More than 2 million persons in North America are on chronic anticoagulation therapy.1 Warfarin is the most widely prescribed oral anticoagulant worldwide.1 It functions by inhibiting the enzyme vitamin K epoxide reductase and preventing the decarboxylation of clotting factors II, VII, IX, and X.2 Other commonly prescribed anticoagulants include aspirin and clopidogrel bisulfate. Aspirin inhibits cyclooxygenase enzyme activity, thereby preventing the formation of thromboxane, which stimulates platelet aggregation.3 Clopidogrel bisulfate (Plavix; Bristol Myers Squibb Sanofi Pharmaceuticals Partnership, New York, NY) inhibits the binding of adenosine diphosphate to its platelet receptors, thus preventing platelet aggregation.4
Orthopaedic patients under consideration for emergent or elective surgery may be on chronic anticoagulation to manage other medical conditions. A recent prospective observational cohort study of 1,024 patients at 101 clinical sites identified atrial fibrillation as the most common indication for the use of warfarin (54% of patients).5 Other indications for warfarin administration included venous thromboembolism (VTE) and prosthetic heart valve (14% and 13%, respectively). The remaining patients were receiving treatment for cerebrovascular disease, hypercoagulable states, and recurrent myocardial infarction (MI). Aspirin and clopidogrel bisulfate are typically used to treat patients with cardiac stents, history of stroke, and history of MI.
Orthopaedic patients on chronic anticoagulation therapy are at risk of thromboembolic and hemorrhagic complications. To establish the most effective anticoagulation regimen, the surgeon must stratify patients according to risk of thromboembolism and consider the specific clinical scenario, including the bleeding risk associated with the planned surgical procedure. This allows the treating physician to establish a protocol for managing the anticoagulation status of the patient throughout the perioperative period.
Guidelines for perioperative management of chronic anticoagulation differ with respect to the specific indication for anticoagulation. For example, standard guidelines exist for perioperative management of anticoagulation in patients on warfarin to manage atrial fibrillation or a mechanical heart valve. These recommendations are based on studies that define the risk of thrombosis associated with discontinuation of anticoagulation and the large volume of experience with this population. However, with patients who are on warfarin because of a history of thrombosis, there is more variability in anticoagulation management depending on the timing of the previous thrombosis in relation to the proposed surgery, whether the thrombosis was arterial or venous, and the patient's hypercoagulable condition.
We propose guidelines to assist the orthopaedic surgeon in defining the clinical scenario, estimating the risk of thromboembolism, and establishing an effective regimen for the perioperative management of anticoagulation. Perioperative management of anticoagulation is challenging. We recommend a team approach involving the primary care physician and a hematologist or cardiologist.
Perioperative Hematologic Complications
Orthopaedic patients are at risk of hematologic complications during the perioperative period. The patient is at risk of arterial thromboembolism (ATE) and VTE during the period when the usual anticoagulation regimen is altered. Furthermore, there is a risk of clinically significant hemorrhage after surgery while the anticoagulation regimen is being re-instated, particularly when aggressive measures are used to prevent thrombosis.
Interruption of a patient's usual anticoagulation regimen around the time of surgery increases the risk of thromboembolism.6 There is also the theoretical risk of a rebound hypercoagulable effect due to increased thrombin generation and platelet activation.7 Dunn and Turpie8 reported a 0.6% increase in ATE events in patients with atrial fibrillation or a mechanical heart valve whose anticoagulation regimen was discontinued during surgery. Carrel et al9 reported 70% disability from a transient, residual, or irreversible defect after cerebral embolism, and a 15% to 30% rate of fatal embolic stroke in patients with mechanical heart valves who underwent noncardiac surgery while off their anticoagulation regimen with no bridging therapy.
