Background

Major orthopedic surgery carries a high risk for venous thromboembolism (VTE)—deep vein thrombosis (DVT) and pulmonary embolism (PE).¹ The major orthopedic surgeries of greatest concern include total knee replacement (TKR), total hip replacement (THR), and hip fracture (HFx) surgeries. PE, an obstruction of a pulmonary artery or its branches usually by an embolic thrombus, is potentially life-threatening and can result in chronic complications with generally poor prognosis, such as thromboembolic pulmonary hypertension.^2–4 DVTs are the principal intermediate process necessary for surgery-related PE and increase the risk of PE.⁵ In addition, about 5 to 10 percent of patients with symptomatic DVTs develop severe postthrombotic syndrome, which may include venous ulcers, intractable edema, and chronic pain; although, these outcomes may take 10 years or more to develop.⁶ Estimates suggest that in the contemporary era about 4.7 percent of patients undergoing major orthopedic surgery would have symptomatic VTE without prophylaxis.¹ Although, the rate of postoperative VTE is decreasing over time, likely due in part to a combination of more universal thromboprophylaxis and increasing use of early mobilization and decreased used of postoperative narcotics.

A variety of strategies to prevent VTE are available, including pharmacological (antiplatelet, anticoagulant) and mechanical devices.¹ Pharmacologic prophylactic treatments include unfractionated heparin (UFH), low molecular weight heparin (LMWH), vitamin K antagonists (VKA), antithrombin III-mediated selective factor Xa inhibitors, direct factor Xa inhibitors (FXaI), bivalent and univalent direct thrombin inhibitors (DTI), and antiplatelet agents (such as aspirin). Mechanical prophylaxis aims to minimize stasis, the principal putative factor resulting in venous thrombosis; it may also stimulate fibrinolysis, another mechanism to limit thrombosis. It can be dynamic and intermittent (e.g., intermittent pneumatic compression device [IPC]) or static (e.g., graduated compression stockings [GCS]). The modalities can be used alone or in combination, at variable doses (of drugs) or regimens (of mechanical devices; e.g., different pressure or compression frequency), and for different durations. However, prophylaxis with pharmacologic strategies also has important potential harms (risks) including major bleeding, prosthetic joint infections, and the need for reoperation, all of which may lead to major morbidities, death, permanent removal of the prosthetic joint, and increased hospital length of stay and costs.⁷ Postoperative bleeding and hematoma formation are considered direct risk factors for the development of prosthetic joint infections.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. Mechanical devices (when used alone), however, are thought to be inferior to pharmacological agents to prevent VTE.

VTE prophylaxis (or “thromboprophylaxis”) is now standard of care for patients undergoing lower extremity major orthopedic surgery. Prophylaxis has been demonstrated to reduce the incidence of symptomatic and asymptomatic DVT (in comparison to placebo or no prophylaxis); however, because of rarity of postoperative PE,¹ the body of randomized controlled trial (RCT) evidence is not adequately powered to demonstrate the effect of prophylaxis on PE. The effect of prophylaxis on DVT risk reduction is generally considered an adequate proxy for likely PE risk reduction, but it remains unknown to what extent reducing the incidence of DVTs impacts the magnitude of any reduction in the incidence of PEs. This is particularly true for “total” DVT, which includes both symptomatic and asymptomatic, and both distal and proximal, DVTs. Asymptomatic DVTs can be found only with diagnostic testing, which is done routinely only in the research study setting. The link between distal or asymptomatic DVTs and PEs is unclear. Nevertheless, avoiding DVT is a clinically worthwhile goal to reduce the incidence of lower extremity venous disease,⁹ such as postphlebitic syndrome, venous insufficiency,^{10, 11} and phlegmasia cerulean dolens (resulting in edema, pain, and gangrene).¹²

Scope

The 2012 Comparative Effectiveness Review on Venous Thromboembolism Prophylaxis in Orthopedic Surgery¹³ (hereafter “the 2012 VTE report”) addressed many of the uncertainties in this area, including questions regarding the natural history of VTE, predictors of VTE, and the likelihood that DVTs result in PE in patients undergoing THR, TKR, or HFx surgery; the comparative efficacy of VTE prophylaxis strategies with no VTE prophylaxis, within and between classes of VTE prophylaxis modalities, and duration of VTE prophylaxis in patients undergoing these surgeries; and the efficacy of VTE prophylaxis in nonmajor orthopedic surgeries (knee arthroscopy, surgical repair of lower extremity injuries distal to the hip, and elective spine surgery). The 2012 VTE report included studies published from 1980 through May 2011. It found a general dearth of evidence regarding important clinical outcomes (nonfatal PE, fatal PE, major bleeding, reoperation), but high strength of evidence (SoE) that pharmacologic VTE prophylaxis reduces the risk of DVT compared to no VTE prophylaxis and increases the risk of minor bleeding. Comparisons of mechanical device VTE prophylaxis versus no VTE prophylaxis did not provide strong evidence that mechanical devices reduced the risk of VTE, including, specifically, DVT. The comparisons of different classes of VTE prophylaxis modalities (e.g., different pharmacologic classes or pharmacologic versus mechanical devices) provided neither adequate evidence for important clinical outcomes nor strong evidence for other outcomes, including DVT. There were few studies evaluating the new FXaIs. In general, different interventions within classes were not statistically significantly different in their effects on DVT or bleeding. There was not strong evidence for other Key Questions.

