➢ Cessation of warfarin is based on risk stratification for thromboembolic events and bleeding risk, with cessation and bridging therapy recommended if patients are at high risk for thromboembolic events or bleeding; warfarin should be withdrawn five days prior to surgery with bridging instituted upon cessation and regular dosing resumed twelve to twenty-four hours after surgery.
➢ Bridging therapy with therapeutic-dose intravenous unfractionated heparin should be stopped four to six hours before surgery, whereas patients on therapeutic-dose subcutaneous, low-molecular-weight heparin should take their last dose approximately twenty-four hours prior to surgery.
➢ Patients within the high cerebrovascular and cardiovascular risk group should maintain aspirin with bridging therapy and may also maintain clopidogrel in emergencies as long as they are not undergoing high-risk procedures.
➢ Patients taking rivaroxaban or dabigatran may undergo emergency surgery if drug levels are ≤30 ng/mL at admission.
➢ There are few to no evidence-based data in the area of perioperative management of anticoagulation in patients undergoing orthopaedic surgery and the ideas presented in this article should only be considered as recommendations at best.
In the United States, there are 2.2 million patients with atrial fibrillation receiving warfarin therapy1,2. There are also more than 104,000 heart valve replacements performed annually3,4. In addition, an estimated 652,000 patients receive percutaneous coronary intervention with stents each year in the United States, necessitating awareness for orthopaedic surgeons on how to properly manage these patients4. Currently, there is not enough evidence to provide definitive recommendations for perioperative management of anticoagulation in orthopaedic surgery.
Oral anticoagulation reduces the risk for stroke in atrial fibrillation by 60% to 70%5,6. Some studies have suggested that oral anticoagulation with a target international normalized ratio (INR) of 2.0 to 3.0 is likely to be the most effective secondary prevention of stroke in this population7,8. In addition, antiplatelet agents, specifically dual therapy with aspirin and clopidogrel, have been shown to reduce cardiovascular events in those undergoing percutaneous coronary intervention without causing a substantial increase in bleeding9. These therapies reduce the risk for fatal thromboembolism, but alter the patient’s hemodynamics and increase the risk for major intraoperative bleeding.
Surgeons must weigh the risk for major bleeding against that of thromboembolism. To assess the interruption of therapy compared with the use of perioperative bridging with either low-molecular-weight heparin (LMWH) or unfractionated heparin, patients are split into two groups according to periprocedural bleeding risks. The low-risk group includes patients undergoing arthrocentesis or joint injections, hand surgery, carpal tunnel surgery, and arthroscopic surgery. The high-risk group involves procedures such as joint replacements and oncological operations. Each category is then separated into emergency and elective procedures. A summary of the recommendations to follow can be found in Table I.
Vitamin K Antagonists
Approximately 250,000 patients taking vitamin K antagonists are being assessed annually by surgeons in North America10. The most common vitamin K antagonist, warfarin, interferes with the cyclic conversion of vitamin K, preventing the carboxylation of glutamate on coagulation factors II, VII, IX, and X11. Warfarin also causes an early pro-coagulant stage by inhibiting carboxylation of anticoagulant proteins C and S, requiring heparin bridging therapy during treatment initiation12. Oral warfarin is rapidly and completely absorbed and peak plasma concentrations are seen within one hour of ingestion, with a drug half-life of thirty-seven hours. The compound is almost completely bound to albumin, leading to many drug interactions. The target therapeutic range for most patients is an INR of 2.0 to 3.0. The exceptions are patients with certain mechanical heart valves (mitral, caged ball, and so forth), those with antiphospholipid antibody syndrome, and those with mechanical heart valves and concomitant complicating conditions13.
High Bleeding Risk Compared with Low Bleeding Risk During Surgery
With regard to risk for surgical bleeding, we deem hand surgery, arthrocentesis, joint injections, and arthroscopic surgery to be low risk and all other orthopaedic surgeries, including joint replacements, spinal surgery, and femoral nailing, to be high risk. Most literature on discontinuing vitamin K antagonist therapy prior to surgery consists of retrospective studies, observational studies, or review articles.
