Deep vein thrombosis (DVT) is a recognized sequela of isolated lower extremity fractures, with a 10%–40% incidence after isolated fractures of the tibia and distal bones of the lower extremity. Venous thromboembolism (VTE) of lower extremity DVT in the presence and absence of fracture may progress to pulmonary embolism (PE), stroke, and death.1–7 The risks of DVT and VTE are considerably greater in fractures of the femur than in isolated fractures of the tibia and distal.8–13 Although strong evidence and guidelines support routine anticoagulation in pelvis and femoral fractures to prevent VTE morbidity and mortality,13,14 clinical trials and prospective cohort studies of the efficacy of chemical [low-molecular-weight heparins (LMWHs),3–5,7,10,15–18 warfarin,19 aspirin,20 and factor Xa inhibitors6] as well as mechanical (compression stockings21 and intermittent pneumatic calf or foot devices22,23) prophylactic interventions for reducing the occurrence of VTE in patients with isolated fractures distal to the femur treated by immobilization and/or surgery have shown mixed results for preventing PE or VTE-related death.
Rarely does an asymptomatic leg DVT progress proximally to the thigh or lungs after lower leg fracture surgery,24–26 even in the absence of therapeutic anticoagulation.10,12 In particular, lower extremity fractures of the tibia and distal bones represent a lower risk subgroup for which guidelines are unclear and the evidence for VTE prophylaxis is mixed.14,27,28 The majority of the literature relevant to VTE prevention in fracture surgery for this population has focused on prevention of any VTE as the primary outcome.1–7,15–17,19–23,26,29,30 However, medical practice and guidelines have shifted from therapeutic anticoagulation of any isolated lower extremity DVT toward therapy for only those clots that are symptomatic or at higher risk for proximal extension or PE based on size, location, and patient risk factors for PE.13,14,28
A recent trial of VTE prevention in fracture surgery assessed a pragmatic primary end point of “clinically important venous thromboembolism” (CIVTE)—VTE which merits therapeutic anticoagulation by current practice guidelines.10 The following systematic review and meta-analysis appraises the Level I evidence for a treatment effect of chemical prophylaxis in the prevention of both VTE and CIVTE in lower extremity fracture surgery of the tibia or distal bone of the lower extremity.
English, Chinese, French, or German language randomized controlled trials of chemical prophylaxis of VTE with any subgroup of patients included for fractures of the tibia, fibula, talus, calcaneus, cuboid, navicular, cuneiforms, or metatarsals, for which at least some patients underwent operative fixation by open reduction with placement of internal or external skeletal fixation devices for fracture stabilization, were eligible for review. Several different types of studies were excluded: (1) studies specifically investigating pathologic fractures, (2) studies of fractures treated with amputation, (3) cadaver studies, (4) animal studies, (5) prospective or retrospective cohort studies, (6) case series, and (7) case reports. Two reviewers independently assessed studies for inclusion eligibility. When an article was judged by a reviewer to be potentially eligible on the basis of the title or abstract, the full text of the article was reviewed, and any disagreement between the reviewers was resolved by consensus.
We conducted a systematic review of PubMed MEDLINE, Embase, and Biosis for studies published between October 2016 and the first international approval of enoxaparin sodium injection for prevention of DVT in patients with severely restricted mobility during acute illness in December 31, 1987 (Clexane, Sanofi, France). Keyword, title, abstract, and medical subject headings were included in the search parameters (see Figure, Supplemental Digital Content 1, http://links.lww.com/BOT/A987).
Two reviewers identified articles and extracted data in parallel. The information obtained from the articles included anatomic fracture location, intervention studied, comparator group, major bleeding, any VTE and CIVTE defined as asymptomatic proximal DVT on bilateral Doppler ultrasonography (DUS) or contrast venography, or symptomatic DVT or PE, fatal PE, or unexplained death without autopsy at any point during the study period.
