Venous Thromboembolism

Eleanor Fitall; Kendall K. Hall

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Hall KK, Shoemaker-Hunt S, Hoffman L, et al. Making Healthcare Safer III: A Critical Analysis of Existing and Emerging Patient Safety Practices [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2020 Mar.

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Making Healthcare Safer III: A Critical Analysis of Existing and Emerging Patient Safety Practices [Internet].

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16Venous Thromboembolism

Eleanor Fitall, M.P.H. and Kendall K. Hall, M.D., M.S.

Introduction

Background

Venous thromboembolism (VTE) is a disorder that includes deep vein thrombosis (DVT) and pulmonary embolism (PE). A DVT occurs when a blood clot forms in a deep vein, usually in the lower leg, thigh, or pelvis. A PE occurs when a clot breaks loose and travels through the bloodstream to the lungs.¹

It is estimated that 300,000 to 600,000 Americans are affected each year by VTE, making it the third leading vascular diagnosis behind heart attack and stroke, and the leading cause of death due to major orthopedic surgery.²^,³ Common causes for VTE are surgery, cancer, immobilization, or hospitalization.²^,⁴ The risk of VTE is the highest for patients undergoing major orthopedic surgery, such as total knee arthroplasty (TKA), total hip arthroplasty (THA), or hip fracture surgery (HFS).³^,⁵^,⁶ Without appropriate prophylaxis, rates of VTE among these patients have been estimated to be as high as 60 percent.⁷ Given that major orthopedic surgeries typically occur among older adults, the Centers for Medicare & Medicaid Services (CMS) has made the prevention and treatment of VTE a priority among their quality improvement efforts, such as through programmatic measure inclusion and harm area prioritization in initiatives. Accreditation organizations have followed suit, with the Joint Commission and the National Committee for Quality Assurance including measures for VTE treatment and prevention in their hospital accreditation and certification programs.

Method for Selecting Patient Safety Practice

Agency for Healthcare Research and Quality (AHRQ) subject matter experts requested an update of the previous Making Healthcare Safer reports’ coverage of the topic of VTE prophylaxis, with a specific focus on the use of aspirin.

What’s New/Different Since the Last Report

The previous Making Healthcare Safer reports reviewed the effectiveness, safety, cost effectiveness, and indicators for VTE prophylaxis, as well as the most effective VTE prophylaxis regimens and interventions to improve adherence to prevention strategy guidelines. Whereas the last report discussed newer pharmacologic agents on the market and approaches to improve clinical decision making and guideline adherence, this review specifically focuses on the use of aspirin for prophylaxis. With the increase of pharmacologic agents on the market, research has focused primarily on the effectiveness of these agents and, to some degree, their safety. This current review provides an update on the state of the evidence specifically for the use of aspirin as a low-cost, widely available generic option.

References for Introduction

1.: National Heart Lung and Blood Institute. Venous Thromboembolism. https://www.nhlbi.nih.gov/health-topics/venous-thromboembolism. Accessed September 17, 2019.
2.: Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38:(4 Suppl):S495–501. doi: 10.1016/j.amepre.2009.12.017. [PubMed: 20331949] [CrossRef]
3.: Wang Z, Zheng J, Zhao Y, Xiang Y, Chen X, Jin Y. Effectiveness and tolerability of anticoagulants for thromboprophylaxis after major joint surgery: a network meta-analysis. Cell Physiol Biochem. 2017;42(5):1999–2020. doi: 10.1159/000479840. [PubMed: 28793291] [CrossRef]
4.: American Heart Association. What is Venous Theromboembolism (VTE)? https://www.heart.org/en/health-topics/venous-thromboembolism/what-is-venous-thromboembolism-vte.
5.: Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl O E, Schulman S, et al. 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. doi: 10.1378/chest.11-2404. [PMC free article: PMC3278063] [PubMed: 22315265] [CrossRef]
6.: Mistry DA, Chandratreya A, Lee PYF. A systematic review on the use of aspirin in the prevention of deep vein thrombosis in major elective lower limb orthopedic surgery: An update from the past 3 years. Surg J (N Y). 2017;3(4):e191–e6. doi: 10.1055/s-0037-1615817. [PMC free article: PMC5747531] [PubMed: 29302621] [CrossRef]
7.: Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013;47(1):63–74. doi: 10.1345/aph.1R331. [PubMed: 23324504] [CrossRef]

