Background: Aspirin is a safe and effective prophylaxis for the prevention of venous thromboembolism following total joint arthroplasty. The optimal dose of aspirin prophylaxis is unknown. Our hypothesis was that lower-dose aspirin is as effective as higher-dose aspirin for the prevention of venous thromboembolism and is associated with fewer gastrointestinal side effects.
Methods: In a prospective, crossover study, we analyzed 4,651 primary total joint arthroplasty cases performed from July 2013 to June 2015. For 4 weeks, 3,192 patients received enteric-coated 325-mg aspirin twice daily (the 325-mg aspirin group) and 1,459 patients received 81-mg aspirin twice daily (the 81-mg aspirin group). There were no significant differences (p > 0.05) in sex, body mass index, or Charlson Comorbidity Index between the two patient populations. Recorded complications occurring within 90 days postoperatively included symptomatic venous thromboembolism (deep venous thrombosis and pulmonary embolism), gastrointestinal complications, acute periprosthetic joint infection, and death.
Results: The incidence of venous thromboembolism of 0.1% (95% confidence interval [CI], 0% to 0.3%) in the 81-mg aspirin group (1 with deep venous thrombosis and 1 with pulmonary embolism) was not significantly different (p = 0.345) from 0.3% (95% CI, 0.1% to 0.6%) in the 325-mg aspirin group (7 with deep venous thrombosis and 5 with pulmonary embolism). The incidence of gastrointestinal bleeding or ulceration of 0.3% (95% CI, 0% to 0.5%) in the 81-mg aspirin group was slightly, but not significantly (p = 0.66), lower than the 0.4% (95% CI, 0.2% to 0.6%) in the 325-mg aspirin group. The incidence of acute periprosthetic joint infection was 0.2% (95% CI, 0% to 0.4%) in the 81-mg aspirin group compared with 0.5% (95% CI, 0.2% to 0.7%) in the 325-mg aspirin group (p = 0.28). The 90-day mortality rate was similar in both groups at 0.1% (95% CI, 0% to 0.2%) in the 81-mg aspirin group and 0.1% (95% CI, 0% to 0.2%) in the 325-mg aspirin group (p = 0.78).
Conclusions: Our study demonstrates that low-dose aspirin is not inferior to high-dose aspirin for venous thromboembolism prophylaxis following total joint arthroplasty. This is not unexpected, as the available literature demonstrates that low-dose aspirin is as effective as higher-dose aspirin in the prevention of acute coronary syndrome and cerebrovascular events.
Level of Evidence: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.
Aspirin has long been established as an effective drug for preventing arterial thromboembolic events in the setting of cardiovascular and cerebrovascular disease1. Aspirin has also been utilized as an effective modality for the prevention of venous thromboembolism following total joint arthroplasty for many decades. The Pulmonary Embolism Prevention (PEP) trial demonstrated a clear reduction in the incidence of fatal and symptomatic pulmonary embolism and symptomatic deep venous thrombosis in patients with hip fracture and patients undergoing elective total joint arthroplasty who received low-dose aspirin postoperatively2.
Modern-day rates of symptomatic venous thromboembolism have decreased substantially regardless of the venous thromboembolism prophylaxis regimen, likely because of improvements in perioperative protocols such as regional anesthesia and early mobilization3-6. The impetus for aspirin prophylaxis therefore arises from the recent evidence showing that not only does aspirin prophylaxis result in a similar or even a lower rate of venous thromboembolism when compared with other anticoagulation agents, but also it has a better safety profile7-14.
The American College of Chest Physicians (ACCP), directly, and the American Academy of Orthopaedic Surgeons (AAOS), indirectly, endorse aspirin as an effective venous thromboembolism prophylaxis following total joint arthroplasty9,10. The adaptation of the recent ACCP guidelines by the Surgical Care Improvement Project (SCIP) has led to a resurgence in the use of aspirin as venous thromboembolism prophylaxis following total joint arthroplasty9,15-17. The beneficial effect of aspirin, on the venous circulation (so-called dark clots), has also been demonstrated by the Warfarin and Aspirin (WARFASA) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials, when its use was associated with a decrease in the incidence of recurrent venous thromboembolism following discontinuation of oral anticoagulants18,19.