A 2% to 10% incidence of deep vein thrombosis (DVT) or pulmonary embolism (PE) has been reported when anticoagulant therapy is stopped within 3 months of a VTE event;10,11 the risk of recurrent DVT or PE after 3 months of therapy for a VTE event is <2% per year.12 The reported thromboembolic complications related to the discontinuation of aspirin and clopidogrel bisulfate include cerebral embolism and PE, MI, and retinal artery occlusion; the rate of these complications is unknown.13,14
Prior to surgery, an international normalized ratio (INR) of 1.3 or 1.4 is considered safe and has been associated with reduced intraoperative and postoperative bleeding complications.6,15 An elevated INR ≥1.8 is an independent risk factor for major postoperative hemorrhage at the surgical site.12 With respect to regional anesthesia, needle injection into the spinal canal is contraindicated in the setting of an elevated INR ≥1.4 because of the risk of epidural hematoma and neurologic sequelae. Several case reports have documented the development of hematoma in the epidural space in patients on chronic or bridging anticoagulation therapy.16
Wiedermann and Stockner17 reported an increased rate of bleeding complications in patients who continued to take warfarin up to 24 hours preoperatively or perioperatively. Sachs et al18 compared the complications in patients who took warfarin after total knee arthroplasty with those who did not. Compared with the patients who were not anticoagulated, the warfarin group had twice the infection rate (4.7% versus 2.2%) as well as a higher rate of postoperative bleeding. Additional sequelae related to bleeding in patients on warfarin include compartment syndrome, peripheral nerve compression, and spinal epidural hematoma with neurologic deficit.19–24
Bleeding complications have also been documented with the use of other anticoagulant agents in the perioperative period. Carrel et al9 reported a 2% to 4% risk of bleeding or hematoma during bridge therapy with heparin or enoxaparin. A meta-analysis of 474 studies reported that the risk of bleeding increased by a factor of 1.5 in patients on aspirin therapy who underwent surgery.25 An increased rate of perioperative bleeding was the most frequently reported complication in patients on clopidogrel bisulfate before surgery, occurring in 22.6% of patients.26
Two major determinations are necessary to establish the appropriate anticoagulation regimen in the perioperative period. First, the surgeon should analyze the specific clinical scenario with respect to the timing of surgical intervention. Second, the surgeon should assess the patient's risk of hematologic complications. The combined analysis will allow the medical team to establish the methods necessary to reverse and restore the anticoagulant effect.
The approach we use in this article, involving risk stratification with specific recommendations based on the urgency of surgery and bleeding risk, is similar to the methodology used in the guidelines for prevention of thrombotic events developed by the American Academy of Orthopaedic Surgeons.27 Patient stratification based on the risk of a thrombotic event and the associated prevention methods are based on recommendations made by the American College of Chest Physicians.15
The clinical scenarios to consider are urgent surgery, semiurgent surgery, and elective (ie, nonurgent) surgery. Each scenario dictates a specific rate and method of reversal of the anticoagulant effect.
Urgent surgical intervention, defined as surgery initiated ≤24 hours after presentation, requires rapid reversal of the INR to reduce surgical complications.28–30 Examples of clinical conditions that require urgent surgical management include open fracture, fracture associated with vascular injury, femoral neck fracture in the young patient, compartment syndrome, and spinal pathology associated with major neurologic compromise (eg, epidural abscess with spinal cord dysfunction, lumbar disk herniation with cauda equina syndrome).
Semiurgent surgery, defined as surgery performed within 24 to 72 hours of presentation, offers more time in which to reverse the anticoagulant effect. Clinical conditions that fall into this category include femoral neck or intertrochanteric fracture in the elderly patient, femoral shaft fracture, and spinal pathology (eg, lumbar disk herniation) with a progressive nerve root deficit.
Elective surgery is typically performed >4 to 5 days after the onset of an acute orthopaedic condition or for a chronic musculoskeletal problem. Closed ankle fracture, extremity joint osteoarthrosis, and spinal pathology (eg, disk herniation, stenosis) with minor or no neurologic deficit fall into this category.
Estimation of Complication Risk
The second major step in establishing the perioperative anticoagulation regimen consists of assessing and estimating the risk of thromboembolism and postoperative hemorrhage. This analysis is useful in guiding the formulation of the pharmacologic protocol. Specific decisions are required regarding the need for preoperative bridge therapy during reversal of the chronic anticoagulant effect as well as the method of resumption of anticoagulation after surgery.
The thromboembolic risk profile is the primary determinant of whether bridge therapy with heparin or enoxaparin is necessary during the reversal of chronic anticoagulation. No standardized scoring system exists for estimating thromboembolic risk in the orthopaedic surgery patient. Factors to be considered include the underlying medical indication for chronic anticoagulation therapy, the timing of the last thrombosis, if any, coexistent predisposing factors for thromboembolism (eg, advanced age, cancer, diabetes, hypertension), and the inherent risk of VTE with certain orthopaedic conditions and/or procedures. The medical team must consider the entire clinical profile to categorize a patient as high, intermediate, or low risk.
