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We read with interest the cohort study by Cheung et al1 reporting that use of proton-pump inhibitors (PPIs) after Helicobacter pylori eradication is associated with an increased risk of gastric cancer (GC). We believe that the significantly elevated HR of GC with PPI use (HR 2.44; 95% CI 1.42 to 4.20) is a consequence of two time-related biases. Immortal time bias was introduced by misclassifying exposure,2–4 while latency bias was introduced by not incorporating latency in the exposure definition, a major issue for potential carcinogenic drug effects.5 6
Immortal time in a cohort study refers to a period of follow-up time when the outcome could not occur.3 It arises in this study from the definition of frequency of PPI use, ‘calculated by dividing the total treatment duration by the duration of follow-up’, namely the average use over the entire follow-up. Exposure to PPIs was then categorised ‘into non-regular use (<weekly use; reference group) and regular use (at least weekly use)’.1 Thus, the PPI ‘non-users’ included authentic non-users of PPIs and the non-regular PPI users (less than weekly use), together making up the reference group against which the risk …
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