Alan R. Ellis

Infection Risk with Bolus versus Maintenance Iron Supplementation in Hemodialysis Patients

Intravenous iron may promote bacterial growth and impair host defense, but the risk of infection associated with iron supplementation is not well defined. We conducted a retrospective cohort study of hemodialysis patients to compare the safety of bolus dosing, which provides a large amount of iron over a short period of time on an as-needed basis, with maintenance dosing, which provides smaller amounts of iron on a regular schedule to maintain iron repletion. Using clinical data from 117,050 patients of a large US dialysis provider merged with data from Medicares ESRD program, we estimated the effects of iron dosing patterns during repeated 1-month exposure periods on risks of mortality and infection-related hospitalizations during the subsequent 3 months. Of 776,203 exposure/follow-up pairs, 13% involved bolus dosing, 49% involved maintenance dosing, and 38% did not include exposure to iron. Multivariable additive risk models found that patients receiving bolus versus maintenance iron were at increased risk of infection-related hospitalization (risk difference [RD], 25 additional events/1000 patient-years; 95% confidence interval [CI], 16 to 33) during follow-up. Risks were largest among patients with a catheter (RD, 73 events/1000 patient-years; 95% CI, 48 to 99) and a recent infection (RD, 57 events/1000 patient-years; 95% CI, 19 to 99). We also observed an association between bolus dosing and infection-related mortality. Compared with no iron, maintenance dosing did not associate with increased risks for adverse outcomes. These results suggest that maintenance iron supplementation may result in fewer infections than bolus dosing, particularly among patients with a catheter.

Treating Depression After Initial Treatment Failure: Directly Comparing Switch and Augmenting Strategies in STAR*D

Objective Augmenting and switching antidepressant medications are the 2 most common next-step strategies for depressed patients failing initial medication treatment. These approaches have not been directly compared; thus, our objectives are to compare outcomes for medication augmentation versus switching for patients with major depressive disorder in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical trial. Methods We conducted a retrospective analysis of participants aged 18 to 75 years with DSM-IV nonpsychotic depression who failed to remit with initial treatment in the STAR*D clinical trial (N = 1292). We compared depressive symptom remission, response, and quality of life among participants in each study arm using propensity score matching to minimize selection bias. Results The propensity-score-matched augment (N = 269) and switch (N = 269) groups were well balanced on measured characteristics. Neither the likelihood of remission (risk ratio, 1.14; 95% confidence level, 0.82–1.58) or response (risk ratio, 1.14; 95% confidence level, 0.82–1.58), nor the time to remission (log-rank test, P = 0.946) or response (log-rank test, P = 0.243) differed by treatment strategy. Similarly, quality of life did not differ. Post hoc analyses suggested that augmentation improved outcomes for patients tolerating 12 or more weeks of initial treatment and those with partial initial treatment response. Conclusions For patients receiving and tolerating aggressive initial antidepressant trials, there is no clear preference for next-step augmentation versus switching. Findings tentatively suggest that those who complete an initial treatment of 12 weeks or more and have a partial response with residual mild depressive severity may benefit more from augmentation relative to switching.

Intravenous Iron Supplementation Practices and Short-Term Risk of Cardiovascular Events in Hemodialysis Patients

Background & Objectives Intravenous iron supplementation is widespread in the hemodialysis population, but there is uncertainty about the safest dosing strategy. We compared the safety of different intravenous iron dosing practices on the risk of adverse cardiovascular outcomes in a large population of hemodialysis patients. Design settings, participants, & measurements A retrospective cohort was created from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the United States Renal Data System. Dosing comparisons were (1) bolus (consecutive doses ≥ 100 mg exceeding 600 mg during one month) versus maintenance (all other iron doses during the month); and (2) high (> 200 mg over 1 month) versus low dose (≤ 200 mg over 1 month). We established a 6-month baseline period (to identify potential confounders and effect modifiers), a one-month iron exposure period, and a three-month follow-up period. Outcomes were myocardial infarction, stroke, and death from cardiovascular disease. Results 117,050 patients contributed 776,203 unique iron exposure/follow-up periods. After adjustment, we found no significant associations of bolus dose versus maintenance, hazards ratio for composite outcome, 1.03 (95% C.I. 0.99, 1.07), or high dose versus low dose intravenous iron, hazards ratio for composite outcome, 0.99 (95% C.I. 0.96, 1.03). There were no consistent associations of either high or bolus dose versus low or maintenance respectively among pre-specified subgroups. Conclusions Strategies favoring large doses of intravenous iron were not associated with increased short-term cardiovascular morbidity and mortality. Investigation of the long-term safety of the various intravenous iron supplementation strategies may still be warranted.

The Role of Prediction Modeling in Propensity Score Estimation: An Evaluation of Logistic Regression, bCART, and the Covariate-Balancing Propensity Score

The covariate-balancing propensity score (CBPS) extends logistic regression to simultaneously optimize covariate balance and treatment prediction. Although the CBPS has been shown to perform well in certain settings, its performance has not been evaluated in settings specific to pharmacoepidemiology and large database research. In this study, we use both simulations and empirical data to compare the performance of the CBPS with logistic regression and boosted classification and regression trees. We simulated various degrees of model misspecification to evaluate the robustness of each propensity score (PS) estimation method. We then applied these methods to compare the effect of initiating glucagonlike peptide-1 agonists versus sulfonylureas on cardiovascular events and all-cause mortality in the US Medicare population in 2007-2009. In simulations, the CBPS was generally more robust in terms of balancing covariates and reducing bias compared with misspecified logistic PS models and boosted classification and regression trees. All PS estimation methods performed similarly in the empirical example. For settings common to pharmacoepidemiology, logistic regression with balance checks to assess model specification is a valid method for PS estimation, but it can require refitting multiple models until covariate balance is achieved. The CBPS is a promising method to improve the robustness of PS models.

