Journal Logo

Review Article

Preoperative Management of Antithrombotics in Arthroplasty

Barlow, Brian T. MD; Hannon, Matthew T. MD; Waldron, Jacob E. DO

Author Information
Journal of the American Academy of Orthopaedic Surgeons: December 1, 2019 - Volume 27 - Issue 23 - p 878-886
doi: 10.5435/JAAOS-D-17-00827
  • Free

Abstract

Antithrombotic medications can be subdivided into two basic classes: anticoagulants and antiplatelets.1,2 The essential components for thrombus formation include fibrin and platelets. Although fibrin plays a role in both arterial and venous thromboembolic (VTE) disease, it is more relevant for venous thromboembolism prevention. On the other hand, platelets are essential for the development of arterial thrombosis. Anticoagulants inhibit the formation of fibrin clots and are effective in the prevention of both venous and arterial thrombosis, whereas antiplatelet medications are used primarily for the management of arterial disease.3 Some common indications for antithrombotic therapy include chronic atrial fibrillation (AF), thrombophilia, recent or recurrent venous thromboembolism, recent percutaneous coronary intervention (PCI), cardiac valve replacement, coronary artery bypass graft surgery (CABG), and known malignancy.4-6 Given the various indications for antithrombotic therapy and patient heterogeneity, defining the risk-benefit ratio can be challenging.

It is estimated that approximately six million people worldwide currently require chronic antithrombotic therapy.2 Up to 250,000 or 10% of patients in North America alone require temporary antithrombotic interruption (ATI) annually for surgical procedures.1,2 Orthopaedic surgeons should always collaborate with their colleagues in cardiology, anesthesia, and other specialties during the preoperative evaluation of a medically complex patient, including those on antithrombotics (Tables 1–3), for appropriate risk stratification. When considering ATI, the risk of a thrombotic event must be weighed against the risk of bleeding. Patient factors that increase perioperative bleeding risk include hemophilia, liver disease, renal disease, and a history of major bleeding.7 However, all patients undergoing total joint arthroplasty (TJA) have high bleeding risk in accordance with the AAOS, ACC, and ASRA guidelines.1,7,8

Table 1 - Summary of Pharmacologic Properties of Reviewed Antithrombotics
Mechanism Time to Peak Effect (Hours) Half-Life (Hours) Renal Clearance Monitoring Reversal Agent
Warfarin (Coumadin) Vitamin K antagonist 24–96 20–60 No INR Vitamin K
PCC
FFP
Factor VII
Dabigatran (Pradaxa) Direct thrombin inhibitor 1–2 12–17 Yes (80%) TT, aPTT, and ECT (unreliable) Idarucizumab (Praxbind)
Rivaroxaban (Xarelto) Direct Xa inhibitor 2–4 20–45 yr: 5–9 Yes (36%) PT, aPTT, and anti-FXa (unreliable) None available
60–76 yr: 11–13
Apixaban (Eliquis) Direct Xa inhibitor 3–4 12 Yes (27%) PT, aPTT, and INR (unreliable) None available
Endoxaban (Savaysa) Direct Xa inhibitor 1–2 10–14 Yes (50%) PT, aPTT, and INR (unreliable) None available
Aspirin COX inhibitor 1–2 6 Variable Bleeding time, platelet aggregation, and blood salicylate level Alkalinization
Hemodialysis
Clopidogrel (Plavix) P2Y12 receptor inhibitor 1–2 6 No Bleeding time and platelet aggregation None available
Prasugrel (Effient) P2Y12 receptor inhibitor 1–2 7 No Bleeding time and platelet aggregation None available
Ticagrelor (Brilinta) P2Y12 receptor inhibitor 1–5 9 No Bleeding time and platelet aggregation None available
aPTT = activated partial thromboplastin time, ECT = ecarin clotting time, FFP = fresh frozen plasma, PCC = prothrombin complex concentrate, TT = thrombin time