16.1. Patient Safety Practice: Use of Aspirin for VTE Prophylaxis

16.1.1. Practice Description

As VTE, in particular DVT, can be very difficult to diagnose, actively employing prevention techniques is critical to ensuring patient safety. Prevention methods include both mechanical and pharmacologic prophylaxis. Mechanical prophylaxis includes the use of compression devices, such as stockings and foot pumps. Pharmacologic prophylaxis is available via a number of different anticoagulant and antiplatelet drugs, including heparin derivatives, vitamin K antagonists, direct thrombin inhibitors, direct factor Xa inhibitors, and aspirin.

There are two different types of pharmacologic agents available for VTE prophylaxis—anticoagulants and antiplatelets. Aspirin is an antiplatelet, and while there are other antiplatelets used for other cardiovascular conditions, these are not recommended for use in VTE prophylaxis and are therefore not the focus of this review. There is slight variation in existing guidelines regarding the use of aspirin for pharmacologic prophylaxis. The American Society of Hematology (ASH)¹ the American College of Chest Physicians (ACCP),² and the American Academy of Orthopedic Surgeons (AAOS)³ all recommend pharmacologic prophylaxis and/or mechanical prophylaxis for patients undergoing THA, TKA, or HFS. ASH and AAOS further recommend that patients receive both forms of prophylaxis, particularly patients who are at an increased risk for VTE. However, ASH and ACCP provide a list of recommended pharmacologic agents that specifically includes aspirin, whereas AAOS does not make recommendations regarding specific pharmacologic agents. Further, ACCP recommends low molecular weight heparin (LMWH) over other pharmacologic prophylaxis agents, whereas other guidelines have not made such a specific recommendation statement specifying the use of one type of pharmacologic prophylaxis agent over another.

Key Findings

Use of aspirin following major orthopedic surgery was generally found to be of similar effectiveness as other agents.
An overwhelming majority of studies concluded that aspirin has a lower bleeding risk rate than other pharmacologic agents, which, combined with its lower cost, makes it an appealing option for VTE prophylaxis, particularly in low-risk patients.
More prospective randomized controlled trials are needed to directly compare the effectiveness of aspirin with other prophylactic methods across patient risk levels.

Many hospitals include the use of aspirin in their surgical protocols for patients undergoing major orthopedic surgery. For prescribing surgeons, its use is at their discretion based on guideline recommendations, perceived patient risk, and the need to balance prevention with safety concerns, such as bleeding risk. This balance has become increasingly important as a growing number of studies have found that newer anticoagulant drugs are associated with a higher incidence of bleeding than prophylaxis agents.⁴ The review’s key findings are located in the box to the right.

16.1.2. Methods

To answer the question, “Is aspirin safe and effective for post-operative VTE prophylaxis in patients undergoing surgery?” two databases (CINAHL^® and MEDLINE^®) were searched for “Venous Thrombosis/Prevention & Control,” “deep vein thrombosis,” “pulmonary embolism,” and related synonyms, as well as “Aspirin/therapeutic use,” “Surgical Procedures, Operative,” “Perioperative Care/methods,” “Postoperative Complications/prevention & control,” and other similar terms. Articles included were published from 2008 to 2018. The initial search yielded 123 results. Once duplicates were removed and additional relevant articles from selected other sources were added, a total of 63 articles were screened for inclusion and full-text articles were retrieved. Of those, 33 were selected for inclusion in this review. Articles were excluded if the outcomes were not relevant to this review, the article was out of scope (including not quantitative), or study design was insufficiently described. As the results of this literature review were predominantly about major orthopedic surgery, relevance to this review included limiting articles to patients undergoing major orthopedic surgery.

General methods for this report are described in the Methods section of the full report.

For this patient safety practice, a PRISMA flow diagram and evidence table, along with literature-search strategy and search-term details, are included in the report appendixes A through C.