Medical literature has shown that higher-dose aspirin (325 to 650 mg daily) is not superior to lower-dose aspirin (75 to 100 mg daily) in the prevention of cerebrovascular events and acute coronary syndrome20,21. Furthermore, there is evidence that lower-dose aspirin (81 mg) may even be more effective than higher-dose aspirin following carotid endarterectomy in preventing stroke and death22. Gastrointestinal toxicity with aspirin has clearly been shown to be dose-related23. Therefore, the lowest effective dose of aspirin should be utilized to minimize gastrointestinal complications. However, it is unclear whether low-dose aspirin is as effective as higher-dose aspirin in the prevention of venous thromboembolism following total joint arthroplasty. The initial AAOS guideline recommending 325-mg aspirin twice a day is grade 1C, because of a lack of comparative studies to determine the optimal dose of aspirin for the prevention of venous thromboembolism following total joint arthroplasty.
This prospective, crossover study was designed to examine the efficacy and adverse-event profile of two different regimens of aspirin in patients undergoing total joint arthroplasty.
Materials and Methods
This prospective, crossover study began after institutional review board approval was obtained. Six adult reconstruction surgeons agreed to enroll patients into the study. Three surgeons prescribed 325-mg aspirin twice a day to their patients for a defined period of time (the 325-mg aspirin group) and then switched to 81-mg aspirin twice a day (the 81-mg aspirin group) for the remainder of the study. The other three surgeons would do the same but in a reverse order. The study began on July 1, 2013. Through June 30, 2015, we enrolled 4,651 patients undergoing primary total joint arthroplasty.
Patients were excluded if they were determined to be at high risk for venous thromboembolism by the treating surgeon and on the basis of our institutional protocol24. The high-risk patients are those with a history of venous thromboembolism, active malignancy, or known prothrombotic condition and patients requiring anticoagulation for preexisting conditions. Patients were also excluded if aspirin or nonsteroidal anti-inflammatory drug use was contraindicated because of peptic ulcer disease, intolerance, or other reasons.
All participating surgeons used either 81-mg aspirin (enteric-coated or plain) twice a day or enteric-coated 325-mg aspirin twice a day beginning the evening of the procedure for 4 weeks in addition to sequential compression devices during the hospitalization period. At the time of the latest follow-up, 3,192 patients had received enteric-coated 325-mg aspirin twice a day and 1,459 patients had received 81-mg aspirin twice a day. Of the 1,459 patients, 525 (36%) received enteric-coated 81-mg aspirin twice a day, and 934 (64%) received plain 81-mg aspirin twice a day. The determination of whether a patient received plain or enteric-coated 81-mg aspirin twice a day was based on surgeon preference. Physical therapy commenced either on the day of the surgical procedure or the next day and continued throughout the hospital stay.
Complications occurring within 90 days postoperatively were recorded, including symptomatic venous thromboembolism (deep venous thrombosis and pulmonary embolism), gastrointestinal complications including bleeding or ulceration, acute periprosthetic joint infection, and death. Deep venous thrombosis was detected using lower-extremity ultrasound (LEUS), and pulmonary embolism was diagnosed using chest computed tomography (CT) or ventilation perfusion (VQ) studies. Patients were not routinely screened for venous thromboembolism; LEUS and chest CT/VQ scans were only performed in cases of suspected symptomatic venous thromboembolism, following AAOS and ACCP recommendations. Gastrointestinal complications were defined as upper gastrointestinal bleeding or ulceration confirmed by endoscopy. Periprosthetic joint infection was confirmed using the Musculoskeletal Infection Society’s definition25. Patient demographic characteristics, comorbidities, and operative details were collected.
Institutional review board approval was obtained to conduct a record review to determine the outcome of the patients in this study. Because of the substantial literature supporting the efficacy and safety of low-dose aspirin in the prevention of venous thromboembolism and cardiovascular disease, both 325-mg aspirin twice a day and 81-mg aspirin twice a day were considered by our institutional review board to be acceptable postoperative venous thromboembolism prophylaxis protocols1,2,18,19,26,27.
Statistical analyses were performed with SPSS version 22 (IBM). Based on a 0.1% historical incidence of symptomatic venous thromboembolism at our institution, the necessary sample size was calculated as 1,978 per group using a power of 0.8 and an alpha of 0.05. A 0.25% non-inferiority margin was utilized on the basis of a historical 0.25% difference in pulmonary embolism rates between patients receiving warfarin and 325-mg aspirin twice a day for venous thromboembolism prophylaxis with contemporary perioperative protocols28. This was a significant and clinically important difference (along with higher rates of periprosthetic joint infection and bleeding complications in patients receiving warfarin) that prompted abandoning the use of warfarin in our standard-risk patients. Therefore, we powered this study to detect a similar difference between the 325-mg aspirin arm and the 81-mg aspirin arm. Our patient sample, with 3,192 patients in the 325-mg aspirin arm and 1,459 patients in the 81-mg aspirin arm, had an effective sample size of 2,002 patients per arm13. The chi-square and Wilcoxon signed rank tests were utilized to compare demographic characteristics, comorbidities, and complication rates between patients receiving 81-mg aspirin twice a day and those receiving 325-mg aspirin twice a day for prophylaxis. A generalized linear mixed model was utilized to adjust for slight differences in age, body mass index (BMI), and distribution of surgeons. Significance was defined as p < 0.05.
