Orthopaedic Advances
Venous Thromboembolism in Orthopaedic Trauma Abstract John A. Scolaro, MD Ryan Metri Taylor, MD Nathan A. Wigner, MD, PhD
Patients who sustain orthopaedic trauma are at risk for developing deep venous thrombosis and symptomatic pulmonary emboli. The prevention of venous thromboembolism has moved to the forefront of patient safety initiatives, resulting in the formation of various guidelines to assist the practitioner. Recommendations for venous thromboembolism prophylaxis in the orthopaedic trauma patient exist, but there is insufficient evidence in the literature to make strong recommendations regarding type and duration of prophylaxis. The associated morbidity of chemical anticoagulants used in the orthopaedic trauma patient must also be taken into consideration, specifically the increased risk of bleeding. Mechanical prophylaxis is used in place of, or in addition to, these medications in certain situations. New, potentially superior anticoagulants have been developed but are still understudied. Larger studies are needed to further define the type and duration of deep venous thrombosis prophylaxis in the orthopaedic trauma patient.
V From the University of California, Irvine, Orange, CA (Dr. Scolaro) and the University of Pennsylvania, Philadelphia, PA (Dr. Taylor and Dr. Wigner). None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Scolaro, Dr. Taylor, and Dr. Wigner. J Am Acad Orthop Surg 2015;23:1-6 http://dx.doi.org/10.5435/ JAAOS-23-01-1 Copyright 2014 by the American Academy of Orthopaedic Surgeons.
January 2015, Vol 23, No 1
enous thromboembolism (VTE) can result in significant morbidity and mortality. Despite identification by healthcare initiatives as a preventable clinical event, data indicate that neither increased awareness nor more recent prophylactic regimens have resulted in a significant change to the overall incidence and mortality from VTE. Deep vein thrombosis (DVT) accounts for most thrombotic events, but prevention of clinically significant pulmonary embolus (PE) is the primary goal of prophylaxis. Various recommendations have been generated to help guide VTE prophylaxis in the orthopaedic patient1-5 (Table 1). Unfortunately, little high-level evidence is available on the topic, especially with regard to the orthopaedic trauma patient. In addition, there is little evidence to help practitioners decide which orthopaedic trauma patients require prophylaxis and the duration of treatment. Initiation of
pharmacologic prophylaxis in the trauma patient must also balance the benefits of therapy with the risk of bleeding. The advent of more recent anticoagulants has increased the pharmacologic options available to the orthopaedic surgeon, but their comparative efficacy has been incompletely evaluated.
Incidence The incidence of DVT in trauma patients without prophylaxis is cited to be as high as 80%. Stannard et al6 reported that initiation of chemical prophylaxis in orthopaedic trauma patients reduced the overall rate of DVT to 11% and of nonfatal PE to 1%. The reported incidence of DVT varies with method of detection, mode of prophylaxis, location of thrombus, and sample size, thus resulting in a wide range of numbers in the
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Venous Thromboembolism in Orthopaedic Trauma
Table 1 Current Guidelines for Venous Thromboembolism Prophylaxis in Orthopaedics Source Orthopaedic Trauma Association1,a
American College of Chest Physicians2,b
American Academy of Orthopaedic Surgeons3,c
Eastern Association for the Surgery of Trauma4,d
Cochrane Review5
Guidelines Major orthopaedic surgery LMWH is considered the agent of choice and should be initiated within 24 hr provided there are no contraindications (Strong) Combined LMWH and calf pneumatic compressive devices over either regimen alone (Strong) Continuation of VTE prophylaxis for at least 1 mo after discharge (Limited) Recommend against routine screening protocols for DVT in asymptomatic trauma patients (Strong) Isolated lower extremity injury Do not recommend routine chemical prophylaxis in patients who do not have additional risk factors and are independently mobile (Moderate) Recommend against routine screening protocols for DVT in asymptomatic trauma patients (Strong) Major orthopaedic surgery Extend outpatient prophylaxis for up to 35 d postop (2B) Dual prophylaxis with pharmacologic agent and IPCD while inpatient (2C) Recommend against screening Doppler ultrasonography before discharge (1B) Hip fracture surgery Prophylaxis for a minimum of 10-14 d (1B) Start LMWH either 12 h or more preop or 12 h or more postop (1B) Recommend use of LMWH, fondaparinux, LDUH, adjusted-dose aspirin (1B) or IPCD (1C) LMWH is preferred to other agents (2B/2C) Isolated lower extremity injury No prophylaxis in patients who require leg immobilization (2C) Elective total joint arthroplasty Pharmacologic agents and/or mechanical compressive devices for VTE prevention for those who are not at elevated risk (Moderate) No specific agent recommended (Inconclusive) Patients and physicians discuss duration of treatment (Consensus) Recommend against routine duplex ultrasonography screening postoperatively (Strong) LDH has little proven efficacy in prevention of VTE as sole agent in high-risk trauma patients (Level II) IPCD may have some benefit in isolated studies (Level III) LMWH can be used in trauma patients with pelvic fractures, complex lower extremity fractures, and spinal cord injury when bleeding risk is acceptable (Level II) IVCF should be considered in very high-risk trauma patients who cannot receive pharmacologic prophylaxis or have an injury pattern that would leave them immobilized for long periods of time (Level III) Duplex ultrasonography may be used to diagnose symptomatic patients with suspected DVT without venography (Level I) No evidence that prophylaxis reduces mortality or secondary outcome of pulmonary embolus Pharmacologic prophylaxis is more effective than mechanical prophylaxis LMWH is more effective than UH Insufficient studies for comparison between pharmacologic agents vs placebo or pharmacologic prophylaxis vs mechanical prophylaxis