Table 2 - Summary of Recommendations for Anticoagulants
Half-Life (Hours) Discontinuation Interval Before Total Joint Arthroplasty Discontinuation Interval if Concurrent Neuraxial Anesthesia Discontinuation Interval if CrCl <50 mL/min Increased Thrombosis Risk
Warfarin (Coumadin) 20–60 3 d if INR <2.0a Bridge if mechanical heart valve present, CHA2DS2-VASc score ≥7, or ischemic stroke in the past 3 mo (withhold bridge if intracranial hemorrhage in past 3 mo; delay surgery if thromboembolism in past 3 mo)
5 d if INR ≥2.0a
Dabigatran (Pradaxa) 12–17 2 d 2 d 4 d Bridge if CHA2DS2-VASc score >4 or if CHADS2 score >2 and creatinine clearance <50 mL/min
Rivaroxaban (Xarelto) 20–45 yr: 5–9 2 d 2 d 3 d
60–76 yr: 11–13
Apixaban (Eliquis) 12 2 d 2 d 3 d
Endoxaban (Savaysa) 10–14 2 d 2 d 3 d
aProcedures with a high risk of bleeding are generally considered safe when the INR is less than 1.5; this takes 5 d to reach in approximately 93% of patients at therapeutic INR level.16 Measure the INR 1 week before surgery to determine discontinuation interval and recheck the INR 24 hr before surgery.

Table 3 - Summary of Recommendations for Antiplatelets
Half-Life (Hours) Discontinuation Interval Before Total Joint Arthroplasty Discontinuation Interval if Concurrent Neuraxial Anesthesia Discontinuation Interval if CrCl <50 mL/min Increased Thrombosis Risk
Aspirin (low-dose, 75–100 mg) 6 Continue Continue Continue No change
Clopidogrel (Plavix) 8 5 d 5 d 5 d Continue low-dose aspirin in patients treated with DAPT
Delay surgery if recent PCI (30 d for bare-metal stent, 6 mo for drug-eluting stent)
Consider discontinuing prasugrel at 5 d in patients with a history of acute coronary syndrome
Prasugrel (Effient) 7 5 d 7 d 5 d
Ticagrelor (Brilinta) 9 5 d 5 d 5 d

A rapidly evolving topic in this realm is the use of tranexamic acid (TXA), an antifibrinolytic medication, in the perioperative setting to decrease blood loss. TXA has been shown to be efficacious in reducing blood loss regardless of the method of administration (IV, topical, or oral). Although more research is needed to determine the safety of TXA in patients at high risk for VTE, the lack of evidence proving harm and its generally well-documented safety profile thus far is reassuring. These data are summarized in the recently published combined clinical practice guidelines led by the American Association of Hip and Knee Surgeons.9

Although most TJAs in the United States are completed under general anesthesia, neuraxial anesthesia is increasingly popular for elective arthroplasty, and the risks of epidural and intrathecal hemorrhage must be considered in addition to surgical site bleeding. The incidence of spinal hematoma after neuraxial anesthesia is rare and difficult to estimate but frequently results in catastrophic permanent neurologic dysfunction.10

AF is the most prevalent sustained arrhythmia; antithrombotics are prescribed for patients with AF to reduce the risk of stroke and systemic embolism.1 For patients with nonvalvular AF, tools have been developed to predict the risk of thrombosis.2 The CHADS2 and more recent CHA2DS2-VASc (see Table 4) scoring systems were developed to stratify the risk of thrombotic events.11,12 The annual stroke risk without antithrombotic therapy can range from as low as 1.9% (CHADS2 score 0) to as high as 18.2% (CHADS2 score >5).11 The CHA2DS2-VASc scoring system improves the predictive value by incorporating additional risk factors with an increased emphasis on age.12 Using CHA2DS2-VASc, the annual stroke risk without antithrombotic therapy has been reported to be as low as 0% (CHA2DS2-VASc score 0) to as high as 100% (CHA2DS2-VASc score 9).12 In regard to valvular AF, all patients are considered to be at high risk for a thrombotic event.2

Table 4 - CHA2DS2-Vasc Score
Risk Factor Points Assigned
Congestive heart failure/left ventricular dysfunction 1
Hypertension 1
Age ≥75 yr 2
Diabetes mellitus 1
Stroke, TIA, or thromboembolism 2
Vascular disease (previous MI, PAD, or aortic plaque) 1
Age 65–74 yr 1
Female sex 1
Adapted with permission from Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest 2010;137:263-272. Adaptations are themselves works protected by copyright. Thus, to publish these adaptations, authorization must be obtained both from the owner of the copyright in the original work and from the owner of the copyright in the translation or adaptation.
MI = myocardial infarction, PAD = peripheral artery disease, TIA = transient ischemic attack

Previous VTE is a strong risk factor for recurrent thromboembolic events. Without antithrombotic therapy, patients with a previous VTE more than 12 months ago are considered to be at low risk (annual rate <5%), whereas those with a VTE within the past 3 to 12 months are at moderate risk (annual rate 5% to 10%) and patients with a VTE in the past 3 months are at high risk (annual rate >10%) for recurrence, propagation, and embolization of thrombi.2 Elective procedures including TJA should be delayed in patients with a thrombotic event within the past 3 months.1 Hypercoagulable disorders such as factor V Leiden, activated protein C resistance, protein C or S deficiency, antithrombin deficiency, and prothrombin G20210A mutation increase the risk of VTE, but specific recommendations regarding discontinuation intervals are not provided by ACC, ACCP, or ASRA guidelines.

