Postoperative aspirin use and its effect on bone healing in the treatment of ankle fractures

Journal Pre-proof

Postoperative Aspirin Use and its Effect on Bone Healing in the Treatment of Ankle Fractures Allison M. Hunter MD Orthopaedic Resident;PGY-4 , Tyler P. Montgomery BS Orthopaedic Research Fellow , Charles Pitts MD Orthopaedic Resident;PGY-3 , Leonardo Moraes MD Foot and Ankle Surgeon , Matthew Anderson BS Medical Student;MS3 , John Wilson BS Medical Student;MS3 , Gerald McGwin PhD Epidemiologist and Statistician , Ashish Shah MD Foot and Ankle Surgeon;Primary Investigator PII: DOI: Reference:

S0020-1383(19)30760-0 https://doi.org/10.1016/j.injury.2019.11.039 JINJ 8471

To appear in:

Injury

Accepted date:

25 November 2019

Please cite this article as: Allison M. Hunter MD Orthopaedic Resident;PGY-4 , Tyler P. Montgomery BS Orthopaedic Research Fellow , Charles Pitts MD Orthopaedic Resident;PGY-3 , Leonardo Moraes MD Foot and Ankle Surgeon , Matthew Anderson BS Medical Student;MS3 , John Wilson BS Medical Student;MS3 , Gerald McGwin PhD Epidemiologist and Statistician , Ashish Shah MD Foot and Ankle Surgeon;Primary Investigator , Postoperative Aspirin Use and its Effect on Bone Healing in the Treatment of Ankle Fractures, Injury (2019), doi: https://doi.org/10.1016/j.injury.2019.11.039

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Ltd.

HIGHLIGHTS   

Post-operative Aspirin administration was non-inferior to no Aspirin after ankle fracture fixation in time to healing and radiographic union. Post-operative deep vein thrombosis was not significantly different between Aspirin and no Aspirin after ankle fracture fixation. Non-steroidal anti-inflammatories may be a reasonable choice for venous thromboembolism prophylaxis after ankle fracture fixation.

1

Postoperative Aspirin Use and its Effect on Bone Healing in the Treatment of Ankle Fractures Allison M. Hunter, MD1 Orthopaedic Resident, PGY-4 Tyler P. Montgomery, BS1 Orthopaedic Research Fellow Charles Pitts, MD1 Orthopaedic Resident, PGY-3 Leonardo Moraes, MD1 Foot and Ankle Surgeon Matthew Anderson, BS1 Medical Student, MS3 John Wilson, BS1 Medical Student, MS3 Gerald McGwin, PhD3 Epidemiologist and Statistician Ashish Shah, MD1 Foot and Ankle Surgeon, Primary Investigator 1

Department of Orthopaedic Surgery, University of Alabama at Birmingham; Birmingham, AL 2 School of Medicine, University of Alabama at Birmingham; Birmingham, AL 3 Department of Epidemiology, University of Alabama at Birmingham; Birmingham, AL Corresponding Author: Ashish Shah, MD1 1313 13th Street South, Birmingham, AL 35202 (p) 402-238-5608 [email protected]

ABSTRACT Background: There is hesitancy to administer nonsteroidal anti-inflammatories (NSAIDs) within the postoperative period following fracture care due to concern for 2

delayed union or nonunion. However, aspirin (ASA) is routinely used for chemoprophylaxis of deep vein thrombosis (DVT) and is gaining popularity for use after treatment of ankle fractures. The current study examines the incidence of nonunion of operative ankle fractures and risk of DVT in patients who did and did not receive postoperative ASA. Methods: A retrospective chart review was performed on all patients treated between 2008 and 2018 for ankle fractures requiring operative fixation by three Foot and Ankle fellowship trained orthopaedic surgeons at a single institution. Demographics, preoperative comorbidities, and postoperative medical and surgical complications were compared between patients who did and did not receive ASA postoperatively. For both groups, union was evaluated by clinical exam as well as by radiograph, for those with 6week, 12-week, or 24-week follow-up. Results: Five-hundred and six patients met inclusion criteria: 152 who received ASA and 354 who did not. Radiographic healing at six weeks was demonstrated in 95.9% (94/98) and 98.6% (207/210) respectively (p-value .2134). There was no significant difference in time to radiographic union between groups. The risk of postoperative DVTs in those with and without ASA was not significantly different (0.7% (1/137) vs 1.2% (4/323), respectively; p-value .6305).

