Replicating Randomized Trial Results with Observational Data Using the Parametric g-Formula: An Application to Intravenous Iron Treatment in Hemodialysis Patients.

Background Reproducibility of clinical and epidemiologic research is important to generalize findings and has increasingly been scrutinized. A recently published randomized trial, PIVOTAL, evaluated high vs low intravenous iron dosing strategies to manage anemia in hemodialysis patients in the UK. Our objective was to assess the reproducibility of the PIVOTAL trial findings using data from a well-established cohort study, the Dialysis Outcomes and Practice Patterns Study (DOPPS). Methods To overcome the absence of randomization in the DOPPS, we applied the parametric g-formula, an extension of standardization to longitudinal data. We estimated the effect of a proactive high-dose vs reactive low-dose iron supplementation strategy on all-cause mortality (primary outcome), hemoglobin, two measures of iron concentration (ferritin and TSAT), and erythropoiesis-stimulating agent dose over 12 months of follow-up in 6325 DOPPS patients. Results Comparing high- vs low-iron dose strategies, the 1-year mortality risk difference was 0.020 (95% CI: 0.008, 0.031) and risk ratio was 1.20 (95% CI: 1.07, 1.33), compared with null 1-year findings in the PIVOTAL trial. Differences in secondary outcomes were directionally consistent but of lesser magnitude than in the PIVOTAL trial. Conclusion Our findings are somewhat consistent with the recent PIVOTAL trial, with discrepancies potentially attributable to model misspecification and differences between the two study populations. In addition to the importance of our results to nephrologists and hence hemodialysis patients, our analysis illustrates the utility of the parametric g-formula for generalizing results and comparing complex and dynamic treatment strategies using observational data.