Publications by Year: 2011

Gagne JJ, Patrick AR, Mogun H, Solomon DH. Antidepressants and fracture risk in older adults: a comparative safety analysis. Clin Pharmacol Ther. 2011;89 (6) :880-7.Abstract
We examined variations in fracture rates among patients initiated on antidepressant drug treatment as identified from Medicare data in two US states and assessed whether the observed variation could be explained by affinity for serotonin transport receptors. We used Cox proportional hazards models to compare fracture rates of the hip, humerus, pelvis, wrist, and a composite of these, among propensity score-matched cohorts of users of secondary amine tricyclics, tertiary amine tricyclics, selective serotonin reuptake inhibitors (SSRIs), and atypical antidepressants. As compared with secondary amine tricyclics, SSRIs showed the highest association with composite fracture rate (hazard ratio 1.30; 95% confidence interval (CI) 1.12-1.52), followed by atypical antidepressants (hazard ratio 1.12; 95% CI 0.96-1.31) and tertiary amine tricyclics (hazard ratio 1.01; 95% CI 0.87-1.18). The results were robust to sensitivity analyses. Although SSRI use was associated with the highest rate of fractures, variation in fracture risk across specific antidepressant medications did not depend on affinity for serotonin transport receptors.
Schneeweiss S, Gagne JJ, Glynn RJ, Ruhl M, Rassen JA. Assessing the comparative effectiveness of newly marketed medications: methodological challenges and implications for drug development. Clin Pharmacol Ther. 2011;90 (6) :777-90.Abstract
Comparative-effectiveness research (CER) aims to produce actionable evidence regarding the effectiveness and safety of medical products and interventions as they are used outside of controlled research settings. Although CER evidence regarding medications is particularly needed shortly after market approval, key methodological challenges include (i) potential bias due to channeling of patients to the newly marketed medication because of various patient-, physician-, and system-related factors; (ii) rapid changes in the characteristics of the user population during the early phase of marketing; and (iii) lack of timely data and the often small number of users in the first few months of marketing. We propose a mix of approaches to generate comparative-effectiveness data in the early marketing period, including sequential cohort monitoring with secondary health-care data and propensity score (PS) balancing, as well as extended follow-up of phase III and phase IV trials, indirect comparisons of placebo-controlled trials, and modeling and simulation of virtual trials.
Power MC, Weuve J, Gagne JJ, McQueen MB, Viswanathan A, Blacker D. The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis. Epidemiology. 2011;22 (5) :646-59.Abstract
BACKGROUND: Many epidemiologic studies have considered the association between blood pressure (BP) and Alzheimer disease, yet the relationship remains poorly understood. METHODS: In parallel with work on the AlzRisk online database (, we conducted a systematic review to identify all epidemiologic studies meeting prespecified criteria reporting on the association between hypertension, systolic BP, or diastolic BP and incident Alzheimer disease. When possible, we computed summary measures using random-effects models and explored potential heterogeneity related to age at BP assessment. RESULTS: Eighteen studies reporting on 19 populations met the eligibility criteria. We computed summary relative risks (RR(Σ)) for 3 measures of BP: hypertension (RR(Σ) = 0.97 [95% confidence interval = 0.80-1.16]); a 10-mm Hg increase in systolic BP (RR(Σ) = 0.95 [0.91-1.00]); and a 10-mm Hg increase in diastolic BP (RR(Σ) = 0.94 [0.85-1.04]). We were unable to compute summary estimates for the association between categories of systolic or diastolic BP and Alzheimer disease; however, there did not appear to be a consistent pattern across studies. After stratifying on age at BP assessment, we found a suggestion of an inverse association between late-life hypertension and Alzheimer disease and a suggestion of an adverse association between midlife diastolic hypertension and Alzheimer disease. CONCLUSIONS: Based on existing epidemiologic research, we cannot determine whether there is a causal association between BP and Alzheimer disease. Selection bias and reverse causation may account for the suggested inverse association between late-life hypertension on Alzheimer disease, but, given the expected direction of these biases, they are less likely to account for the suggestion that midlife hypertension increases risk. We advocate continuing systematic review; the AlzRisk database entry on this topic (, which was completed in parallel with this work, will be updated as new studies are published.
Goldberg NH, Schneeweiss S, Kowal MK, Gagne JJ. Availability of comparative efficacy data at the time of drug approval in the United States. JAMA. 2011;305 (17) :1786-9.Abstract
CONTEXT: Comparative effectiveness is taking on an increasingly important role in US health care, yet little is known about the availability of comparative efficacy data for drugs at the time of their approval in the United States. OBJECTIVE: To quantify the availability of comparative efficacy data for new molecular entities (NMEs) approved in the United States. DATA SOURCES: Approval packages publicly available through the online database of drug products approved by the US Food and Drug Administration (FDA). STUDY SELECTION: Identification of efficacy studies that supported approval of each NME approved by FDA between 2000 and 2010. DATA EXTRACTION: We determined whether eligible studies were head-to-head active controlled trials and whether the results of such studies were available in the approval packages. We recorded the approved indication, whether the NME was an orphan product, whether the NME had undergone priority review, and whether the control group was a specific active comparator or standard care. RESULTS: Of 197 NMEs identified that met eligibility criteria, 100 (51% [95% confidence interval {CI}, 44%-58%]) met criteria for having comparative efficacy data available at the time of market authorization. After excluding NMEs designated as orphan products (n = 37) and those approved for indications for which no alternative treatments existed (n = 17), this proportion increased to 70% (95% CI, 62%-77%). The proportions of NMEs with available comparative efficacy data varied widely by therapeutic area, from 33% (95% CI, 9%-67%) for hormones and contraceptives to 89% (95% CI, 56%-99%) for diabetes medications. CONCLUSION: Publicly available FDA approval packages contain comparative efficacy data for about half of NMEs recently approved in the United States and for more than two-thirds of NMEs for which alternative treatment options exist. We did not investigate the extent to which available comparative efficacy information is useful for clinical guidance.