We conducted a surveillance review of new studies potentially eligible to update all Key Questions from the 2012 VTE report. The surveillance review is summarized in the online protocol for this review.¹⁴ Briefly, we screened and extracted basic data from abstracts found in PubMed from January 2010 to 16 July 2015. We evaluated the number and characteristics of studies—including RCT, nonrandomized comparative studies, systematic reviews, meta-analyses, and network meta-analyses—of potentially relevant articles. The updated literature search yielded 617 citations. Using the 2012 report’s eligibility criteria, 160 articles were of potential interest (based on information available in their abstracts). Of these, 48 were existing systematic reviews, 49 were RCTs, 19 were pooling studies (meta-analysis or otherwise) of previous published or unpublished trials, and 44 were nonrandomized comparative studies (with at least 750 participants per study). We used this information to help determine the scope of the systematic review update. Upon discussion of the current state of the evidence with a panel of technical experts, we determined that a focused update of the 2012 Agency for Healthcare Research and Quality (AHRQ) report would be of greatest value. The panel included 10 members, including four orthopedic surgeons, two hematologists, one pulmonologist, one pharmacist, one physical therapist, and one nurse practitioner. Based on their input and the findings of the surveillance review, we focused the update on comparisons between specific prophylaxis interventions; different classes of interventions; different doses, regimens, and treatment durations of interventions; different combinations of interventions; and different timing of starting prophylaxis (in relation to the time of surgery).

Several topics covered in the 2012 VTE report are not updated, including Key Questions related to “natural history” in patients not given thromboprophylaxis and incidence or predictors of VTE and comparing thromboprophylaxis to no thromboprophylaxis. In the modern era, it is rare for patients to not have some form of thromboprophylaxis; therefore, this question is of less clinical interest, and it is unlikely that there will be substantial new evidence regarding these topics. Therefore, these topics (regarding no prophylaxis) are not updated. We also do not update the Key Question evaluating DVT as a proxy (or predictor) for PE, as no new evidence was expected. Finally, all questions related to orthopedic surgeries other than TKR, THR, and HFx surgery are not updated, since only very limited new studies were found during the surveillance review; thus, conclusions and SoE are unlikely to change compared to the 2012 VTE report.

The objectives for the systematic review are to update the 2012 VTE report focused on the comparative effectiveness (for VTE outcomes and harms) of different thromboprophylaxis interventions for patients undergoing major orthopedic surgery (THR, TKR, and HFx surgery).

Key Questions

The following are the Key Questions (KQs) addressed by the review:

KQ 1 (update of original KQ 5)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy between classes of thromboprophylaxis interventions on venous thromboembolism outcomes, treatment adherence, major bleeding, and other adverse events?

KQ 2 (update of original KQ 6)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy of individual thromboprophylaxis interventions within classes (low molecular weight heparin, factor Xa inhibitors, direct thrombin inhibitors, and mechanical devices) on venous thromboembolism outcomes, treatment adherence, major bleeding, and other adverse events?

KQ 3 (new KQ based on original KQ 8)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy of different doses, regimens, or treatment durations of the same thromboprophylaxis interventions (low molecular weight heparin, factor Xa inhibitors, direct thrombin inhibitors, and mechanical devices) on venous thromboembolism outcomes, treatment adherence, major bleeding, and other adverse events?

KQ 4 (update of original KQ 7 plus expansion)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy of combined classes of thromboprophylaxis interventions versus single classes on venous thromboembolism outcomes, treatment adherence, major bleeding, and other adverse events?

KQ 5 (new KQ)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), based on network meta-analysis, what are the comparative effects of thromboprophylaxis interventions on deep vein thrombosis and, separately, major bleeding?

5.1.

What are the comparative effects of different classes of thromboprophylaxis interventions?

5.2.

What are the comparative effects of different individual thromboprophylaxis interventions?

KQ 6 (new KQ)

In patients undergoing major orthopedic surgery (total hip or knee replacement, hip fracture surgery), what is the comparative efficacy of starting pharmacologic thromboprophylaxis at different times (i.e., preoperative, intraoperative, postoperative) on venous thromboembolism outcomes, treatment adherence, major bleeding, and other adverse events?

Analytic Framework

To guide the assessment of studies that examine the effect of thromboprophylaxis on final, intermediate, and adverse outcomes in patients undergoing major orthopedic surgery the analytic framework maps the specific linkages associating the populations of interest, the interventions, modifying factors, and outcomes of interest (Figure 1). The analytic framework depicts the chains of logic that evidence must support to link the studied interventions studied.

Figure 1

Analytic framework for the comparative effectiveness of venous thromboembolism prophylaxis in orthopedic surgery. Abbreviations: DVT = deep vein thrombosis, HFx = hip fracture, HIT = heparin-induced thrombocytopenia, IVC = inferior vena cava, KQ = Key (more...)