DVT = deep vein thrombosis, IPCD = intermittent pneumatic compression devices, IVCF = inferior vena cava filter, LDH = low-dose heparin, LDUH = low-dose unfractionated heparin, LMWH = low-molecular-weight heparin, UH = unfractionated heparin, VTE = venous thromboembolism a OTA recommendation strengths: Strong = greater than two high-quality (level I) studies to support the recommendation; Moderate: one high-quality (level I) or two moderate-quality (level II or III) studies to support the recommendation; Limited = one moderate-quality (level II or III) or two low-quality (level IV) studies to support the recommendation; Inconclusive = one low-quality (level IV) study or lack of evidence to support the recommendation; Consensus = expert work-group opinion (no studies) b American College of Chest Physicians recommendation strengths: 1B = strong recommendation, moderate-quality evidence, benefits clearly outweigh risk and burdens or vice versa; 1C = strong recommendation, low-quality or very low–quality evidence, benefits clearly outweigh risks and burdens or vice versa; 2B = weak recommendation, moderate-quality evidence, benefits closely balanced with risks and burdens; 2C = weak
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John A. Scolaro, MD, et al
literature. Interestingly, evidence of peripheral DVT by venous ultrasonography or postmortem analysis is not always present in those who develop a symptomatic PE. Although it has been thought that all PEs are the result of distal thrombi that travel proximally, the findings of Stannard et al6 question this relationship. The use of pharmacologic prophylaxis has been shown to significantly lower the rate of DVT formation, but PE-related morbidity and mortality remain high, indicating an important clinical disparity. The development of VTE is not unique to any specific patient type or injury pattern. No one prophylactic protocol has been found to demonstrate superior results with regard to the reduction of both DVT and PE in hospitalized patients. Unfortunately, evidence has shown that even across surgical intensive care units at major academic medical institutions in the United States, adherence to VTE prophylaxis guidelines is poor.7 As such, the Agency for Healthcare Research and Quality now ranks VTE prophylaxis as among the most important interventions to improve patient safety.8 Despite all the attention given to preventing VTE in hospitalized trauma patients, however, there is little in the way of strong evidencebased recommendations to guide the orthopaedic surgeon.
Pathophysiology and Risk Factors Virchow’s triad of venous stasis, endothelial injury, and hypercoagu-
lability is traditionally considered the harbinger of thrombus formation. Major trauma is believed to lead to one, if not all three, risk factors. Specific risk factors, including but not limited to spinal cord injury, pelvic fractures, lower extremity fractures, high injury severity, and longer ventilation times, place these patients at increased risk for symptomatic VTE. Recent studies have explored the effects of circulating procoagulant and thrombogenic microparticles, as well as a decrease in antithrombin III levels, on thrombus formation in an effort to better understand the pathophysiology behind clot formation and embolization.9 Basic science investigators will continue to explore the potential modifiable factors involved in both in vitro and in vivo clot formation.
Diagnosis The diagnosis of VTE remains a challenge. Clot formation is often a clinically silent or subtle event. The Wells criteria have been used to determine the pre-test probability of PE before diagnostic testing is performed. The scoring system was first reported in nontrauma patients and has not been validated outside this population. Young et al10 recently evaluated alternative and standard interpretations of the Wells criteria in a large number of orthopaedic trauma patients and found no predictive relationship between the test scores and the development of PE. Routine venous ultrasonography has been used in an effort to capture
early peripheral DVT. A positive result obtained from a screening study performed in an asymptomatic person places the practitioner in a position to decide whether therapeutic anticoagulation is required. Although therapeutic anticoagulation may prevent progression of thrombotic disease, the physician and patient assume the responsibility of increased medical costs and the risk of bleeding. Recent literature has shown that sequential duplex ultrasonography screening does not decrease the rates of PE in orthopaedic trauma patients. 11 In fact, recent recommendations from both the American Academy of Orthopaedic Surgeons and Orthopaedic Trauma Association recommend against the use of duplex ultrasonography to screen asymptomatic orthopaedic joint arthroplasty and trauma patients, respectively, for peripheral VTE.1,3 Use of duplex ultrasonography is therefore recommended when the physician identifies patient or injury-related risk factors or specific clinical signs or symptoms of VTE. CT pulmonary angiography is used as a definitive diagnostic tool when PE is suspected; it has no role as a screening tool. The examination is expensive and requires the use of potentially nephrotoxic intravenous contrast material. The study has the ability to locate and characterize clots but cannot determine or predict their clinical significance. For this reason, injudicious use can result in unnecessary cost, morbidity, and use of pharmacologic anticoagulation.