Surgeries deemed to be low-risk for surgical bleeding demonstrate no benefit with cessation of warfarin therapy, suggesting that it should be continued14. Thumboo and O’Duffy performed thirty-two low-risk procedures and reported no joint or soft-tissue hemorrhages, making these procedures safe without discontinuation of warfarin therapy15. Multiple studies have shown no perioperative or postoperative complications in patients who underwent hand surgery and who were on anticoagulant therapy with warfarin, again suggesting that cessation would be unnecessary16,17.
Patients undergoing orthopaedic surgeries with high risk for major bleeding should cease warfarin therapy. It is estimated that two days of heparin therapy will increase the absolute rate of major postoperative bleeding by about 3%18. Although anticoagulation will increase the rate of major bleeding, only 3% of those episodes are fatal and almost 50% of those patients will experience a full recovery19.
High Risk Compared with Low Risk for Thromboembolism
Most studies have classified patients into one of three groups to determine whether or not bridging therapy should be used upon discontinuation of vitamin K antagonist therapy: patients with mechanical heart valves, those with atrial fibrillation, or those with venous thromboembolism. The patients were then further classified as being at high risk, moderate risk, or low risk for thromboembolism complications.
Mechanical Heart Valves
The annual rate of major thromboembolism in patients with mechanical heart valves who are not on anticoagulant therapy is estimated at 8% per year. Anticoagulation reduces this risk by approximately 75%20,21. These events were also found to result in a mortality rate of 40% and a major disability rate of 20%14. Patients with a mechanical heart valve and at high risk for a thromboembolic event are those who have a mitral valve prosthesis, an older caged ball or tilting disc aortic valve prosthesis, or a recent transient ischemic attack or stroke within the past six months10,22. The moderate-risk category includes those who have a bileaflet aortic valve prosthesis; those who have atrial fibrillation, prior stroke, prior transient ischemic attack, hypertension, diabetes, or congestive heart failure; or those who are older than seventy-five years of age10,22. Patients at low risk for thromboembolic events include those with a bileaflet aortic valve and no atrial fibrillation or other risk factors for stroke10,22.
Non-valvular atrial fibrillation is associated with arterial thromboembolism in patients who are not on anticoagulant therapy at a rate of 4.5% annually23. Anticoagulation has been shown to reduce the risk for stroke in patients with atrial fibrillation by 66%18,24. Those patients who are undergoing warfarin therapy for atrial fibrillation are categorized as being at high, moderate, or low risk based on the CHADS2 classification system10. This scoring system includes hypertension, age of more than seventy-five years, congestive heart failure, diabetes, and prior stroke or transient ischemic attack10,25. Risks for arterial thromboembolism were denoted as low (a CHADS2 score of 0 to 2 and no previous transient ischemic attack or stroke), moderate (a CHADS2 score of 3 to 4), or high (a CHADS2 score of 5 to 6, a stroke or transient ischemic attack within the past three months, or rheumatic valvular heart disease)10,22.
The rate of repeat acute deep venous thromboembolism in patients without anticoagulation is about 40% in the first month and 10% in the second and third months18. Treatment with oral anticoagulation will reduce this risk by 80%18. The mortality rate with recurrent venous thromboembolism is 6%, and 2% will suffer serious permanent disability26,27. High-risk patients are those with recent thromboembolism within the past three months or a severe thrombophilia (protein C or S deficiency, antithrombin deficiency, antiphospholipid antibodies)10,22. The moderate-risk group includes patients who have experienced a venous thromboembolism within the past three to twelve months, those who have experienced a recurrent venous thromboembolism, those who have active cancer, and those who have non-severe thrombophilia (heterozygous Factor V Leiden, prothrombin gene mutation)10,22. Low-risk patients have had a single venous thromboembolism that occurred more than twelve months ago and have no other risk factors for venous thromboembolism10,22.
Perioperative Bridging Therapy
We could not find studies in which double-blind, randomized controlled trials were performed comparing patients undergoing vitamin K antagonist therapy who were bridged with LMWH or unfractionated heparin and patients undergoing vitamin K antagonist therapy who had no bridging therapy. According to updated CHEST guidelines10, bridging therapy with therapeutic-dose intravenous unfractionated heparin should be stopped four to six hours before surgery (Grade-2C recommendation)10. Patients undergoing bridging therapy with therapeutic-dose subcutaneous LMWH should have their last dose approximately twenty-four hours prior to surgery (Grade 2C)10. The updated guidelines have also suggested that therapeutic-dose LMWH should be resumed no more than forty-eight to seventy-two hours after surgery in patients who underwent operations with a high risk for bleeding (Grade 2C). For patients undergoing operations with a non-high risk for bleeding, therapeutic-dose LMWH should be resumed twenty-four hours after surgery10. For vitamin K antagonists, the American College of Chest Physicians (ACCP) has recommended that patients cease warfarin five days prior to surgery (Grade 1C) and regular warfarin dosing can be resumed in twelve to twenty-four hours if adequate hemostasis was maintained (Grade 2C)10.
