Publications

OBJECTIVES: A "chiral switch" occurs in the pharmaceutical market when a drug made up of 2 enantiomer forms is replaced with a purified single-enantiomer version, often in the context of a patent expiration. We studied the prevalence of chiral switching in the United States over the past decade, including trends in use of, and expenditures on, these products in Medicaid.

STUDY DESIGN: Retrospective analysis.

METHODS: We used US Adopted Names prefixes (lev/levo/ar/es/dex/dextro) to identify all single-enantiomer drugs approved from 2001 to 2011. From publicly available US Food and Drug Administration (FDA) approval documents, we extracted the characteristics of the pivotal premarket trials for the single enantiomers. Specifically, we evaluated whether the single enantiomer was directly compared with the precursor racemic drug and whether there was evidence of superior efficacy. We used quarterly drug expenditure data from each state Medicaid program to chart trends in use of, and spending on, the single-enantiomer products and their racemic precursors during the study period.

RESULTS: From 2001 to 2011, the FDA approved 9 single-enantiomer products: dexlansoprazole, levoleucovorin, levocetirizine, armodafinil, arformoterol, eszopiclone, escitalopram, dexmethylphenidate, and esomeprazole. Of those 9 drugs, 3 had at least 1 pre-approval randomized trial that included the racemic precursor as a direct comparator, but there was no evidence of superiority of the single enantiomer over the racemic at comparable doses. Between 2001 and 2011, US Medicaid programs spent approximately $6.3 billion on these 9 single-enantiomer drugs.

CONCLUSIONS: Recently approved single-enantiomer drugs showed no evidence of superior efficacy over the older racemic precursors in the pivotal trials leading to their approval, and in a majority of cases, they were not directly compared.

BACKGROUND: Clinical trials often compare hypoglycemic medications on the basis of glycemic control but do not examine long-term outcomes (e.g., mortality). This study demonstrates an alternative approach to lengthening clinical trials to assess these long-term outcomes.

OBJECTIVE: To use observational quasi-experimental methods using instrumental variables (IVs) to compare the effect of two hypoglycemic medications, sulfonylureas (SUs) and thiazolidinediones (TZDs), on long-term outcomes.

METHODS: This study used administrative data from the Veterans Health Administration and Medicare from 2000 to 2010. The study population included US veterans dually enrolled in Medicare who received a prescription for metformin and then initiated SUs or TZDs. Patients could either continue on or discontinue metformin after the initiation of the second agent. Treatment was defined as starting either a SU or a TZD. Local variations in SU prescribing rates were used as instruments in IV models to control for selection bias. Survival models predicted all-cause mortality, ambulatory care sensitive condition hospitalizations, and stroke or heart attack (acute myocardial infarction).

RESULTS: Starting on SUs compared to TZDs significantly increased the likelihood of experiencing mortality and ACSC hospitalization. The estimated hazard ratio for the effect of starting on SUs compared to TZDs was 1.50 (95% confidence interval [CI] 1.09-2.09) for all-cause mortality, 1.68 (95% CI 1.31-2.15) for ambulatory care sensitive condition hospitalization, and 1.15 (95% CI 0.80-1.66) for acute myocardial infarction or stroke.

CONCLUSIONS: Our findings suggest increased risk of major adverse events associated with SUs as a second-line agent. Quasi-experimental IV methods may be an important alternative to lengthening clinical trials to assess long-term outcomes.

OBJECTIVES: To assess the association between multiple pharmacy use and medication adherence and potential drug-drug interactions (DDIs) in older adults.

DESIGN: Cross-sectional propensity score-weighted analysis.

SETTING: 2009 claims data.

PARTICIPANTS: A nationally representative sample of 926,956 Medicare Part D beneficiaries aged 65 and older continuously enrolled in fee-for-service Medicare and Part D that year who filled one or more prescriptions at a community retail or mail order pharmacy.

MEASUREMENTS: Multiple pharmacy use was defined as concurrent (overlapping time periods) or sequential use (non-overlapping time periods) of ≥ 2 pharmacies in the year. Medication adherence was calculated using a proportion of days covered of 0.80 or greater for eight therapeutic categories (beta-blockers, renin angiotensin system antagonists, calcium channel blockers, statins, sulfonylureas, biguanides (metformin), thiazolidinediones, and dipeptidyl peptidase-IV inhibitors). Potential DDIs arising from use of certain drugs across a broad set of classes were defined as the concurrent filling of two interacting drugs.