recommendation, low-quality or very low–quality evidence, uncertainty in the estimates of benefits, risks, and burdens; benefits, risk, and burden may be closely balanced c American Academy of Orthopaedic Surgeons recommendation strengths: Consensus = expert opinion supports the guideline even though there is no available empirical evidence that meets the inclusion criteria of the guideline’s systematic review; Strong = benefits of the recommended approach clearly exceed the potential harm and the quality of supporting evidence is high; Moderate = the benefits exceed the potential harm but the quality/ applicability of the supporting evidence is not strong; Inconclusive = lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm d Eastern Association for the Surgery of Trauma recommendation strengths: Level I recommendation = convincingly justifiable on the basis of scientific information alone through class I data; Level II recommendation = reasonably justifiable on the basis of a preponderance of class II data; Level III recommendation = supported only by class III data; Class I data = prospective randomized controlled trial; Class II data = clinical study with prospectively collected data or large retrospective analyses with reliable data; Class III data = retrospective data, expert opinion, or a case report
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Venous Thromboembolism in Orthopaedic Trauma
Prophylaxis A recent systematic review demonstrated that both pharmacologic and mechanical prophylaxis reduces the risk of DVT in trauma patients.5 The decision to begin pharmacologic prophylaxis must frequently balance the benefits of early therapy with the concern for complications related to bleeding, specifically in the setting of concurrent solid organ, intracranial, or spinal injury. A recent study by Phelan et al12 evaluated early versus delayed administration of VTE prophylaxis in patients, with a subset of patients with small traumatic brain injuries who had stable head CT scans 24 hours following injury. The authors found that early use of enoxaparin did not place patients at increased risk for intracranial bleeding compared with placebo. A recent study looking at complications associated with anticoagulant administration in orthopaedic trauma patients with diagnosed pulmonary emboli demonstrated a 10% and 6% rate of surgical site and “other” site bleeding, respectively. The authors did identify the various anticoagulants used but did not stratify results between each type. The authors concluded that anticoagulant use in the orthopaedic trauma patient with a diagnosed PE should take into consideration the risk and size of the PE and that further work was needed to refine treatment algorithms.13 Nonpharmacologic interventions include inferior vena cava filters and static compressive or intermittent pneumatic compression devices. Vena cava filters are frequently placed in high-risk patients when pharmacologic prophylaxis is contraindicated. A recent systematic review and metaanalysis by Haut et al14 demonstrated a consistent reduction in PE and fatal PE with inferior vena cava filter placement, without reduction in DVT
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or mortality. Compression stockings and intermittent pneumatic compression devices are most often used in conjunction with pharmacologic prophylaxis. The National Institute for Health and Clinical Excellence guidelines recommend the use of combined mechanical and pharmacologic agents.15 The use of compressive stockings alone has been shown to reduce the risk of DVT compared with no intervention; their addition to pharmacologic prophylaxis resulted in overall lower DVT rates but did not affect the development of PE.5 The duration of prophylaxis in orthopaedic trauma patients is also poorly defined. Sobieraj et al8 compared standard versus prolonged thromboprophylaxis after total knee and hip replacement surgery, as well as hip fracture surgery, in a recent systematic review. Although prolonged therapy was beneficial (ie, reduction in PE and symptomatic VTE) in patients following total hip arthroplasty, data were insufficient to draw the same conclusions in hip fracture patients. Further studies are needed to identify the optimal therapy and duration of prophylaxis in orthopaedic trauma patients with the various treatment options available. Standard pharmacologic interventions include low-dose unfractionated heparin, low-molecularweight heparin (LMWH), such as enoxaparin and dalteparin, as well as aspirin and warfarin. These medications have been well studied, but new drugs are being developed and tested. The ultra-LMWH semuloparin has been recently studied in both joint arthroplasty and hip fracture patients.16 Another recent study assessed the efficacy and risk profile of the factor Xa inhibitor rivaroxaban in patients with hip and lower extremity fractures. The authors found no difference in regard to major bleeding events between patients treated with LMWH and Xa inhibitors, but they
did report statistically lower rates of symptomatic VTE and distal VTE in patients treated with rivaroxaban.17 Unfortunately, the few studies evaluating these more recent medications specifically in orthopaedic trauma or fracture patients are insufficient to draw definite conclusions from; more data are needed to evaluate their efficacy and adverse effect profiles. The ideal prophylactic medication must demonstrate superior efficacy in clot prevention, be easy to administer and reversible, require minimal follow-up, be available at a low cost, and be associated with minimal unwanted events.
Lower Extremity Trauma Nonsurgical VTE can occur following isolated lower extremity injuries, including those treated without surgery. Small clinical series show that the rate of DVT with lower extremity cast and brace immobilization is between zero and 17%; in these series, all diagnoses were made by screening asymptomatic patients.18 A recent Cochrane review demonstrated that outpatient prophylactic LMWH significantly reduced or eliminated the number of VTE which occurred during cast or brace immobilization.18 Significant variation exists in the use of VTE prophylaxis in immobilized patients. In a study by Batra et al,19 62% of physicians reported using no prophylaxis at all and only 41% reported continuing prophylaxis until immobilization was finished.
Surgical Multiple studies have evaluated VTE in patients following lower extremity trauma. Sems et al20 reported a DVT incidence of 2.1% in patients treated with a joint-spanning external fixator who had been placed on LMWH within 24 hours of admission.
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John A. Scolaro, MD, et al
A retrospective review of more than 57,000 ankle fractures treated with surgery revealed a 0.05% readmission rate as a result of DVT; no record of the use or type of DVT prophylaxis was recorded in this study.21 Smith et al22 reported in a prospective study of patients with operative hip and femur fractures that 10% developed a DVT. All patients had been treated initially with pharmacologic prophylaxis. The study also showed that delay in surgical care increased the rate of DVT. Pelvic and acetabular injuries have historically been associated with increased rates of VTE. A large systematic review by Slobogean et al23 on thromboprophylaxis in pelvic and acetabular surgery concluded that strong evidence-based recommendations could not be made based on the available literature. In their review, early administration of LMWH was the only intervention that decreased both DVT and PE. The preference of these authors is to manage patients with an isolated lower extremity injury with both mechanical and pharmacologic prophylaxis while the patients are hospitalized. Continuation of therapy following discharge is based on each patient’s risk factors and degree of mobility.
Upper Extremity Trauma Few prospective studies have evaluated the prevalence of VTE in patients with isolated fractures of the upper limb. Despite limited evidence, the incidence of VTE in patients who have sustained an isolated upper extremity injury is estimated to be 1% to 5%. A recent retrospective study by Hsu et al24 at a level I trauma center showed that the rate of VTE in upper extremity trauma patients was 4.95%, identical to the rate of VTE in all trauma patients in the study. In addition, when upper extremity surgery for acute trauma is compared with elective surgery, no January 2015, Vol 23, No 1
significant increase in VTE rates has been found. These data suggest that not only is the presence of upper extremity trauma not an independent risk factor for VTE, but also that the presence of upper extremity trauma does not necessitate more aggressive anticoagulation, nor does it confer additional risk of VTE beyond those risks stemming from individual patient-related factors. The authors suggest that patients with upper extremity trauma not receive additional VTE prophylaxis unless they have increased risk factors, such as positive history of VTE, a known clotting disorder, concurrent injuries that would otherwise require VTE prophylaxis, or a known catheterrelated upper extremity VTE that may necessitate treatment.
