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In Reply We thank Bergquist and colleagues for their interest in our article1 on the association of aspirin use with biliary tract cancer (BTC) survival in the UK’s Clinical Practice Research Datalink (CPRD). We agree that the results cannot be the sole justification to incorporate aspirin therapy into the standard management of BTCs. For that, careful replication of the findings and, if possible, a randomized clinical trial are needed to provide further evidence. We also agree that the analysis has limitations that are typical with the use of electronic databases for observational research. We appreciate the opportunity to respond to these limitations beyond what was discussed in our article.
Although all observational studies are subject to error, not all potential sources of error will nullify the results. For instance, surgical status is not a strong enough confounder to completely explain our findings.1 Klatskin tumors are very rare, making up approximately 3% of cholangiocarcinomas2; therefore, the benefit of surgical resection for a small subset of these BTC cases is unlikely to confound the results. Furthermore, failure to account for surgery in patients with cholangiocarcinoma would not explain the findings for the other BTCs.
The survival curves we presented are a graphical presentation of the differences between 2 groups accounting for time-varying aspirin use.1 We agree that fewer events occur after 12 months than within the first year. However, this does not affect the associations represented by the hazard ratios, which should be interpreted as averages over the investigated time period. Clearly, there is no information contributing to those estimates when there are no more events the aspirin group.
To reduce misclassification bias, we required 2 or more prescriptions recorded in the CPRD to classify patients as aspirin users, which is a valid measure of adherence for chronic medications.3 Because aspirin is available over the counter in the UK, some true aspirin users may have been misclassified as nonusers. This misclassification would dilute the findings by making the 2 groups more alike, in which case the true survival benefit would be higher than what we reported.
We chose not to link to the National Cancer Data Repository or Office of National Statistics data because they only cover a percentage of the practices in England (approximately 57% of the CPRD).4 Case ascertainment is not usually a concern in studies of survival wherein both comparison groups are patients with cancer. Validation studies show high levels of concordance between the National Cancer Data Repository and the CPRD for both cancer incidence and mortality.4 On the other hand, a linked analysis would have reduced the sample size, power, and generalizability.4 Although lack of data on disease stage is a limitation, BTCs are nearly always fatal with short survival time after diagnosis, largely owing to the late stage at diagnosis; it is likely that mortality was attributable to BTC in this analysis. Although our study1 has limitations that hamper any analysis of electronic medical data, the big advantage is that the results can truly be thought of as representative of the case population and not a selected subset.
Corresponding Author: Sarah S. Jackson, PhD, MPH, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Dr, Room 6-E210, Bethesda, MD 20892 (firstname.lastname@example.org).
Published Online: March 19, 2020. doi:10.1001/jamaoncol.2020.0125
Conflict of Interest Disclosures: None reported.
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Jackson SS, Pfeiffer RM, Koshiol J. Questionable Survival Benefit of Aspirin Use in Patients With Biliary Tract Cancer—Reply. JAMA Oncol. Published online March 19, 2020. doi:10.1001/jamaoncol.2020.0125
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