33 – What VTE prophylaxis should be administered to a patient who is allergic to aspirin?

Graham S. Goh, Terence L. Thomas, Henry Fu.

Response/Recommendation: As it remains uncertain whether the use of non-aspirin agents due to a true allergy is associated with a higher incidence of venous thromboembolism (VTE), surgeons may opt to prescribe an alternative VTE prophylactic agent for these patients.  However, in light of the advantageous safety profile and cost-effectiveness of aspirin, a detailed workup to confirm true hypersensitivity to aspirin should be strongly considered unless systemic allergic reactions have been reported.  Patients determined to have true aspirin-exacerbated respiratory disease (AERD) or mucocutaneous reactions may then undergo a desensitization protocol.  On the rare occasion that a patient has a systemic allergic reaction to aspirin, desensitization should be avoided, and alternative agents for VTE prophylaxis should be used.

Strength of Recommendation: Limited.

Rationale: Aspirin is a safe and cost-effective agent for VTE prevention in orthopaedic surgery1–7.  This chemoprophylactic agent has been endorsed in the most recent guidelines of the American Academy of Orthopaedic Surgeons (AAOS)8 and the American College of Chest Physicians (ACCP)9.  Despite the increased utilization of aspirin in recent years3,4, there is still a paucity of evidence to guide the selection of an alternative prophylactic agent in patients with a true or self-reported aspirin allergy2.  As the number of orthopaedic procedures requiring VTE prophylaxis grows annually10–13, it is imperative that surgeons understand how to manage this patient population.

Aspirin intolerance has been estimated to occur in 6-20% of the population, with 0.6-2.4% being a ‘true’ aspirin allergy14,15.  Patients with asthma, chronic rhinosinusitis, chronic urticaria, and nasal polyps have a higher prevalence of up to 20-30%16–18.  Notwithstanding, the prevalence of aspirin allergies is thought to be under-reported since no reliable skin or blood test for hypersensitivity currently exists15,19.  While provocative challenge testing can be used to confirm an aspirin allergy, potential risks for life-threatening systemic reactions limit its diagnostic practicality14,19.

The underlying pathophysiology of aspirin allergies can be pharmacologic and/or immunologic14,20.  A variety of classification systems utilize patient symptoms to determine the underlying mechanism and proper treatment18,19,21,22.  Most commonly, aspirin allergy has been classified into the following hypersensitivity reactions: (1) asthma and rhinitis, or aspirin-exacerbated respiratory disease (AERD), (2) worsened urticaria and angioedema in the setting of chronic urticaria, (3) urticaria and angioedema induced by multiple non-steroidal anti-inflammatory drugs (NSAID), and (4) isolated single NSAID-induced reactions19,22.  For treatment purposes, reactions to aspirin can be further classified into AERD, mucocutaneous, and systemic18.

Literature on the assessment and treatment of patients with an aspirin allergy has been largely restricted to cardiac patients14,15,19,21.  A variety of protocols suggest that nearly all patients with a history of aspirin allergy can be successfully treated with a graded dose challenge or desensitization14,19,23–27.  However, these reports were limited by the fact that aspirin allergies were not confirmed in the respective cohorts26,27.  Current evidence suggests that the reliability of self-reported allergies is extremely low28.  It is possible that patient-reported allergies to aspirin or NSAID may preclude certain patients from receiving aspirin for VTE prophylaxis following an orthopaedic procedure.  However, it remains uncertain whether the use of non-aspirin agents due to these allergies is associated with a higher incidence of VTE.

To adequately protect against VTE, a physician must first ensure an allergy exists, yet the rate of true allergic reactions in patients who self-report an allergy remains unknown.  It is not uncommon for patients to mistake side effects including tinnitus, easy bruising, or gastrointestinal symptoms for an allergy; or believe that an allergy to another NSAID suggests a coexisting allergy to aspirin19.  Therefore, hypersensitivity must be confirmed using a provocative challenge test. Secondly, the allergy must be identified as AERD, mucocutaneous, or systemic.  For patients with AERD, it is recommended that premedication be utilized for their AERD, followed by a desensitization protocol19,29.  Patients with mucocutaneous reactions do not require pretreatment prior to the desensitization protocol.  However, ensuing a mucocutaneous reaction, antihistamines and/or leukotriene receptor agonists are suggested19.  On the rare occasion that patients experience systemic reactions to aspirin, many authors suggest avoiding desensitization and consider alternative agents for VTE prophylaxis14,19.