Conclusion Patients who have sustained traumatic orthopaedic injuries are at risk for developing VTE. Prevention of VTE, specifically symptomatic and fatal PE, is a preventable cause of morbidity and mortality. Despite various attempts at early VTE detection and pharmacologic programs, rates of symptomatic and fatal PE remain relatively unchanged. Although administration of pharmacologic prophylaxis has been shown to decrease the development of DVT, there is little consensus on the optimal prophylactic regimen. The American Academy of Orthopaedic Surgeons has provided recommendations for VTE prophylaxis in the orthopaedic patient, but there is limited high-quality evidence available to help formulate these guidelines. We recommend initiation of VTE prophylaxis as early as possible in patients following orthopaedic trauma, with consideration given to the severity of injury, associated nonorthopaedic injuries, and overall risk-benefit assessment. LMWH has been recommended by both the Orthopaedic
Trauma Association and well as the American College of Chest Physicians. The use of mechanical prophylaxis should be used when possible to supplement any regimen. Duration of therapy is based on the severity of the injury as well as the patient’s associated VTE risk factors. Further studies and multicenter trials are needed to help refine these guidelines.
References: Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 6 is a level I study, reference 12 is a level II study, and reference 13 is a level III study. References printed in bold type are those published within the past 5 years. 1. Sagi HC, Ciesla D, Collinge C, et al; Orthopedic Trauma Association Evidence Based Quality Value and Safety Committee: Synopsis of current practice patterns and a suggested evidence-based therapeutic algorithm for venous thromboembolism prophylaxis in orthopaedic trauma patients. J Orthop Trauma, forthcoming. 2. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians: Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141 (2, suppl):e278S-e325S. 3. Jacobs JJ, Mont MA, Bozic KJ, et al: American Academy of Orthopaedic Surgeons clinical practice guideline: Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am 2012;94 (8):746-747. 4. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA: Practice management guidelines for the prevention of venous thromboembolism in trauma patients: The EAST practice management guidelines work group. J Trauma 2002;53(1):142-164. 5. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH: Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev 2013;3: CD008303. 6. Stannard JP, Lopez-Ben RR, Volgas DA, et al: Prophylaxis against deep-vein
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Copyright Ó the American Academy of Orthopaedic Surgeons. Unauthorized reproduction of this article is prohibited.
Venous Thromboembolism in Orthopaedic Trauma thrombosis following trauma: A prospective, randomized comparison of mechanical and pharmacologic prophylaxis. J Bone Joint Surg Am 2006;88 (2):261-266. 7. Schleyer AM, Schreuder AB, Jarman KM, Logerfo JP, Goss JR: Adherence to guideline-directed venous thromboembolism prophylaxis among medical and surgical inpatients at 33 academic medical centers in the United States. Am J Med Qual 2011;26(3): 174-180. 8. Sobieraj DM, Coleman CI, Tongbram V, et al: Venous Thromboembolism Prophylaxis in Orthopedic Surgery. Rockville, MD: Agency for Healthcare Research and Quality, 2012. http://www. ncbi.nlm.nih.gov/pubmedhealth/ PMH0041828. Accessed October 29, 2014. 9. Park MS, Owen BA, Ballinger BA, et al: Quantification of hypercoagulable state after blunt trauma: Microparticle and thrombin generation are increased relative to injury severity, while standard markers are not. Surgery 2012;151(6):831-836. http://dx. doi.org/10.1016/j.surg.2011.12.022 10. Young MD, Daniels AH, Evangelista PT, et al: Predicting pulmonary embolus in orthopedic trauma patients using the Wells score. Orthopedics 2013;36(5): e642-e647. 11. Moed BR, Miller JR, Tabaie SA: Sequential duplex ultrasound screening for proximal deep venous thrombosis in asymptomatic patients with acetabular and pelvic fractures treated operatively. J Trauma Acute Care Surg 2012;72(2): 443-447.
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12. Phelan HA, Wolf SE, Norwood SH, et al: A randomized, double-blinded, placebocontrolled pilot trial of anticoagulation in low-risk traumatic brain injury: The Delayed Versus Early Enoxaparin Prophylaxis I (DEEP I) study. J Trauma Acute Care Surg 2012;73(6):1434-1441. 13. Bogdan Y, Tornetta P III, Leighton R, et al: Treatment and complications in orthopaedic trauma patients with symptomatic pulmonary embolism. J Orthop Trauma 2014;28(suppl 1):S6-S9. 14. Haut ER, Garcia LJ, Shihab HM, et al: The effectiveness of prophylactic inferior vena cava filters in trauma patients: A systematic review and meta-analysis. JAMA Surg 2014;149(2):194-202. 15. National Institute for Health and Care Excellence: Venous thromboembolism: Reducing the risk. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital. National Institute for Health and Care Excellence, London, UK, 2010. http://www.nice.org. uk/CG92. Accessed October 29, 2014. 16. Lassen MR, Fisher W, Mouret P, et al; SAVE Investigators: Semuloparin for prevention of venous thromboembolism after major orthopedic surgery: Results from three randomized clinical trials, SAVE-HIP1, SAVE-HIP2 and SAVEKNEE. J Thromb Haemost 2012;10(5): 822-832. 17. Long A, Zhang L, Zhang Y, et al: Efficacy and safety of rivaroxaban versus low-molecular-weight heparin therapy in patients with lower limb fractures. J Thromb Thrombolysis 2014;38(3): 299-305.