In patients at high risk for thromboembolic events, most authors recommend that warfarin therapy should be stopped approximately five days prior to surgery and therapeutic dosing of intravenous unfractionated heparin or subcutaneous LMWH should be given10,18,22,28-32. One study showed that stopping warfarin therapy five days prior to surgery is usually enough to bring the INR down to 1.533. In these patients, the INR should be checked the day before surgery. If >1.5, 1 mg to 2.5 mg of vitamin K should be administered orally or subcutaneously10,22. Vitamin K administration preoperatively does not have a negative impact on returning to a therapeutic INR postoperatively34. Intravenous vitamin K should be avoided because of hypersensitivity risk. Fresh frozen plasma should also be avoided unless necessary for urgent or emergency surgery. In general, bridging therapy is preferred if a patient is at high risk for thromboembolism14.
Most authors agree that bridging therapy with therapeutic-dose unfractionated heparin or LMWH is not indicated for low-risk patients10,14,22,28-32. Eckman et al. found that intravenous unfractionated heparin therapy would produce an average gain in life expectancy of less than one day and would cost more than $1 million per additional quality-adjusted life-year35. As with high-risk patients, the INR should be checked one to two days prior to surgery and vitamin K should be given if the INR is above 1.5. The ACCP condones the use of prophylactic-dose LMWH if desired by the physician or the patient10,22.
No clear guidelines have been produced for this group, and the risks from bleeding are often near the risks from thromboembolism. Dunn et al., Garcia, and the ACCP have agreed that bridging therapy for these patients is not required, but could be done with therapeutic-dose LMWH or unfractionated heparin if the patient or doctor prefers10,22,28,30. If preferred, one to two days of prophylactic-dose LMWH or unfractionated heparin can be given postoperatively instead30. In those patients receiving prophylactic-dose LMWH, there is no indication for preoperative or intraoperative unfractionated heparin for deep venous thromboembolism prophylaxis36-38.
LMWH has often been found to be a favorable option over unfractionated heparin for bridging therapy in patients requiring interruption of warfarin therapy. LMWH can be administered subcutaneously, in a fixed weight-based dose, and without the need for laboratory monitoring or hospitalization24. This can lead to substantially reduced health-care costs39. Several vascular medicine studies have shown a superior risk-benefit ratio of LMWH compared with that of unfractionated heparin40-42. LMWH as bridging therapy has proven to be at least as safe as unfractionated heparin43.
Two commonly used LMWHs are enoxaparin and dalteparin. It is important to give the last dose of enoxaparin at least twenty-four hours prior to surgery and the last dose of dalteparin at least twelve hours prior to surgery to prevent bleeding complications intraoperatively44,45. The recommended dosing is enoxaparin 1 mg/kg twice daily or dalteparin 100 IU/kg twice daily subcutaneously44,45. When using LMWH, there may be some pre-procedural anticoagulant effect, which can be measured by anti-Xa activity. Douketis et al. found that eleven (30%) of thirty-seven patients receiving therapeutic-dose LMWH with the last dose more than twenty-four hours before the procedure had pre-procedural residual anticoagulant (anti-Xa) effect46. They also found that a residual anticoagulant effect was more likely to be found in those with increasing age and less likely to be found in those with increasing body weight and with twice-daily dosing46. LMWH has been found to be associated with a prolonged time to a dry postoperative wound and with an increased prevalence and severity of wound infections36,37.
Intraoperative or preoperative unfractionated heparin or LMWH does not confer any additional protective value in patients only receiving a prophylactic dose of LMWH. It increases the risk for bleeding and surgical complications and, therefore, should not be used38,47,48. As there have been studies showing that warfarin and LMWH have similar efficacies in preventing thromboembolism in hip and knee arthroplasty, warfarin should be used alone once the INR becomes therapeutic49,50. Data have shown that extended-duration prophylaxis after total hip arthroplasty is more economically feasible with warfarin than with LMWH. Therefore, warfarin therapy should be resumed immediately, usually the night after surgery51.
