Corinne Mirkazemi, Jesus M. Villa, Tejbir S. Pannu, Carlos A. Higuera.
Response/Recommendation: There seems to be no difference between low dose and regular dose aspirin for the prevention of venous thromboembolism (VTE) following orthopaedic procedures. The gastrointestinal side effect profile of regular dose aspirin seems to be poorer.
Strength of Recommendation: Limited.
Rationale: Despite the relative abundance of literature comparing aspirin thromboprophylaxis at different doses with other regimens, most investigations comparing low-dose (e.g. 81mg PO-BID) to regular-dose (e.g. 325mg PO-BID) aspirin have been conducted in a retrospective manner. Only two prospective studies comparing the efficacy and safety of low-dose to regular-dose aspirin have been performed to date. Both studies used aspirin for approximately one month and included primary hip and knee arthroplasty patients. In their prospective open-label crossover study (N=4,651), Parvizi et al., reported similar rates of 90-day VTE between both groups (0.1% low-dose and 0.3% regular-dose, p=0.345), and there were no differences either in gastrointestinal (GI), bleeding/ulceration, acute periprosthetic joint infection, or mortality1. Similarly, Feldstein et al., (N=643) reported no difference in the incidence of GI bleeding between both regimens, although the authors did note an increased risk of nausea and GI distress with regular-dose (3.2%) compared to low-dose aspirin (0.8%) (p=0.04). Only one patient (0.3%) developed deep venous thrombosis (DVT) in the 81mg group, which was not statistically different from the regular-dose group (0.3% vs. 0%). However, due to the small sample size as well as the low incidence of VTE post-arthroplasty, the study was likely underpowered to compare both regimens1,2.
Seven retrospective studies have directly compared the two dosing regimens in orthopedic surgery. In these studies, aspirin was provided for 4-6 weeks, and all data (VTE, bleeding, mortality, etc.) was reported at 90 days postoperatively. The following data presented in parentheses compares the outcome low-dose to regular-dose aspirin, respectively. In the first retrospective study, Faour et al., (N=5,666) reported an initial reduction in VTE incidence (0.7% vs. 1.5%, p=0.02) following elective primary total knee arthroplasty (TKA). However, regression modeling showed no difference after adjusting for age, gender, body mass index (BMI), Charlson comorbidity index (CCI), and surgeon. Bleeding and mortality rates were also similar between the groups (0.2% and 0.1%, respectively)3. Faour et al. later reported the results of a similar study (N=3,936) in total hip arthroplasty (THA) patients, with no difference in VTE (0.6% vs. 1.0%, p=0.35), bleeding (0.5% vs 0.8%, p=0.75), or death (0.1% both), even after adjusting for confounders in adjusted regression analyses4.
Retrospective studies by Tang et al., in revision THA (N=1,361) and TKA (N=1,438) patients also reported similar VTE rates between the groups (0.77% vs. 1.34%, p=0.38, and 0.23% vs. 0.9%, p=0.16, respectively), which were also noted in regression analyses after adjusting for differences in age and race5,6. The authors also reported no significant difference in bleeding, infection, and mortality rates between the dosing regimens.
Merkow et al., conducted a substantially larger (N=12,866) study in patients with standard VTE risk undergoing primary TKA7. While they reported a significant reduction in VTE incidence in patients receiving low-dose aspirin (0.23% vs. 1.41%, p<0.001), analyses were limited to univariate analyses and no cohort comparisons were included. Shohat et al., also compared dosing regimens in primary TKA patients (N=9,208) and reported no significant difference in VTE rates (0.9% vs. 1.0%, p=0.669)8. Although both groups were demographically and medically similar, there were statistically significant differences in surgical variables that were not accounted for8. Uvodich et al., also conducted a retrospective review, but unlike other studies in this review, it included data as far back as 20009. All other papers limited the data collection period to at least 2010 onwards. In their study of primary TKA and THA patients (N=3,512), Uvodich et al., reported no difference in VTE or mortality (0% vs. 0.1%, p=0.79, and 0.3% vs. 0.1%, p=0.24, respectively). While cohorts showed significant baseline differences, these differences were small and likely clinically irrelevant. Multivariate analyses were not performed due to the small event rate.
In contrast to the studies discussed hitherto, Halbur et al., retrospectively compared the efficacy and safety of two aspirin protocols in 2,284 standard-risk primary elective total joint arthroplasty patients10. The first cohort received 81mg BID and the second either 81mg BID (if <120kg) or 325mg BID (if ≥120kg), dependent on their weight. Outcomes were compared at 6 weeks and 6 months postoperatively. The adjusted relative risk (RR) of VTE was found to be significantly lower in the weight-based aspirin dosing group: RR 0.31 (95% confidence interval [CI] 0.12-0.82, p=0.03) at 42 days and 0.38 (95% CI 0.18-0.80, p=0.03) at 6 months, with an overall RR reduction of 62%. There was no difference in the relative risk of GI bleeding events between cohorts at 6 weeks or 6 months. In a subgroup analysis of patients weighing ≥120kg, the incidence of VTE was significantly higher in the cohort receiving 81mg (n=111) compared to the cohort receiving 325mg (n=180) (3.48% vs. 0%, p=0.02). There was no difference in VTE incidence between both cohorts in patients weighing <120kg. Subgroup analyses using only patients weighing ≥120kg revealed no increased risk of bleeding in those who received 325mg versus 81mg.