18. Testroote M, Stigter W, de Visser DC, Janzing H: Low molecular weight heparin for prevention of venous thromboembolism in patients with lower-leg immobilization. Cochrane Database Syst Rev 2008;4: CD006681. 19. Batra S, Kurup H, Gul A, Andrew JG: Thromboprophylaxis following cast immobilisation for lower limb injuries: Survey of current practice in United Kingdom. Injury 2006;37(9):813-817. 20. Sems SA, Levy BA, Dajani K, Herrera DA, Templeman DC: Incidence of deep venous thrombosis after temporary joint spanning external fixation for complex lower extremity injuries. J Trauma 2009;66(4): 1164-1166. 21.
SooHoo NF, Eagan M, Krenek L, Zingmond DS: Incidence and factors predicting pulmonary embolism and deep venous thrombosis following surgical treatment of ankle fractures. Foot Ankle Surg 2011;17(4):259-262.
22.
Smith EB, Parvizi J, Purtill JJ: Delayed surgery for patients with femur and hip fractures-risk of deep venous thrombosis. J Trauma 2011;70(6):E113-E116.
23. Slobogean GP, Lefaivre KA, Nicolaou S, O’Brien PJ: A systematic review of thromboprophylaxis for pelvic and acetabular fractures. J Orthop Trauma 2009;23(5):379-384. 24.
Hsu JE, Namdari S, Baldwin KD, Esterhai JL, Mehta S: Is upper extremity trauma an independent risk factor for lower extremity venous thromboembolism? An 11-year experience at a level I trauma center. Arch Orthop Trauma Surg 2011; 131(1):27-32.
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Venous Thromboembolism in Orthopaedic Trauma Abstract John A. Scolaro, MD Ryan Metri Taylor, MD Nathan A. Wigner, MD, PhD
Patients who sustain orthopaedic trauma are at risk for developing deep venous thrombosis and symptomatic pulmonary emboli. The prevention of venous thromboembolism has moved to the forefront of patient safety initiatives, resulting in the formation of various guidelines to assist the practitioner. Recommendations for venous thromboembolism prophylaxis in the orthopaedic trauma patient exist, but there is insufficient evidence in the literature to make strong recommendations regarding type and duration of prophylaxis. The associated morbidity of chemical anticoagulants used in the orthopaedic trauma patient must also be taken into consideration, specifically the increased risk of bleeding. Mechanical prophylaxis is used in place of, or in addition to, these medications in certain situations. New, potentially superior anticoagulants have been developed but are still understudied. Larger studies are needed to further define the type and duration of deep venous thrombosis prophylaxis in the orthopaedic trauma patient.
V From the University of California, Irvine, Orange, CA (Dr. Scolaro) and the University of Pennsylvania, Philadelphia, PA (Dr. Taylor and Dr. Wigner). None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Scolaro, Dr. Taylor, and Dr. Wigner. J Am Acad Orthop Surg 2015;23:1-6 http://dx.doi.org/10.5435/ JAAOS-23-01-1 Copyright 2014 by the American Academy of Orthopaedic Surgeons.
January 2015, Vol 23, No 1
enous thromboembolism (VTE) can result in significant morbidity and mortality. Despite identification by healthcare initiatives as a preventable clinical event, data indicate that neither increased awareness nor more recent prophylactic regimens have resulted in a significant change to the overall incidence and mortality from VTE. Deep vein thrombosis (DVT) accounts for most thrombotic events, but prevention of clinically significant pulmonary embolus (PE) is the primary goal of prophylaxis. Various recommendations have been generated to help guide VTE prophylaxis in the orthopaedic patient1-5 (Table 1). Unfortunately, little high-level evidence is available on the topic, especially with regard to the orthopaedic trauma patient. In addition, there is little evidence to help practitioners decide which orthopaedic trauma patients require prophylaxis and the duration of treatment. Initiation of
pharmacologic prophylaxis in the trauma patient must also balance the benefits of therapy with the risk of bleeding. The advent of more recent anticoagulants has increased the pharmacologic options available to the orthopaedic surgeon, but their comparative efficacy has been incompletely evaluated.
Incidence The incidence of DVT in trauma patients without prophylaxis is cited to be as high as 80%. Stannard et al6 reported that initiation of chemical prophylaxis in orthopaedic trauma patients reduced the overall rate of DVT to 11% and of nonfatal PE to 1%. The reported incidence of DVT varies with method of detection, mode of prophylaxis, location of thrombus, and sample size, thus resulting in a wide range of numbers in the
1
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Venous Thromboembolism in Orthopaedic Trauma
Table 1 Current Guidelines for Venous Thromboembolism Prophylaxis in Orthopaedics Source Orthopaedic Trauma Association1,a
American College of Chest Physicians2,b
American Academy of Orthopaedic Surgeons3,c
Eastern Association for the Surgery of Trauma4,d
Cochrane Review5
Guidelines Major orthopaedic surgery LMWH is considered the agent of choice and should be initiated within 24 hr provided there are no contraindications (Strong) Combined LMWH and calf pneumatic compressive devices over either regimen alone (Strong) Continuation of VTE prophylaxis for at least 1 mo after discharge (Limited) Recommend against routine screening protocols for DVT in asymptomatic trauma patients (Strong) Isolated lower extremity injury Do not recommend routine chemical prophylaxis in patients who do not have additional risk factors and are independently mobile (Moderate) Recommend against routine screening protocols for DVT in asymptomatic trauma patients (Strong) Major orthopaedic surgery Extend outpatient prophylaxis for up to 35 d postop (2B) Dual prophylaxis with pharmacologic agent and IPCD while inpatient (2C) Recommend against screening Doppler ultrasonography before discharge (1B) Hip fracture surgery Prophylaxis for a minimum of 10-14 d (1B) Start LMWH either 12 h or more preop or 12 h or more postop (1B) Recommend use of LMWH, fondaparinux, LDUH, adjusted-dose aspirin (1B) or IPCD (1C) LMWH is preferred to other agents (2B/2C) Isolated lower extremity injury No prophylaxis in patients who require leg immobilization (2C) Elective total joint arthroplasty Pharmacologic agents and/or mechanical compressive devices for VTE prevention for those who are not at elevated risk (Moderate) No specific agent recommended (Inconclusive) Patients and physicians discuss duration of treatment (Consensus) Recommend against routine