Aspirin is an irreversible inhibitor of cyclooxygenase (COX), thus preventing the formation of thromboxane A2 (TxA2), a substance used in platelet aggregation. Aspirin is rapidly absorbed in the stomach, reaches peak levels approximately two hours following ingestion, and has a dose-dependent half-life ranging from two to fifteen hours. Although platelet inhibition can lead to hemorrhagic complications, it does reduce mortality from thrombotic complications in patients undergoing cardiac and vascular surgery52-54. Several studies have shown that aspirin therapy should never be discontinued following a coronary or cerebrovascular event55-58. The cessation of aspirin increases the prevalence of myocardial infarction, mortality, and drug-eluting stent thrombosis and is an independent predictor of death and major ischemic events59-62.
Clopidogrel is a thienopyridine antithrombotic agent, which prevents adenosine diphosphate (ADP)-mediated platelet aggregation. This leads to an inhibition of fibrinogen binding to glycoproteins GPIIb and GPIIIa on the platelet surface. The half-life of clopidogrel is approximately eight hours. With a 300-mg loading dose, effects could be seen in as little as two hours12,63. Furthermore, the effects of clopidogrel can be seen for seven days after discontinuation. There can be interpersonal variation in recovery of platelet function with clopidogrel usage, which is more dependent on the amount of initial inhibition by the drug and previous duration of therapy than on the number of days since cessation of the medication12,63-66.
Urgent Compared with Elective Surgery
Aspirin and clopidogrel are usually eliminated from the body within twenty-four hours after cessation. However, due to irreversible effects on platelets, seven to ten days are required before complete platelet recovery. For this reason, orthopaedic management of these patients should be grouped into two categories: urgent or emergency surgery and elective surgery. With urgent surgery, early intervention must be weighed against minimizing bleeding complications. For example, delaying surgical fixation by more than four days in patients with hip fracture can lead to increased mortality67-71. Lavelle et al. investigated how programs in North America treated patients taking clopidogrel who needed urgent or emergency orthopaedic surgery and found variation in protocols among the seventy-four respondents72. If emergency surgery is needed, sixty-six respondents (89%) said that there should be no wait to perform the surgery; if urgent but not emergency surgery is needed, fifty-four respondents (73%) said that waiting three days or less is acceptable and seventeen respondents (23%) said that no delay is needed. Because aspirin and clopidogrel have similar effects on platelets, it is recommended to wait two days before operative intervention and to transfuse platelets if necessary72. However, it should be noted that this recommendation is based on polling of surgeons and not on scientific investigation72. Another study found that withdrawing clopidogrel five or more days before hip or knee arthroplasty may lead to a lower rate of bleeding events73. Once stopped, clopidogrel therapy can be restarted immediately after surgery without an increase in bleeding-related events73.
In elective hip arthroplasty, the continuation of aspirin therapy has been shown to lead to an increased rate of bleeding and transfusion. However, in a separate study, it was found that continuation of aspirin did not increase surgical morbidity or mortality74,75. Although aspirin therapy increases surgical bleeding by 20% to 30%, surgeons were unable to differentiate patients on aspirin from those taking a placebo76. In studies involving osteosynthesis of femoral neck fractures, spinal instrumentation, and multilevel fusion, no significant increase in the rate of bleeding or transfusions was found77,78. However, clopidogrel has been noted in coronary artery bypass graft surgery to be an independent predictor of reoperation for control of hemorrhage, transfusions, and length of stay in the intensive care unit79-81. Even with these increases in bleeding complications from clopidogrel, surgical outcomes and operative mortality were unchanged from standard practice80. In non-cardiac surgery, such as orthopaedic surgery, to our knowledge, there are fewer studies on the effects of clopidogrel on bleeding and outcomes82.