16.1.3. Review of Evidence

A box summarizing key findings related to the use of aspirin for the prevention of VTE in patients undergoing major orthopedic surgery is located in the Practice Description section. This section reviews applicable studies, organized by the scope of the intervention the patient received (aspirin alone, aspirin in combination with another pharmacologic prophylaxis agents, and aspirin in combination with mechanical prophylaxis) before discussing implementation considerations and any potential unintended consequences.

All included studies took place in the hospital setting and addressed patients undergoing total joint arthroplasty (TJA), THA, TKA, or HFS, with one notable exception of a study analyzing VTE outcomes in patients receiving surgery to remove cancerous tissue from a lower limb. Findings in this chapter can be best summarized by the conclusions reached in the six systematic reviews that met our inclusion criteria. Findings from these reviews varied in their determination of the efficacy of aspirin as a VTE prophylaxis and its benefits over other pharmacologic prophylaxis agents with regard to safety outcomes, predominant operative site, and other major bleeding.

One pooled analysis by Brown (2009) reviewed 14 randomized clinical trials to determine whether aspirin decreased the rate of operative site bleeding, without increasing the rate of thromboembolic events in patients undergoing THA, TKA, or HFS. The analysis found that the rates of VTE were not significantly different with aspirin when compared with vitamin K antagonists, LMWH, and pentasaccharides, but that the risk of bleeding was lower with aspirin.⁵ Similarly, Mistry et al. (2017) reviewed eight articles published from 2014 to 2017 on the use of aspirin for VTE prophylaxis following TKA or THA. Five of the articles concluded that aspirin was effective, and the systematic review noted that aspirin had a lower rate of complications while also being more cost effective than other available anticoagulants.⁶ Finally, a meta-analysis performed by Wang et al. (2017) sought to provide a comprehensive review of pharmacologic prophylaxis agents and reviewed 104 trials, 30 different drugs, and outcomes in 110,643 patients. Researchers found that aspirin, along with factor XI antisense oligonucleotide (FXI-ASO), ardeparin, and apixaban, were the most effective drugs at both preventing all-cause VTE and avoiding unintended bleeding events. While the meta-analysis findings were supportive of the use of aspirin, apixaban was found to have the most favorable outcomes.⁴

Conversely, Drescher et al. (2014) found in the eight clinical trials included in their review that, while overall the rate of DVT did not differ between aspirin and anticoagulants, aspirin may be associated with a higher risk of DVT following hip fracture repair when compared with anticoagulants, although it may be associated with lower bleeding risk.⁷ Similarly, Wilson et al. (2016) found in their analysis of 13 studies that, while there is evidence from one of their included studies that aspirin has similar rates of VTE following TKA when compared with LMWH, the majority of trials included were at a moderate to severe risk of bias and had insufficient evidence that aspirin was more or less effective than LMWH, warfarin, or dabigatran.⁸ Finally, in their review of 14 studies to assess the appropriateness of aspirin as a prophylaxis in high-risk patients undergoing THA, TKA, or HFS, Stewart and Freshour (2013) determined that the evidence is inconsistent as to whether aspirin is effective at preventing VTE and whether there is a decreased risk of bleeding in comparison with other anticoagulants. This may indicate a need for patient risk stratification when determining the appropriateness of aspirin, as discussed later in this chapter.⁹

16.1.3.1. Aspirin as Sole Prophylaxis Treatment

Five studies included in our review discussed aspirin as the sole prophylaxis used in patients at risk for developing VTE following surgery. A number sought to directly compare its effectiveness as a sole approach with other pharmacologic approaches. Goel et al. (2018) found that, in patients undergoing simultaneous bilateral TKA, the risk for PE was significantly lower for patients prescribed aspirin (n=1528) versus warfarin (n=2157) after accounting for baseline VTE risk (p=0.005). Goel et al. also found that the risk for combined VTE, consisting of both PE and DVT, was nearly significantly lower for those on aspirin (p=0.052).¹⁰