Patients with coronary artery disease treated with PCI are another commonly encountered population on chronic antithrombotic therapy. Dual antiplatelet therapy (DAPT) is typically used after PCI to decrease the risk of stent thrombosis. Although the duration of DAPT in patients who receive drug-eluting stents (DES) and bare-metal stents is controversial and beyond the scope of this article, it is well-demonstrated that discontinuation of DAPT in the immediate weeks after stent placement is a strong risk factor for stent thrombosis.13 The 2016 ACC/AHA guidelines recommend delaying elective procedures such as TJA in patients with bare-metal stent placement within the past 30 days and DES placement in the past 6 months.13 Of note, this updates the previous 2014 guideline recommendation of delaying elective noncardiac surgery for one year after PCI with DES placement.14

Methods

This summary of preoperative antithrombotic management was developed by reviewing the guidelines from the American Society of Regional Anesthesia and Pain Medicine (ASRA), the American College of Chest Physicians (ACCP), and the American College of Cardiologists (ACC). The pertinent literature referenced in the society guidelines and manufacturer drug pharmacokinetic data was reviewed to develop the ATI recommendations specific to arthroplasty.

Anticoagulant Agents

Warfarin (Coumadin)

Warfarin is a vitamin K antagonist indicated for the prophylaxis and management of VTE and pulmonary embolism (PE), particularly in patients with AF or a mechanical heart valve and secondary prophylaxis against recurrent myocardial infarction (MI) and thromboembolism. It inhibits the synthesis of vitamin K-dependent clotting factors II (thrombin), VII, IX, and X, in addition to anticoagulant proteins C and S. Peak anticoagulant effect can take up to 4 days to achieve, with a lengthy half-life ranging from 20 to 60 hours. Regular monitoring using international normalized ratio (INR) is required to maintain optimal anticoagulation. Warfarin is metabolized by the CYP450 class of hepatic enzymes including CYP2C9, a polymorphic enzyme with variant alleles that decrease warfarin clearance. The metabolism of warfarin is also affected by certain drugs, supplements, and foods that induce (ie, carbamazepine, phenobarbital, or rifampin) or inhibit (ie, amiodarone, fluconazole, famotidine, or oral contraceptive pills) CYP450, speeding up or slowing down the clearance of warfarin. Most inactive metabolites are ultimately excreted in the urine; however, renal impairment does not markedly alter the anticoagulant effect. Reversal can be achieved with vitamin K, prothrombin complex concentrate, fresh frozen plasma, or activated factor VII.15

Because of warfarin's lengthy half-life and variable metabolism, a baseline INR 1 week before surgery is recommended. One study demonstrated that 93% of patients with a baseline INR ≥2.0 reached a level below 1.5 when measured 5 days after discontinuing warfarin. No factors other than baseline INR were predictive of time to INR normalization.16 The 2017 ACC guidelines recommend checking a baseline INR 5 to 7 days before surgery. The patient's INR should then be rechecked within 24 hours of surgery to ensure normalization.1

Given this prolonged interruption of warfarin before most procedures, bridging anticoagulation, typically with unfractionated heparin or low-molecular-weight heparin (LMWH), is often initiated to prevent a thrombotic event. However, emerging literature suggests that the average patient has an increased risk of bleeding with no reduction in thrombotic events with bridging anticoagulation. The blinded prospective BRIDGE (Bridging Anticoagulation in Patients who Require Temporary Interruption of VKA Therapy for an Elective Invasive Procedure or Surgery) trial randomized 1,813 patients with nonvalvular AF to LMWH bridging up until 24 hours before surgery or a placebo after stopping warfarin 5 days before surgery. The group bridged with LMWH had an increased risk of major bleeding (3.2% versus 1.3%); however, no difference in the thromboembolism rates was observed between the two groups.17

The ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) trial was a prospective observational study of 2,200 patients undergoing either warfarin or dabigatran interruption treated with either unfractionated heparin or LMWH bridging or no bridging. Bleeding events were more common in bridged patients (5.0% versus 1.3%; adjusted odds ratio 3.84; P < 0.0001) with no difference in thromboembolic events.18 Similarly, a cohort study of 1,178 patients on chronic warfarin for secondary VTE prevention found a markedly increased risk of bleeding within 30 days of procedural intervention in the bridged group (2.7% compared with 0.2% in the control group) and no difference in rate of recurrent VTE.4

The 2017 ACC guidelines recommend bridging anticoagulation only in patients at high thrombotic risk, defined as a CHA2DS2-VASc score of seven or more (greater than 10% annual risk of stroke or embolism) or a thrombotic event within the past 3 months.1 The 2017 ACC guidelines also specify that preprocedural bridging is contraindicated in a patient with recent intracranial hemorrhage (within the past 3 months).1

Direct Oral Anticoagulants

DOACs are a relatively new class of oral antithrombotic medications that directly inhibit a specific factor in the coagulation cascade. Unlike warfarin, these medications do not require routine laboratory monitoring. DOACs have been approved for the prevention of stroke and systemic embolism in nonvalvular AF and for the prevention and management of VTE. They have a faster onset of action and are eliminated faster than warfarin. DOACs will variably prolong thrombin time, activated partial thromboplastin time, and ECT at therapeutic doses; however, these laboratory tests are not reliable for monitoring the anticoagulation effect.

The 2017 ACC guidelines recommend against preoperative bridging anticoagulation during DOAC ATI for most patients.1 A collaborative decision is recommended for patients with a high thrombotic risk profile to determine whether bridging is appropriate during DOAC ATI.

Dabigatran (Pradaxa)

Dabigatran is a direct inhibitor of thrombin (factor II) that was approved in 2010 for the prevention of stroke and systemic embolism in nonvalvular AF and the management and prevention of VTE and PE. Unlike other DOACs, dabigatran is primarily excreted through the kidneys (80% of total clearance) with reduced dosing required in the setting of renal impairment.19 In the event of overdose, its effect can be reversed by hemodialysis and idarucizumab (Praxbind).

The RE-LY study investigated preprocedural dabigatran20 ATI and found bridging therapy increased the bleeding risk by 6.5% compared with 1.8% without bridging, without any difference found in thromboembolic events between the two groups.21 For high bleed risk procedures such as TJA, the ACC guidelines recommend an 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 recommended.1 Of note, the fourth edition 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 performed.22

Rivaroxaban (Xarelto)

Rivaroxaban is a selective factor Xa inhibitor approved in 2011 for the prevention of stroke and systemic embolism in nonvalvular AF and for the management and prevention of VTE and PE. Rivaroxaban has a time to maximum concentration of 2 to 4 hours; the half-life is 5 to 9 hours in healthy subjects aged 20 to 45 years and 11 to 13 hours in subjects aged 60 to 76 years. Similar to warfarin, rivaroxaban is a substrate of CYP3A4 and P-gp, making the antithrombotic effect and bleeding risk susceptible to drugs that induce (ie, carbamazepine, phenytoin, or rifampin) and inhibit (ie, ketoconazole and ritonavir) these enzymes.21 Unlike dabigatran, no specific reversal agent exists and it is not removed by hemodialysis.23

The ACC guidelines recommend a discontinuation period of 2 days before high bleed risk procedures such as TJA, with a longer ATI of 3 days in the setting of renal impairment (creatinine clearance less than 30 mL/min).1 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 recommended.22

Apixaban (Eliquis)

Apixaban is another factor Xa inhibitor approved in 2012 for the prevention of stroke and systemic embolism in nonvalvular AF and VTE prevention and management. Among the DOACs, apixaban has the longest time to maximum concentration of 3 to 4 hours with a half-life of 12 hours. Like warfarin and rivaroxaban, apixaban is metabolized by the enzymes CYP3A4 and P-gp. No specific reversal agent exists for apixaban.24 Using data from the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial, a subgroup analysis of 5,924 patients chronically anticoagulated with either apixaban or warfarin was performed, which identified a similar low rate of both periprocedural bleeding and VTE between the two anticoagulants, regardless of whether anticoagulation was withheld or not.25 However, the safety of continuing apixaban before TJA cannot be concluded from this study based on the inclusion of minor procedure such as endoscopy and dental work.