In addition to the aforementioned studies, there are two additional retrospective studies comparing aspirin to an anticoagulant, in which some patients in the aspirin cohort received either 81mg BID or 325mg BID. These studies included subanalyses comparing outcomes for both aspirin cohorts. Goel et al., compared the safety and efficacy of a one-month course of aspirin against warfarin for VTE prevention following either unilateral or bilateral TKA11. In their subanalysis (n=1,527 bilateral TKA), they reported a similar 90-day incidence of VTE and pulmonary embolism (PE) between the cohorts (1.22% vs. 2.20%, p=0.14, and 0.82% vs. 1.47%, p=0.23, respectively). Azboy et al., (n=683) compared three hip preservation surgery cohorts receiving: (1) low-dose aspirin, (2) regular-dose aspirin, or (3) warfarin12. The authors similarly reported no difference in VTE rates among the three cohorts.
Hood et al., specifically explored patient compliance in patients prescribed one month of either low-dose or regular-dose aspirin after TKA and THA (n=404)13. There was no significant difference in the proportion of patients who completed their course of therapy, nor the proportion who attributed new GI symptoms to the initiation of aspirin (7% vs. 10.5%, p>0.30).
1. 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
2. Feldstein MJ, Low SL, Chen AF, Woodward LA, Hozack WJ. A Comparison of Two Dosing Regimens of ASA Following Total Hip and Knee Arthroplasties. J Arthroplasty. 2017;32(9S):S157-S161. doi:10.1016/j.arth.2017.01.009
3. Faour M, Piuzzi NS, Brigati DP, et al. Low-Dose Aspirin Is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty. J Arthroplasty. 2018;33(7S):S131-S135. doi:10.1016/j.arth.2018.03.001
4. Faour M, Piuzzi NS, Brigati DP, et al. No Difference Between Low- and Regular-dose Aspirin for Venous Thromboembolism Prophylaxis After THA. Clin Orthop Relat Res. 2019;477(2):396-402. doi:10.1097/CORR.0000000000000613
5. Tang A, Zak S, Iorio R, Slover J, Bosco J, Schwarzkopf R. Low-Dose Aspirin Is Safe and Effective for Venous Thromboembolism Prevention in Patients Undergoing Revision Total Hip Arthroplasty: A Retrospective Cohort Study. J Arthroplasty. 2020;35(8):2182-2187. doi:10.1016/j.arth.2020.03.040
6. Tang A, Zak SG, Waren D, et al. Low-Dose Aspirin is Safe and Effective for Venous Thromboembolism Prevention in Patients Undergoing Revision Total Knee Arthroplasty: A Retrospective Cohort Study. J Knee Surg. Published online September 8, 2020. doi:10.1055/s-0040-1716377
7. Merkow DB, Tang A, Iorio R, Slover JD, Bosco JA, Schwarzkopf R. Low dose aspirin is effective in preventing venous thromboembolism in patients undergoing primary total knee arthroplasty. J Orthop. 2021;24:26-28. doi:10.1016/j.jor.2021.02.005
8. Shohat N, Ludwick L, Goel R, Ledesma J, Streicher S, Parvizi J. Thirty Days of Aspirin for Venous Thromboembolism Prophylaxis Is Adequate Following Total Knee Arthroplasty, Regardless of the Dose Used. J Arthroplasty. Published online May 8, 2021:S0883-5403(21)00416-2. doi:10.1016/j.arth.2021.05.002
9. Uvodich ME, Siljander MP, Taunton MJ, Mabry TM, Perry KI, Abdel MP. Low-Dose vs Regular-Dose Aspirin for Venous Thromboembolism Prophylaxis in Primary Total Joint Arthroplasty. J Arthroplasty. 2021;36(7):2359-2363. doi:10.1016/j.arth.2021.02.007
10. Halbur CR, Gulbrandsen TR, West CR, Brown TS, Noiseux NO. Weight-Based Aspirin Dosing May Further Reduce the Incidence of Venous Thromboembolism Following Primary Total Joint Arthroplasty. J Arthroplasty. Published online June 12, 2021:S0883-5403(21)00548-9. doi:10.1016/j.arth.2021.06.008
11. 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. doi:10.1302/0301-620X.100B1.BJJ-2017-0587.R1
12. Azboy I, M Kheir M, Huang R, Parvizi J. Aspirin provides adequate VTE prophylaxis for patients undergoing hip preservation surgery, including periacetabular osteotomy. J Hip Preserv Surg. 2018;5(2):125-130. doi:10.1093/jhps/hny010
13. Hood B, Springer B, Odum S, Curtin BM. No difference in patient compliance between full-strength versus low-dose aspirin for VTE prophylaxis following total hip and total knee replacement. Eur J Orthop Surg Traumatol. 2021;31(4):779-783. doi:10.1007/s00590-020-02833-w