Publications

2019
Connolly JG, Schneeweiss S, Glynn RJ, Gagne JJ. Quantifying bias reduction with fixed-duration versus all-available covariate assessment periods. Pharmacoepidemiol Drug Saf. 2019;28 (5) :665-670.Abstract
PURPOSE: Implementing a cohort study in longitudinal healthcare databases requires looking back over some covariate assessment period (CAP) preceding cohort entry to measure confounders. We used simulations to compare fixed-duration versus all-available CAPs for confounder adjustment in the presence of differences in available baseline time between exposure groups. METHODS: We simulated cohorts of 10 000 patients with binary variables for a single confounder, exposure, and outcome. Baseline time was simulated based on the observed distribution in a claims-based comparison of statin users versus nonusers. We compared bias after measuring confounders using fixed-duration and all-available CAPs, both when exposure groups had similar and discrepant amounts of available baseline time. RESULTS: When the comparison groups had similar amounts of baseline time, an all-available CAP was less biased than a fixed-duration CAP. When baseline time differed between comparison groups, the preferable CAP approach depended on the direction of confounding and which exposure group had higher covariate sensitivity. These findings were consistent in direction across sensitivity analyses. CONCLUSION: In certain settings of differential available baseline time between exposure groups, the all-available CAP was more biased than the fixed-duration CAP. The relative directions and strengths of confounding and misclassification biases are an important consideration when choosing between a fixed-duration or all-available CAP, but they are often unknown. Therefore, we recommend comparing the amount of available baseline time between exposure groups. When there is a large discrepancy, despite appropriate design choices, we recommend a fixed-duration approach to avoid potential increases in bias because of differential data availability.
Gagne JJ, Sarpatwari A, Desai RJ. Role of Authorized Generics in Postapproval Surveillance of Generic Drug Products. Clin Pharmacol Ther. 2019;105 (2) :313-315.
Sarpatwari A, Gagne JJ, Lu Z, Campbell EG, Carman WJ, Enger CL, Dutcher SK, Jiang W, Kesselheim AS. A Survey of Patients' Perceptions of Pill Appearance and Responses to Changes in Appearance for Four Chronic Disease Medications. J Gen Intern Med. 2019;34 (3) :420-428.Abstract
BACKGROUND: Generic versions of a drug can vary in appearance, which can impact adherence. OBJECTIVE: To assess the preferences, perceptions, and responses of patients who experienced a change in the appearance of a generic medication. DESIGN: Cross-sectional survey of patients from a large commercial health plan. PARTICIPANTS: Adults receiving generic versions of lisinopril, fluoxetine, lamotrigine, or simvastatin who experienced a change in the color or shape of their pills between March 2014 and November 2015. MAIN MEASURES: Likert-scale responses to questions concerning perceptions of generic drug safety and effectiveness, reliance on and preferences for pill appearance, and responses to pill appearance changes. Multivariable logistic regression-modeled predictors of seeking advice and adjusting use following a pill appearance change. KEY RESULTS: Of 814 respondents (response rate = 41%), 72% relied on pill appearance to ensure they took the correct medication. A similar percentage wanted their pills to remain the same color (72%), shape (71%), and size (75%) upon refill, but 58% would not have paid a $1 premium on a $5 co-pay to ensure such consistency. Most respondents (86%) wanted their pharmacists to notify them about pill appearance changes, but only 37% recalled such notification; 21% thought they received the wrong medication, and 8% adjusted medication use. Younger respondents (18-33 vs. 50-57 years) were more likely to seek advice (odds ratio [OR] = 1.91; 95% confidence interval [CI],1.02-3.59), and respondents with lower household income (< $30,000 vs. > $100,000) were more likely to adjust medication use (OR = 3.40; 95% CI,1.09-10.67). CONCLUSIONS: Requiring uniform pill appearance may help increase adherence but presents challenges. Standardized pharmacy notification and education policies may be a more feasible short-term solution.