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 impairment.1 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).22

Edoxaban (Savaysa)

Edoxaban is a factor Xa inhibitor and the newest of the DOACs; it was approved in 2015 for the prevention of stroke and embolism in nonvalvular AF. Edoxaban is not currently approved for the management of VTE. Unlike rivaroxaban and apixaban, it is not a substrate of the CYP450 enzymes. It has a rapid time to peak effect of 1 to 2 hours and a half-life of 10 to 14 hours. Half (50%) of edoxaban is cleared through the kidneys; as such, a reduced dose is recommended for patients with a creatinine clearance of 50 mL/min or less. No specific reversal agent exists, and hemodialysis is ineffective for clearance.26

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 impairment.1 The recently published fourth edition 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).22

Antiplatelet Agents

Aspirin

Acetylsalicylic acid is an antiplatelet drug that exerts its effect by irreversibly inhibiting cyclooxygenase, preventing production of the platelet-aggregating factor thromboxane A2. It has numerous indications including the management of acute MI, prevention of recurrent MI and stroke, and use after revascularization procedures as part of DAPT. Aspirin is rapidly metabolized (within 1 to 2 hours) to salicylic acid and has a half-life of 6 hours; it is eliminated by zero order kinetics. It irreversibly affects the platelets for the duration of its circulatory life span (approximately 7 days). It causes a prolongation in bleeding time and can potentially elevate other laboratory indices including liver enzymes, blood urea nitrogen, and creatinine. Renal excretion is dependent on urine pH, with more salicylate cleared through the kidneys as the pH increases. Overdose is potentially fatal; urine alkalization or hemodialysis may be indicated in life-threatening overdose.27

The role of aspirin in the prevention of cardiovascular disease may be primary (no history of a previous cardiovascular event) or secondary prevention against recurrent cardiovascular disease. A meta-analysis of six trials found the efficacy of aspirin in the primary prevention against serious vascular events (relative risk [RR] 0.88, P = 0.0001) and nonfatal MI to be significant (RR 0.77, P < 0.0001), with no significant decrease in mortality from cardiovascular disease or stroke.28 The same study published the results of a meta-analysis of 16 secondary prevention trials, noting a more significant decrease in the incidence of serious vascular events (RR 0.81, P < 0.00001) and a decrease in vascular mortality that approached significance (RR 0.91, P = 0.06). There were markedly more gastrointestinal and extracranial bleeds in patients on aspirin.28 Aspirin is a ubiquitous medication in the United States; a recent study reported that 52% of surveyed US adults between the ages of 45 and 75 years were taking aspirin regularly.29

Bleeding risk while taking aspirin in the perioperative period has been extensively studied, but contradictory results have been found. The prospective randomized controlled POISE-2 (Perioperative Ischemic Evaluation 2) trial assigned approximately 10,000 patients undergoing noncardiac surgery (including orthopaedic procedures) to receive 200 mg aspirin daily for at least 7 days or placebo before surgery. No significant difference in death or MI in either group was observed, but there was a notable increase in major (excluding life-threatening) bleeding in the group taking aspirin (hazard ratio [HR] 1.23, P = 0.04).30 Likewise, a large meta-analysis of periprocedural continuation of low-dose aspirin for secondary prevention found an increase in rate of bleeding complications (median rate of increase by 1.5, interquartile range of 1.0 to 2.5) without an increase in the severity of bleeding complications. The dosage of aspirin used was not discussed for most of the included studies; however, several of the studies included dosages up to 4,000 mg per day. The authors noted the paucity of randomized trials in their meta-analysis, pointing out that patients taking low-dose aspirin for secondary prevention is likely an indicator of increased comorbidity with higher risk for complications.31

On the other hand, several studies have demonstrated the safety of continuing aspirin during elective hip and knee surgery. The elective arthroplasty subgroup (n = 2,648) of the large randomized placebo-controlled Pulmonary Embolism Prevention trial did not find an increase in the transfusion rate or any other bleeding complication in patients taking aspirin 160 mg daily compared with the controls.32 A retrospective review comparing 175 patients who either continued or stopped taking aspirin before TJA found no difference in blood loss, no change in hemoglobin, or no change in the transfusion rate. The patients who discontinued aspirin were noted to have an increased rate of cardiac events including cardiac arrest and myocardial infarction that approached significance (P = 0.107).33 Another study examined the transfusion rates and changes in hemoglobin after knee arthroplasty in patients taking aspirin compared with patients not taking any antiplatelet medications. Similarly, no differences in estimated blood loss, transfusion rates, or hemoglobin drop were identified in a series of patients who continued aspirin compared with patients not taking antiplatelet medications after total knee arthroplasty.34