Conclusion: Postoperative use of ASA does not delay radiographic union of operative ankle fractures or affect the rate of postoperative DVT. This is the first and largest study to examine the effect of ASA on time to union of ankle fractures. Level of Evidence: III Keywords: Ankle fracture; Nonunion; Nonsteroidal anti-inflammatory, Aspirin

3

4

INTRODUCTION

Ankle fractures are among the most common fracture types treated in the orthopaedic community, with an incidence of 137 to 168 fractures per 100,000 patients treated per year18,13, accounting for 10.2% of all bony injuries.13 A large portion of these require operative intervention, usually necessitating a period of postoperative immobilization.9 For patients who have undergone open reduction and internal fixation (ORIF) of an ankle fracture, there is a reported risk of deep vein thrombosis (DVT) and fatal pulmonary thromboembolism in the literature.40,28 As such, the risk of symptomatic venous thromboembolism (VTE) is of increasing concern, both from a practical and medicolegal perspective. Despite this, the use of chemical DVT prophylaxis in the setting of foot and ankle surgery and ankle fracture fixation is controversial. 28 In total joint arthroplasty, aspirin (ASA) is endorsed by the American Academy of Orthopaedic Surgeons (AAOS) as a DVT chemoprophylactic agent in low risk patients and is comparable to low molecular weight heparin in incidence of postoperative thromboembolic phenomena in total knee arthroplasty.6 However, there are no documented guidelines for thromboembolic prophylaxis following ankle fracture fixation.

Overall, a number of reviews in the literature report low rates of pulmonary emboli requiring readmission (0.32%-0.34%) following ORIF.34,38 For low risk patients, these concluded that the need for postoperative chemical prophylaxis is unknown, and possibly unnecessary.18, 34, 38 In spite of equivocal research findings and the lack of clear recommendations, many foot and ankle surgeons choose to treat patients who have undergone ankle ORIF with thromboembolic prophylaxis, such as ASA due to its ease of

5

administration, availability, and low cost. Despite these advantages, the use of ASA is not without complication, particularly in the setting of fracture healing.

Both basic science and clinical research suggests that non-steroidal anti-inflammatory drugs (NSAIDs), such as ASA, impair fracture healing. 2, 11, 13, 19, 23 In the process of fracture healing, a complex and sequential set of events are required in the three phases of inflammation, repair, and remodeling. The inflammatory phase is marked by hematoma formation at the fracture site, providing a source of hemopoietic cells, such as macrophages and platelets that release inflammatory cytokines (PDGF, TNF-, TBG-, IL-2, 6, 10, 12) growth factors, and prostaglandins. 7 Fibroblasts and mesenchymal cells then migrate to the fracture site to form granulation tissue and ultimately pre-osteoblasts, followed by local osteoblasts to form new bone.

NSAIDs are thought to alter bone healing by tempering the inflammatory phase, though the true mechanism is most likely multifaceted. Inhibition of COX-2, the cyclooxygenase pathway responsible for upregulation of inflammation, represses runx-2/osterix, which is integral for differentiation of osteoblasts, thereby reducing the number of viable osteoblasts and theoretically accounting for decreased bone healing. 22, 41 Angiogenesis is also thought to be affected by NSAIDs, as COX-2 metabolic products (PG) stimulate angiogenesis, essential for fracture healing. 17

6

In animal studies, NSAIDs and ASA were shown to decrease the rate of fracture healing in both a rat and rabbit model.2,23 In humans, tibial shaft fractures treated with intramedullary fixation and postoperative ASA displayed delayed progression of radiographic healing.11 Furthermore, NSAIDs have been shown to negatively affect long bone fracture healing and may even predispose to higher rates of infection.13,19 However, little work has focused specifically on the effect of NSAIDS on foot and ankle fractures.

