Journal Club

Presented byDr Dipendra MaharjanDepartment of OrthopaedicsShree Birendra Hospital

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.

• 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

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

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

• 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

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.

• 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.

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

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

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.

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 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

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.

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.

• 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

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.

Thank you!