Study Quality Assessment
The methodologic quality of each study was assessed with regard to randomization (present and concealed), concealment of allocation, blinding of outcome assessors, and commercial funding by a pharmaceutical corporation.
Evaluation of Heterogeneity
Before data analysis, we considered potential sources of between-study variability attributable to true differences between studies (heterogeneity). We hypothesized that heterogeneity may be attributable to differences in the timing of the study (earlier studies vs. later studies), pharmacologic effectiveness of the intervention (brand of LWMH), assessment (modality and laterality of test used to detect DVT), and assessor (technologist performing and radiologist interpreting assessment).
Data were abstracted to an Excel database (Microsoft, Redmond, WA) and analyzed with STATA 13 (StataCorp LP, College Station, TX). We then pooled studies comparing chemoprophylaxis to no intervention or placebo, and we calculated relative risks (RRs) and associated 95% confidence intervals (CIs) for the outcomes of any VTE and CIVTE using a random-effects model to account for between-trial variance as a residual source of heterogeneity in treatment effects. The heterogeneity was calculated as the I2 statistic. Inverted funnel plots of the magnitude of the RR against sample size were used to assess publication bias. A sensitivity analysis was conducted by subtracting individual studies one at a time, repeating the meta-analysis, and comparing to the over-all pooled estimate, for each end point.
The literature search yielded 1502 unique citations and 16 eligible articles based on title and abstract (Fig. 1). Full-text review further eliminated 11 studies because the fracture cohort did not include patients with fractures of the tibia or distal bones managed surgically, no chemical prophylaxis was administered, or the comparator group did not receive either placebo or treatment. The outcome of CIVTE could not be assessed for the trial by Lassen et al.5 Thus, 5 studies were available for inclusion for the outcome of any VTE and 4 studies for the outcome of CIVTE.
All studies were Level I randomized controlled trials (Table 1). Four studies were placebo-controlled trials of LMWHs versus prefilled saline syringes. Jørgensen et al4 investigated LMWH versus no intervention, and participants and personnel were not blinded to the intervention. The distributions of fractures studied were 7% tibial plateau, 13% tibial shaft, 44% pilon, 40% ankle or hindfoot, and 2% midfoot or forefoot. There was no pooled significant difference in anatomic location between intervention and comparator groups (paired 2-tailed t test P = 0.986). Two studies were sponsored by pharmaceutical manufacturers of the investigative medication.5,7
Assessment of VTE
The modality used to screen asymptomatic DVT or confirm symptomatic DVT varied: 3 studies used venography alone,1,4,5 1 used DUS alone,10 and 1 used venography or DUS without protocol.7 Laterality of screening was also heterogeneous with 3 (42.9%) studies screening the lower extremity ipsilateral to the operation for DVT at a mean 0.7–1.8 months from the operation,4,5,7 whereas the remainder performed bilateral screening at 0.5–6 months postoperatively. The outcome assessors were staff radiologists,10 24 or 3 senior radiologists1,5 or not specified,7 who interpreted examinations performed by an unspecified number of vascular technicians. The outcome assessors were explicitly blinded to the intervention in all studies.
Treatment Effect of Chemical Prophylaxis for VTE
Chemical prophylaxis with an LMWH significantly reduced the risk of VTE after operatively managed fractures of the tibia and distal [pooled RR = 0.696, 95% CI (0.490–0.989), P = 0.043; test for homogeneity P = 0.818, I2 = 0%] (Fig. 2). However, chemical prophylaxis with an LMWH did not significantly reduce the risk of CIVTE after operatively managed fractures of the tibia and distal [RR = 0.865, 95% CI (pooled RR 0.112–3.863), P = 0.790; test for homogeneity P = 0.718, I2 = 0%] (Fig. 3). The funnel plots did not suggest publication bias (Fig. 4 and see Figure, Supplemental Digital Content 2, http://links.lww.com/BOT/A988). The number needed to treat was 31 patients treated with chemoprophylaxis using an LMWH to prevent 1 VTE and would be 584 patients to prevent 1 CIVTE, although CIVTE risk reduction was not statistically significant.
