Aspirin versus anticoagulation for prevention of venous thromboembolism major lower extremity orthopedic surgery: a systematic review and metaanalysis

ORIGINAL RESEARCH Aspirin Versus Anticoagulation for Prevention of Venous Thromboembolism Major Lower Extremity Orthopedic Surgery: A Systematic Review and Meta-analysis Frank S. Drescher, MD1*, Brenda E. Sirovich, MD, MS2, Alexandra Lee, MS3, Daniel H. Morrison, MD, MS4, Wesley H. Chiang, MS2, Robin J. Larson, MD, MPH2 1Geisel School of Medicine at Dartmouth, Pulmonary and Critical Care Medicine, Veterans Affairs Medical Center, White River Junction, Vermont;2Geisel School of Medicine at Dartmouth, and the Dartmouth Institute for Health Policy and Clinical Practice, Center for Education, Lebanon, NewHampshire; 3Herbert Wertheim College of Medicine at Florida International University, Miami, Florida; 4Geisel School of Medicine at Dartmouth, Sec-tion of Otolaryngology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
BACKGROUND: Hip fracture surgery and lower extremity screened participants for deep venous thrombosis (DVT).
arthroplasty are associated with increased risk of both Overall rates of DVT did not differ statistically between aspi- venous thromboembolism and bleeding. The best pharma- rin and anticoagulants (relative risk [RR]: 1.15 [95% confi- cologic strategy for reducing these opposing risks is dence interval {CI}: 0.68–1.96]). Subgrouped by type of surgery, there was a nonsignificant trend favoring anticoa-gulation following hip fracture repair but not knee or hip PURPOSE: To compare venous thromboembolism (VTE) arthroplasty (hip fracture RR: 1.60 [95% CI: 0.80–3.20], 2 tri- and bleeding rates in adult patients receiving aspirin versus als; arthroplasty RR: 1.00 [95% CI: 0.49–2.05], 5 trials). The anticoagulants after major lower extremity orthopedic risk of bleeding was lower with aspirin than anticoagulants following hip fracture repair (RR: 0.32 [95% CI: 0.13–0.77], 2 DATA SOURCES: Medline, Cumulative Index to Nursing trials), with a nonsignificant trend favoring aspirin after and Allied Health Literature, and the Cochrane Library arthroplasty (RR: 0.63 [95% CI: 0.33–1.21], 5 trials). Rates through June 2013; reference lists,, and of pulmonary embolism were too low to provide reliable scientific meeting abstracts.
STUDY SELECTION: Randomized trials comparing aspirin CONCLUSION: Compared with anticoagulation, aspirin to anticoagulants for prevention of VTE following major may be associated with higher risk of DVT following hip lower extremity orthopedic surgery.
fracture repair, although bleeding rates were substantially lower. Aspirin was similarly effective after lower extremity extracted data on rates of VTE, bleeding, and mortality.
arthroplasty and may be associated with lower bleedingrisk. Journal of Hospital Medicine 2014;000:000–000.
DATA SYNTHESIS: Of 298 studies screened, 8 trials includ- C 2014 Society of Hospital Medicine ing 1408 participants met inclusion criteria; all trials Each year in the United States, over 1 million adults ity and mortality for patients, as well as substantial undergo hip fracture surgery or elective total knee or costs to the healthcare system.6 Although VTE is con- sidered to be a preventable cause of hospital admis- improving functional status and quality of life,2,3 each sion and death,7,8 the postoperative setting presents a of these procedures is associated with a substantial particular challenge, as efforts to reduce clotting must risk of developing a deep vein thrombosis (DVT) or be balanced against the risk of bleeding.
pulmonary embolism (PE).4,5 Collectively referred to Despite how common this scenario is, there is no as venous thromboembolism (VTE), these clots in the consensus regarding the best pharmacologic strategy.
venous system are associated with significant morbid- thromboprophylaxis," leaving the clinician to selectthe specific agent.4,5 Explicitly endorsed optionsinclude aspirin, vitamin K antagonists (VKA), unfrac-tionated heparin, fondaparinux, low-molecular-weight *Address for correspondence and reprint requests: Frank Drescher,MD, Assistant Professor of Medicine, Geisel School of Medicine at Dart- heparin (LMWH) and IIa/Xa factor inhibitors. Among mouth, Pulmonary and Critical Care Medicine, Veterans Affairs Medical these, aspirin, the only nonanticoagulant, has been the Center,(111) 215 North Main Street, White River Junction, VT 05009;Telephone: 802-295-9363; Fax: 802-291-6257; E-mail: source of greatest controversy.4,9,10 Two previous systematic reviews comparing aspirin Additional Supporting Information may be found in the online version of to anticoagulation for VTE prevention found conflict- this article.
