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PURPOSE: Differences in the benefits of treatment on 5-year overall survival have been observed in 12 randomized phase III colon cancer adjuvant clinical trials from the ACCENT group. We investigated the reasons for these differences by incorporating the distribution of the observed covariates from each trial. MATERIALS AND METHODS: We applied state-of-the-art transportability methods on the basis of causal inference, and compared them with a conventional meta-analysis approach to predict the treatment effect for the target population. Prediction errors were defined to evaluate whether the identifiability conditions necessary for causal inference were satisfied among the 12 trials, and to measure the performance of each method. RESULTS: In the one-trial-at-a-time transportability analysis, the ranks of prediction errors for the target population were mostly consistent with the discrepancy in treatment effects among the 12 trials across the three models. The overall prediction errors between the leave-one-trial-out transportability method and the conventional individual participant data meta-analysis approach were very similar, and more than 40% lower than the overall prediction errors from the one-trial-at-a-time transportability method. CONCLUSION: The discrepancy in treatment effects among the 12 trials is unlikely to arise from the choice of model specification or distribution of observed covariates but from the distribution of unobserved covariates or study-level features. The ability to quantify heterogeneity among the 12 trials was greatly reduced in both the leave-one-trial-out transportability method and the conventional meta-analysis approach compared with the one-trial-at-a-time transportability method.
Assuntos
Neoplasias do Colo , Humanos , Neoplasias do Colo/terapiaRESUMO
OBJECTIVE: Therapeutic inertia threatens the potential long-term benefits of achieving early glycemic control after type 2 diabetes diagnosis. We evaluated temporal trends in second-line diabetes medication initiation among individuals initially treated with metformin. RESEARCH DESIGN AND METHODS: We included data from 199,042 adults with type 2 diabetes in the U.S. Department of Veterans Affairs health care system initially treated with metformin monotherapy from 2005 to 2013. We used multivariable Cox proportional hazards and linear regression to estimate associations of year of metformin monotherapy initiation with time to second-line diabetes treatment over 5 years of follow-up (primary outcome) and with hemoglobin A1c (HbA1c) at the time of second-line diabetes treatment initiation (secondary outcome). RESULTS: The cumulative 5-year incidence of second-line medication initiation declined from 47% among metformin initiators in 2005 to 36% in 2013 counterparts (P < 0.0001) despite a gradual increase in mean HbA1c at the end of follow-up (from 6.94 ± 1.28% to 7.09 ± 1.42%, Ptrend < 0.0001). In comparisons with metformin monotherapy initiators in 2005, adjusted hazard ratios for 5-year initiation of second-line diabetes treatment ranged from 0.90 (95% CI 0.87, 0.92) for 2006 metformin initiators to 0.68 (0.66, 0.70) for 2013 counterparts. Among those receiving second-line treatment within 5 years of metformin initiation, HbA1c at second-line medication initiation increased from 7.74 ± 1.66% in 2005 metformin initiators to 8.55 ± 1.92% in 2013 counterparts (Ptrend < 0.0001). CONCLUSIONS: We observed progressive delays in diabetes treatment intensification consistent with therapeutic inertia. Process-of-care interventions early in the diabetes disease course may be needed to reverse adverse temporal trends in diabetes care.