In a more comprehensive analysis of available pharmacologic prophylaxis options, Agaba et al. (2017) conducted a retrospective review of patients undergoing THA using a nationwide private and Medicare insurance database. Patients studied received either aspirin alone or one of five anticoagulants. The analysis found that patients given aspirin alone had a significantly lower rate of both DVT and PE at 30 and 90 days following surgery, with an insignificant bleeding risk. Following a review of the effectiveness and safety side effects of each of the pharmacologic agents included in the study, Agaba et al. concluded that while rivaroxaban and fondaparinux have lower bleeding and thromboembolic events compared with other newer anticoagulants, aspirin also meets these criteria. In addition, aspirin is an easy-to-use, inexpensive option for prophylaxis following THA.¹¹ In a similar study reviewing TKAs over a 9-year period in a combined Humana and Medicare database, Bala et al. (2017) compared outcomes of patients receiving aspirin (n=1016) matched by age and sex with patients receiving enoxaparin (n=6096), warfarin (n=6096), and factor Xa inhibitors (n=5080). Factor Xa inhibitors were found to have the lowest incidence of DVT and PE (p<0.01) at 90 days, and there was no difference in bleeding-related complications between the agents (p=0.81). However, researchers concluded that aspirin had the lowest incidence of postoperative anemia (p<0.01) and blood transfusion (p<0.01) at 90 days, and provided VTE prophylaxis comparable to Xa inhibitors and more effective than enoxaparin and warfarin.¹²

Mendez et al. (2017) conducted a retrospective review of medical records for patients who underwent lower-limb surgery as a component of their oncology treatment. Patients either received 325 mg of aspirin twice daily (n=103) or were assigned to the non-aspirin group (n=39) (which included LMWH, unfractionated heparin, warfarin, and intermittent pneumatic compression device only). No patient in the aspirin group developed a VTE. Aspirin for VTE prophylaxis in patients undergoing orthopedic oncologic surgery appears to be effective, but more robust study may be necessary.¹³

16.1.3.2. Multimodal Prophylaxis

16.1.3.2.1. Aspirin in Combination With Other Pharmacologic Prophylaxis

Several of the studies reviewed addressed the use of aspirin in combination with other pharmacologic prophylactic agents. Anderson et al. (2013) conducted a randomized controlled trial at 12 tertiary care orthopedic referral centers in Canada. All patients undergoing elective THA surgery were prescribed a 10-day course of LMWH before being randomly assigned to either 28 days of continued LMWH (n=400) or 28 days of aspirin (n=386). Findings indicate that switching patients to aspirin following an initial course of LMWH was not worse (p<0.001) but not better than continued use of LMWH. Additionally, clinically significant bleeding occurred in five patients with a continued course of LMWH (1.3%), versus two (0.5%) who switched to aspirin (p=0.45).¹⁴

In a similar study, Anderson et al. (2018) conducted a double-blind randomized controlled trial at 15 university-affiliated health centers in Canada. Patients undergoing elective unilateral primary or revision hip or knee arthroplasty received once-daily oral rivaroxaban for the first 5 days following surgery, and then were randomized to either continue the course of rivaroxaban or switch to aspirin for the next 9 days after TKA, or 30 days after THA. Findings indicate that aspirin is not worse (p<0.001) but not better than continued use of rivaroxaban. Additionally, there was not a significant difference in bleeding between the two groups (p=0.43).¹⁵

Finally, Hamilton et al. (2012) conducted a retrospective review of patients receiving aspirin prophylaxis after primary hip and knee arthroplasties. Patients received a course of enoxaparin during their inpatient stay, followed by a course of aspirin for 28 days following discharge. Patients were compared with a control group that first received enoxaparin for 2 weeks following discharge before receiving a course of aspirin for a further 2 weeks. Researchers concluded that a protocol of only inpatient enoxaparin and then aspirin post discharge was both safe and effective in standard-risk patients.¹⁶