The platelet rebound effect describes the increased thrombotic state after aspirin discontinuation. The clinical effect of this has been demonstrated in a large meta-analysis that found increased rates of myocardial infarction, stent thrombosis, and death (odds ratio [OR] 3.14, P = 0.0001) shortly after discontinuing aspirin (an average of 10.66 days from discontinuation to the event).35 The rebound phenomenon has been supported by quantitative evidence showing increased levels of thromboxane and prostacyclin to levels beyond those of the control subjects in the first 7 to 14 days after discontinuing aspirin.36

The 2012 ACCP guidelines recommend continuing aspirin 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 period. The patients described as being moderate to high risk include patients with ischemic heart disease, congestive heart failure (CHF), diabetes mellitus (DM), renal insufficiency, or cerebrovascular disease.6 The ASRA guidelines recommend continuation of aspirin without consideration for dosage or indication before neuraxial procedures, citing multiple studies demonstrating that aspirin does not present a notable additional risk in the development of spinal hematomas in neuraxial blocks.22 In addition, the 2016 ACC/AHA guideline focused update on DAPT recommends continuing low-dose aspirin (75 to 100 mg) in the perioperative setting to reduce the risk of stent thrombosis while discontinuing any concurrent P2Y12 inhibitors such as clopidogrel, prasugrel, or ticagrelor.13

Clopidogrel (Plavix)

Clopidogrel is an antiplatelet medication indicated for the management of acute MI and for the prevention of recurrent MI and ischemic stroke. Clopidogrel is not approved for the prevention or management of VTE. Clopidogrel prevents activation of the platelet aggregation promoting glycoprotein GPIIb/IIIa by irreversibly inhibiting the binding of ADP to the P2Y12 platelet receptor. Like aspirin, this effect lasts the length of the platelet circulation life. The time to peak effect is approximately 1 to 2 hours, and the half-life is 6 hours. Clopidogrel is metabolized by the CYP450 class of enzymes, altering treatment effect in the presence of variant CYP2C19 alleles or drugs that interact with the expression of these enzymes. Clopidogrel is eliminated over 5 days equally through the GI tract and renally; however, renal impairment does not prolong effect clearance.37

The large prospective multicenter Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial for the management of acute coronary syndrome without ST-segment elevation (non-ST-elevation myocardial infarction [NSTEMI]) found that patients treated with clopidogrel and aspirin had lower rates of cardiovascular mortality, nonfatal MI, and stroke and also a higher rate of major bleeding during CABG than those treated with aspirin alone.38

The 2012 ACCP guidelines recommend stopping clopidogrel or prasugrel 5 days before cardiac surgery6 based on CURE trial findings that there was no increase in major bleeding requiring transfusion in patients undergoing CABG who stopped clopidogrel at least 5 days before surgery compared with placebo (RR 1.53, P = 0.06).38 The ASRA guidelines recommend discontinuing clopidogrel 5 days before neuraxial procedures.22 Bridging is not required during temporary clopidogrel discontinuation in the perioperative setting, but aspirin should be continued in patients on DAPT after stent placement.14

Prasugrel (Effient)

Prasugrel is also an irreversible P2Y12 platelet receptor inhibitor approved in 2009 for the management of acute MI and after PCI, and this medication is not approved for the management or prevention of VTE. Its peak effect is rapidly achieved within 1 to 2 hours and has a half-life of approximately 7 hours. Prasugrel is also metabolized by the CYP450 enzyme class, and its effect is altered by the presence of variant CYP2C19 alleles or drugs that interact with these enzymes. It is inactivated by S-methylation and cysteine conjugation, and most (68%) inactive metabolites are excreted in the urine, yet renal impairment does not affect dosing. No available reversal agent exists.39

No published data exist describing the safety of continuing prasugrel in the setting of orthopaedic surgery. In a large trial of patients presenting with acute coronary syndrome randomized to receive either clopidogrel or prasugrel while awaiting PCI, those started on prasugrel were noted to have a notable decrease in cardiovascular mortality but a markedly increased risk of both procedural and nonprocedural bleeding.40 A study conducted in healthy volunteers demonstrated that platelet aggregation normalizes within 7 days of discontinuing prasugrel.41 The 2012 ACCP guidelines recommend stopping clopidogrel or prasugrel 5 days before cardiac surgery6; the ASRA guidelines recommend discontinuing prasugrel 7 days before neuraxial block.22