Demographic characteristics and comorbidities were similar between the 81-mg aspirin group and the 325-mg aspirin group (Table I). The mean age was 63.7 years in the 81-mg aspirin group compared with 64.7 years in the 325-mg aspirin group (p = 0.006). The mean BMI was 29.4 kg/m2 in the 81-mg aspirin group compared with 29.7 kg/m2 in the 325-mg aspirin group (p = 0.197). Distributions of sex (p = 0.393) and Charlson Comorbidity Index (p = 0.779) were not significantly different between the groups.
Overall, the incidence of symptomatic venous thromboembolism following total joint arthroplasty in all patients was 0.28% (13 of 4,651 patients) (Table II). There was no significant difference (p = 0.35) in the incidence of venous thromboembolism between the two aspirin dose groups: 0.1% (95% confidence interval [CI], 0% to 0.3%) in the 81-mg aspirin group (1 distal deep venous thrombosis in a patient who received plain 81-mg aspirin and 1 pulmonary embolism in a patient who received enteric-coated 81-mg aspirin), compared with 0.3% (95% CI, 0.1% to 0.6%) in the 325-mg aspirin group (7 with deep venous thrombosis [5 distal deep venous thromboses and 2 proximal deep venous thromboses] and 5 with pulmonary embolism); the difference between groups was 0.21% (95% CI, 0.03% to 0.5%). Following total knee arthroplasty, the incidence of symptomatic venous thromboembolism was 0.1% (95% CI, 0% to 0.4%) in the 81-mg aspirin group (1 pulmonary embolism), compared with 0.4% (95% CI, 0.1% to 0.8%) in the 325-mg aspirin group (3 with deep venous thrombosis and 5 with pulmonary embolism); the difference between groups was 0.29% (95% CI, −0.1% to 0.7%), but this was not significant (p = 0.73) (Table III). Following total hip arthroplasty, the incidence of symptomatic venous thromboembolism was 0.1% (95% CI, 0% to 0.4%) in the 81-mg aspirin group (1 pulmonary embolism), compared with 0.3% (95% CI, 0% to 0.5%) in the 325-mg aspirin group (4 with deep venous thrombosis and 0 with pulmonary embolism); the difference between groups was 0.12% (95% CI, −0.2% to 0.5%) and was not significant (p = 0.92) (Table IV).
The incidence of gastrointestinal bleeding or ulceration following total joint arthroplasty was 0.3% (95% CI, 0% to 0.5%) in the 81-mg aspirin group compared with 0.4% (95% CI, 0.2% to 0.6%) in the 325-mg aspirin group; the difference between the groups was 0.13% (95% CI, −0.2% to 0.5%) and was not significant (p = 0.66). Within the 81-mg aspirin group, gastrointestinal bleeding occurred in 1 (0.2%) of 525 patients who received enteric-coated 81-mg aspirin and 3 (0.3%) of 934 patients who received plain 81-mg aspirin (p = 0.647). The acute infection rate following total joint arthroplasty was 0.2% (95% CI, 0% to 0.4%) in the 81-mg aspirin group compared with 0.5% (95% CI, 0.2% to 0.7%) in the 325-mg aspirin group; the difference between groups was 0.26% (95% CI, −0.7% to 0.6%) and was not significant (p = 0.28). Finally, the 90-day mortality rate following total joint arthroplasty was 0.1% (95% CI, 0% to 0.2%) in the 81-mg aspirin group (1 patient) compared with 0.1% (95% CI, 0% to 0.2%) in the 325-mg aspirin group (3 patients); the difference between the groups was 0.03% (95% CI, −0.1% to 0.2%) and was not significant (p = 0.78) (Table II). The cause of death was unknown for 2 patients, 1 in each group. The third death was due to a myocardial infarction after discharge on postoperative day 3, and the fourth death was due to respiratory failure of an indeterminate cause.