A known complication in the operative treatment of ankle fractures is nonunion, or pseudarthrosis. However, non-union is relatively rare and not well reported in the literature.7 A recent review of fractures in Scotland found the nonunion rate among ankle fractures to be 0.9%.30 Currently, there are no studies describing the relationship between postoperative chemoprophylactic ASA and bony union in ankle fractures. The purpose of this study is to examine the incidence of nonunion of the lateral, posterior, or medial malleolus following open reduction and internal fixation of ankle fractures in patients who did and did not receive postoperative aspirin, as well as the risk of DVT in these two groups.

MATERIALS AND METHODS

This study was reviewed and approved by the Institutional Review Board in accordance with the Declaration of Helsinki. A retrospective chart review was performed on all patients with medial or lateral malleolar, bimalleolar, or trimalleolar ankle fractures, requiring operative fixation, with or without postoperative administration of ASA for DVT chemoprophylaxis between 2008 and 2018. Patients were excluded with 7

polytrauma or those with previous history of anticoagulation therapy prior to surgery. Once patients were identified, data extraction was performed by three independent reviewers and verified for correctness.

Data Collection Patient demographics, preoperative comorbidities, and postoperative medical and surgical complications were compared between patients that received aspirin for postoperative DVT prophylaxis and those who did not. Preoperative variables including age at the time of surgery, sex, race, body mass index (BMI), history of tobacco use (current, former, or lifetime smokers), active alcohol or substance abuse, and American Society of Anesthesiologists (ASA) classification. Reviewers also recorded the presence of relevant comorbidities, including cardiopulmonary disease (hypertension, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease), neuropathy, immune deficiency (chronic steroid use, human immunodeficiency virus (HIV), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE)), renal dysfunction, and history of stroke or paralysis.

Postoperative complications, including superficial wound infection, deep wound infection, wound dehiscence, sepsis, deep vein thrombosis (DVT) were identified. The need for revision surgery, including implant failure or implant removal were recorded.

Finally, follow up clinic visits were evaluated for clinical outcomes, including pain scores and time to union over the course of 2-week, 6-week, 3-month, 6-month, and 12-month postoperative follow up using radiographic review. Clinical healing was based on retrospective chart review and defined as minimal to no tenderness on palpation of the fracture site, ability to fully weight bear through the extremity, and physician evaluation 8

of radiographs with resolution of fracture line defined as union. Those patients with delayed union (persistent fracture line at 12 weeks), nonunion (persistent fracture line at 24 weeks), or malunion in both groups were identified and compared. Those with 6week, 12-week, or 24-week follow-up were evaluated for union at those timeframes.Wound complications were defined as any superficial or deep infection requiring local wound care, postoperative antibiotics, or return to the operating room.

Operative Protocol Surgeries were performed by three Foot and Ankle fellowship trained orthopaedic surgeons at a single institution. Fracture stability was achieved using a combination of plate and screw constructs, and, when indicated by pre or intraoperative stress exam, syndesmotic fixation was achieved using screw fixation or a TightRope (Arthrex Inc, Naples, FL).

Postoperative Care Each patient was placed into a splint following surgery and made non-weightbearing for a minimum of 6-8 weeks. Weightbearing status was measured by asking patients at their clinical visits about their compliance with their weightbearing restrictions. Clinical and radiographic assessments were performed at 2-week, 6-week, 3-month, 6-month, 12month visits. Clinically, attention was paid to skin appearance, pain, neurovascular status, and ankle range of motion, while radiographic evaluation consisted of anteroposterior (AP), lateral, and mortise ankle x-rays. Between 2-3 weeks, special attention was paid to wound healing and suture removal. At 6-8 weeks, weightbearing was advanced using a walking boot. If clinical or radiographic union was delayed, continued non-weightbearing was recommended for an additional 2-6 weeks. Diabetic patients were made nonweightbearing for 12 weeks. 9

Postoperative Aspirin Patients were prescribed once daily Aspirin (325mg) from the first postoperative day, until they were fully weightbearing (generally 6-8 weeks). Patients who did not receive postoperative aspirin also did not receive any other type of anticoagulation therapy. All other aspects of their care were the same.

Statistical Analysis T- and chi-square tests were used to compare continuous and categorical variables, respectively, between patients who did and did not receive post-operative ASA. Nonparametric and Fisher’s exact tests were used when deemed necessary. P-values of <0.05 were considered statistically significant.

