This study compared the effectiveness of low-dose aspirin (81 mg twice daily) to high-dose aspirin (325 mg twice daily) for preventing venous thromboembolism (VTE) following total joint arthroplasty. The study included over 4,600 patients undergoing primary total joint replacement who received either low-dose or high-dose aspirin for 4 weeks post-operatively. The results found no significant difference in VTE rates between the low-dose and high-dose aspirin groups, indicating low-dose aspirin is not inferior to high-dose aspirin for VTE prophylaxis after total joint arthroplasty.

1. Journal Club
Presented by
Dr Dipendra Maharjan
Department of Orthopaedics
Shree Birendra Hospital

2. Introduction
• Aspirin is an effective drug for preventing arterial thromboembolic events
in the setting of cardiovascular and cerebrovascular disease.(1)
• 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 postoperatively. (2)
1. BaigentC,BlackwellL,Collins R,Emberson J,GodwinJ,PetoR,BuringJ,Hennekens C, Kearney P, Meade T, Patrono C, Roncaglioni MC, Zanchetti
A; Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-
analysis of individual participant data from randomised trials. Lancet. 2009 May 30;373(9678):1849-60.
2. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet.
2000 Apr 15;355 (9212):1295-302.

3. • 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 syndrome
• 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.

4. Rothman Institute at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania

5. Clinical questions
• Population
– 4,651primary total joint arthroplasty
• Intervention
– enteric-coated 325-mg aspirin twice daily for 4 weeks
• Comparison
– With or without enteric coated 81 mg aspirin twice daily for 4 weeks
• Outcome
– low-dose aspirin is not inferior to high-dose aspirin for venous
thromboembolism prophylaxis following total joint arthroplasty

6. Participants
• Key selection criteria
– Primary total joint arthroplasty
• Excluding criteria
– high-risk patients for VTE
• active malignancy, or known prothrombotic condition
• patients requiring anticoagulation for preexisting conditions.
– aspirin or nonsteroidal anti-inflammatory drug use was
contraindicated because of peptic ulcer disease, intolerance, or other
reasons.
• Inclusion/exclusion criteria suitable for the study

7. • Study type
– Prospective crossover type
– Comparative, randomized
• Study population
– Enrolled were all primary total joint arthroplasty
• Randomization
– As per operating surgeons choice
• Bias
– Exposed
– Randomization
– Not blinded to reduce experimental bias

8. Intervention and comparison
• Prospective, comparative, crossover study
• 6 adult reconstruction surgeons agreed to enroll.
• Study began on July 1, 2013 till June 30, 2015.
• Enrolled 4,651 patients undergoing primary total joint arthroplasty.

9. • During their time period of study,
– 3,192 patients (enteric-coated 325-mg aspirin)
– 1,459 patients (81-mg aspirin)
• Of the 1,459 patients,
– 525 (36%) enteric-coated 81-mg aspirin
– 934 (64%) plain 81-mg aspirin.
• Physical therapy commenced either on the day of the surgical procedure
or the next day and continued throughout the hospital stay.

10. Methodology
• Based on their 0.1% historical incidence of symptomatic venous
thromboembolism, the necessary sample size was calculated as 1,978 per
group using a power of 0.8 and an alpha of 0.05
– powered the study to detect a similar difference between the 325-mg
aspirin arm and the 81-mg aspirin arm.
– Their patient sample had an effective sample size of 2,002 patients per
arm.
• with 3,192 patients in the 325-mg aspirin arm and 1,459 patients
in the 81-mg aspirin arm

11. Methodology
• The chi-square and Wilcoxon signed rank tests were utilized to compare
demographic characteristics, comorbidities, and complication rates
between patients
– Method and approach to the study were diligent
– Process was consistent
– Follow complete in both the groups
– Outcome measures and appropriate
– Statistical tools used were suitable and correctly interpreted

12. Results
Demographic characteristics and comorbidities were similar between the 81-mg aspirin group and the
325-mg aspirin group.
Distributions of sex (p = 0.393) and Charlson Comorbidity Index (p = 0.779) were not significantly
different between the groups.

13. 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; the difference between groups was 0.21%
(95% CI, 0.03% to 0.5%)

14. 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, 20.1% to 0.7%), but this was not significant (p = 0.73)

15. 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 compared with 0.3% (95% CI, 0% to 0.5%) in the 325-mg aspirin group (4 with deep
venous thrombosis);
the difference between groups was 0.12% (95% CI, 20.2% to 0.5%) and was not significant (p = 0.92)

16. 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 or
venous thromboembolism.

17. Increased age was associated with increased rate of gastrointestinal complications.

18. Discussion and interpretation
• Strength and weakness of the study
– All patients underwent the surgical procedure in a single institution, in
which they were given standard
• their perioperative care
• The type of anesthesia,
• fixation mode of the prostheses,
• rehabilitation protocol,
• pain management,
• perioperative antibiotics
• Postoperative management

19. Discussion and interpretation
• Strength and weakness of the study
– Multiple aspects of their 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.
– The study only evaluated the incidence of clinically important venous
thromboembolism and routine screening was not employed, some
silent venous thromboembolism events may have gone undetected.

20. Discussion and interpretation
• Strength and weakness of the study
– study was not a true randomized study
– study was not powered to detect superiority of 81-mg aspirin twice a
day compared with 325-mg aspirin twice a day
– the determination of whether a patient received enteric-coated or
plain 81-mg aspirin twice a day was not standardized.
– although a standardized protocol for work-up of venous
thromboembolism was utilized during patients’ hospital stays, the
work-up was not regulated after discharge.

21. • Result support the conclusion
– 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.
– 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
– the ideal frequency of aspirin for venous thromboembolism
prophylaxis warrants further study.
– 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

22. Conclusion
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 thrombo-embolism.

23. Thank you!