RESULTS: Overall, 38.1% of the sample used multiple pharmacies. Those using multiple pharmacies (concurrently or sequentially) consistently had higher adjusted odds of nonadherence (ranging from 1.10 to 1.31, P < .001) across all chronic medication classes assessed after controlling for sociodemographic, health status, and access to care factors than single pharmacy users. The adjusted predicted probability of exposure to a DDI was also slightly higher for those using multiple pharmacies concurrently (3.6%) than for single pharmacy users (3.2%, adjusted odds ratio (AOR) = 1.11, 95% confidence interval (CI) = 1.08-1.15) but lower in individuals using multiple pharmacies sequentially (2.8%, AOR = 0.85, 95% CI = 0.81-0.91).

CONCLUSIONS: Filling prescriptions at multiple pharmacies was associated with lower medication adherence across multiple chronic medications and a small but statistically significant greater likelihood of DDIs in concurrent pharmacy users.

BACKGROUND: Little is known about how Medicare Part D plan features influence choice of generic versus brand drugs.

OBJECTIVES: To examine the association between Part D plan features and generic medication use.

METHODS: Data from a 2009 random sample of 1.6 million fee-for-service, Part D enrollees aged 65 years and above, who were not dually eligible or receiving low-income subsidies, were used to examine the association between plan features (generic cost-sharing, difference in brand and generic copay, prior authorization, step therapy) and choice of generic antidepressants, antidiabetics, and statins. Logistic regression models accounting for plan-level clustering were adjusted for sociodemographic and health status.

RESULTS: Generic cost-sharing ranged from $0 to $9 for antidepressants and statins, and from $0 to $8 for antidiabetics (across 5th-95th percentiles). Brand-generic cost-sharing differences were smallest for statins (5th-95th percentiles: $16-$37) and largest for antidepressants ($16-$64) across plans. Beneficiaries with higher generic cost-sharing had lower generic use [adjusted odds ratio (OR)=0.97, 95% confidence interval (CI), 0.95-0.98 for antidepressants; OR=0.97, 95% CI, 0.96-0.98 for antidiabetics; OR=0.94, 95% CI, 0.92-0.95 for statins]. Larger brand-generic cost-sharing differences and prior authorization were significantly associated with greater generic use in all categories. Plans could increase generic use by 5-12 percentage points by reducing generic cost-sharing from the 75th ($7) to 25th percentiles ($4-$5), increasing brand-generic cost-sharing differences from the 25th ($25-$26) to 75th ($32-$33) percentiles, and using prior authorization and step therapy.

CONCLUSIONS: Cost-sharing features and utilization management tools were significantly associated with generic use in 3 commonly used medication categories.

OBJECTIVES: To describe changes in rosiglitazone prescribing following the US Food and Drug Administration (FDA) warning of potentially increased risk of myocardial infarction and removal from the Department of Veterans Affairs National Formulary (VANF), assess patient-level factors associated with rosiglitazone discontinuation, and evaluate changes in glucose control.

STUDY DESIGN: Historical cohort.

METHODS: Veterans with an active outpatient prescription for rosiglitazone on April 1, 2007, were followed until June 30, 2008. Incidence rate ratios (IRRs) of rosiglitazone discontinuation were compared over time using Poisson methods. We identified patient-level factors associated with stopping rosiglitazone using multivariable Poisson regression and compared glycated hemoglobin (A1C) values across time among patients who discontinued/continued rosiglitazone using linear mixed models.

RESULTS: Of 95,539 veterans with an active outpatient rosiglitazone prescription, 86.7% discontinued rosiglitazone. Discontinuation rates increased significantly after the FDA warning, with IRRs from 1.6 to 1.8. After removal from the VANF, rosiglitazone discontinuation rates again increased significantly. Discontinuing rosiglitazone was associated with the FDA warning, removal from the VANF, female sex, black race, Hispanic ethnicity, comorbidity, A1C greater than 9%, and use of rosiglitazone as first- or second-line therapy. Among patients who did and did not receive a replacement medication, the mean changes in A1C from baseline were 0.12% and 0.46%, respectively. For those who continued rosiglitazone, the mean change in A1C was -0.02%.

CONCLUSION: The rosiglitazone discontinuation rate increased following the FDA warning and increased further following removal of rosiglitazone from the VANF. Glucose control may have declined among those who discontinued rosiglitazone.