ing results.11,12 In addition, both used indirect com- Received: February 12, 2014; Revised: May 9, 2014; Accepted: May 20, parisons, a method in which the intervention and comparison data come from different studies, and sus- 2014 Society of Hospital Medicine DOI 10.1002/jhm.2224Published online in Wiley Online Library (
ceptibility to confounding is high.13,14 We aimed to An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014 VTE Prevention After Orthopedic Surgery overcome the limitations of prior efforts to address our inclusion criteria. We used exploded Medical Sub- this commonly encountered clinical question by con- ject Headings terms and key words to generate sets ducting a systematic review and meta-analysis of for "aspirin" and "major orthopedic surgery" themes, randomized controlled trials that directly compared then used the Boolean term, "AND," to find their the efficacy and safety of aspirin to anticoagulants for VTE prevention in adults undergoing common high-risk Additional Search Methods We manually reviewed references of relevant articlesand MATERIAL AND METHODS ongoing studies or unpublished data. We further searched the following sources: American College of Prior to conducting the review, we outlined an Chest Physicians (ACCP) Evidence-Based Clinical approach to identifying and selecting eligible studies, Practice Guidelines,4,17 American Academy of Ortho- prespecified outcomes of interest, and planned sub- paedic Surgeons guidelines (AAOS),5 and annual group analyses. The meta-analysis was performed meeting abstracts of the American Academy of Ortho- according to the Preferred Reporting Items for System- paedic Surgery,18 the American Society of Hematol- ogy,19 and the ACCP.20 Study Eligibility Criteria Two pairs of 2 reviewers independently scanned the We prespecified the following inclusion criteria: (1) titles and abstracts of identified studies, excluding only the design was a randomized controlled trial; (2) the those that were clearly not relevant. The same reviewers population consisted of patients undergoing major independently reviewed the full text of each remaining orthopedic surgery including hip fracture surgery or study to make final decisions about eligibility.
total knee or hip arthroplasty; (3) the study compared Data Extraction and Quality Assessment aspirin to 1 or more anticoagulants: VKA, unfractio- Two reviewers independently extracted data from nated heparin, LMWH, thrombin inhibitors, pentasac- each included study and rendered judgments regarding charides (eg, fondaparinux), factor Xa/IIa inhibitors the methodological quality using the Cochrane Risk dosed for VTE prevention; (4) subjects were followed for at least 7 days; and (5) the study reported at least1 prespecified outcome of interest. We allowed the use of pneumatic compression devices, as long as devices We used Review Manager (RevMan 5.1) to calculate were used in both arms of the study.
pooled risk ratios using the Mantel-Haenszel methodand random-effects models, which take into account the presence of variability among included stud- We designated the rate of proximal DVT (occurring ies.16,22 We also manually pooled absolute event rates in the popliteal vein and above) as the primary out- for each study arm using the study weights assigned in the pooled risk ratio models.
included rates of PE, PE-related mortality, and all-cause mortality. We required that DVT and PE were Assessment of Heterogeneity and Reporting Biases diagnosed by venography, computed tomography We assessed statistical variability among the studies (CT) angiography of the chest, pulmonary angiogra- contributing to each summary estimate and considered phy, ultrasound Doppler of the legs, or ventilation/ studies unacceptably heterogeneous if the test for het- perfusion scan. We allowed studies that screened par- erogeneity P value was <0.10 or the I2 exceeded ticipants for VTE (including the use of fibrinogen leg 50%.14,16 We constructed funnel plots to assess for publication bias but had too few studies for reliable A bleeding event was defined as any need for post- operative blood transfusion or otherwise clinically sig-nificant bleeding (eg, prolonged postoperative wound Subgroup Analyses bleeding). We further defined major bleeding as the We prespecified subgroup analyses based on the indica- requirement for blood transfusion of more than 2 U, tion for the surgery: hip fracture surgery versus total hematoma requiring surgical evacuation, and bleeding knee or hip arthroplasty, and according to class of anti- into a critical organ.
coagulation used: VKA versus heparin compounds.