RESULTS In total, 506 patients met the inclusion criteria for this study and were included in the final analysis (152 who received ASA and 354 who did not). The demographic characteristics of ASA and non-ASA patients are, respectively, mean age of 43.8 and 41.7 years (p-value .1693), 43.4% (66/152) and 46.2% (163/353) male (p-value .5684), 51.3% (78/152) and 51.1% (180/352) Caucasian (p-value .5182), mean BMI of 31.2 and 30.5 (p-value .2845), with a majority in both groups being American Society of Anesthesiologists Class 2, 48.7% (74/152) versus 53.7% (189/352) (p-value .0983). There were no significant differences in medical comorbidities between the ASA and non-ASA patients, respectively (Table 1), except for immunosuppressant use (0.7% (1/137) versus 4.6% (15/324); p-value .0366) and hypertension (41.6% (59/142) versus 29.1% (95/327); p-value .0081).

10

Complication risks among ASA and non-ASA patients (Table 2), respectively, were 3.6% (5/138) versus 6.5% (21/324) for superficial infection (p-value .2224), 0.7% (1/137) versus 3.4% (11/323) for deep infection (p-value .0997), 4.4% (6/138) versus 4.0% (13/323) for wound dehiscence (p-value .8730), 0.7% (1/137) versus 0.0% (0/323) for sepsis (p-value .1243), and 9.4% (13/138) versus 8.3% (27/324) for hardware failure (pvalue .7038). Mean pain scores (Table 2) at 2, 6, 12, and 24 weeks were not significantly different between groups.

Radiographic healing was assessed at 6, 12, and 24 weeks. The percent showing expected radiographic healing among ASA and non-ASA patients were, respectively, 95.9% (94/98) versus 98.6% at 6 weeks (207/210) (p-value .2134), 96.0% (72/75) versus 94.9% (149/157) at 12 weeks (p-value .8998), and 95.9% (94/98) versus 98.6% (207/210) at 24 weeks. (p-value .2134). Nonunion risks at 24 weeks (Table 2) between the ASA and nonASA patients were, respectively, 3.1% (3/98) and 1.0% (2/210) (p-value .2134). None of the nonunions occurred in patients on immunosuppressive therapy.

With respect to the incidence of DVT within the postoperative period, there was no statistical difference found between groups, with a 0.7% (1/137) risk of DVT in those who received prophylactic ASA versus 1.2% (4/323) in those that did not (p-value .6305).

A subgroup analysis based on risk factors (tobacco use, alcohol use, illicit drug use, diabetes, HIV, immunosuppressant use, peripheral neuropathy, chronic kidney disease, RA) was also performed (Table 3). Outcomes were delineated based on ASA use and whether a patient had one of the listed risk factors. ASA use was not associated with a statistically significant difference in complication risk, healing risks, or pain scores 11

(Table 3). Of note, patients with at least one risk factor who received ASA had shorter follow-up than those with at least one risk factor who did not receive aspirin.

DISCUSSION The role of inflammation in fracture healing is key, thus in theory the inhibition of the COX-2 pathway by NSAIDs, such as the ASA prescribed in the postoperative period for DVT prophylaxis, may play a role in nonunion. However, this clinical question has not been posed in the setting of ankle fractures and rates of nonunion. McDonald et al. 29 recently reported on the postoperative use of ketorolac, another non-selective COX inhibitor, for analgesia following ankle fracture fixation and found no difference in time to union when compared to published literature. Weaknesses of McDonald et al.’s study include the lack of a control group, fewer patients, single-surgeon series, and brief administration of the medication. Comparably, however, the current study has a large control group, treated by three surgeons, and similarly suggests that no differences exist in time to radiographic union in those treated with or without the nonselective COX inhibitor ASA in the postoperative period.

Currently, no clinical practice guidelines or standard of care is recognized by the AAOS in DVT prophylaxis for patients undergoing surgery for an ankle fracture. However, due to an increase in litigation and a growing body of knowledge relating to DVT prevention, ASA and other pharmacologic agents are increasingly utilized in the postoperative period following ankle ORIF. Ahmad et al.1 found the risk for symptomatic VTE after orthopaedic foot and ankle surgery to be very low at 0.79% within the 90 follow up period, with obesity being the highest risk factor in those that did develop VTE. Our results show a comparable rate of VTE and are consistent with this prior published work.

