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

Angelo Karaboyas,1,2 Hal Morgenstern,3 Nancy L Fleischer,2 Douglas E Schaubel,4,5 Bruce M Robinson1,6 1Arbor Research Collaborative for Health, Ann Arbor, MI, USA; 2University of Michigan, Department of Epidemiology, Ann Arbor, MI, USA; 3University of Michigan, Departments of Epidemiology and Environmental Health Sciences, School of Public Health, and Department of Urology, Medical School, Ann Arbor, MI, USA; 4University of Michigan, Department of Biostatistics, Ann Arbor, MI, USA; 5University of Pennsylvania, Department of Biostatistics, Epidemiology and Informatics, Philadelphia, PA, USA; 6University of Michigan, Department of Internal Medicine, Ann Arbor, MI, USACorrespondence: Angelo KaraboyasArbor Research Collaborative for Health, 3700 Earhart Road, Ann Arbor, MI 48105, USATel +1 (734) 665-4108Email Angelo.Karaboyas@ArborResearch.orgBackground: 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.Keywords: reproducibility, causal inference, nephrology, dialysis, anemia, iron