Ticagrelor (Brilinta)

Ticagrelor is another P2Y12 platelet inhibitor approved in 2011 for the prevention of recurrent MI, stroke, stent thrombosis, and this medication is not approved for the management or prevention of VTE. Unlike clopidogrel and prasugrel, it exerts its effect on the P2Y12 receptor in a reversible manner. It is metabolized to its active form by CYP450 within 1.5 to 5 hours; the half-life of the active metabolite is 9 hours. Ticagrelor's treatment effect is particularly prone to inhibition and induction of CYP3A by other drugs.42 Ticagrelor is predominantly excreted through the GI tract, and hepatic impairment has been shown to increase plasma concentrations of both the drug and its metabolites, but did not alter platelet inhibition in comparison with the controls.43 No known specific reversal agent exists.42 Like prasugrel, no data exist regarding continuing ticagrelor before orthopaedic surgery. Platelet aggregation returns to normal within 5 days of discontinuation of ticagrelor.44 The ASRA guidelines recommend discontinuing ticagrelor 5 days before any procedure.22

Summary

Perioperative anticoagulation management is a collaborative effort with the goal of balancing the risks of thrombosis and bleeding. The consequences of both thrombosis (including MI, stent thrombosis, cerebrovascular accident, and VTE/PE) and bleeding (epidural hematoma, draining wounds, hematoma, and transfusion) are severe.

The following recommendations are a summary of the society guidelines from the ACC, ACCP, and ASRA. These recommendations are not meant to supplant clinical judgment, but rather to provide a common ground for discussions between primary care, cardiology, anesthesiologists, and orthopaedic surgeons in the care of future patients. Resumption of antithrombotic therapy after arthroplasty is beyond the scope of this discussion; this should be performed in accordance with cardiology and anesthesia recommendations.

References

References printed in bold type are those published within the past 5 years.

