Journal ClubPresented byDr Dipendra MaharjanDepartment of OrthopaedicsShree Birendra Hospital
IntroductionAspirin 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.
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.
Rothman Institute at Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
Hypothesislow dose aspirin in comparison with high dose of aspirin is a safe and effective modality for the prevention of venous thromboembolism following total joint arthroplasty.
Clinical questionsPopulation4,651primary total joint arthroplasty
Interventionenteric-coated 325-mg aspirin twice daily for 4 weeks
ComparisonWith or without enteric coated 81 mg aspirin twice daily for 4 weeks
Outcomelow-dose aspirin is not inferior to high-dose aspirin for venous thromboembolism prophylaxis following total joint arthroplasty
ParticipantsKey selection criteriaPrimary total joint arthroplasty
Excluding criteriahigh-risk patients for VTEactive malignancy, or known prothrombotic conditionpatients 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
Study typeProspective crossover typeComparative, randomized
Study populationEnrolled were all primary total joint arthroplasty
RandomizationAs per operating surgeons choice
BiasExposedRandomizationNot blinded to reduce experimental bias
Intervention and comparisonProspective, 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.
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.
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.
The determination of whether a patient received plain or enteric-coated 81-mg aspirin twice a day was based on surgeon preference.10
MethodologyBased 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
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 consistentFollow complete in both the groupsOutcome measures and appropriateStatistical tools used were suitable and correctly interpreted
Authors made power statement, The power of study has been stated as .8
0.05 has been used as significance level
Power analysis carried out
Sufficiently powered to eliminate errors
Do the data exhibit low variabilityEffect size
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.
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%)
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)
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)
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.
Increased age was associated with increased rate of gastrointestinal complications.
Discussion and interpretationStrength and weakness of the studyAll patients underwent the surgical procedure in a single institution, in which they were given standardtheir perioperative careThe type of anesthesia, fixation mode of the prostheses, rehabilitation protocol, pain management, perioperative antibioticsPostoperative management
Discussion and interpretationStrength and weakness of the studyMultiple 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.
Discussion and interpretationStrength and weakness of the studystudy 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.
Result support the conclusiona 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
Statistical significance vs clinical significanceStatistically significant and comparable between two groupsApplicable in out context as wellBut there is limiation of standardized pre-op and post-op protocals which may limit our use of low dose aspirin
Article acknowledge the relevant literature and other approachesPEP trialUnpublished studyCardiovascular journals regarding safety and efficacy of aspirin
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.