IMPORTANCE The left atrial appendage is a key site of thrombus formation in atrial fibrillation (AF) and can be occluded or removed at the time of cardiac surgery. There is limited evidence regarding the effectiveness of surgical left atrial appendage occlusion (S-LAAO) for reducing the risk of thromboembolism. OBJECTIVE To evaluate the association of S-LAAO vs no receipt of S-LAAO with risk of thromboembolism among older patients undergoing cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of a nationally representative Medicare-linked cohort from the Society of Thoracic Surgeons Adult Cardiac Surgery Database (2011–2012). Patients ≥65 years old with AF undergoing cardiac surgery (coronary artery bypass grafting [CABG], mitral valve surgery ± CABG, aortic valve surgery ± CABG) with and without concomitant S-LAAO were followed until December 31, 2014. EXPOSURE S-LAAO vs. no S-LAAO. MAIN OUTCOME MEASURES Primary outcome was readmission for thromboembolism (stroke, transient ischemic attack, or systemic embolism) at up to 3 years follow-up, as defined by Medicare claims data. Secondary endpoints included hemorrhagic stroke, all-cause mortality, and a composite endpoint (thromboembolism, hemorrhagic stroke, all-cause mortality). RESULTS Among 10,524 patients undergoing surgery (median age of 76 years; 39% female; median CHA2DS2-VASc score of 4), 3,892 (37%) underwent S-LAAO. Overall, at a mean follow-up of 2.6 years, thromboembolism occurred in 5.4%, hemorrhagic stroke in 0.9%, death in 21.5%, and the composite endpoint in 25.7%. S-LAAO, compared with no S-LAAO, was associated with lower unadjusted rates of thromboembolism (4.2% vs. 6.2%), all-cause mortality (17.3% vs. 23.9%), and the composite endpoint (20.5% vs. 28.7%), but no significance difference in rates of hemorrhagic stroke (0.9% vs. 0.9%). After inverse probability-weighted adjustment, S-LAAO was associated with a significantly lower rate of thromboembolism (subdistribution hazard ratio [HR] 0.67, confidence interval [CI] 0.56–0.81, p<0.0001), death (HR 0.88, CI 0.79–0.97, p=0.001), and the composite endpoint (HR 0.83, CI 0.76–0.91, p<0.001), but not hemorrhagic stroke (subdistribution HR 0.84, 0.53–1.32, p=0.44). S-LAAO, compared with no S-LAAO, was associated with a lower risk of thromboembolism among those discharged without anticoagulation (unadjusted rate 4.2% vs. 6.0%, adjusted subdistribution HR 0.26, CI 0.17–0.40, p<0.001), but not among those discharged with anticoagulation (unadjusted rate 4.1% vs. 6.3%, adjusted subdistribution HR 0.88, CI 0.56–1.39, p=0.59). CONCLUSIONS AND RELEVANCE Among older patients with AF undergoing concomitant cardiac surgery, S-LAAO compared with no S-LAAO, was associated with a lower risk of readmission for thromboembolism over the three years. These findings are supportive of S-LAAO, but randomized trials are necessary to provide definitive evidence.

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For the assessment of biosimilarity of biosimilar products, the United States (US) Food and Drug Administration (FDA) proposed a stepwise approach for providing the totality-of-the-evidence of similarity between a proposed biosimilar product and a US-licensed (reference) product. The stepwise approach starts with the assessment of critical quality attributes (CQAs) that are relevant to clinical outcomes in structural and functional characterization in the manufacturing process of the proposed biosimilar product. FDA suggests that these critical quality relevant attributes be identified and classified into three tiers depending on their criticality or risk ranking. To assist the sponsors, FDA also suggests some statistical approaches for the assessment of analytical similarity for CQAs from different tiers, namely equivalence test for Tier 1, quality range approach for Tier 2, and descriptive raw data and graphical comparison for Tier 3. Analytical similarity assessment for CQAs in Tier 1 is performed based on the equivalence acceptance criterion (EAC), which depends upon the estimate of variability of the reference product. The FDA's recommended approach often underestimates the variability of the reference product because it does not take the worst possible lots into consideration. In this article, we examine the statistical properties of the FDA's recommended approach and proposed alternative methods in establishing an alternative approach under the scenario where multiple samples drew from each lot.

Supplementary data are available at Bioinformatics online.