Study Identification We searched Medline (January 1948 to June 2013), Results of Search Cochrane Library (through June 2013), and CINAHL Figure 1 shows the number of studies that we eval- (January 1974 to June 2013) to locate studies meeting uated during each stage of the study selection process.
An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014

VTE Prevention After Orthopedic Surgery FIG. 1. Flow diagram of the search results. ACCP, American College of Chest Physicians; AOOS, American Academy of Orthopedic Surgeons; ASH; AmericanSociety of Hematology; CINAHL, Cumulative Index to Nursing and Allied Health Literature.
After full-text review, 8 randomized trials met all was 7 to 21 days. Clinical follow-up extended up to 6 months after surgery. Patients in all included studieswere screened for DVT during the trial period by I- fibrinogen leg scanning,23,25–27 venography,24,28 or Table 1 presents the characteristics of the 8 included ultrasound29,30; some trials also screened all partici- randomized trials. All were published in peer-reviewed pants for PE with ventilation/perfusion scanning.27,28 journals from 1982 through 2006.23–30 The trialsincluded a combined total of 1408 subjects, and took Methodological Quality of Included Studies place in 4 different countries, including the United Only 3 studies described their method of random States,24,26,28–30 Spain,23 Sweden,27 and Canada.25 sequence generation,24–26 and 2 studies specified their Enrolled patients had a mean age of 76 years (range, method of allocation concealment.25,26 Only 1 study 74–77 years) among hip fracture surgery studies and used placebo controls to double blind the study arm 66 years (range, 59–69 years) among elective knee/hip assignments.25 We judged the overall potential risk of bias among the eligible studies to be moderate.
Pneumatic compression devices were used in addi- tion to pharmacologic prevention in 2 studies.29,30 Rate of Proximal DVT The different classes of anticoagulants used included Pooling findings of all 7 studies that reported proxi- warfarin,26,28,30 heparin,23,27 LMWH,29 heparin or mal DVT rates, we observed no statistically significant warfarin,24 and danaparoid.25 Treatment duration difference between aspirin and anticoagulants (10.4% An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014

VTE Prevention After Orthopedic Surgery TABLE 1. Characteristics of Included Studies Aspirin (Total/Day) Heparin or warfarin NOTE: Abbreviations: N/A, not available; THA, total hip arthroplasty; TKA, total knee arthroplasty.
*Gent reported venous thromboembolism events in the subset of screened patients only: aspirin: n 5 84, danaparoid: n 5 88.
FIG. 2. Effects of aspirin versus anticoagulation on rates of proximal deep venous thrombosis. CI, confidence interval; M-H, Mantel-Haenszel.
vs 9.2%, relative risk [RR]: 1.15 [95% confidence 0.9%, RR: 1.83 [95% CI: 0.64, 5.21], I2 5 0%). The interval {CI}: 0.68-1.96], I2 5 41%). Although rates very small number of events rendered extremely wide did not statistically differ between aspirin and anticoa- 95% CIs in operative subgroup analyses (Figure 3).
gulants in either operative subgroup, there appearedto be a nonsignificant trend favoring anticoagulation Rates of All-Cause Mortality after hip fracture repair (12.7% vs 7.8%, RR: 1.60 Only 2 trials, both evaluating aspirin versus anticoa- [95% CI: 0.80-3.20], I2 5 0%, 2 trials) but not gulation following hip fracture repair, reported death following knee or hip arthroplasty (9.3% vs 9.7%, events, both after 3 months follow-up.25,26 Pooling RR: 1.00 [95% CI: 0.49-2.05], I2 5 49%, 5 trials) these results, there was no statistically significant dif- ference (7.3% vs 6.8%, RR: 1.07 [95% CI: 0.51–2.21], I2 5 0%).