duplex ultrasonography screening postoperatively (Strong) LDH has little proven efficacy in prevention of VTE as sole agent in high-risk trauma patients (Level II) IPCD may have some benefit in isolated studies (Level III) LMWH can be used in trauma patients with pelvic fractures, complex lower extremity fractures, and spinal cord injury when bleeding risk is acceptable (Level II) IVCF should be considered in very high-risk trauma patients who cannot receive pharmacologic prophylaxis or have an injury pattern that would leave them immobilized for long periods of time (Level III) Duplex ultrasonography may be used to diagnose symptomatic patients with suspected DVT without venography (Level I) No evidence that prophylaxis reduces mortality or secondary outcome of pulmonary embolus Pharmacologic prophylaxis is more effective than mechanical prophylaxis LMWH is more effective than UH Insufficient studies for comparison between pharmacologic agents vs placebo or pharmacologic prophylaxis vs mechanical prophylaxis
DVT = deep vein thrombosis, IPCD = intermittent pneumatic compression devices, IVCF = inferior vena cava filter, LDH = low-dose heparin, LDUH = low-dose unfractionated heparin, LMWH = low-molecular-weight heparin, UH = unfractionated heparin, VTE = venous thromboembolism a OTA recommendation strengths: Strong = greater than two high-quality (level I) studies to support the recommendation; Moderate: one high-quality (level I) or two moderate-quality (level II or III) studies to support the recommendation; Limited = one moderate-quality (level II or III) or two low-quality (level IV) studies to support the recommendation; Inconclusive = one low-quality (level IV) study or lack of evidence to support the recommendation; Consensus = expert work-group opinion (no studies) b American College of Chest Physicians recommendation strengths: 1B = strong recommendation, moderate-quality evidence, benefits clearly outweigh risk and burdens or vice versa; 1C = strong recommendation, low-quality or very low–quality evidence, benefits clearly outweigh risks and burdens or vice versa; 2B = weak recommendation, moderate-quality evidence, benefits closely balanced with risks and burdens; 2C = weak
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John A. Scolaro, MD, et al
literature. Interestingly, evidence of peripheral DVT by venous ultrasonography or postmortem analysis is not always present in those who develop a symptomatic PE. Although it has been thought that all PEs are the result of distal thrombi that travel proximally, the findings of Stannard et al6 question this relationship. The use of pharmacologic prophylaxis has been shown to significantly lower the rate of DVT formation, but PE-related morbidity and mortality remain high, indicating an important clinical disparity. The development of VTE is not unique to any specific patient type or injury pattern. No one prophylactic protocol has been found to demonstrate superior results with regard to the reduction of both DVT and PE in hospitalized patients. Unfortunately, evidence has shown that even across surgical intensive care units at major academic medical institutions in the United States, adherence to VTE prophylaxis guidelines is poor.7 As such, the Agency for Healthcare Research and Quality now ranks VTE prophylaxis as among the most important interventions to improve patient safety.8 Despite all the attention given to preventing VTE in hospitalized trauma patients, however, there is little in the way of strong evidencebased recommendations to guide the orthopaedic surgeon.
Pathophysiology and Risk Factors Virchow’s triad of venous stasis, endothelial injury, and hypercoagu-
lability is traditionally considered the harbinger of thrombus formation. Major trauma is believed to lead to one, if not all three, risk factors. Specific risk factors, including but not limited to spinal cord injury, pelvic fractures, lower extremity fractures, high injury severity, and longer ventilation times, place these patients at increased risk for symptomatic VTE. Recent studies have explored the effects of circulating procoagulant and thrombogenic microparticles, as well as a decrease in antithrombin III levels, on thrombus formation in an effort to better understand the pathophysiology behind clot formation and embolization.9 Basic science investigators will continue to explore the potential modifiable factors involved in both in vitro and in vivo clot formation.
Diagnosis The diagnosis of VTE remains a challenge. Clot formation is often a clinically silent or subtle event. The Wells criteria have been used to determine the pre-test probability of PE before diagnostic testing is performed. The scoring system was first reported in nontrauma patients and has not been validated outside this population. Young et al10 recently evaluated alternative and standard interpretations of the Wells criteria in a large number of orthopaedic trauma patients and found no predictive relationship between the test scores and the development of PE. Routine venous ultrasonography has been used in an effort to capture
early peripheral DVT. A positive result obtained from a screening study performed in an asymptomatic person places the practitioner in a position to decide whether therapeutic anticoagulation is required. Although therapeutic anticoagulation may prevent progression of thrombotic disease, the physician and patient assume the responsibility of increased medical costs and the risk of bleeding. Recent literature has shown that sequential duplex ultrasonography screening does not decrease the rates of PE in orthopaedic trauma patients. 11 In fact, recent recommendations from both the American Academy of Orthopaedic Surgeons and Orthopaedic Trauma Association recommend against the use of duplex ultrasonography to screen asymptomatic orthopaedic joint arthroplasty and trauma patients, respectively, for peripheral VTE.1,3 Use of duplex ultrasonography is therefore recommended when the physician identifies patient or injury-related risk factors or specific clinical signs or symptoms of VTE. CT pulmonary angiography is used as a definitive diagnostic tool when PE is suspected; it has no role as a screening tool. The examination is expensive and requires the use of potentially nephrotoxic intravenous contrast material. The study has the ability to locate and characterize clots but cannot determine or predict their clinical significance. For this reason, injudicious use can result in unnecessary cost, morbidity, and use of pharmacologic anticoagulation.