12

Aspirin is a readily available, easy-to-administer and inexpensive modality with a low risk of bleeding-related complications. As a result, this medication is gaining popularity in orthopaedic postoperative care. The role of NSAIDs and inhibition of bone healing has been studied at both the basic science level, in animal models, veterinary medicine, as well as the clinical setting.3-5,11,23 An increasing body of evidence suggests that the use of NSAIDs decreases bone healing rates, increases the likelihood for nonunion, and even leads to decrease fusion mass in spine patients15,25,36; however, a larger systematic analysis controlling for high-quality studies suggested that there was no increase in nonunion risk with NSAID exposure in spinal fusion surgery.10 For those that support the idea of healing inhibition by NSAIDs, the exact mechanism is unknown and thought to be multifactorial, affecting various steps in fracture healing.

Strengths of this study include the large patient population and control group. Additionally, none of the treating physicians were involved in the radiographic review of postoperative radiographs, limiting sources of bias. The retrospective nature of the current study meant that the study variables were limited to those available in the patient medical records. Patient compliance with ASA could not be routinely verified outside of the medical record and patient intake medication list at each clinic visit. Another potential weakness is that clinical and radiographic findings were used to define union. Computed tomography can be used to assess union,26 but it is not routinely used in clinical practice to evaluate union for both practical and financial reasons, limiting patient’s exposure to radiation and unnecessary cost in the routine management of ankle fracture care. However, both clinical and radiographic evaluation was performed for all patients with a minimum of 3 months follow-up, and our rate of union for both groups is similar to previously reported values.33 CT was reserved only in the evaluation and treatment of suspected nonunion, where it would be used to direct further clinical care. 13

CONCLUSION

Overall, there is a great amount of variability in the literature with regards to the safety of NSAIDs in bone healing, with results ranging from safe and efficacious to high-risk for delayed union or nonunion.23 Our work emphasizes that ASA may not influence time to union after an ankle fracture. Future studies should aim to help clarify these discrepancies, both at the level of basic science and in the clinical setting through prospective, randomized controlled studies.

This is the first and largest study to examine the effect of ASA as DVT on time to union of ankle fractures. The results suggest that the use of ASA for DVT prophylaxis in ankle fracture patients is safe and without risk for delayed union, nonunion or malunion. Additionally, no difference was seen in the rate of symptomatic VTE in those patients receiving ASA compared to those who did not.

REFERENCES 1.

Ahmad J, Lynch MK, Maltenfort M. Incidence and Risk Factors of Venous Thromboembolism After Orthopaedic Foot Ankle Surg. Foot Ankle Spec. 2017;10(5):449-54.

2.

Allen HL, Wase A, Bear WT. Indomethacin and aspirin: effect of nonsteroidal antiinflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand. 1980;51(4):595-600.

3.

Barry S. Non-steroidal anti-inflammatory drugs inhibit bone healing: a review. Vet Comp Orthop Traumatol. 2010;23(6):385-92.

14

4.

Bo J, Sudmann E, Marton PF. Effect of indomethacin on fracture healing in rats. Acta Orthop Scand. 1976;47(6):588-99.

5.

Borgeat A, Ofner C, Saporito A, Farshad M, Aguirre J. The effect of nonsteroidal anti-inflammatory drugs on bone healing in humans: A qualitative, systematic review. J Clin Anesth. 2018;49:92-100.

6.

Bozic KJ, Vail TP, Pekow PS, Maselli JH, Lindenauer PK, Auerbach AD. Does aspirin have a role in venous thromboembolism prophylaxis in total knee arthroplasty patients? J Arthroplasty. 2010;25(7):1053-60.

7.

Capogna BM, Egol KA. Treatment of Nonunions After Malleolar Fractures. Foot Ankle Clin. 2016;21(1):49-62.

8.

Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res. 2002;17(3):513-20.

9.

Court-Brown CM. Rockwood and Green’s Fractures in Adults, Vol 8. USA: Wolters Kluwer; 2015.

10.

Dodwell ER, Latorre JG, Parisini E, et al. NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies. Calcif Tissue Int. 2010;87(3):193202.

11.