Table 1 presents a risk stratification model for the prevention of thromboembolism based on the indication for anticoagulant therapy and medical risk factors.10,31,32 Gage et al31 compared the CHADS2 (congestive heart failure, hypertension, age ≤75 years, diabetes mellitus, previous stroke/transient ischemic attack) stroke risk index with two other classification systems in a study of 1,733 patients with atrial fibrillation. The CHADS2 index was found to be the most accurate predictor of stroke in such patients. According to this model, high-risk patients with atrial fibrillation have a >10% chance of experiencing an ATE or VTE event within 1 year if their anticoagulation therapy is discontinued. This risk falls to 2% to 10% for the intermediate-risk patient and to <2% to 5% for the low-risk patient.10,32,33 Definitive scientific data regarding the risk of ATE and VTE during the 3 to 7 days postoperatively when anticoagulant therapy is interrupted are not available.
In patients who are on warfarin for a history of VTE, the risk associated with interruption of anticoagulation is related to the timing between the thrombotic event and the proposed surgery. Within the first month after an acute VTE there is a 1% daily risk of recurrent thrombosis, and this risk remains high within the first 3 months following a VTE event.34 The increased probability of VTE associated with certain orthopaedic surgical procedures is another relevant consideration in estimating the perioperative complication risk.15Table 2 outlines the reported rate of VTE and fatal PE associated with surgical procedures that are commonly performed without pharmacologic prophylaxis.
The risk of postoperative wound hemorrhage must be estimated to establish a safe protocol for postoperative resumption of anticoagulation. Thachil et al36 reviewed 72 articles that demonstrated the bleeding risk of various surgical procedures. Total joint arthroplasty fell into the intermediate-risk category; extensive spinal procedures (eg, multilevel decompression and fusion) fell into the high-risk category. Arthroscopic procedures and lumbar diskectomy were considered to be low risk.
The surgeon must also inform the medical team of procedure-specific sequelae that could result from bleeding. For example, epidural hematoma after posterior cervical decompression has the potential to cause spinal cord damage and quadriplegia. In all cases, the postoperative pharmacologic regimen must balance the risk of bleeding with the need for thromboembolic prophylaxis.
Anticoagulation Management Protocol
In the setting of urgent surgery, the two main pharmacologic options used to reverse the INR are freshfrozen plasma (FFP) and prothrombin concentrate complex (PCC). PCC has been shown to be more effective than FFP in achieving rapid reversal in patients with a lower risk profile37,38 (Table 3). The INR should be checked immediately before surgical intervention.5,15 Vitamin K, which takes approximately 1 to 2 days to achieve the target INR, is not typically used as first-line treatment in the setting of urgent surgery.39 However, it is used as an adjunct in certain cases because the half-lives of FFP and PCC are relatively short. Vitamin K promotes new factor production while the effect of FFP and PCC is diminishing.
In the setting of semiurgent surgery, vitamin K can be used to reverse anticoagulation within the appropriate time frame (24 to 72 hours after presentation).6,15,39 The mechanism of action of vitamin K involves carboxylation of glutamine residues, which increases production of clotting factors II, VII, IX, and X.40 Typically, normalization of the INR is achieved within 48 to 72 hours.
Oral administration of vitamin K is preferred because of the associated anaphylactic and cutaneous reactions with intravenous and intramus-cular routes, respectively.41 The required dose of vitamin K can be determined based on the INR at presentation. One prospective study used the formula
16 − [17 × (INRdesired/INRinitial)]
to calculate the dose of vitamin K needed to reverse a therapeutic INR; successful reversal was achieved within 48 hours in 99% of patients.42 In the setting of semiurgent surgery, a single low dose of vitamin K (2.5 to 5.0 mg) is recommended.15 The INR should be monitored daily and checked immediately before surgery to ensure proper reversal.5,15 Although vitamin K is easy to administer, its efficacy can be altered by patient factors such as weight, age, and INR at presentation.32,33 Vitamin K overdose can result in postoperative resistance to warfarin.33
In elective orthopaedic procedures, warfarin can be discontinued 5 days before surgery to achieve a target INR of ≤1.3.7,10,15,33 Vitamin K can be used as an adjunct in refractory cases.32,43 The INR level should be measured the day before elective surgery to ensure normalization of the coagulation status.15 Bridging therapy with a heparin product can also be considered in the setting of elective surgery during the 4 to 5 days preoperatively when warfarin is not being administered. In general, there is a relative indication for preoperative bridging therapy in the patient at high or intermediate risk of ATE or VTE3 (Figure 1).
