflicting results have been reported4,5. In particular, several studies have demonstrated the safety of continuing ASA during elective hip and knee surgery4,5.
Recent guidelines recommend continuing ASA in patients at moderate to high risk of cardiovascular events and discontinuing ASA 7 to 10 days before surgery in patients at low risk of cardiovascular events, acknowledging that the discontinuation of ASA may carry an increased risk of thrombotic events in patients with strong cardiovascular risk factors5,34.
Surgery should not be postponed in patients receiving ASA as the low risk of bleeding does not justify the surgical delay7,35,36. The ASRA guidelines also recommend continuing ASA regardless of dosage or indication before neuraxial procedures, citing multiple studies demonstrating that ASA does not significantly increase the risk of spinal hematomas following neuraxial blocks29. Notwithstanding, there is a risk of bleeding if ASA is taken in combination with other thromboprophylactic medication, hence ASA may be withheld during inpatient stay unless indicated for unstable angina or recent/frequent transient ischemic attacks23.
Clopidogrel: The 2012 American College of Chest Physicians (ACCP) guidelines recommend stopping clopidogrel or prasugrel 5 days before surgery34. Similarly, the ASRA guidelines recommend discontinuing clopidogrel 5 days before neuraxial procedures. The recent Scottish Intercollegiate Guidelines Network (SIGN) recommend that surgery should not be delayed, and platelets should not be administered prophylactically, although marginally greater blood loss should be anticipated. This is also associated with an increased risk of spinal hematoma when regional anesthesia is employed23. Bridging is not required during temporary clopidogrel discontinuation in the perioperative setting, but ASA should be continued in patients on dual antiplatelet therapy (DAPT) after stent placement37.
The antiplatelet effect of clopidogrel can only be overcome with platelet transfusions, since clopidogrel irreversibly inhibits platelet function and there is no known antidote for this drug. Platelet concentrates may be administered if platelet dysfunction is documented in a patient who requires urgent surgery, suffers continued bleeding, or sustains an intracranial hemorrhage. Desmopressin (0.3 μg/kg) may also be administered in such patients11.
Prasugrel: No data on the safety of continuing prasugrel in the setting of orthopaedic surgery has been published. The AACP recommends stopping clopidogrel or prasugrel 5 days before cardiac surgery34, whereas the ASRA recommends discontinuing prasugrel 7 days before neuraxial block29. No available reversal agent for prasugrel exists.
Ticagrelor: No data exists regarding the continuation of ticagrelor in orthopaedic procedures. Platelet aggregation returns to normal within 5 days of discontinuation of ticagrelor38. Consequently, the ASRA guidelines recommend discontinuing ticagrelor 5 days before any procedure29.
No specific reversal agent exists. PB2452, a monoclonal antibody fragment that binds ticagrelor, is being developed as an antidote for patients requiring urgent surgery or experiencing life-threatening bleeding39,40.
Conclusion: Given the varying indications for antithrombotics, medication diversity and patient heterogeneity, defining the optimal strategy for patients on these medications who present with acute lower extremity trauma and require urgent surgery remains a challenging task. Periprocedural interruption and/or correction of anticoagulant therapy is often a complex risk-benefit intervention, requiring a thorough assessment of the patient’s bleeding and thrombotic risks. The need to reverse the effect of the anticoagulant or antiplatelet drug should be determined by the need to perform surgery urgently. If surgery cannot be delayed, reversal agents or other corrective measures should be administered. Ultimately, orthopaedic surgeons should always strive to manage these patients in collaboration with their colleagues in cardiology, anesthesia, and other medical specialties.
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