Dombroski D, MacKenzie J, Man L, et al. Postoperative aspirin use is associated with delayed progression of radiographic healing in tibial fractures treated with internal fixation. U Penn Ortho J. 2010. 20: 16-18.

12.

Egol KA, Tejwani NC, Walsh MG, Capla EL, Koval KJ. Predictors of short-term functional outcome following ankle fracture surgery. J Bone Joint Surg Am. 2006;88(5):974-9.

13.

Elsoe R, Ostgaard SE, Larsen P. Population-based epidemiology of 9767 ankle fractures. Foot Ankle Surg. 2018;24(1):34-9. 15

14.

Giannoudis PV, MacDonald DA, Matthews SJ, Smith RM, Furlong AJ, De Boer P. Nonunion of the femoral diaphysis. The influence of reaming and non-steroidal antiinflammatory drugs. J Bone Joint Surg Br. 2000;82(5):655-8.

15.

Glassman SD, Rose SM, Dimar JR, Puno RM, Campbell MJ, Johnson JR. The effect of postoperative nonsteroidal anti-inflammatory drug administration on spinal fusion. Spine (Phila Pa 1976). 1998;23(7):834-8.

16.

Hatipoglu MG, Inal S, Kabay S, et al. The Influence of Different Nonsteroidal AntiInflammatory Drugs on Alveolar Bone in Rats: An Experimental Study. Acta Stomatol Croat. 2015;49(4):325-30.

17.

Hausman MR, Schaffler MB, Majeska RJ. Prevention of fracture healing in rats by an inhibitor of angiogenesis. Bone. 2001;29(6):560-4.

18.

Huntley SR, Abyar E, Lehtonen EJ, Patel HA, Naranje S, Shah A. Incidence of and Risk Factors for Venous Thromboembolism After Foot and Ankle Surgery. Foot Ankle Spec. April 2018: Epub ahead of print.

19.

Jameson SS, Augustine A, James P, et al. Venous thromboembolic events following foot and ankle surgery in the English National Health Service. J Bone Joint Surg Br. 2011;93(4):490-7.

20.

Jeffcoach DR, Sams VG, Lawson CM, et al. Nonsteroidal anti-inflammatory drugs' impact on nonunion and infection rates in long-bone fractures. J Trauma Acute Care Surg. 2014;76(3):779-83.

21.

Kellinsalmi M, Parikka V, Risteli J, et al. Inhibition of cyclooxygenase-2 downregulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro. Eur J Pharmacol. 2007;572(2-3):102-10.

22.

Lack WD, Fredericks D, Petersen E, et al. Effect of aspirin on bone healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am. 2013;95(6):488-96.

16

23.

Leiberman et al: AAOS Comprehensive Orthopaedic Review, American Academy of Orthopaedic Surgeons, 2009.

24.

Li Q, Zhang Z, Cai Z. High-dose ketorolac affects adult spinal fusion: a meta-analysis of the effect of perioperative nonsteroidal anti-inflammatory drugs on spinal fusion. Spine (Phila Pa 1976). 2011;36(7):E461-8.

25.

Lisowska B, Kosson D, Domaracka K. Positives and negatives of nonsteroidal antiinflammatory drugs in bone healing: the effects of these drugs on bone repair. Drug Des Devel Ther. 2018;12:1809-14.

26.

Mandi DM. Ankle fractures. Clin Podiatr Med Surg. 2012; 29(2):155-186.

27.

Marquez-Lara A, Hutchinson ID, Nunez F, Jr., Smith TL, Miller AN. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev. 2016;4(3).

28.

Matson AP, Barchick SR, Adams SB. Comparison of Open Reduction and Internal Fixation Versus Closed Reduction and Percutaneous Fixation for Medial Malleolus Fractures. J Am Acad Orthop Surg Glob Res Rev. 2017 Nov1;1(8):e048.

29.

McDonald E, Winters B, Nicholson K, et al. Effect of Postoperative Ketorolac Administration on Bone Healing in Ankle Fracture Surgery. Foot Ankle Int. 2018 Oct;39(10):1135-1140.

30.

Mills LA, Aitken SA, Simpson AHRW. The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthop. 2017;88(4):434-439.

31.

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. 2011;19(12):768-76.

17

32.

Morshed S. Current Options for Determining Fracture Union. Adv Med. 2014;2014:1-12.