16.1.3.2.2. Aspirin in Combination With Mechanical Prophylaxis

The majority of articles reviewed (20) included the use of an anticoagulant or antiplatelet in combination with other mechanical prophylaxis methods. Seventeen of the articles reviewed concluded that aspirin was safe and effective when used in combination with mechanical prophylaxis methods. For example, Deirmengian et al. (2016) conducted a retrospective review of patients undergoing TJA. All patients received mechanical prophylaxis and then either warfarin (n=2463) or aspirin (n=534). The study found that the differences between the groups with regard to DVT or PE alone were not statistically significant (p=0.15; p=0.06, respectively). Fisher’s exact test showed a significantly higher risk for any symptomatic VTE in patients receiving warfarin (43 events, 1.75%) compared with patients receiving aspirin (3 events, 0.56%; odds ratio [OR]: 3.2; 95% confidence interval [CI], 1.03 to 16.3; p=0.03).¹⁷ Similarly, Raphael et al. (2014) conducted a retrospective analysis of patients undergoing TJA. Patients were treated with compression devices while at the same time receiving either aspirin (n=2,800) or warfarin (n=26,123) prophylaxis. The analysis found that the overall symptomatic PE rate was lower (p<0.001) in patients receiving aspirin (0.14%) than in the patients receiving warfarin (1.07%). The incidence of symptomatic DVT was significantly lower in the aspirin group (0.29%) than in the warfarin group (0.99%) (OR=3.50; 95% CI, 1.75 to 8.19; p<0.001) and the risk of symptomatic DVT remained lower in the aspirin group than in the warfarin group even after propensity score matching was performed.¹⁸

Only two studies among those reviewed assessed whether the effectiveness of aspirin was improved by the use of mechanical devices, with mixed findings. Daniel et al. (2008) performed a retrospective study comparing the incidence of VTE in patients undergoing THA and hip resurfacing among those who received aspirin for 30 days following surgery (n=258) and those who received aspirin and mechanical prophylaxis for 30 days (n=229). Results indicate a statistically significant difference in DVT prevalence, indicating aspirin in combination with mechanical prophylaxis is more effective than aspirin alone.¹⁹ However, Hamilton et al. (2012), in their retrospective review of patients receiving primary hip and knee arthroplasties, compared patients receiving enoxaparin and mechanical compression prior to a 28-day course of aspirin post discharge, versus enoxaparin alone during the inpatient stay prior to an outpatient 2-week course of enoxaparin followed by a 2-week course of aspirin. There was a trend toward a lower rate of DVT among those who received mechanical compression compared with those who did not, but this difference did not near statistical significance until using a Fisher exact test (p=0.07). Additionally, there was no significant difference between the two groups in the number of patients with the following outcomes: pulmonary embolus, deep infection, superficial infection, readmission, or death.¹⁶

Three articles did not reach a conclusion as to whether aspirin in conjunction with mechanical prophylaxis was safe and effective for preventing VTE in orthopedic patients. In two studies, this was because either the incidence of VTE in the patient population was so low that it was too difficult to achieve statistical significance in the data analysis²⁰ or the incidence was so low that there were no DVTs or PEs identified in the patient population.²¹ However, in one of the three studies, the authors concluded that antiplatelet agents were not effective in preventing symptomatic VTE in HFS patients after those who received an aspirin or other antiplatelet had a VTE incidence of 4.8 percent, compared with no antiplatelet use with an incidence of 4.3 percent (p=0.718).²²

16.1.3.3. Aspirin Dosing Considerations

Several included studies examined the impact of different aspirin doses on clinical outcomes following surgery. In their retrospective analysis, Faour et al. (2018) analyzed the medical records of patients receiving aspirin twice daily for 4 to 6 weeks following TKA. Patients received low-dose, 81 mg, aspirin (n=1,327) or standard-dose, 325 mg (n=2,903). Analysis concluded that aspirin is safe and effective but that there was a significant difference in the incidence of VTE and DVT between the two groups (p=0.02 and p<0.001, respectively), with those receiving a standard dose experiencing a higher incidence of VTE and DVT (1.5% vs. 0.7% and 1.4% vs. 0.3%). However, there was not a significant difference in the incidence of PE (p=0.13), and a regression analysis showed no correlation between aspirin doses and the incidence of VTE (both DVT and PE) or DVT alone (p=0.94 and 0.20). Further, there is no statistically significant difference in the incidence of gastrointestinal (GI) or wound bleeding (p=0.62). Faour et al. reached similar conclusions when conducting the same retrospective analysis for patients undergoing THA (2018),²³ but Feldstein et al. (2017) noted there may be more GI distress and nausea when patients are prescribed standard-dose aspirin versus low-dose aspirin following TJA.²⁴

