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Sobieraj DM, Coleman CI, Tongbram V, et al. Venous Thromboembolism Prophylaxis in Orthopedic Surgery [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012 Mar. (Comparative Effectiveness Reviews, No. 49.)

Cover of Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Venous Thromboembolism Prophylaxis in Orthopedic Surgery [Internet].

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Introduction

Background

Major orthopedic surgery (total hip replacement, total knee replacement or hip fracture surgery) carries a high risk of venous thromboembolism. Pulmonary embolism following orthopedic surgery is reported to be rare.1 However, without prophylaxis, historical data suggest that hospital acquired deep venous thrombosis has been estimated to occur in 40 to 60 percent of cases in the 7 to 14 days following surgery compared with 10 to 40 percent among medical or general surgical patients.2 While asymptomatic deep vein thrombosis is identified more frequently than symptomatic deep vein thrombosis in clinical trials due to routine screening, there is disagreement as to the clinical relevance of asymptomatic cases.3,4 While certain patient characteristics (i.e. age, immobility, comorbidities) have been suggested to increase the risk of venous thromboembolism regardless of the clinical setting, major orthopedic surgery contributes additional factors such as use of general anesthesia which may prolong immobility and surgical involvement of the femoral vein.5,6

A variety of strategies to prevent venous thromboembolism are available and with routine use, the rate of symptomatic venous thromboembolism in patients within 3 months of surgery is 1.3 to 10 percent.2 The main limitation of pharmacologic venous thromboembolism prophylaxis is the risk of bleeding. Based on historical data major bleeding following total hip replacement and total knee replacement is estimated to be 1 to 3 percent.1 Determining the incidence of major bleeding with pharmacologic thromboprophylaxis is complicated by the variability in the definitions used in published literature and paucity of data in control patients. Additionally, complications such as postoperative bleeding and hematoma formation are considered risk factors for the development of early onset prosthetic joint infections.7,8 Reoperation is frequently required for debridement with or without removal of the infected prosthesis. Following removal of an infected prosthesis and extended intravenous antibiotic treatment further surgery may be required to either implant a new prosthesis or perform an arthrodesis of the joint.

There are many unknowns that need to be explored in a comparative effectiveness review. In contemporary practice, the risk of venous thromboembolism, pulmonary embolism, and deep vein thrombosis, and the causal link between deep vein thrombosis and pulmonary embolism has not been well established. Previous observations of the incidence of pulmonary embolism in patients who have undergone orthopedic surgery with confirmed deep vein thrombosis suggests that pulmonary embolism and deep vein thrombosis are related disorders.9 However, whether the presence of deep vein thrombosis affects the risk of pulmonary embolism and to what degree if so remains unclear in the literature.3,4 Widespread use of anticoagulants to treat venous thrombomebolism for many decades along with the evolution of diagnostic strategies have limited the availability of literature regarding the natural history of venous thromboembolism.10 In addition to major orthopedic surgery, there are a variety of other orthopedic surgeries in which the impact of venous thromboembolic prophylaxis has not been well evaluated. These orthopedic surgeries of interest include knee athroscopy, surgical repair of lower extremity injuries distal to the hip, and elective spine surgery. While prophylactic strategies may decrease the risk of venous thromboembolism, pulmonary embolism, and deep vein thrombosis, the magnitude of benefit in contemporary practice using rigorous definitions of endpoints and the impact of duration of prophylaxis on outcomes is not well delineated. Whether dual prophylactic strategies are superior to a single modality is not well defined. In addition, in order to determine comparative effectiveness, both the benefits and harms need to be appreciated. Finally, several previous meta-analyses and guidelines allowed the use of medications or devices that are not available for use in the United States reducing their applicability.

Objective

To perform a comparative effectiveness review examining the benefits and harms associated with venous thromboembolism prophylaxis in patients undergoing major orthopedic surgery, knee arthroscopy, or other orthopedic surgeries including surgical repair of a lower extremity injury distal to the hip and elective spine surgery. The analytic framework is presented in Figure 1.

Key Questions

Key Question 1. In patients undergoing major orthopedic surgery (total hip or knee replacement or hip fracture surgery) what is the baseline postoperative risk of venous thromboembolism and bleeding outcomes in contemporary practice?

Key Question 2. In patients undergoing major orthopedic surgery (total hip or knee replacement or hip fracture surgery) what patient, surgical or postsurgical characteristics predict or differentiate patient risk of venous thromboembolism and bleeding outcomes in contemporary practice?

Key Question 3. In patients undergoing major orthopedic surgery (total hip or knee replacement or hip fracture surgery), in the absence of final health outcomes, can the risk for such outcomes reliably be estimated by measuring surrogate outcomes, such as deep vein thrombosis (asymptomatic or symptomatic, proximal or distal) as detected by venography or ultrasound?