Generalized linear mixed model analysis utilizing age, sex, BMI, and surgeon as random effects demonstrated no significant correlation (p > 0.05) between dosage of aspirin and the incidence of deep venous thrombosis, pulmonary embolism, venous thromboembolism, or gastrointestinal complications (Table V). This also held true when holding age and BMI as fixed predictors in the generalized linear mixed model. Increased age was associated with increased rate of gastrointestinal complications (Table VI).
Aspirin has been proven to be safe and effective for venous thromboembolism prophylaxis following total joint arthroplasty8,13. However, to our knowledge, few studies have evaluated the efficacy of low-dose aspirin in the prevention of venous thromboembolism following total joint arthroplasty2. The PEP trial randomized 13,356 patients undergoing a hip fracture surgical procedure and 4,088 patients undergoing elective total hip or knee arthroplasty to receive low-dose aspirin (160 mg daily) or placebo for 35 days. The authors found a significant reduction in the incidence of pulmonary embolism in both cohorts of hip fracture and elective total joint arthroplasty who received low-dose aspirin (p = 0.002). Since the publication of the PEP trial, there have been numerous other studies that have confirmed the efficacy of aspirin as a venous thromboembolism prophylaxis following total joint arthroplasty2,3,7,9,10,12,13,29-41. The results of our study corroborate the findings of the PEP study and the others that have followed, in that aspirin is an effective modality for the prevention of venous thromboembolism following total joint arthroplasty and that low-dose aspirin, as in the PEP trial, is as effective as the higher dose.
Our study had a number of limitations and strengths. First, our study was not a true randomized study. In an effort to equalize patient demographic characteristics and comorbidities in each arm of the study, all surgeons planned to switch from either 81-mg aspirin twice a day or 325-mg aspirin twice a day to the other dosing protocol at the midpoint of the study. However, a few surgeons did not switch protocols at the midpoint. The reason for the unwillingness to switch was based on the fact that patients on low-dose aspirin appeared to do as well as patients on the full-dose aspirin with a lower incidence of tolerance issues and upper gastrointestinal adverse effects. The entire cohort of patients has been included in this analysis despite the lack of crossover by some surgeons. In spite of this, there were no significant differences between the groups in terms of BMI, Charlson Comorbidity Index, and sex, and only a clinically unimportant difference of 1 year in age between the 81-mg aspirin group and the 325-mg aspirin group.
Second, our study was not powered to detect superiority of 81-mg aspirin twice a day compared with 325-mg aspirin twice a day. The main objective of the study was to demonstrate the non-inferiority of 81-mg aspirin twice a day in the prevention of our primary end point of symptomatic venous thromboembolism following total joint arthroplasty.
Third, the determination of whether a patient received enteric-coated or plain 81-mg aspirin twice a day was not standardized. Enteric coating was utilized in 36% of patients receiving the protocol of 81-mg aspirin twice a day. Our study was not powered to assess whether there was a difference in the efficacy and complication profile of enteric-coated compared with plain 81-mg aspirin. Although some published studies have suggested that enteric-coated, low-dose aspirin has similar antiplatelet effects compared with plain, low-dose aspirin27, others have shown lower bioavailability and uninhibited platelet function with enteric-coated, low-dose aspirin26,42.
Fourth, although a standardized protocol for work-up of venous thromboembolism was utilized during patients’ hospital stays, the work-up was not regulated after discharge. Finally, our study did not identify any episodes of fatal pulmonary embolism. However, none of the patients who died received an autopsy, making it difficult to be certain that none of these deaths were due to a pulmonary embolism.
There were numerous strengths to this prospective study. All patients underwent the surgical procedure in a single institution, in which their perioperative care was standardized. The type of anesthesia, fixation mode of the prostheses, rehabilitation protocol, pain management, perioperative antibiotics, and many other aspects of their care were standardized. This removed the influence of many confounding variables that can influence the incidence of venous thromboembolism.
The incidence of venous thromboembolism in the study cohort was very low in both aspirin dose groups, confirming the efficacy of aspirin as a good prophylactic modality. Multiple aspects of our postoperative regimen, aside from aspirin prophylaxis, may have played a role in minimizing the risk of venous thromboembolism after total joint arthroplasty, including the use of spinal anesthesia, early mobilization, and the supplemental use of sequential compression devices during the hospital stay of the patients. However, it is important to note that this study only evaluated the incidence of clinically important venous thromboembolism and, as routine screening was not employed, some silent venous thromboembolism events may have gone undetected.