In their retrospective multi-institutional study, Goel et al. (2018) reviewed the outcomes for patients receiving either aspirin or warfarin following unilateral or bilateral TKA. Patients in the aspirin group received either regular-dose (325 mg) or low-dose aspirin (81 mg), at the surgeons’ discretion. The results showed that regardless of the dosing, aspirin was more effective than warfarin and deemed an appropriate agent for VTE prophylaxis for patients in all risk categories.¹⁰

16.1.3.4. Economic Outcomes

When considering the use of aspirin for VTE prophylaxis in patients undergoing major orthopedic surgery, cost considerations are a factor noted in a number of the articles reviewed. While there were no cost-effectiveness analyses included in the identified articles, Hamilton et al. (2012) noted that limiting enoxaparin to the inpatient setting and prescribing only aspirin post discharge saved on average $400.30 per case in medication costs.¹⁶ Further, Mendez et al. (2017) estimated that, in 2010 wholesale drug prices, 14 days of aspirin therapy is approximately $0.38, versus $730.50 for 14 days of twice-daily LMWH.¹³ Similarly, Jiang et al. (2014) also found a cost savings in the use of aspirin when compared with rivaroxaban and LMWH.²⁵ Other study authors frequently noted that use of aspirin should be considered, particularly among low-risk patients, due to not only its similar efficacy but also its low cost—compared with both direct and indirect costs associated with other pharmacologic agents—as a “widely available generic agent.” (Anderson et al., 2018).¹¹^,¹⁴^,¹⁵^,¹⁷^,²³^,²⁶

16.1.3.5. Unintended Consequences

16.1.3.5.1. Positive Unintended Consequences

There are a number of potential positive unintended consequences associated with the use of aspirin for VTE prophylaxis. As previously mentioned, generic aspirin is widely available and significantly cheaper than alternative medications. Additionally, administrative costs are lower than with some alternative pharmacologic prophylaxis agents that require intravenous delivery or ongoing laboratory monitoring, such as with warfarin. Ease of administration may in turn have a positive impact on patient quality of life during the treatment period and support medication adherence.

16.1.3.5.2. Negative Unintended Consequences

As with other pharmacologic prophylaxis agents, there is the potential risk that patients prescribed aspirin following major orthopedic surgery will experience operative site or major bleeding. The analysis of the incidence of these events was a priority for many of the articles included in this review. Twenty-three of the studies specifically addressed unintended patient safety outcomes in their analysis and conclusions. Of those, 22 concluded that overall aspirin was safer than other pharmacologic options, or had comparable risk. For example, Jiang et al. (2014) found that patients in the aspirin group had a lower blood loss index than patients who received LMWH or rivaroxaban following TKA (p=0.000), and Deirmengian et al. (2016) found a higher rate of bleeding events in patients prescribed warfarin versus aspirin (p=0.02) following TJA.¹⁷^,²⁵ The identified systematic reviews reached similar conclusions, with two of the reviews determining that use of aspirin has a lower bleeding relative risk than other pharmacologic options.⁵^,⁶ Other studies found no difference in bleeding risk between aspirin and other therapies. For example, Anderson et al. (2018) found there was no statistical difference in major bleeding and clinically nonmajor bleeding between aspirin and rivaroxaban following THA or TKA (p=0.43).¹⁵ Similarly, Zou et al. (2014) found no significant differences in hidden blood loss between patients receiving aspirin, rivaroxaban, or LMWH, and Huang et al. (2016) found no significant difference in GI complications between patients receiving warfarin or aspirin.²⁶^,²⁷