Individual exclusion of the study by Lassen et al, Lapidus et al, or Goel et al resulted in a nonsignificant pooled association between LMWH administration and any DVT. The association between LMWH and the primary outcome of CIVTE did not change in magnitude or become statistically significant with the exclusion of any single study.
Major bleeding was recorded for 4 of 5 studies. No major bleeding occurred in the comparator or intervention group in any of these studies. Major bleeding was variously defined as severe bleeding occurrences4; clinically apparent bleeding was associated with a decrease of at least 20 g/dL in the hemoglobin level, requirement for transfusion of at least 2 units of packed red cells, retroperitoneal or intracranial bleeding or other bleeding that the investigators decided required permanent discontinuation of treatment5; bleeding requiring blood transfusion/resurgery, or bleeding at a critical site (intraocular, intracranial, intraspinal, or retroperitoneal)7; fall in hemoglobin of ≥2 g/dL within a 24-hour period resulting in transfusion of ≥2 units of blood, intracranial, intraspinal, intraocular, retroperitoneal or pericardial bleeding, and causing death1 or overt bleeding occurring between the first dose of study drug and 2 days after the last dose that was fatal, life-threatening or involved a critical organ or a major joint, required surgical intervention, the transfusion of 1 or more units of red blood cells within 48 hours of the bleeding event, or was associated with a drop in hemoglobin of at least 20 g/L within 48 hours of the bleeding event.10
Our systematic review with meta-analysis of chemoprophylaxis of VTE following surgical treatment of an isolated fracture of the tibia or distal bone of the lower extremity demonstrates a significant treatment effect on the reduction of VTE, no significant treatment effect on the prevention of CIVTE, and no increased risk of major bleeding with chemoprophylaxis of VTE.
Venous thrombosis after femur fracture is fundamentally different than VTE after fracture distal to the knee, with regard to both occurrence of thrombosis and likelihood of proximal embolization.13 This may be related to the extent of the zone of injury as well as the energy required to create a fracture of the lower extremity, which generally decrease with distance from the axial skeleton, for example, femur versus tibia versus midfoot. The size of thrombi and risk of embolism are positively correlated with venous luminal diameter, and average venous luminal diameter also decreases with distance down the limb. In the absence of routine perioperative DVT prophylaxis, the data from Abelseth et al11 and Solis and Saxby12 support a positive correlation of more distal anatomic fracture location with both lower DVT incidence and lower incidence of proximal progression among patients who received early definitive fracture fixation. It is not surprising that Selby et al found an incidence of symptomatic VTE in 0.6% (95% CI 0.2%–1.2%) in their prospective cohort of lower leg fractures without chemoprophylaxis,9 and 1.9% (95% CI 0.7%–4.7%) of their surgical cohort of isolated fractures below the knee with no significant difference between dalteparin and placebo either for CIVTE or safety.10
Observational cohort studies have reported conflicting associations between chemoprophylaxis and the occurrence of symptomatic thrombosis after operatively treated lower leg fractures. Jameson et al reported that the rates of DVT, PE, and mortality were 0.12%, 0.17%, and 0.37%, respectively, after 45,949 ankle fracture surgeries in the National Health Service. The authors noted that chemoprophylaxis was not associated with a significantly reduced risk of these adverse events.31 Lapidus et al32 reported an increased RR of any VTE in an observational cohort study after tibial plateau, tibial shaft, and ankle fracture surgery in which patients received 7–10 days of chemoprophylaxis with dalteparin 5000 IU subcutaneously daily for 7–10 days postoperatively. Shibuya et al33 reported that a low incidence of DVT and PE, respectively, 0.28% and 0.21%, after foot and ankle fracture surgery in the National Trauma Data Bank may not warrant routine chemoprophylaxis. The differences in study design, target populations, interventions, and outcome measurement make synthesis of these observational studies difficult.