In conclusion, it is important to confirm a true allergy in patients with a suspected allergy to aspirin or NSAID due to the low reliability of self-reporting.  Although, the mechanism underlying aspirin allergy has been well described, there are no studies that directly investigate the efficacy of alternative VTE prophylactic agents in orthopaedic patients with a true aspirin or NSAID allergy.  As such, surgeons may opt to prescribe an alternative VTE prophylactic agent for these patients.  However, in light of the advantageous safety profile and cost-effectiveness of aspirin, desensitization protocols should be strongly considered in this population unless systemic allergic reactions have been reported.  Nevertheless, further research is required to validate the safety and efficacy of provocative challenge testing and desensitization in orthopaedic patients.


1.         Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical Effectiveness and Safety of Aspirin for Venous Thromboembolism Prophylaxis After Total Hip and Knee Replacement: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2020;180(3):376-384. doi:10.1001/jamainternmed.2019.6108

2.         Azboy I, Barrack R, Thomas AM, Haddad FS, Parvizi J. Aspirin and the prevention of venous thromboembolism following total joint arthroplasty. Bone Jt J. 2017;99-B(11):1420-1430. doi:10.1302/0301-620X.99B11.BJJ-2017-0337.R2

3.         Murphy RF, Williams D, Hogue GD, et al. Prophylaxis for Pediatric Venous Thromboembolism: Current Status and Changes Across Pediatric Orthopaedic Society of North America From 2011. J Am Acad Orthop Surg. 2020;28(9):388-394. doi:10.5435/JAAOS-D-19-00578

4.         Mendez GM, Patel YM, Ricketti DA, Gaughan JP, Lackman RD, Kim TWB. Aspirin for Prophylaxis Against Venous Thromboembolism After Orthopaedic Oncologic Surgery. J Bone Joint Surg Am. 2017;99(23):2004-2010. doi:10.2106/JBJS.17.00253

5.         Alyea E, Gaston T, Austin LS, et al. The Effectiveness of Aspirin for Venous Thromboembolism Prophylaxis for Patients Undergoing Arthroscopic Rotator Cuff Repair. Orthopedics. 2019;42(2):e187-e192. doi:10.3928/01477447-20181227-05

6.         Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 2018;378(8):699-707. doi:10.1056/NEJMoa1712746

7.         Parvizi J, Huang R, Restrepo C, et al. Low-Dose Aspirin Is Effective Chemoprophylaxis Against Clinically Important Venous Thromboembolism Following Total Joint Arthroplasty: A Preliminary Analysis. J Bone Joint Surg Am. 2017;99(2):91-98. doi:10.2106/JBJS.16.00147

8.         Johanson NA, Lachiewicz PF, Lieberman JR, et al. Prevention of Symptomatic Pulmonary Embolism in Patients Undergoing Total Hip or Knee Arthroplasty: J Am Acad Orthop Surg. 2009;17(3):183-196. doi:10.5435/00124635-200903000-00007

9.         Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in Orthopedic Surgery Patients. Chest. 2012;141(2):e278S-e325S. doi:10.1378/chest.11-2404

10.       Sloan M, Premkumar A, Sheth NP. Projected Volume of Primary Total Joint Arthroplasty in the U.S., 2014 to 2030. J Bone Joint Surg Am. 2018;100(17):1455-1460. doi:10.2106/JBJS.17.01617

11.       Schwartz AM, Farley KX, Guild GN, Bradbury TL. Projections and Epidemiology of Revision Hip and Knee Arthroplasty in the United States to 2030. J Arthroplasty. 2020;35(6S):S79-S85. doi:10.1016/j.arth.2020.02.030

12.       Inacio MCS, Paxton EW, Graves SE, Namba RS, Nemes S. Projected increase in total knee arthroplasty in the United States – an alternative projection model. Osteoarthritis Cartilage. 2017;25(11):1797-1803. doi:10.1016/j.joca.2017.07.022

