When reporting results from randomized experiments, researchers often choose to present a per-protocol effect in addition to an intention-to-treat effect. However, these per-protocol effects are often described retrospectively, for example, comparing outcomes among individuals who adhered to their assigned treatment strategy throughout the study. This retrospective definition of a per-protocol effect is often confounded and cannot be interpreted causally because it encounters treatment-confounder feedback loops, where past confounders affect future treatment, and current treatment affects future confounders. Per-protocol effects estimated using this method are highly susceptible to the placebo paradox, also called the “healthy adherers” bias, where individuals who adhere to placebo appear to have better survival than those who don’t. This result is generally not due to a benefit of placebo, but rather is most often the result of uncontrolled confounding. Here, we aim to provide an overview to causal inference for survival outcomes with time-varying exposures for static interventions using inverse probability weighting. The basic concepts described here can also apply to other types of exposure strategies, although these may require additional design or analytic considerations. We provide a workshop guide with solutions manual, fully reproducible R, SAS, and Stata code, and a simulated dataset on a GitHub repository for the reader to explore.
IMPORTANCEThe Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database may provide insights into the comparative effectiveness of oncological treatments for elderly individuals who are underrepresented in clinical trials. OBJECTIVE To evaluate the suitability of SEER-Medicare data for assessing the effectiveness of adding a drug to an existing treatment regimen on the overall survival of elderly patients with cancer. DESIGN, SETTING, AND PARTICIPANTS This comparative effectiveness study analyzed SEER-Medicare data from 9549 individuals who received a new diagnosis of stage II colorectal cancer (2008-2012) and 940 patients who received a new diagnosis of advanced pancreatic adenocarcinoma (2007-2012), with follow-up to December 31, 2013 (SEER-Medicare data released in 2015). Two (hypothetical) target trials were designed and emulated based on 2 existing randomized clinical trials: (1) adjuvant fluorouracil after curative surgery for individuals with stage II colorectal cancer and (2) erlotinib added to gemcitabine for individuals with advanced pancreatic adenocarcinoma. Data were analyzed January 2018 to March 2019. EXPOSURES The following treatment strategies were compared: (1) fluorouracil initiation vs no initiation within 3 months of tumor resection and (2) erlotinib initiation vs no initiation within 12 weeks of gemcitabine initiation. MAIN OUTCOMES AND MEASURES All-cause mortality within 60 months of baseline for the fluorouracil trial and within 72 weeks for the erlotinib trial. RESULTS Compared with 3293 individuals in the existing fluorouracil trial, 9549 eligible individuals included in the present analyses were more likely to have colon cancer (8565 [90%] vs 2291 [71%]) and were older (median [interquartile range], 79 [73-84] vs 63 [56-68] years). The 5-year risk difference for initiation vs noninitiation of fluorouracil after surgery was −3.8% (95% CI, −14.8% to 12.6%), and the mortality hazard ratio (HR) was 0.95 (95% CI, 0.85-1.04). Compared with 569 individuals in the existing erlotinib trial, 940 eligible patients included in the present analysis were older (median [range], 74 [66-93] vs 64 [36-92] years) and more likely to be male (547 [58%] vs 298[52%]). The 1-year risk difference for initiation vs noninitiation of erlotinib was 4.7% (95% CI, −9.4% to 18.0%), and the corresponding mortality HR was 1.04 (95% CI, 0.86-1.42). In naive analyses, the mortality HR estimate was 1.14 (95% CI, 0.95-1.36) for the fluorouracil emulation and 0.68 (95% CI, 0.54-0.87) for the erlotinib emulation.
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