33.

Murnaghan M, Li G, Marsh DR. Nonsteroidal anti-inflammatory drug-induced fracture nonunion: an inhibition of angiogenesis? J Bone Joint Surg Am. 2006; 88 Suppl 3:140-7.

34.

O'Connor JP, Lysz T. Celecoxib, NSAIDs and the skeleton. Drugs Today (Barc). 2008;44(9):693-709.

35.

Pelet S, Roger ME, Belzile EL, Bouchard M. The incidence of thromboembolic events in surgically treated ankle fracture. J Bone Joint Surg Am. 2012;94(6):502-6.

36.

Phillips WA, Schwartz HS, Keller CS, et al. A prospective, randomized study of the management of severe ankle fractures. J Bone Joint Surg Am. 1985;67(1):67-78.

37.

Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth. 2005;52(5):506-12.

38.

SooHoo N, Krenek L, Eagan M, et al. Complication rates following open reduction and internal fixation of ankle fractures. J Bone Joint Surg Am. 2009. 91(5): 1042-1049.

39.

Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic Clin Pharmacol Toxicol. 2008;102(1):10-4.

40.

Wang F, Wera G, Knoblich GO, Chou LB. Pulmonary embolism following operative treatment of ankle fractures: a report of three cases and review of the literature. Foot Ankle Int. 2002;23(5):406-10.

41.

Zhang X, Schwarz EM, Young DA, et al. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest. 2002;109(11):1405-15.

18

42.

Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255-258.

LEGENDS

Table 1. Demographics of participants organized by study arm.

Aspirin Use Yes

No

P-value*

N = 152

N = 354

-

Mean Age (SD; range) Sex

43.8 (16-87) 43.4% (66/152) Male

41.7 (13-83) 46.2% (163/353) Male

.1693 .5684

Ethnicity Caucasian African-American Hispanic Other

51.3% (78/152) 41.5% (63/152) 3.3% (5/152) 3.96% (6/152)

51.1% (180/352) 41.2% (145/352) 2.6% (9/352) 5.11% (18/352)

.5182

Mean BMI (SD; range)

31.2 (18.6-53.4)

30.5 (16.3-55.4)

.2845

ASA Class 1 2 3 4 Tobacco Use

9.9% (15/152) 48.7% (74/152) 38.8% (59/152) 2.6% (4/152) 43.4% (66/152)

14.2% (50/352) 53.7% (189/352) 31.3% (110/352) 0.9% (3/352) 35.6% (125/351)

.0983

Alcohol Use

45.4% (69/152)

45.9% (161/351)

.6399

Illicit Drug Use

11.2% (17/152)

10.5% (37/351)

.7884

Diabetes

13.7% (19/139)

8.9% (29/325)

.1241

1.45% (

1.54% (

.9397

0.7% (1/137) 0.7% (1/139)

4.6% (15/324) 1.2% (4/324)

.0366 .6230

HIV Immunosuppressant Use Peripheral Vascular Disease

.0975

2.9% (4/137)

4.6% (15/323)

.3954

41.6% (59/142)

29.1% (95/327)

COPD

4.3% (6/139)

2.2% (7/325)

.0081 .1960

Congestive Heart Failure

0.7% (1/138)

0.3% (1/324)

.5331

5.1% (7/138)

2.2% (7/325)

Peripheral Neuropathy Hypertension

.0934 Chronic Kidney Disease Acronym Legend: BMI = body mass index; ASA class = American Society of Anesthesiologist’s Class; HIV = human immunodeficiency virus; COPD = chronic obstructive pulmonary disease *Significant values are highlighted in bold

19

Table 2. Complications, Follow-up, Radiographic Healing, and Mean Pain Scores of study participants, organized by study arm.