16.1.4. Implementation

16.1.4.1. Patient Risk Stratification

An important consideration when establishing the appropriateness and potential efficacy of aspirin following major orthopedic surgery is the patient risk profile. While 24 of the 27 included studies determined aspirin is safe and as effective, if not more effective, than other prophylaxis methods, a potential confounding or even misleading factor is the risk stratification of patients. In almost 50 percent of studies, some degree of patient risk stratification occurred. For example, Kaye et al. (2015) conducted a randomized prospective study comparing the use of standard-dose aspirin with no form of chemoprophylaxis among patients undergoing arthroscopic knee surgery (n=170). They found that there were no incidences of DVT or PE regardless of treatment status, and a logistical regression found that aspirin was not statistically significant for a decreased risk of complications following arthroscopic knee surgery. However, they conducted this study specifically in low-risk patients and no conclusions can be made for other risk groups.²¹ Parvizi et al. (2017) similarly excluded patients at high risk from their prospective data collection protocol.²⁸ Among retrospective studies, Raphael et al. (2014) specifically removed patients considered at high risk for VTE from their retrospective data analysis and Deirmengian et al. (2016) indicated that treatment was based on the surgeons’ discretion, which may imply some risk stratification in treatment determinations as part of normal practice.¹⁷^,¹⁸

16.1.4.2. Resources To Assist With Implementation

Resources to help identify patient VTE risk are available from:

AHRQ
-
Preventing Hospital-Associated Venous Thromboembolism: A Guide for Effective Quality Improvement: https://www.ahrq.gov/professionals/quality-patient-safety/patient-safety-resources/resources/vtguide/vtguide4.html^p
- This guide includes a chapter that provides an overview of the major categories and characteristics of VTE risk assessment models to support the development of a VTE prevention protocol within the facility.
The Center for Outcomes Research at the University of Massachusetts Medical School: https://www.outcomes-umassmed.org/risk_models_improve_vte.aspx^q
-
The IMPROVE VTE Risk Calculator is a clinical decision tool for VTE risk assessment and prophylaxis that can be accessed via computer, iPhone, and iPad.
The University of Michigan: https://www.med.umich.edu/clinical/images/VTE-Risk-Assessment.pdf^r
-
A thrombosis risk factor assessment checklist is available to be printed for manual use. This checklist is for elective general surgery but may be modified for patients undergoing major orthopedic surgery.

16.1.5. Gaps and Future Directions

16.1.5.1. Gaps

There are a number of gaps in current literature highlighted by our review. First, only eight of the included studies were prospective and only six included patient randomization to an intervention. As previously mentioned, risk stratification of patients for treatment determination may play an important role in ultimate patient outcomes. So, while the overarching evidence from this review does indicate that aspirin is an effective and safe option for VTE prophylaxis following major orthopedic surgery, there may be limitations to the generalizability of these findings. There is a need for more prospective, randomized controlled trials directly comparing patient outcomes between those prescribed aspirin and those given other available prophylaxis options across risk levels. Second, there is a lack of studies providing direct comparison between aspirin in conjunction with mechanical prophylaxis versus aspirin alone. Given that the use of mechanical prophylaxis is pervasive in the studies identified, it would be useful to determine whether this makes a difference across different levels of patient risk. Finally, while researchers often note that aspirin is cheaper and more cost effective than other prophylaxis options, formal cost-effectiveness analyses are needed for both chemoprophylaxis and mechanical prophylaxis alternatives.

16.1.5.2. Future Directions

In addition to addressing the gaps noted above, a further area that may help better determine the efficacy of aspirin in different patient populations is research into best methods or approaches for diagnosing VTE, in particular DVT. Additionally, as noted in Stewart and Freshour (2013), individual studies may define “bleeding” differently, posing a challenge when making comparisons across multiple bodies of research. Therefore, a standardized definition may be helpful for researchers and providers alike.⁹

