Immeasurable Time Bias in Observational Studies of Drug Effects on Mortality

Observational studies suggesting that some drugs are effective at reducing mortality may have been subject to "immeasurable time bias" arising from the unidentified presence of hospitalizations when defining drug exposure with computerized health databases. The author illustrates the bias using a case-control study of 1,313 deaths and 1,313 controls selected from a cohort of 2,049 patients with chronic obstructive pulmonary disease from Saskatchewan, Canada, identified from 1990 and followed up through 1999. Different approaches were used to estimate the rate ratio of death associated with inhaled corticosteroid exposure, defined by a prescription dispensed in the 30-day period prior to the index date. More cases had been hospitalized during the 30-day exposure period (72%) than controls (26%), with lower durations of stay for cases who received an inhaled corticosteroid prescription (9.9 vs.16.2 days), thus introducing variations in measurable exposure times. The raw analysis that did not consider hospitalization found a rate ratio of 0.60 (95% confidence interval (CI): 0.50, 0.73). Alternatively, analyses accounting for variations in measurable times resulted in a rate ratio of 0.93 (95% CI: 0.76, 1.14) when weighted by measurable time, while use of the Kaplan-Meier estimator of the 30-day cumulative incidence of exposure found a rate ratio of 1.35 (95% CI: 1.14, 1.60). In conclusion, immeasurable time bias may be present in several observational database studies suggesting that certain drugs are effective at reducing mortality.