Rate of Pulmonary Embolism Just 14 participants experienced a PE across all 6 tri- Pooling all 8 studies, aspirin was associated with a stat- als reporting this outcome (aspirin n 5 9/405 versus istically significant 48% decreased risk of bleeding anticoagulation n 5 5/415). Although PE was numeri- events compared to anticoagulants (3.8% vs 8.0%, RR: cally more likely in the aspirin group, this difference 0.52 [95% CI: 0.31–0.86], I2 5 8%). When subgrouped was not statistically significant (overall: 1.9% vs An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014

VTE Prevention After Orthopedic Surgery FIG. 3. Effects of aspirin versus anticoagulants on pulmonary embolism rates. CI, confidence interval; M-H, Mantel-Haenszel.
statistically significantly lower in the aspirin group fol- anticoagulants. This benefit, however, was associated lowing hip fracture (3.1% vs 10%, RR: 0.32 [95% CI: with a nonsignificant increase in screen-detected proximal 0.13–0.77], I2 5 0%, 2 trials); however, the observed DVT. Conversely, among patients undergoing knee or hip trend favoring aspirin was not statistically significant arthroplasty, we found no difference in proximal DVT following arthroplasty (3.9% vs 7.8%, RR: 0.63 [95% risk between aspirin and anticoagulants and a possible CI: 0.33–1.21], I2 5 14%, 5 trials) (Figure 4).
trend toward less bleeding risk with aspirin. The rarity of Five studies reported major bleeding; event rates pulmonary emboli (and death) made meaningful compari- were low and no statistically significant differences sons between aspirin and anticoagulation impossible for between aspirin and anticoagulants were observed(hip fracture: 3.5% vs 6.3%, RR: 0.46 [95% CI: either type of surgery.
Our systematic review has several strengths that dif- 5 0%, 2 trials; knee/hip arthroplasty: 2.1% vs 0.6%, RR: 2.86 [95% CI: 0.65–12.60], ferentiate it from previous analyses. First, we only included head-to-head randomized trials such that all 5 0%, 3 trials).
included data reflect direct comparisons between aspi-rin and anticoagulation in well-balanced populations.
Subgroup Analysis Conversely, both recent reviews11,12 were based on Rates of proximal DVT did not differ between aspirin indirect comparisons, a type of analysis in which data and anticoagulants when subgrouped according to for the intervention and control arms are taken from anticoagulant class (aspirin vs warfarin: 9.7% vs different studies and thus different populations. This 10.7%, RR: 0.90 [95% CI: 0.56–1.45], I2 5 0%, 3 methodology is not recommended by the Cochrane trials; aspirin vs heparin: 10.5% vs 7.9%, RR: 1.37 Collaboration13,14 because of the increased risk of an [95% CI: 0.47–3.96], I2 5 44%, 4 trials) (data not unbalanced comparison. For example, Brown and col- leagues' meta-analysis, which pooled data from Bleeding rates were lower with aspirin when sub- selected arms of 14 randomized controlled trials, grouped according to type of anticoagulant, but the found the efficacy of aspirin comparable to that of finding was only statistically significant when com- anticoagulants, but all aspirin subjects came from a pared to VKA (aspirin vs VKA: 4.2% vs 11.1%, RR: single trial of patients at such low risk of VTE that a 0.43 [95% CI: 0.22–0.86] I2 5 0%, 4 trials; aspirin vs placebo arm was considered justified.31 Similarly, in heparin: 3.7% vs 7.7%, RR: 0.44 [95% CI: 0.15– the indirect comparison of Westrich and colleagues,12 1.28], I2 5 44, 4 trials) (data not shown).
which found anticoagulation superior to aspirin, thelikelihood of an unbalanced comparison was further heightened by their inclusion of observational studies, We found the balance of risk versus benefit of aspirin with the attendant risk of confounding by indication.
compared to anticoagulation differed markedly according Our systematic review further differs from previous to type of surgery. After hip fracture repair, we found a analyses by examining both beneficial and harmful 68% reduction in bleeding risk with aspirin compared to clinical outcomes, and doing so separately for the 2 An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014

VTE Prevention After Orthopedic Surgery FIG. 4. Effects of aspirin versus anticoagulants on bleeding rates (any significant bleed). CI, confidence interval; M-H, Mantel-Haenszel.
most common types of major orthopedic lower and intermittent pneumatic compression devices are extremity surgery. This allowed us to discover impor- standard prophylaxis against postoperative VTE. In tant differences in the comparative efficacy (benefit vs fact, only 2 trials used concomitant pneumatic com- harm) of aspirin versus anticoagulants across different pression devices, and none treated patients longer procedure types. Finding that aspirin may have lower than 21 days, the current standard being up to 35 efficacy for preventing VTE following hip fracture days.4 Although these limitations may affect overall repair than arthroplasty may not be surprising in light event rates, this bias should be balanced between of the nature of the 2 procedures, the disparate mean ages typical of patients who undergo each procedure, randomized controlled trials.
and the underlying trauma in hip fracture patients.