The Comparative Short-term Effectiveness of Iron Dosing and Formulations in US Hemodialysis Patients

BACKGROUND Intravenous iron is used widely in hemodialysis, yet there are limited data on the effectiveness of contemporary dosing strategies or formulation type. METHODS We conducted a retrospective cohort study using data from the clinical database of a large dialysis provider (years 2004-2008) merged with administrative data from the US Renal Data System to compare the effects of intravenous iron use on anemia management. Dosing comparisons were bolus (consecutive doses ≥100 mg exceeding 600 mg during 1 month) versus maintenance (all other iron doses during the month); and high (>200 mg over 1 month) versus low dose (≤200 mg over 1 month). Formulation comparison was administration of ferric gluconate versus iron sucrose over 1 month. Outcomes were hemoglobin, epoetin dose, transferrin saturation, and serum ferritin during 6 weeks of follow-up. RESULTS We identified 117,050 patients for the dosing comparison, and 66,207 patients for the formulation comparison. Bolus dosing was associated with higher average adjusted hemoglobin (+0.23 g/dL; 95% confidence interval [CI], 0.21-0.26), transferrin saturation (+3.31%; 95% CI, 2.99-3.63), serum ferritin (+151 μg/L; 95% CI, 134.9-168.7), and lower average epoetin dose (-464 units; 95% CI, -583 to -343) compared with maintenance. Similar trends were observed with high-dose iron versus low-dose. Iron sucrose was associated with higher adjusted average hemoglobin (+0.16 g/dL; 95% CI, 0.12-0.19) versus ferric gluconate. CONCLUSIONS Strategies favoring large doses of intravenous iron or iron sucrose lead to improved measures of anemia management. These potential benefits should be weighed against risks, which currently remain incompletely characterized.

Comparing provider perceptions of access and utilization management in full-risk and no-risk medicaid programs for adults with serious mental illness

This article compares provider perceptions of access to services and utilization management (UM) procedures in two Medicaid programs in the same state: a full-risk capitated managed care (MC) program and a no-risk, fee-for-service (FFS) program. Survey data were obtained from 198 mental health clinicians and administrators. The only difference found between respondents in the FFS and MC sites was that outpatient providers in the MC site reported significantly lower levels of access to high-intensity services than did providers in the FFS site (p<.001). Respondents in the two sites reported similar attitudes toward UM procedures, including a strong preference for internal over external UM procedures. These findings support the conclusion that through diffusion of UM procedures, all care in the Medicaid program for persons with a serious mental illness is managed, regardless of risk arrangement. Implications for mental health services and further research are discussed.

Distressing adverse events after antidepressant switch in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial: influence of adverse events during initial treatment with citalopram on development of subsequent adverse events with an alternative antidepressant.

To determine whether distressing adverse events (DAEs) experienced during initial antidepressant treatment are associated with subsequent DAEs after switching to a second antidepressant.

Targeting Trauma-related Interventions and Improving Outcomes for Women with Co-occurring Disorders

National attention to the effects of interpersonal trauma has led mental health systems to adopt policies on trauma-related services; however, there is a lack of clarity regarding targeting of these services. Data from the Women, Co-occurring Disorders and Violence Study (WCDVS) were reanalyzed by grouping women on their baseline PTSD and substance abuse presentation and assessing the differential response to an integrated mental health/substance abuse intervention. Treatment effects were largest for subgroups characterized by high levels of PTSD, whereas the effects for those in the low symptom group were near zero. These findings underscore the need for clinicians to conduct careful assessments of trauma-related symptoms and to target the most intensive trauma-related interventions to individuals with PTSD symptoms.

Do medical homes increase medication adherence for persons with multiple chronic conditions

Background:Medications are an integral component of management for many chronic conditions, and suboptimal adherence limits medication effectiveness among persons with multiple chronic conditions (MCC). Medical homes may provide a mechanism for increasing adherence among persons with MCC, thereby enhancing management of chronic conditions. Objective:To examine the association between medical home enrollment and adherence to newly initiated medications among Medicaid enrollees with MCC. Research Design:Retrospective cohort study comparing Community Care of North Carolina medical home enrollees to nonenrollees using merged North Carolina Medicaid claims data (fiscal years 2008–2010). Subjects:Among North Carolina Medicaid-enrolled adults with MCC, we created separate longitudinal cohorts of new users of antidepressants (N=9303), antihypertensive agents (N=12,595), oral diabetic agents (N=6409), and statins (N=9263). Measures:Outcomes were the proportion of days covered (PDC) on treatment medication each month for 12 months and a dichotomous measure of adherence (PDC>0.80). Our primary analysis utilized person-level fixed effects models. Sensitivity analyses included propensity score and person-level random-effect models. Results:Compared with nonenrollees, medical home enrollees exhibited higher PDC by 4.7, 6.0, 4.8, and 5.1 percentage points for depression, hypertension, diabetes, and hyperlipidemia, respectively (P’s<0.001). The dichotomous adherence measure showed similar increases, with absolute differences of 4.1, 4.5, 3.5, and 4.6 percentage points, respectively (P’s<0.001). Conclusions:Among Medicaid enrollees with MCC, adherence to new medications is greater for those enrolled in medical homes.

Matching on the disease risk score in comparative effectiveness research of new treatments.

We use simulations and an empirical example to evaluate the performance of disease risk score (DRS) matching compared with propensity score (PS) matching when controlling large numbers of covariates in settings involving newly introduced treatments.