The two primary pharmacologic options for bridging therapy are low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH). In 2008, the American College of Chest Physicians published a review article analyzing bridging therapy in approximately 1,400 patients with atrial fibrillation and approximately 1,300 patients with a mechanical heart valve (10 studies and 14 studies, respectively).15 The authors found both LMWH and UFH to be effective forms of bridge therapy. In terms of efficacy, several other studies have shown LMWH to be comparable to UFH, with an overall thromboembolic risk of 0.3%.11,32,33 Other investigators have demonstrated LMWH injection to be superior to intravenous UFH.35,43
LMWH has the advantage of ease of subcutaneous administration on an outpatient basis. In contrast, UFH must be delivered intravenously and requires inpatient monitoring. UFH, however, has a shorter half-life and can be reversed more rapidly. Outpatient LMWH is less costly than nurse-administered LMWH or intravenous hospital-based UFH.44 In the absence of pregnancy or renal failure, outpatient LMWH is recommended as the first choice for preoperative bridging therapy. Although other medications (eg, fondaparinux,45 desirudin46) are available for DVT prophylaxis, no study has documented the efficacy of these newer agents in bridging therapy in the setting of chronic anticoagulation. Both LMWH and UFH carry the risk of heparin-induced thrombocytopenia.47
Mechanical compression is recommended for thromboprophylaxis in all patients during the perioperative period.15,27 It has been shown to reduce the perioperative incidence of DVT.48
In general, preoperative bridging therapy is indicated in the patient at high risk for ATE or VTE.3 A treatment protocol for the high-risk patient is shown in Figure 2.
Warfarin should be stopped 5 days before elective surgery, and outpatient bridging therapy should be initiated with LMWH once the INR is <1.8.6 Bridging therapeutic LMWH should be stopped 24 hours before surgery. In a study of 260 patients who received LMWH within 24 hours of surgery, Dunn et al11 reported a 20% clinical bleeding risk in patients who underwent major surgery.
In patients with renal insufficiency, LMWH clearance can be prolonged, which makes it more difficult to predict when it will be eliminated from the patient. Thus, LMWH should be used with caution in these patients, and intravenous UFH should be considered instead.
When a patient at high risk of VTE is also judged to be at high risk of intraoperative and/or postoperative bleeding, it may be reasonable to forego or modify the bridging regimen. The medical team can consider placement of a retrievable inferior vena cava (IVC) filter as a means of reducing the risk of PE. In a study of 74 spine surgery patients who received IVC filters, Leon et al49 reported that although 23 patients developed lower extremity DVT, only 1% developed nonfatal PE.
Temporary IVC filters are versatile and safe in patients at high risk of PE.46,50 The long-term complications associated with permanent filters (eg, venous stasis, IVC thrombosis, delayed penetration through the IVC wall, late development of DVT51) generally can be avoided with retrievable devices. Van Ha et al52 compared retrievable IVC filters with permanent ones and identified a lower risk of complications and a lower rate of PE with retrievable filters. Although removal of retrievable filters has been recommended within 14 days after implantation to prevent endothelialization,50 several authors have reported safe retrieval times of 14 to 1,217 days.50–52
No optimal solution exists for the patient at high risk of ATE and perioperative bleeding. A frank discussion with the patient and among the medical team is critical to determine whether surgery can be avoided. When surgery is unavoidable, a bridging regimen that minimizes the risk to the patient must be established based on clinical judgment and patient-specific risk factors.
In the patient at high risk of ATE or VTE, warfarin generally can be restarted on the evening of surgery at the preoperative maintenance dose. Loading doses have not been shown to be of benefit in the chronically anticoagulated patient.36 In the patient with an intermediate or low risk of postoperative bleeding, bridging therapy with a full dose of LMWH generally should be started after surgical wound hemostasis is achieved, typically within 24 to 48 hours postoperatively.15 Administration of LMWH is terminated once the INR reaches a therapeutic level.
In the patient at high risk of postoperative bleeding, bridging therapy can be initiated with a prophylactic dose of LMWH (30 to 40 mg subcutaneously twice a day). The duration of prophylactic dosing and the delay to full-dose LMWH may last 1 to 4 days, depending on the clinical significance of wound hemorrhage. For example, the risk of spinal epidural hematoma after cervical decompression may warrant an extended period of prophylactic dosing. Similarly, prophylactic dosing can be considered after total knee arthroplasty when there is significant concern that wound hematoma will produce permanent functional limitations related to joint stiffness.
Patients at intermediate risk of ATE or VTE require an individualized approach to bridging therapy (Figure 3). When the risk of ATE or VTE is substantial and outweighs the risk of perioperative bleeding complications, use of LMWH during the preoperative and postoperative periods may be considered. If bridging therapy is judged to be inappropriate based on the risk of bleeding associated with the surgery, preoperative placement of a retrievable IVC filter is a reasonable alternative to LMWH to reduce the risk of PE.
