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
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