Stratification Based on Risk for Thromboembolism
One study has shown that aspirin taken for primary prevention can be safely withdrawn, but no more than seven days prior to surgery83. For patients taking antiplatelet therapy for secondary prevention, Chassot et al. stratified elective surgery according to the risk for thromboembolism and the surgical risk for bleeding. Patients at low risk for thromboembolism are those who, more than six months ago, had a myocardial infarction, percutaneous coronary intervention and bare metal stent, or coronary artery bypass graft; or those who, more than twelve months ago, had complications from a stroke. Patients at intermediate risk for thromboembolism are those who, six to twenty-four weeks ago, had a myocardial infarction, percutaneous coronary intervention and bare metal stent, coronary artery bypass graft, or stroke without complications; those who, more than twelve months ago, had a drug-eluting stent; those with high-risk stents (multiple, long, or proximal stents); those with a low ejection fraction; and diabetics. Patients at high risk for thromboembolism are those who, less than six weeks ago, had a myocardial infarction, percutaneous coronary intervention and bare metal stent, or coronary artery bypass graft; those who, less than twelve months ago, had a drug-eluting stent; and those who, less than two weeks ago, had a stroke83.
Stratification Based on Risk for Intraoperative Bleeding
Chassot et al. also recommended stratifying operations into groups at low risk, intermediate risk, and high risk for bleeding complications. Minor orthopaedic operations for which transfusions are generally not required, including hand surgery, arthrocentesis, and joint injections, should be included in the low-risk group. The intermediate-risk group includes procedures for which transfusions are frequently required, such as oncological procedures and arthroplasties (hip, knee, shoulder, and elbow). Procedures such as spinal canal surgery in which bleeding could occur in a closed space were included in the high-risk group83.
For patients found to be at low cerebrovascular and cardiovascular risk, it is recommended to maintain aspirin therapy in the low and intermediate-bleeding-risk groups. Aspirin therapy should be discontinued for high-bleeding-risk procedures. In the intermediate cerebrovascular and cardiovascular risk group, it is recommended to maintain both aspirin and clopidogrel for low-bleeding-risk surgery. For both the intermediate and high-risk groups, postponement of elective surgery is recommended. If not possible, aspirin and clopidogrel should be maintained for the intermediate-bleeding-risk group and only aspirin should be maintained for the high-bleeding-risk group. Patients within the high cardiovascular risk group should postpone all elective surgery and high-risk surgery should only be performed if vitally necessary. If surgery is necessary, aspirin should be maintained with a heparin bridge. Emergency procedures for patients undergoing low or intermediate-bleeding-risk surgeries can be performed as long as both aspirin and clopidogrel are maintained throughout83.
If possible, surgical patients receiving dual antiplatelet therapy for a stent should not undergo surgery until six weeks after placement of a bare metal stent and at least six months after placement of a drug-eluting stent10. If surgery is required before this time, dual therapy should be continued10.
Direct Thrombin Inhibitors
Dabigatran, a direct thrombin inhibitor, acts by competitively and reversibly blocking the enzymatic action of thrombin on its substrate84,85. It is currently approved in the United States for stroke prevention in patients with atrial fibrillation and for use in orthopaedic surgery84,86. Use of dabigatran is contraindicated in patients with severe renal dysfunction86. Steady state is achieved in approximately three days and 35% of the drug is bound by plasma proteins. The prophylactic dose of dabigatran for venous thromboembolism is 150 or 220 mg once daily, and the therapeutic dose is 150 mg twice daily and can be used in cases of acute venous thromboembolism87. Dabigatran has fewer drug interactions than warfarin because it is not metabolized by cytochrome (CYP) P450 enzymes. There is no antidote available for an overdose of dabigatran or bleeding complications from its use84,88.
Urgent and emergency surgery can be performed in patients on dabigatran therapy as long as the concentration of the drug is ≤30 ng/mL at the time of admission to the hospital. However, 686 (90%) of 762 patients taking 150 mg of dabigatran twice a day showed a plasma concentration of drug between 40 and 180 ng/mL twelve hours after use89. Surgery in patients with a drug level between 31 and 200 ng/mL should be postponed for twelve hours and the plasma concentration of drug should be measured again. Patients with a concentration between 201 and 400 ng/mL and no renal impairment should wait twenty-four hours before having levels checked again. If the concentration is >200 ng/mL and the patient has a creatinine clearance of <50 mL/min, hemodialysis may be needed and surgery must be delayed for as long as possible89.