Most patients at low risk of ATE or VTE do not require bridging therapy. In these patients, the bleeding risk outweighs the potential for a thromboembolic event.33,53 Bridging anticoagulation is generally inadvisable for patients undergoing spinal procedures, in particular. Warfarin can be resumed on the evening of surgery or on a delayed basis if the consequences of postoperative bleeding are potentially serious. In orthopaedic trauma or arthroplasty patients who are at risk of VTE due to injury or the planned surgical procedure, prophylactic LMWH can be administered before and after surgery (Figure 4).
Data are limited regarding the use of aspirin and clopidogrel bisulfate perioperatively; and no randomized controlled study is available. A history of cerebrovascular disease or of MI, as well as unstable angina or coronary stenting, places a patient in the high-risk category.54 These patients are typically on long-term aspirin. The use of clopidogrel bisulfate has become more popular in the past decade, especially in patients with drug-eluting or noneluting cardiac stents.32 In patients with acute coronary syndrome, aspirin and clopidogrel bisulfate combination therapy has been more effective in reducing mortality than aspirin alone.55 This therapeutic protocol is on the rise, as well.
Urgent and Semiurgent Surgery
In the setting of urgent surgery for trauma or other serious conditions, there is an increased risk of bleeding morbidity and possibly an increased risk of mortality in patients on preoperative antiplatelet therapy.56,57 During the perioperative period, the surgeon must expect the risk of bleeding to be higher in patients who are taking aspirin or clopidogrel bisulfate. Increased blood loss has been reported in patients with proximal femur fractures who were on preoperative aspirin or clopidogrel bisulfate.56,58
Reversal of antiplatelet therapy can include administration of platelets, desmopressin, and recombinant activated factor VII. However, no study has compared any of these modalities with respect to achieving satisfactory reversal of the anticoagulant effect. There is a theoretical risk of creating a hypercoagulable state. McMillian and Rogers57 recommended the use of a 10-pack of platelets to reverse the effects of clopidogrel bisulfate when treating patients with intracranial hemorrhage.
Elective surgery should be avoided in patients on clopidogrel bisulfate in the first 6 months following stent placement.59 Only lifesaving surgery should be considered during this time frame.54 Following placement of a drug-eluting stent, patients typically are maintained on clopidogrel bisulfate for at least 1 year because the morbidity and mortality rate with interruption of anticoagulation therapy can be as high as 40% to 50%.11 A recent prospective study of 6,816 patients showed that discontinuation of clopidogrel bisulfate increased the risk of stent thrombosis during the first 6 months only after implantation.59 If necessary, elective surgery can be performed 6 months after placement of a drug-eluting stent with discontinuation of clopidogrel bisulfate. However, it is ideal to delay elective surgery for the entire year. Following insertion of a bare metal stent, the patient must continue taking clopidogrel bisulfate for at least 3 months to achieve stent endothelialization.
Patients at high risk of a cardiovascular event should be counseled on the risks of discontinuing aspirin or clopidogrel bisulfate. In these patients, an individualized protocol for perioperative management of clopidogrel bisulfate should be developed with the cardiologist.
Patients taking aspirin alone are advised to discontinue the medication 7 to 10 days preoperatively to allow for reversal of the anticoagulant effect.11 The patient's usual aspirin dose can be restarted as soon as postoperative hemostasis is achieved. Clopidogrel bisulfate also must be discontinued 7 to 10 days before surgery to reverse the anticoagulant effect.60 The patient who is taking both aspirin and clopidogrel bisulfate should discontinue clopidogrel bisulfate 7 to 10 days before surgery and stop aspirin closer to the day of surgery, typically 5 days out.54 This allows a longer period of antiplatelet therapy before surgery, thus theoretically reducing the risk of thrombosis in the high-risk patient. In the high-risk patient, it is reasonable to continue aspirin during the perioperative period for orthopaedic procedures that involve minimal blood loss (eg, outpatient arthroscopy, carpal tunnel release).61
Management of chronic anticoagulation during the perioperative period is complex and necessitates a multi-disciplinary approach involving the patient's primary care physician, hematologist, or cardiologist. Stratification of patients according to their risk of ATE or VTE and postoperative hemorrhage as well as determination of the specific clinical scenario are essential in establishing the risk profile. Factors to consider when developing a safe and effective anticoagulation protocol include timing of surgery, thromboembolic risk, and bleeding risk associated with the planned surgery. Retrievable inferior vena cava filters may be a viable alternative to bridging therapy in patients with a high risk of VTE and intraoperative and/or postoperative bleeding.
Citation numbers printed in bold type indicate references published within the past 5 years.
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