1. Doherty JU, Gluckman TJ, Hucker WJ, et al.: 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. J Am Coll Cardiol 2017;23217.
2. Baron TH, Kamath PS, McBane RD: Management of antithrombotic therapy in patients undergoing invasive procedures. N Engl J Med 2013;368:2113-2124.
3. Trevor AJ, Katzung BG, Masters SB, Kruidering-Hall M: Drugs used in coagulation disorders. Katzung & Trevor's Pharmacology, ed 10: McGraw Hill Medical; 2013:297-300.
4. Clark NP, Witt DM, Davies LE, et al.: Bleeding, recurrent venous thromboembolism, and mortality risks during warfarin interruption for invasive procedures. JAMA Intern Med 2015;175:1163-1168.
5. Kearon C, Hirsh J: Management of anticoagulation before and after elective surgery. N Engl J Med 1997;336:1506-1511.
6. Douketis JD, Spyropoulos AC, Spencer FA, et al.: Perioperative management of antithrombotic therapy. Chest 2012;141:e326S-50.
7. Mont MA, Jacobs JJ: AAOS clinical practice guideline: Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg 2011;19:777-778.
8. Narouze S, Benzon HT, Provenzano DA, et al.: Interventional spine and pain procedures in patients on antiplatelet and anticoagulant medications: guidelines from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, the American Academy of pain Medicine, the international Neuromodulation Society, the north American Neuromodulation Society, and the world Institute of Pain. Reg Anesth Pain Med 2015;40:182-212.
9. Fillingham YA, Ramkumar DB, Jevsevar DS, et al.: Tranexamic acid in total ioint arthroplasty: The Endorsed Clinical Practice Guides of the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee Society. J Arthroplasty 2018;33:3065-3069.
10. Horlocker TT, Wedel DJ, Rowlingson JC, et al.: Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American society of regional anesthesia and pain medicine evidence-based guidelines. Reg Anesth Pain Med 2010;35:64-101.
11. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ: Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864-2870.
12. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ: Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest 2010;137:263-272.
13. Levine GN, Bates ER, Bittl JA, et al.: 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines: An Update of the 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention, 2011 ACCF/AHA Guideline for Coronary Artery Bypass Graft Surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease, 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction, 2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes, and 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Circulation 2016;134:e123-e155.
14. Fleisher LA, Fleischmann KE, Auerbach AD, et al.: 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. J Am Coll Cardiol 2014;64:e77-137.
15. Coumadin (R) [package insert]. Bridgewater, NJ, Bristol-Myers Squibb Inc, 2017.
16. Schulman S, Elbazi R, Zondag M, O'Donnell M: Clinical factors influencing normalization of prothrombin time after stopping warfarin: A retrospective cohort study. Thromb J 2008;6:15.
17. Douketis JD, Spyropoulos AC, Kaatz S, et al.: Perioperative bridging anticoagulation in patients with atrial fibrillation. N Engl J Med 2015;373:823-833.
18. Steinberg BA, Peterson ED, Kim S, et al.: Use and outcomes associated with bridging during anticoagulation interruptions in patients with atrial fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation 2015;131:488-494.
19. Pradaxa (R) [package insert]. Ridgefield, CT, Boehringer Ingelheim Pharmaceuticals, Inc, 2015.
20. Douketis JD, Healey JS, Brueckmann M, et al.: Perioperative bridging anticoagulation during dabigatran or warfarin interruption among patients who had an elective surgery or procedure. Thromb Haemost 2015;113:625-632.
21. Xarelto (R) [package insert]. Titusville, NJ, Janssen Pharmaceuticals, Inc, 2016.
22. Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT: Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Fourth Edition). Reg Anesth Pain Med 2018;43:263-309.
23. De Vriese AS, Caluwé R, Bailleul E, et al.: Dose-finding study of rivaroxaban in hemodialysis patients. Am J Kidney Dis 2015;66:91-98.
24. Eliquis (R) [package insert]. Princeton, NJ, Bristol-Myers Squibb Inc, 2012.
25. Garcia D, Alexander JH, Wallentin L, et al.: Management and clinical outcomes in patients treated with apixaban versus warfarin undergoing procedures. Blood 2014;124:3692-3698.
26. Savaysa (R) [package insert]. Tokyo, Japan, Daiichi Sankyo Inc, 2015.
27. Aspirin [product monograph]. Morristown, NJ, Bayer Inc, 2014.
28. Baigent C, Blackwell L, Collins R: Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009;373:1849-1860.
29. Williams CD, Chan AT, Elman MR, et al.: Aspirin use among adults in the US: Results of a national survey. Am J Prev Med 2015;48:501-508.
30. Devereaux PJ, Mrkobrada M, Sessler DI, et al.: Aspirin in patients undergoing noncardiac surgery. N Engl J Med 2014;370:1494-1503.
31. Burger W, Chemnitius JM, Kneissl G, Rücker G: Low-dose aspirin for secondary cardiovascular prevention–cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation–review and meta-analysis. J Intern Med 2005;257:399-414.
32. O'Brien J, Duncan H, Kirsh G, et al.: Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-1302.
33. Meier R, Marthy R, Saely CH, Kuster MS, Giesinger K, Rickli H: Comparison of preoperative continuation and discontinuation of aspirin in patients undergoing total hip or knee arthroplasty. Eur J Orthopaedic Surg Traumatol 2016;26:921-928.
34. Schwab PE, Lavand'homme P, Yombi J, Thienpont E: Aspirin mono-therapy continuation does not result in more bleeding after knee arthroplasty. Knee Surg Sports Traumatol Arthrosc 2017;25:2586-2593.
35. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al.: A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50 279 patients at risk for coronary artery disease. Eur Heart J 2006;27:2667-2674.
36. Vial J, McLeod L, Roberts M: Rebound elevation in urinary thromboxane B2 and 6-keto-PGF1 alpha excretion after aspirin withdrawal. Adv Prostaglandin Thromboxane Leukot Res 1990;21:157-160.
37. Plavix (R) [package insert]. Bridgewater, NJ, Bristol-Myers Squibb, Inc, 2017.
38. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
39. Effient (R) [package insert]. Indianapolis, IN, Eli Lily Inc, 2010.
40. Wiviott SD, Braunwald E, McCabe CH, et al.: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015.
41. Asai F, Jakubowski JA, Naganuma H, et al.: Platelet inhibitory activity and pharmacokinetics of prasugrel (CS-747) a novel thienopyridine P2Y12 inhibitor: A single ascending dose study in healthy humans. Platelets 2006;17:209-217.
42. Brilinta (R) [package insert]. Wilmington DE, AstraZeneca Pharmaceuticals Inc, 2013.
43. Butler K, Teng R: Pharmacokinetics, pharmacodynamics, and safety of ticagrelor in volunteers with mild hepatic impairment. J Clin Pharmacol 2011;51:978-987.
44. Gurbel PA, Bliden KP, Butler K, et al.: Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease. Circulation 2009;120:2577-2585.
Copyright 2019 by the American Academy of Orthopaedic Surgeons.