Four of the studies included in our analysis were individually not adequately powered to detect the prespecified 10%,1,4 20%,7 or 75%10 RR reduction between study groups as the observed incidence of DVT was lower than the estimate provided in the a priori power calculation. The trial by Lassen et al5 was adequately powered to detect 50% risk reduction, but inadequately powered to detect this difference among the operative fracture subcohort alone. The trial steering committee for Selby et al noted a lower event rate of 1.9% than estimated (2.5%), and determined that doubling the sample size would not provide the desired power to detect a 75% RR reduction to achieve a clinically important 3% absolute risk reduction. Therefore, they terminated enrollment without unblinding. Consequently, each study was underpowered to detect the prespecified treatment effect of LMWH on risk of any DVT among operatively isolated fractures of the tibia or distal. With regard to the power of this pooled meta-analysis, the pooled occurrence of any VTE and CIVTE in the comparator groups was 6.8% with placebo or no treatment and 0.6% with placebo, respectively. Two hundred eighty-two and 358 total patients would have been required to detect a conservative 1-tailed 10% RR reduction in VTE and CIVTE, respectively, with 80% power at the 5% significance level. Therefore, our meta-analysis is adequately powered to detect a treatment effect for the outcomes of interest.
No anticoagulation practice guideline specifically comments on chemical prophylaxis after fracture surgery of the tibia or distal bones. The Evidence-Based Quality and Value (EBQV) Committee of the Orthopaedic Trauma Association (OTA) made a strong recommendation that LMWH is the optimal form of VTE prophylaxis and should be initiated in patients with musculoskeletal injury with additional risk factors within 24 hours, provided there are no contraindications. The OTA EBQV Committee also provides a moderate recommendation against chemical prophylaxis in patients with isolated lower extremity fractures and “no other risk factors” for VTE who are able to independently mobilize, but do not distinguish between proximal and distal injuries.14 The NICE CG92 Guideline advises physicians to consider mechanical devices and starting LMWH 6–12 hours after orthopaedic surgery (other than hip replacement, knee replacement, or hip fracture surgery) based on a physician's assessment of risks and after discussion with the patient.27 The American College of Chest Physicians combined the included study by Selby et al10 with a recent Cochrane review of VTE prophylaxis for isolated fractures as well as tendon, cartilage, and soft tissue injuries distal to the knee, including nonoperative injuries,29 and could not endorse a benefit of pharmacologic thromboprophylaxis.34 The heterogeneity of clinical scenarios lumped together in these guidelines—the grouping of a plethora of injuries, operative and nonoperative management, adjacent venous systems affected, and variable use and duration of immobilization—limit real-world application of such guidelines to the counseling or management of individual patients.
Surveys of surgeon preferences for the use or selection of an agent for VTE chemoprophylaxis in lower limb fractures,35–37 foot and ankle trauma,38,39 and foot and ankle surgery40 demonstrate considerable heterogeneity in the choice to anticoagulate as well as in the choice of agent. The finding of variations in care may reflect the lack of evidence for chemical prophylaxis. One illustrative open label cohort study of rivaroxaban for chemoprophylaxis of VTE in fracture surgery was excluded from this review because the authors were unable to define the “standard-of-care” comparator group secondary to heterogeneity in clinician use and choice of pharmacologic prophylaxis between the 76 study centers.6 Shifting preferences over time in the choice to anticoagulate may be related to evolving concepts of clinical relevance of VTE in lower extremity fracture surgery as practices have shifted from prevention of any DVT in the lower extremity1–7,15–17,19–23,26,29,30 to those at clinically significant risk for proximal propagation and more serious complications.10,12,24–26,41 However, a survey distributed by the OTA EBQV Committee found that 61% and 45% of responding orthopaedic trauma surgeons reported use of LMWH in isolated tibia and foot/ankle fractures, respectively, with 76% reporting use of any chemoprophylaxis in isolated foot/ankle fractures. This survey highlighted the use of anticoagulation in the practice of defensive medicine in prescription of anticoagulants in orthopaedic trauma patients: 12% had been used for VTE and 35% of respondents discharged patients with anticoagulation when they felt it was not medically indicated to avoid medical–legal liability.14
Chemoprophylaxis is not without cost or complication. Menakaya reported costs of at £107.54 and £143.99 in 2013 for a mean 46-day course of dalteparin or dabigatran, respectively, for outpatient prophylaxis of VTE after lower extremity injury, which negated 5.3% of annual clinic income.42 Although the present investigation found no occurrence of major bleeding, other adverse events including minor bleeding and compartment syndrome have been reported after both chemical43 and mechanical34 VTE prophylaxis.