recommendation, low-quality or very low–quality evidence, uncertainty in the estimates of benefits, risks, and burdens; benefits, risk, and burden may be closely balanced c American Academy of Orthopaedic Surgeons recommendation strengths: Consensus = expert opinion supports the guideline even though there is no available empirical evidence that meets the inclusion criteria of the guideline’s systematic review; Strong = benefits of the recommended approach clearly exceed the potential harm and the quality of supporting evidence is high; Moderate = the benefits exceed the potential harm but the quality/ applicability of the supporting evidence is not strong; Inconclusive = lack of compelling evidence that has resulted in an unclear balance between benefits and potential harm d Eastern Association for the Surgery of Trauma recommendation strengths: Level I recommendation = convincingly justifiable on the basis of scientific information alone through class I data; Level II recommendation = reasonably justifiable on the basis of a preponderance of class II data; Level III recommendation = supported only by class III data; Class I data = prospective randomized controlled trial; Class II data = clinical study with prospectively collected data or large retrospective analyses with reliable data; Class III data = retrospective data, expert opinion, or a case report
January 2015, Vol 23, No 1
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Venous Thromboembolism in Orthopaedic Trauma
Prophylaxis A recent systematic review demonstrated that both pharmacologic and mechanical prophylaxis reduces the risk of DVT in trauma patients.5 The decision to begin pharmacologic prophylaxis must frequently balance the benefits of early therapy with the concern for complications related to bleeding, specifically in the setting of concurrent solid organ, intracranial, or spinal injury. A recent study by Phelan et al12 evaluated early versus delayed administration of VTE prophylaxis in patients, with a subset of patients with small traumatic brain injuries who had stable head CT scans 24 hours following injury. The authors found that early use of enoxaparin did not place patients at increased risk for intracranial bleeding compared with placebo. A recent study looking at complications associated with anticoagulant administration in orthopaedic trauma patients with diagnosed pulmonary emboli demonstrated a 10% and 6% rate of surgical site and “other” site bleeding, respectively. The authors did identify the various anticoagulants used but did not stratify results between each type. The authors concluded that anticoagulant use in the orthopaedic trauma patient with a diagnosed PE should take into consideration the risk and size of the PE and that further work was needed to refine treatment algorithms.13 Nonpharmacologic interventions include inferior vena cava filters and static compressive or intermittent pneumatic compression devices. Vena cava filters are frequently placed in high-risk patients when pharmacologic prophylaxis is contraindicated. A recent systematic review and metaanalysis by Haut et al14 demonstrated a consistent reduction in PE and fatal PE with inferior vena cava filter placement, without reduction in DVT
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or mortality. Compression stockings and intermittent pneumatic compression devices are most often used in conjunction with pharmacologic prophylaxis. The National Institute for Health and Clinical Excellence guidelines recommend the use of combined mechanical and pharmacologic agents.15 The use of compressive stockings alone has been shown to reduce the risk of DVT compared with no intervention; their addition to pharmacologic prophylaxis resulted in overall lower DVT rates but did not affect the development of PE.5 The duration of prophylaxis in orthopaedic trauma patients is also poorly defined. Sobieraj et al8 compared standard versus prolonged thromboprophylaxis after total knee and hip replacement surgery, as well as hip fracture surgery, in a recent systematic review. Although prolonged therapy was beneficial (ie, reduction in PE and symptomatic VTE) in patients following total hip arthroplasty, data were insufficient to draw the same conclusions in hip fracture patients. Further studies are needed to identify the optimal therapy and duration of prophylaxis in orthopaedic trauma patients with the various treatment options available. Standard pharmacologic interventions include low-dose unfractionated heparin, low-molecularweight heparin (LMWH), such as enoxaparin and dalteparin, as well as aspirin and warfarin. These medications have been well studied, but new drugs are being developed and tested. The ultra-LMWH semuloparin has been recently studied in both joint arthroplasty and hip fracture patients.16 Another recent study assessed the efficacy and risk profile of the factor Xa inhibitor rivaroxaban in patients with hip and lower extremity fractures. The authors found no difference in regard to major bleeding events between patients treated with LMWH and Xa inhibitors, but they
did report statistically lower rates of symptomatic VTE and distal VTE in patients treated with rivaroxaban.17 Unfortunately, the few studies evaluating these more recent medications specifically in orthopaedic trauma or fracture patients are insufficient to draw definite conclusions from; more data are needed to evaluate their efficacy and adverse effect profiles. The ideal prophylactic medication must demonstrate superior efficacy in clot prevention, be easy to administer and reversible, require minimal follow-up, be available at a low cost, and be associated with minimal unwanted events.
Lower Extremity Trauma Nonsurgical VTE can occur following isolated lower extremity injuries, including those treated without surgery. Small clinical series show that the rate of DVT with lower extremity cast and brace immobilization is between zero and 17%; in these series, all diagnoses were made by screening asymptomatic patients.18 A recent Cochrane review demonstrated that outpatient prophylactic LMWH significantly reduced or eliminated the number of VTE which occurred during cast or brace immobilization.18 Significant variation exists in the use of VTE prophylaxis in immobilized patients. In a study by Batra et al,19 62% of physicians reported using no prophylaxis at all and only 41% reported continuing prophylaxis until immobilization was finished.
Surgical Multiple studies have evaluated VTE in patients following lower extremity trauma. Sems et al20 reported a DVT incidence of 2.1% in patients treated with a joint-spanning external fixator who had been placed on LMWH within 24 hours of admission.