Aspirin Use No N=354 6.5% (21/324)

P-value*

Superficial Infection

Yes N=152 3.6% (5/138)

Deep Infection

0.7% (1/137)

3.4% (11/323)

.0997

Dehiscence

4.4% (6/138)

4.0% (13/323)

.8730

Sepsis

0.7% (1/137)

0.0% (0/323)

.1243

DVT

0.7% (1/137)

1.2% (4/323)

.6305

Implant failure

9.4% (13/138)

8.3% (27/324)

.7038

Radiographic Healing at 6 weeks Normal Delayed Nonunion

95.9% (94/98) 1.0% (1/98) 3.1% (3/98)

98.6% (207/210) 0.5% (1/210) 1.0% (2/210)

.2134

Radiographic Healing at 3 months Normal Delayed Nonunion

96.0% (72/75) 1.3% (1/75) 2.7% (2/75)

94.9% (149/157) 2.8% (4/157) 2.6% (4/157)

.8998

Radiographic Healing at 6 months Normal Delayed Nonunion

95.9% (94/98) 1.0% (1/98) 3.1% (3/98)

98.6% (207/210) 0.5% (1/210) 1.0% (2/210)

.2134

298.8 (8-3816)

197.2 (15-1509)

.0031

Mean Pain at 2 weeks

3.97

3.73

.5132

Mean Pain at 6 weeks

2.60

2.83

.5066

Mean Pain at 12 weeks

2.46

2.60

.7083

1.89 Mean Pain at 6 months Acronym Legend: DVT = deep vein thrombosis *Significant values are highlighted in bold

2.51

.1698

Mean Length of follow-up in days (range)

.2224

20

Table 3. Complications, Healing, Follow-up, and Mean Pain Scores, Organized by Risk Factors.

Risk Factors* Aspirin Use

Yes

No

Superficial Infection

Yes N=110 5.1% (5/99)

No N=243 7.8% (17/218)

P-value** .3723

Yes N=47 0.0% (0/44)

No N=105 4.0% (4/100)

P-value+ .2283

Deep Infection

1.0% (1/98)

4.2% (9/217)

.1062

0.0% (0/44)

2.0% (2/100)

.4808

Dehiscence

6.1% (6/99)

4.6% (10/217)

.5849

2.3% (1/44)

3.0% (3/100)

.4142

Sepsis

1.0% (1/98)

0.0% (0/217)

.3111

0.0% (0/44)

0.0% (0/100)

-

DVT

1.0% (1/98)

1.4% (3/217)

.4090

2.3% (1/44)

1.0% (1/100)

.4274

Implant failure

9.1% (9/99)

9.6% (21/218)

.1632

11.4% (5/44)

6.0% (6/100)

.1385

95.6% (65/68) 1.5% (1/68) 2.9% (2/68)

98.0% (146/149) 2.0% (3/149)

.3445

97.1% (33/34) 2.9% (1/34)

100.0% (61/61) -

.3579

96.0% (48/50) 2.0% (1/50) 2.0% (1/50)

94.8% (109/115) 2.6% (3/115) 2.6% (3/115)

.9175

96.6% (28/29) 3.4% (1/29)

95.2% (40/42) 2.4% (1/42) 2.4% (1/42)

.6829

95.6% (65/68) 1.5% (1/68) 2.9% (2/68)

98.0% (146/149) 0.7% (1/149) 1.3% (2/149)

.3445

97.1% (33/34)

.3579

2.9% (134)

100.0% (61/61) -

Mean follow-up in days

154.2

277.4

.0004

300.9

341.6

.5985

Mean Pain at 2 weeks

4.30

4.14

.7165

3.36

2.98

.5415

Mean Pain at 6 weeks

2.96

3.29

.4514

1.81

1.63

.6966

Mean Pain at 12 weeks

2.65

3.04

.3971

1.89

1.54

.5014

Mean Pain at 6 months

2.29

2.68

.4732

1.23

2.24

.1803

Radiographic Healing at 6 weeks Normal Delayed Nonunion Radiographic Healing at 3 months Normal Delayed Nonunion Radiographic Healing at 6 months Normal Delayed Nonunion

Acronym Legend: DVT = deep vein thrombosis *Risk factors included: tobacco use, alcohol use, illicit drug use, diabetes, Human Immunodeficiency Virus, immunosuppressant use, peripheral neuropathy, chronic kidney disease, rheumatoid arthritis. **Significance between aspirin use and no aspirin use amongst those with risk factors; significant values are highlighted in bold. + Significance between aspirin use and no aspirin use amongst those without risk factors; significant values are highlighted in bold.

21

Conflict of Interest Statement: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Financial Disclosure Statement: The author(s) received no financial support for the research, authorship, and/or publication of this article.

22