This study has numerous limitations. We have grouped fractures of the tibia and distal bones managed operatively as a single entity despite variable risk for VTE depending on anatomic location and severity of the injury.26,44–46 Clinical definitions of DVT and VTE vary, which has hindered prior meta-analyses of clinical trials of anticoagulants in fracture surgery.47,48 There is heterogeneity within the included trials with regard to the modality and laterality of screening for asymptomatic DVT, including the use of DUS and/or venography as well as screening of the ipsilateral or bilateral legs. DUS was validated and compared with venography for screening for asymptomatic DVT49 before the publication but during the collection periods of some of the studies included, which explains the use of venography despite its inherently higher complication rate and relative obsolescence compared with DUS. The study by Jørgensen et al4 had a comparator of no treatment rather than a placebo comparator and lacked blinding of the subjects, assessors, and study personnel. There are multiple sources of heterogeneity for which we did not account, including duration of cast immobilization which is associated with VTE in ankle and hindfoot fracture,26,32,50 weight-bearing status and duration which vary between fracture location, fixation method, and surgeon mobilization protocol that could each independently influence VTE rates. CIVTE measures were not explicitly reported in 1 eligible trial, and rates of CIVTE were low across trials, limiting the power of this analysis. Our search criteria may have missed relevant studies including those published in languages other than those investigated.
This study focused on a target population undergoing a single surgical intervention without other risk factors for VTE. The observations of efficacy reported may not be generalizable to lower extremity fracture patients with a history of VTE, polytrauma, prolonged hospital immobilization, pathologic fractures, patients with active oncologic disease or other hypercoagulable states, and those undergoing multiple or staged surgeries such as external fixation with or without limited fixation before a definitive surgical fixation as is routinely performed for pilon, calcaneal, and high-grade tibial shaft or plateau fractures. Nor do our results address the emerging associations of genetic and epigenetic variability with VTE risk.13,51–53 These findings do not illuminate the treatment effect of mechanical prophylaxis alone or mechanical prophylaxis in conjunction with chemoprophylaxis for reducing VTE in these injuries. Only studies of LMWH met inclusion criteria for this review, which reduced the heterogeneity of interventions in this review and strengthened conclusion regarding this modality. These findings do not support inferences regarding other pharmacologic interventions available for chemoprophylaxis of VTE for similar indications.47,54 Our funnel plots argue against publication bias toward trials reporting a positive treatment effect.
Our meta-analysis of existing Level I evidences suggests that routine postoperative anticoagulation after surgical management of an isolated fracture of the tibia or distal bone in patients without risk factors for VTE is unlikely to provide A clinical benefit, based on the absence of a treatment effect for preventing VTE warranting therapeutic anticoagulation. Further research in this area is necessary to demonstrate a role for chemoprophylaxis of CIVTE in specific fractures distal to the femur, to establish thresholds for anticoagulation based on VTE risk stratification, and to investigate the potential cost savings of withholding routine chemoprophylaxis for these indications.
The authors recognize Evans Whitaker, MD, MLIS, of the University of California San Francisco Library for his guidance in the design of this systematic review.
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