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For self-controlled studies of medication-related effects, time-varying confounding by indication can occur if the indication varies over time. We describe how active comparators might mitigate such bias, using an empirical example. Approaches to using active comparators are described for case-crossover design, case-time-control design, self-controlled case-series, and sequence symmetry analyses. In the empirical example, we used Danish data from 1996–2018 to study the association between penicillin and venous thromboembolism (VTE), using roxithromycin, a macrolide antibiotic, as comparator. Upper respiratory infection is a transient risk factor for VTE, thus representing time-dependent confounding by indication. Odds ratios for case-crossover analysis were 3.35 (95% confidence interval: 3.23, 3.49) for penicillin and 3.56 (95% confidence interval: 3.30, 3.83) for roxithromycin. We used a Wald-based method or an interaction term to estimate the odds ratio for penicillin with roxithromycin as comparator. These 2 estimates were 0.94 (95% confidence interval: 0.87, 1.03) and 1.03 (95% confidence interval: 0.95, 1.13). Results were similar for the case-time-control analysis, but both the self-controlled case-series and sequence symmetry analysis suggested a weak protective effect of penicillin, seemingly explained by VTE affecting future exposure exclusively for penicillin. The strong association of antibiotics with VTE suggests presence of confounding by indication. Such confounding can be mitigated by using an active comparator. [ABSTRACT FROM AUTHOR]

Background. Clostridium difficile infection (CDI) is the most common cause of nosocomial infectious diarrhea and may result in severe complications including death. We conducted a prospective study to identify risk factors for complications of CDI (cCDI). Methods. Adult inpatients with confirmed CDI in 10 Canadian hospitals were enrolled and followed for 90 days. Potential risk factors were measured within 24 hours of diagnosis. Isolates were typed by polymerase chain reaction ribotyping. cCDI was defined as 1 or more of the following: colonic perforation, toxic megacolon, colectomy, admission to an intensive care unit for cCDI, or if CDI contributed to death within 30 days of enrollment. Risk factors for cCDI were investigated by logistic regression. Results. A total of 1380 patients were enrolled. cCDI was observed in 8% of patients. The ribotype was identified in 922 patients, of whom 52% were infected with R027. Age =80 years, heart rate >90/minute, respiratory rate >20/ minute, white cell count <4 × 109/L or =20 × 109/L, albumin <25 g/L, blood urea nitrogen >7 mmol/L, and C-reactive protein =150 mg/L were independently associated with cCDI. A higher frequency of cCDI was observed among R027-infected patients (10.9% vs 7.2%), but the association was not significant in adjusted analysis. Conclusions. CDI complications were associated with older age, abnormal blood tests, and abnormal vital signs. These factors, which are readily available to clinicians at the time of diagnosis, could be used for outcome prediction and risk stratification to select patients who may need closer monitoring or more aggressive therapy. [ABSTRACT FROM AUTHOR]