Key Question 4. In patients who had major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the relative impact of thromboprophylaxis compared with no thromboprophylaxis on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism-related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation? Thromboprophylaxis includes any pharmacologic agent within the defined classes (oral antiplatelet agents, injectable low molecular weight heparins, injectable unfractionated heparin, injectable or oral factor Xa inhibitors, injectable or oral direct thrombin inhibitors, oral vitamin K antagonists) or any external mechanical intervention within the defined classes (graduated compression stockings, intermittent pneumatic compression devices, or venous foot pumps)]?

Key Question 5. In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy between classes of agents on outcomes: symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism, pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation? Classes include oral antiplatelet agents, injectable low molecular weight heparins, injectable unfractionated heparin, injectable or oral factor Xa inhibitors, injectable or oral direct thrombin inhibitors, oral vitamin K antagonists, and mechanical interventions.

Key Question 6. In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy of individual agents within classes (injectable low molecular weight heparin or mechanical) on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation?

Key Question 7. In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what are the effect estimates of combined pharmacologic and mechanical modalities versus single modality on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation?

Key Question 8. In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), regardless of thromboprophylaxis method, what are the effects of prolonging thromboprophylaxis for 28 days or longer compared with thromboprophylaxis for 7 to 10 days on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation?

Key Question 9. In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery) who have known contraindications to antithrombotic agents, what is the relative impact of prophylactic inferior vena cava filter placement compared with any external mechanical intervention on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, reoperation or IVC filter placement-associated insertion site thrombosis?

Key Question 10. In patients requiring knee arthroscopy, surgical repair of a lower extremity injury distal to the hip, or elective spine surgery what is the relative impact of thromboprophylaxis (any agent, any mechanical intervention) compared with no thromboprophylaxis intervention on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation?

Key Question 11. In patients requiring knee arthroscopy, surgical repair of a lower extremity injury distal to the hip, or elective spine surgery what is the relative impact of injectable antithrombotic agents (low molecular weight heparin agents, injectable unfractionated heparin, injectable factor Xa inhibitors, injectable direct thrombin inhibitors) compared with mechanical interventions on symptomatic objectively confirmed venous thromboembolism, major venous thromboembolism (proximal deep vein thrombosis, pulmonary embolism or venous thromboembolism related mortality), pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, post thrombotic syndrome, mortality, mortality due to bleeding, deep vein thrombosis (asymptomatic or symptomatic, proximal or distal deep vein thrombosis), asymptomatic deep vein thrombosis, symptomatic deep vein thrombosis, proximal deep thrombosis, distal deep vein thrombosis, major bleeding, major bleeding leading to reoperation, minor bleeding, surgical site bleeding, bleeding leading to infection, bleeding leading to transfusion, heparin-induced thrombocytopenia, discomfort, readmission, and reoperation?

Analytic Framework

To guide our assessment of trials and studies examining the association between using prophylaxis to prevent venous thromboembolism in patients undergoing orthopedic surgery and various benefits and harms, we developed an analytic framework mapping specific linkages from comparisons to subpopulations of interest, mechanisms of benefit, and outcomes of interest. The analytic framework is a logic chain that supports the link from the intervention to the outcomes of interest. The population includes patients undergoing major orthopedic surgery, knee arthroscopy, surgical repair of a lower extremity injury distal to the hip, or elective spine surgery. The interventions of interest are pharmacologic and mechanical methods of thromboprophyalxis compared to no thromboprophyalxis, a combination of pharmacologic and mechanical methods compared to single modality of prophylaxis, individual methods of prophylaxis to each other, and longer versus shorted duration of prophylaxis. The outcomes are separated into harms, intermediate health outcomes and final health outcomes. The harms of interest include bleeding (major, major leading to reoperation, minor, bleeding leading to infection, bleeding leading to transfusion), heparin-induced thrombocytopenia, discomfort, readmission, reoperation, and insertion site thrombosis. The intermediate outcome of interest includes deep vein thrombosis (asymptomatic or symptomatic, proximal or distal). The final health outcomes of interest include symptomatic venous thromboembolism, major venous thromboembolism, pulmonary embolism, fatal pulmonary embolism, nonfatal pulmonary embolism, mortality, mortality due to bleeding, and post-thrombotic syndrome

Figure 1Analytic framework for the comparative effectiveness of venous thromboembolism prophylaxis in orthopedic surgery

DVT = deep vein thrombosis; HIT = heparin induced thrombocytopenia; PE = pulmonary embolism; PTS = post thrombotic syndrome; VTE = venous thromboembolism

* Mortality is all-cause mortality.

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