Although it was expected that the lower dose of aspirin would confer a lower risk of gastrointestinal side effects, the study with the current number of patients did not demonstrate this effect. A separate study at our institution, collecting detailed data from patients receiving the two different doses of aspirin, has been able to confirm that lower-dose aspirin does indeed reduce the incidence of gastrointestinal side effects (unpublished data). The incidence of periprosthetic joint infection within 90 days of the surgical procedure was also not significant between the 81-mg aspirin group and the 325-mg aspirin group. Most importantly, 90-day postoperative mortality rates were universally low at 0.1% within both groups. This is consistent with previously reported mortality rates of 0% to 0.29% following total joint arthroplasty using a multimodal approach to venous thromboembolism prophylaxis including the use of aspirin4,12,33. The observed mortality rate in this study at 90 days is lower than the 90-day mortality rate that has been reported in patients who underwent total joint arthroplasty and received potent anticoagulants, such as low-molecular-weight heparin and warfarin32,43.
The efficacy of aspirin as an antithrombotic agent has been well studied. Low-dose aspirin is an effective platelet aggregation inhibitor that suppresses thromboxane A2, and higher-dose aspirin suppresses prostacyclin, another antiplatelet aggregation agent produced by endothelial cells, with very high doses thought to have a paradoxical thrombotic effect22. Cardiovascular literature has demonstrated definitively that low-dose aspirin is as effective as high-dose aspirin for the prevention of acute coronary syndrome and cerebrovascular disease15. In the setting of carotid endarterectomy, 81-mg aspirin daily has been shown to result in a lower ischemic stroke and death risks when compared with higher doses of aspirin22. In line with the PEP trial, our study also demonstrated that low-dose aspirin is an effective antithrombotic agent on the low-pressure venous system.
It is not known whether the drug should be administered once or twice a day. The decision to utilize aspirin using a twice-daily dosing schedule following total joint arthroplasty has been based on convention; early studies evaluating the efficacy of aspirin for venous thromboembolism prophylaxis after total joint arthroplasty have utilized twice-daily dosing11,44-46. The PEP trial utilized enteric-coated 160-mg aspirin daily and demonstrated good results in venous thromboembolism prevention. However, to our knowledge, there has been no substantial support or opposition in the orthopaedic literature for twice-a-day or daily dosing of aspirin.
For the prevention of cardiovascular events, a daily dosing of aspirin is now standard for most patients. Nevertheless, recent studies in cardiovascular disease prevention have demonstrated a higher level of biological efficacy of aspirin twice a day compared with the efficacy of daily dosing in patients with type-2 diabetes mellitus and essential thrombocytosis, likely due to increased platelet turnover in these conditions47,48. Similarly, secondary thrombocytosis has been observed following total joint arthroplasty, which may indicate increased platelet production and turnover following the surgical procedure49. Nevertheless, laboratory findings of increased platelet count following total joint arthroplasty have not been associated with increased venous thromboembolism rates49. Thus, the ideal frequency of aspirin for venous thromboembolism prophylaxis warrants further study.
Aspirin is associated with an elevated risk of gastrointestinal bleeding and gastric ulceration50. However, gastro-protective strategies can be utilized to minimize this risk. One strategy involves the use of enteric-coated aspirin formulations that have been shown to reduce gastroduodenal injury compared with uncoated aspirin, without a significant decrease in the antithrombotic effects27. It is not clear whether efficacy for venous thromboembolism prevention following total joint arthroplasty is equivalent. In our study, gastrointestinal complication rates were similar with both enteric-coated, 325-mg aspirin and plain, 81-mg aspirin. Further studies are needed to evaluate whether there is a difference between enteric-coated and plain 81-mg aspirin in the prevention of venous thromboembolism and the adverse-effect profile. Although not evaluated in our study, the coadministration of proton pump inhibitors with aspirin therapy may reduce the upper gastrointestinal bleeding rate by as much as 50%51,52.
In conclusion, this comparative prospective study demonstrates that aspirin combined with in-hospital mechanical prophylaxis is a safe and effective modality for the prevention of venous thromboembolism following total joint arthroplasty. The study revealed that a low dose of aspirin (81 mg twice a day), both plain and enteric-coated, is not inferior to a higher dose of enteric-coated aspirin (325 mg twice a day) in the prevention of venous thromboembolism.
Investigation performed at the Rothman Institute at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
A commentary by James A. Shaw, MD, is linked to the online version of this article at jbjs.org.
Disclosure: No external funding for this study was provided. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work and “yes” to indicate that the author had a patent and/or copyright, planned, pending, or issued, broadly relevant to this work.
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