For elective surgery in patients with normal renal function, it is recommended to discontinue dabigatran two to three days prior to the procedure90. In higher-bleeding-risk procedures, surgeons should consider discontinuation four days prior to the surgery to increase drug clearance. Results of routine coagulation tests such as the prothrombin time and activated partial thromboplastin time (PT/aPTT) can be near normal with concentrations still present, so drug plasma levels should be measured. Although methods for measurement of plasma levels exist, they are not readily available and the results for the same sample may vary between laboratories91. Bridging therapy is generally not required in these patients because of the rapid offset and onset of action of this drug and should only be considered in those with a very high thromboembolic risk.
Resumption of dabigatran is usually two to three days after high-bleeding-risk procedures and the following day in low-bleeding-risk procedures90. Prophylactic-dose LMWH can be used in the immediate postoperative period to bridge the gap between surgery and the resumption of dabigatran90. Further studies are needed to better delineate the role of dabigatran in orthopaedic surgery.
Rivaroxaban and apixaban are competitive inhibitors of factor Xa that do not require antithrombin85. In patients with normal renal function, the elimination half-life is seven to eleven hours for rivaroxaban and eight to thirteen hours for apixaban. Caution should be used in patients with severe renal impairment86. Dosing for the prevention of venous thromboembolism following total knee replacement can be 2.5, 5, 20, or 30 mg twice daily92. Treatment of acute proximal deep venous thromboembolism is effective at rivaroxaban doses of 10, 20, and 30 mg twice daily as well as 40 mg daily92. These drugs inhibit the production of thrombin by the intrinsic and extrinsic pathways. Unlike dabigatran, factor-Xa inhibitors are metabolized by CYP3A4 and produce a number of drug interactions86.
Anti-factor-Xa assays are relatively fast and currently readily available for monitoring LMWH levels, but are also sensitive and specific for rivaroxaban levels when calibrated with rivaroxaban controls93. Results may be difficult to interpret because plasma levels may differ on the basis of the time since the last dose94. There seems to be no evidence supporting measurement after a standard number of hours. Surgeons should check their respective institutions for the availability of these tests. In emergency or urgent surgery, patients taking rivaroxaban may proceed with a plasma concentration of ≤30 ng/mL. At a plasma concentration between 31 and 200 ng/mL, the surgery should be delayed for twelve hours and the plasma concentration should be measured again. If the plasma concentration is between 201 and 400 ng/mL, surgery should be avoided if possible and the concentration should be rechecked in twenty-four hours. Patients with a concentration of >400 ng/mL are at substantial risk for major bleeding and any procedures should be delayed as long as possible89.
Rivaroxaban may be discontinued two to three days prior to the planned procedure, with shorter intervals for minor surgery and longer intervals for those with renal impairment90. Bridging therapy is often not necessary because of the rapid onset and offset of action of this drug, and should only be considered in those with high thromboembolic risk. Prophylactic-dose rivaroxaban can be administered the day after surgery, but therapeutic dosing should be delayed for two to three days in those with high bleeding risk and may resume following surgery in those with low bleeding risk90.
There are limited data on the efficacy of apixaban and its use during orthopaedic surgery, but one article stated that 2.5 mg of apixaban twice daily showed a reduction in mortality and prevalence of venous thromboembolism when compared with enoxaparin. The same article also explained that apixaban leads to a lower risk for major or clinically relevant bleeding. In terms of perioperative management, patients taking apixaban should have procedures performed at least twenty-four to forty-eight hours after dosing to ensure that drug levels are as low as possible86. Although we discovered no current guidelines for apixaban and orthopaedic procedures, the recommendations should be the same as those for rivaroxaban because the pharmacokinetics and pharmacodynamics of these two drugs are similar.
In conclusion, management of patients taking antiplatelet and anticoagulant medications is becoming increasingly pertinent. To our knowledge, there are few quality studies and almost no randomized controlled trials directed at how to best manage these patients perioperatively. Because some of the ideas in this article are based on literature from other surgical specialties, they can be considered recommendations at best. These recommendations are summarized in Table I. Final judgment should be reserved for the surgeon and the patient on a case-by-case basis. More studies should be encouraged in this field, especially in the moderate-risk groups where benefit may be seen but no clear guidelines can be proposed on the basis of the current data.
Source of Funding: No outside funding was provided for this study.
Investigation performed at the Department of Orthopaedic Surgery, Sports Medicine & Rehabilitation, Boonshoft School of Medicine, Wright State University, Dayton, Ohio
Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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