Maio V, Marino M, Robeson M, Gagne JJ. Beta-blocker initiation and adherence after hospitalization for acute myocardial infarction. Eur J Cardiovasc Prev Rehabil. 2011;18 (3) :438-45.Abstract
AIMS: We sought to: (1) estimate the proportion of patients who initiated beta-blocker therapy after acute myocardial infarction (AMI) in Regione Emilia-Romagna (RER); (2) examine predictors of post-AMI beta-blocker initiation; and (3) assess adherence to such therapy. METHODS AND RESULTS: Using healthcare claims data covering all of RER, we identified a cohort of 24,367 patients with a hospitalization for AMI between 2004 and 2007, who were discharged from the hospital alive and without contraindications to beta-blocker therapy. We estimated the proportion of eligible patients with at least one prescription for a beta-blocker following discharge and performed a multivariable logistic regression analysis to identify independent predictors of post-AMI beta-blocker initiation. We computed the proportion of days covered (PCD) as a measure of medication adherence at 6 and 12 months post-discharge. Following discharge, 16,383 (67%) cohort members initiated beta-blocker therapy. Independent predictors of beta-blocker initiation included age and receipt of invasive procedures during hospitalization, such as coronary artery bypass graft surgery (odds ratio [OR], 2.37; 95% confidence interval [CI], 2.00-2.81), percutaneous transluminal coronary angioplasty (OR, 1.42; 95% CI, 1.31-1.54), and cardiac catheterization (OR, 1.21; 95% CI, 1.11-1.32). Among initiators, adherence to beta-blocker treatment at 6 and 12 months was low and decreased in each study year. CONCLUSION: Overall, use of and adherence to post-AMI beta-blocker therapy was suboptimal in RER between 2004 and 2007. Older patients and those with indicators of frailty were less likely to initiate therapy. The proportion of patients adherent at 6 and 12 months decreased over time.
Gagne JJ, Glynn RJ, Avorn J, Levin R, Schneeweiss S. A combined comorbidity score predicted mortality in elderly patients better than existing scores. J Clin Epidemiol. 2011;64 (7) :749-59.Abstract
OBJECTIVE: To develop and validate a single numerical comorbidity score for predicting short- and long-term mortality, by combining conditions in the Charlson and Elixhauser measures. STUDY DESIGN AND SETTING: In a cohort of 120,679 Pennsylvania Medicare enrollees with drug coverage through a pharmacy assistance program, we developed a single numerical comorbidity score for predicting 1-year mortality, by combining the conditions in the Charlson and Elixhauser measures. We externally validated the combined score in a cohort of New Jersey Medicare enrollees, by comparing its performance to that of both component scores in predicting 1-year mortality, as well as 180-, 90-, and 30-day mortality. RESULTS: C-statistics from logistic regression models including the combined score were higher than corresponding c-statistics from models including either the Romano implementation of the Charlson Index or the single numerical version of the Elixhauser system; c-statistics were 0.860 (95% confidence interval [CI]: 0.854, 0.866), 0.839 (95% CI: 0.836, 0.849), and 0.836 (95% CI: 0.834, 0.847), respectively, for the 30-day mortality outcome. The combined comorbidity score also yielded positive values for two recently proposed measures of reclassification. CONCLUSION: In similar populations and data settings, the combined score may offer improvements in comorbidity summarization over existing scores.
Myers JA, Rassen JA, Gagne JJ, Huybrechts KF, Schneeweiss S, Rothman KJ, Joffe MM, Glynn RJ. Effects of adjusting for instrumental variables on bias and precision of effect estimates. Am J Epidemiol. 2011;174 (11) :1213-22.Abstract
Recent theoretical studies have shown that conditioning on an instrumental variable (IV), a variable that is associated with exposure but not associated with outcome except through exposure, can increase both bias and variance of exposure effect estimates. Although these findings have obvious implications in cases of known IVs, their meaning remains unclear in the more common scenario where investigators are uncertain whether a measured covariate meets the criteria for an IV or rather a confounder. The authors present results from two simulation studies designed to provide insight into the problem of conditioning on potential IVs in routine epidemiologic practice. The simulations explored the effects of conditioning on IVs, near-IVs (predictors of exposure that are weakly associated with outcome), and confounders on the bias and variance of a binary exposure effect estimate. The results indicate that effect estimates which are conditional on a perfect IV or near-IV may have larger bias and variance than the unconditional estimate. However, in most scenarios considered, the increases in error due to conditioning were small compared with the total estimation error. In these cases, minimizing unmeasured confounding should be the priority when selecting variables for adjustment, even at the risk of conditioning on IVs.
Gagne JJ, Choudhry NK. How many "me-too" drugs is too many?. JAMA. 2011;305 (7) :711-2.