What is a clinician to do? Based on our findings, The limitations of our review largely reflect the current guidelines recommending aspirin prophylaxis quality of the studies we were able to include. First, against VTE as an alternative following major lower our pooled sample size remains relatively small, mean- extremity surgery may not be universally appropriate.
ing that observed nonsignificant differences between We found that although overall bleeding complica- aspirin and anticoagulation groups (eg, a nonsignifi- tions are lower with aspirin, concerns about poor effi- cant 60% increased risk of DVT for aspirin after hip cacy remain, specifically for patients undergoing hip repair, 95% CI: 0.80–3.20) could reasonably reflect fracture repair. Although some have suggested that up to 3-fold differences in DVT risk and 5-fold differ- aspirin use be restricted to low risk patients, this strat- ences in PE rates. Second, screening for DVT, which egy has not been experimentally evaluated.33 On the is neither recommended nor common in clinical prac- other hand, switching to aspirin after a brief initial tice, was used in all studies. Reported DVT incidence, course of LMWH may be an approach warranting therefore, is undoubtedly higher than what would be further study, in light of a recent randomized con- observed in practice; however, the effect on the direc- trolled trial of 778 patients after elective hip replace- tion and magnitude of observed relative risks is unpre- ment, which found equivalent efficacy using 10 days dictable. Third, included studies used a wide range of of LMWH followed by aspirin versus additional aspirin doses, as well as a variety of anticoagulant LMWH for 28 days.34 types. Although supratherapeutic aspirin doses are We are able to be more definitive, based on our unlikely to confer additional benefit for venous throm- study of best available trial data, in making recom- boprophylaxis, they may be associated with excess mendations to investigators embarking on further bleeding risk.32 Finally, several of the studies were study of optimal VTE prophylaxis following major conducted more than10 years ago. Given changes in orthopedic surgery. First, distinguishing a priori treatment practices, surgical technique, and prophy- between the 2 major types of lower extremity major laxis options, the findings of these studies may not orthopedic surgery is a high priority. Second, both reflect current practice, in which early mobilization bleeding and thromboembolic outcomes must be An Official Publication of the Society of Hospital Medicine Journal of Hospital Medicine Vol 00 No 00 Month 2014 VTE Prevention After Orthopedic Surgery evaluated. Third, only symptomatic events should be 12. Westrich GH, Haas SB, Mosca P, Peterson M. Meta-analysis of thromboembolic prophylaxis after total knee arthroplasty. J Bone used to measure VTE outcomes; clinical follow-up Joint Surg Br. 2000;82(6):795–800.
must continue well beyond discharge, for at least 3 13. Song F, Loke YK, Walsh T, Glenny A-M, Eastwood AJ, Altman DG.
months to ensure ascertainment of clinically relevant Methodological problems in the use of indirect comparisons for evalu-ating healthcare interventions: survey of published systematic reviews.
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15. Moher D, Liberati A, Tetzlaff J, Altman DG; the PRISMA Group. Pre- ferred reporting items for systematic reviews and meta-analyses: the In summary, although definitive recommendations PRISMA statement. PLoS Med. 2009;6(7):e1000097.
for or against the use of aspirin instead of anticoagu- 16. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evalu- lation for VTE prevention following major orthope- ate health care interventions: explanation and elaboration. PLoS Med.
dic surgery are not possible, our findings suggest 17. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous throm- that, following hip fracture repair, the lower risk of boembolism: American College of Chest Physicians evidence-based bleeding with aspirin is likely outweighed by a prob- clinical practice guidelines (8th edition). Chest. 2008;133(6 suppl):381S–453S.
able trend toward higher risk of VTE. On the other 18. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical hand, the balance of these opposing risks may favor patients: antithrombotic therapy and prevention of thrombosis, 9thed: American College of Chest Physicians evidence-based clinical prac- aspirin after elective knee or hip arthroplasty. A tice guidelines. Chest. 2012;141(2 suppl):e195S–e226S.
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Disclosures: Nothing to report.
24. Harris WH, Athanasoulis CA, Waltman AC, Salzman EW. High and low-dose aspirin prophylaxis against venous thromboembolic diseasein total hip replacement. J Bone Joint Surg Am. 1982;64(1):63–66.
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