References for Section 16.1

1.: American Society of Hematology. ASH Draft Recommendations for VTE Prevention in Surgical Hospitalized patients. https://www.hematology.org/Clinicians/Guidelines-Quality/Documents/8732.aspx.Accessed September 17, 2019.
2.: Falck-Ytter Y, Francis CW, Johanson NA, et al. 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.10.1378/chest.11-2404. [PMC free article: PMC3278063] [PubMed: 22315265] [CrossRef]
3.: Mont MA, Jacobs JJ, Boggio LN, et al. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Am Acad Orthop Surg. 2012;19(12):768–76 [PubMed: 22134209]
4.: Wang Z, Zheng J, Zhao Y, et al. Effectiveness and tolerability of anticoagulants for thromboprophylaxis after major joint surgery: A network meta-analysis. Cell Physiol Biochem. 2017;42(5):1999–2020.10.1159/000479840. [PubMed: 28793291] [CrossRef]
5.: Brown GA. Venous thromboembolism prophylaxis after major orthopaedic surgery: a pooled analysis of randomized controlled trials. J Arthroplasty. 2009;24:(6 Suppl):77–83.10.1016/j.arth.2009.06.002. [PubMed: 19628366] [CrossRef]
6.: Mistry DA, Chandratreya A, Lee PYF. A systematic review on the use of aspirin in the prevention of deep vein thrombosis in major elective lower limb orthopedic surgery: An update from the past 3 years. Surg J (N Y). 2017;3(4):e191–e6.10.1055/s-0037-1615817. [PMC free article: PMC5747531] [PubMed: 29302621] [CrossRef]
7.: Drescher FS, Sirovich BE, Lee A, et al. Aspirin versus anticoagulation for prevention of venous thromboembolism major lower extremity orthopedic surgery: A systematic review and meta-analysis. J Hosp Med. 2014;9(9):579–85.10.1002/jhm.2224. [PubMed: 25045166] [CrossRef]
8.: Wilson DG, Poole W E, Chauhan SK, et al. Systematic review of aspirin for thromboprophylaxis in modern elective total hip and knee arthroplasty. Bone Joint J. 2016;98-b(8):1056–61.10.1302/0301-620x.98b8.36957. [PubMed: 27482017] [CrossRef]
9.: Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother. 2013;47(1):63–74.10.1345/aph.1R331. [PubMed: 23324504] [CrossRef]
10.: Goel R, Fleischman AN, Tan T, et al. Venous thromboembolic prophylaxis after simultaneous bilateral total knee arthroplasty: aspirin versus warfarin. Bone Joint J. 2018;100-b(1 Supple A):68–75.10.1302/0301-620x.100b1.Bjj-2017-0587.R1. [PMC free article: PMC6424442] [PubMed: 29292343] [CrossRef]
11.: Agaba P, Kildow BJ, Dhotar H, et al. Comparison of postoperative complications after total hip arthroplasty among patients receiving aspirin, enoxaparin, warfarin, and factor xa inhibitors. J Orthop. 2017;14(4):537–43.10.1016/j.jor.2017.08.002. [PMC free article: PMC5574820] [PubMed: 28878512] [CrossRef]
12.: Bala A, Huddleston JI, 3rd, Goodman SB, et al. Venous Thromboembolism prophylaxis after TKA: aspirin, warfarin, enoxaparin, or factor xa inhibitors? Clin Orthop Relat Res. 2017;475(9):2205–13.10.1007/s11999-017-5394-6. [PMC free article: PMC5539035] [PubMed: 28569372] [CrossRef]
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Conclusion and Comment

The Patient Safety Practice reviewed in this chapter aims to reduce VTE by providing an effective, safe, and low-cost approach to pharmacologic prophylaxis in patients undergoing major orthopedic surgery. This review of the evidence generally finds that use of aspirin following these surgical procedures—either as the sole prophylaxis agent in combination with other pharmacologic agents or in conjunction with mechanical prophylaxis—is equivalent to other agents or has a better safety profile. Many studies were retrospective and/or included patient risk stratification either in the treatment allocation or in the exclusion of data for analysis. This indicates a need for prospective randomized controlled trials directly comparing the impact of different prophylaxis methods across patient risk categories. However, this review provides greater insight into the effectiveness of aspirin for preventing VTE in patients following major orthopedic surgery.

Footnotes

p: Agency for Healthcare Research and Quality. Preventing Hospital-Associated Venous Thromboembolism: Chapter 4—Choose the Model to Assess VTE and Bleeding Risk. https://www.ahrq.gov/professionals/quality-patient-safety/patient-safety-resources/resources/vtguide/vtguide4.html.
q: University of Massachusetts Medical School. Center for Outcomes Research: Risk Assessment Models—IMPROVE (VTE). https://www.outcomes-umassmed.org/risk_models_improve_vte.aspx.
r: University of Michigan. Deep Vein Thrombosis Prophylaxis Orders: Thrombosis Risk Factor Assessment. https://www.med.umich.edu/clinical/images/VTE-Risk-Assessment.pdf.

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