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John A. Scolaro, MD, et al
A retrospective review of more than 57,000 ankle fractures treated with surgery revealed a 0.05% readmission rate as a result of DVT; no record of the use or type of DVT prophylaxis was recorded in this study.21 Smith et al22 reported in a prospective study of patients with operative hip and femur fractures that 10% developed a DVT. All patients had been treated initially with pharmacologic prophylaxis. The study also showed that delay in surgical care increased the rate of DVT. Pelvic and acetabular injuries have historically been associated with increased rates of VTE. A large systematic review by Slobogean et al23 on thromboprophylaxis in pelvic and acetabular surgery concluded that strong evidence-based recommendations could not be made based on the available literature. In their review, early administration of LMWH was the only intervention that decreased both DVT and PE. The preference of these authors is to manage patients with an isolated lower extremity injury with both mechanical and pharmacologic prophylaxis while the patients are hospitalized. Continuation of therapy following discharge is based on each patient’s risk factors and degree of mobility.
Upper Extremity Trauma Few prospective studies have evaluated the prevalence of VTE in patients with isolated fractures of the upper limb. Despite limited evidence, the incidence of VTE in patients who have sustained an isolated upper extremity injury is estimated to be 1% to 5%. A recent retrospective study by Hsu et al24 at a level I trauma center showed that the rate of VTE in upper extremity trauma patients was 4.95%, identical to the rate of VTE in all trauma patients in the study. In addition, when upper extremity surgery for acute trauma is compared with elective surgery, no January 2015, Vol 23, No 1
significant increase in VTE rates has been found. These data suggest that not only is the presence of upper extremity trauma not an independent risk factor for VTE, but also that the presence of upper extremity trauma does not necessitate more aggressive anticoagulation, nor does it confer additional risk of VTE beyond those risks stemming from individual patient-related factors. The authors suggest that patients with upper extremity trauma not receive additional VTE prophylaxis unless they have increased risk factors, such as positive history of VTE, a known clotting disorder, concurrent injuries that would otherwise require VTE prophylaxis, or a known catheterrelated upper extremity VTE that may necessitate treatment.
Conclusion Patients who have sustained traumatic orthopaedic injuries are at risk for developing VTE. Prevention of VTE, specifically symptomatic and fatal PE, is a preventable cause of morbidity and mortality. Despite various attempts at early VTE detection and pharmacologic programs, rates of symptomatic and fatal PE remain relatively unchanged. Although administration of pharmacologic prophylaxis has been shown to decrease the development of DVT, there is little consensus on the optimal prophylactic regimen. The American Academy of Orthopaedic Surgeons has provided recommendations for VTE prophylaxis in the orthopaedic patient, but there is limited high-quality evidence available to help formulate these guidelines. We recommend initiation of VTE prophylaxis as early as possible in patients following orthopaedic trauma, with consideration given to the severity of injury, associated nonorthopaedic injuries, and overall risk-benefit assessment. LMWH has been recommended by both the Orthopaedic
Trauma Association and well as the American College of Chest Physicians. The use of mechanical prophylaxis should be used when possible to supplement any regimen. Duration of therapy is based on the severity of the injury as well as the patient’s associated VTE risk factors. Further studies and multicenter trials are needed to help refine these guidelines.
References: Evidence-based Medicine: Levels of evidence are described in the table of contents. In this article, reference 6 is a level I study, reference 12 is a level II study, and reference 13 is a level III study. References printed in bold type are those published within the past 5 years. 1. Sagi HC, Ciesla D, Collinge C, et al; Orthopedic Trauma Association Evidence Based Quality Value and Safety Committee: Synopsis of current practice patterns and a suggested evidence-based therapeutic algorithm for venous thromboembolism prophylaxis in orthopaedic trauma patients. J Orthop Trauma, forthcoming. 2. Falck-Ytter Y, Francis CW, Johanson NA, et al; American College of Chest Physicians: Prevention of VTE in orthopedic surgery patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141 (2, suppl):e278S-e325S. 3. Jacobs JJ, Mont MA, Bozic KJ, et al: American Academy of Orthopaedic Surgeons clinical practice guideline: Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am 2012;94 (8):746-747. 4. Rogers FB, Cipolle MD, Velmahos G, Rozycki G, Luchette FA: Practice management guidelines for the prevention of venous thromboembolism in trauma patients: The EAST practice management guidelines work group. J Trauma 2002;53(1):142-164. 5. Barrera LM, Perel P, Ker K, Cirocchi R, Farinella E, Morales Uribe CH: Thromboprophylaxis for trauma patients. Cochrane Database Syst Rev 2013;3: CD008303. 6. Stannard JP, Lopez-Ben RR, Volgas DA, et al: Prophylaxis against deep-vein
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Venous Thromboembolism in Orthopaedic Trauma thrombosis following trauma: A prospective, randomized comparison of mechanical and pharmacologic prophylaxis. J Bone Joint Surg Am 2006;88 (2):261-266. 7. Schleyer AM, Schreuder AB, Jarman KM, Logerfo JP, Goss JR: Adherence to guideline-directed venous thromboembolism prophylaxis among medical and surgical inpatients at 33 academic medical centers in the United States. Am J Med Qual 2011;26(3): 174-180. 8. Sobieraj DM, Coleman CI, Tongbram V, et al: Venous Thromboembolism Prophylaxis in Orthopedic Surgery. Rockville, MD: Agency for Healthcare Research and Quality, 2012. http://www. ncbi.nlm.nih.gov/pubmedhealth/ PMH0041828. Accessed October 29, 2014. 9. Park MS, Owen BA, Ballinger BA, et al: Quantification of hypercoagulable state after blunt trauma: Microparticle and thrombin generation are increased relative to injury severity, while standard markers are not. Surgery 2012;151(6):831-836. http://dx. doi.org/10.1016/j.surg.2011.12.022 10. Young MD, Daniels AH, Evangelista PT, et al: Predicting pulmonary embolus in orthopedic trauma patients using the Wells score. Orthopedics 2013;36(5): e642-e647. 11. Moed BR, Miller JR, Tabaie SA: Sequential duplex ultrasound screening for proximal deep venous thrombosis in asymptomatic patients with acetabular and pelvic fractures treated operatively. J Trauma Acute Care Surg 2012;72(2): 443-447.
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