13.       Klug A, Gramlich Y, Rudert M, et al. The projected volume of primary and revision total knee arthroplasty will place an immense burden on future health care systems over the next 30 years. Knee Surg Sports Traumatol Arthrosc Off J ESSKA. Published online July 15, 2020. doi:10.1007/s00167-020-06154-7

14.       Lambrakis P, Rushworth GF, Adamson J, Leslie SJ. Aspirin hypersensitivity and desensitization protocols: implications for cardiac patients. Ther Adv Drug Saf. 2011;2(6):263-270. doi:10.1177/2042098611422558

15.       Pfaar O, Klimek L. Aspirin desensitization in aspirin intolerance: update on current standards and recent improvements. Curr Opin Allergy Clin Immunol. 2006;6(3):161-166. doi:10.1097/01.all.0000225153.45027.6a

16.       Schubert B, Perdekamp MTG, Pfeuffer P, Raith P, Bröcker E-B, Trautmann A. Nonsteroidal anti-inflammatory drug hypersensitivity: fable or reality? Eur J Dermatol. 2005;15(3):164-167.

17.       Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma, aspirin intolerance, nasal polyposis and chronic obstructive pulmonary disease in a population-based study. Int J Epidemiol. 1999;28(4):717-722. doi:10.1093/ije/28.4.717

18.       Kowalski ML, Woessner K, Sanak M. Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug-related urticaria and angioedema. J Allergy Clin Immunol. 2015;136(2):245-251. doi:10.1016/j.jaci.2015.06.021

19.       Woessner KM, Simon RA. Cardiovascular prophylaxis and aspirin “allergy.” Immunol Allergy Clin North Am. 2013;33(2):263-274. doi:10.1016/j.iac.2012.11.004

20.       Castells M. Desensitization for drug allergy. Curr Opin Allergy Clin Immunol. 2006;6(6):476-481. doi:10.1097/ACI.0b013e3280108716

21.       McMullan KL. Aspirin allergy in patients with myocardial infarction: the allergist’s role. Ann Allergy Asthma Immunol Off Publ Am Coll Allergy Asthma Immunol. 2014;112(2):90-93. doi:10.1016/j.anai.2013.11.020

22.       Kowalski ML, Stevenson DD. Classification of reactions to nonsteroidal antiinflammatory drugs. Immunol Allergy Clin North Am. 2013;33(2):135-145. doi:10.1016/j.iac.2012.10.008

23.       Silberman S, Neukirch-Stoop C, Steg PG. Rapid desensitization procedure for patients with aspirin hypersensitivity undergoing coronary stenting. Am J Cardiol. 2005;95(4):509-510. doi:10.1016/j.amjcard.2004.10.022

24.       Dalmau G, Gaig P, Gázquez V, Mercé J. Rapid desensitization to acetylsalicylic acid in acute coronary syndrome patients with NSAID intolerance. Rev Esp Cardiol. 2009;62(2):224-225. doi:10.1016/s1885-5857(09)71543-9

25.       Fajt ML, Petrov AA. Outpatient aspirin desensitization for patients with aspirin hypersensitivity and cardiac disease. Crit Pathw Cardiol. 2011;10(1):17-21. doi:10.1097/HPC.0b013e318213d5a6

26.       Wong JT, Nagy CS, Krinzman SJ, Maclean JA, Bloch KJ. Rapid oral challenge-desensitization for patients with aspirin-related urticaria-angioedema. J Allergy Clin Immunol. 2000;105(5):997-1001. doi:10.1067/mai.2000.104571

27.       Rossini R, Angiolillo DJ, Musumeci G, et al. Aspirin desensitization in patients undergoing percutaneous coronary interventions with stent implantation. Am J Cardiol. 2008;101(6):786-789. doi:10.1016/j.amjcard.2007.10.045

28.       Macy E, Contreras R. Health care use and serious infection prevalence associated with penicillin “allergy” in hospitalized patients: A cohort study. J Allergy Clin Immunol. 2014;133(3):790-796. doi:10.1016/j.jaci.2013.09.021

29.       Stevenson DD, Simon RA. Selection of patients for aspirin desensitization treatment. J Allergy Clin Immunol. 2006;118(4):801-804. doi:10.1016/j.jaci.2006.06.019