Gagne JJ, He M, Bateman BT. Trends in Opioid Prescription in Children and Adolescents in a Commercially Insured Population in the United States, 2004-2017. JAMA Pediatr. 2019;173 (1) :98-99.
Wang SV, Schneeweiss S, Gagne JJ, Evers T, Gerlinger C, Desai R, Najafzadeh M. Using Real-World Data to Extrapolate Evidence From Randomized Controlled Trials. Clin Pharmacol Ther. 2019;105 (5) :1156-1163.Abstract
Randomized controlled trials (RCTs) provide evidence for regulatory agencies, shape clinical practice, influence formulary decisions, and have important implications for patients. However, many patient groups that are major consumers of drugs are under-represented in randomized trials. We review three methods to extrapolate evidence from trial participants to different target populations following market approval and discuss how these could be implemented in practice to support regulatory and health technology assessment decisions. Although these methods are not a substitute for less restrictive pre-approval RCTs or rigorous observational studies when sufficient data are available in the post-approval setting, they can help to fill the evidence gap that exists in the early marketing period. Early evidence using real-world data and methods for extrapolating evidence should be reported with clear explanation of assumptions and limitations especially when used to support regulatory and health technology assessment decisions.
Desai RJ, Mahesri M, Gagne JJ, Hurley E, Tong A, Chitnis T, Minden S, Spettell CM, Matlin OS, Shrank WH, et al. Utilization Patterns of Oral Disease-Modifying Drugs in Commercially Insured Patients with Multiple Sclerosis. J Manag Care Spec Pharm. 2019;25 (1) :113-121.Abstract
BACKGROUND: The approval of new oral disease-modifying drugs (DMDs), such as fingolimod, dimethyl fumarate (DMF), and teriflunamide, has considerably expanded treatment options for relapsing forms of multiple sclerosis (MS). However, data describing the use of these agents in routine clinical practice are limited. OBJECTIVE: To describe time trends and identify factors associated with oral DMD treatment initiation and switching among individuals with MS. METHODS: Using data from a large sample of commercially insured patients, we evaluated changes over time in the proportion of MS patients who initiated treatment with an oral DMD and who switched from an injectable DMD to an oral DMD between 2009 and 2014 in the United States. We evaluated predictors of oral DMD use using conditional logistic regression in 2 groups matched on calendar time: oral DMD initiators matched to injectable DMDs initiators and oral DMD switchers matched to those who switched to a second injectable DMD. RESULTS: Our cohort included 7,576 individuals who initiated a DMD and 1,342 who switched DMDs, of which oral DMDs accounted for 6% and 39%, respectively. Oral DMD initiation and switching steadily increased from 5% to 16% and 35% to 84%, respectively, between 2011 and 2014, with DMF being the most commonly used agent. Of the potential predictors with clinical significance, a recent neurologist consultation (OR = 1.60; 95% CI = 1.20-2.15) and emergency department visit (OR = 1.43; 95% CI = 1.01-2.01) were significantly associated with oral DMD initiation. History of depression was noted to be a potential predictor of oral DMD initiation; however, the estimate for this predictor did not reach statistical significance (OR = 1.35; 95% CI = 0.99-1.84). No clinically relevant factors measured in our data were associated with switching to an oral DMD. CONCLUSIONS: Oral DMDs were found to be routinely used as second-line treatment. However, we identified few factors predictive of oral DMD initiation or switching, which implies that their selection is driven by patient and/or physician preferences. DISCLOSURES: This study was funded by CVS Caremark through an unrestricted research grant to Brigham and Women's Hospital. Shrank and Matlin were employees of, and shareholders in, CVS Health at the time of the study; they report no financial interests in products or services that are related to the subject of this study. Spettell is an employee of, and shareholder in, Aetna. Chitnis serves on clinical trial advisory boards for Novartis and Genzyme-Sanofi; has consulted for Bayer, Biogen Idec, Celgene, Novartis, Merck-Serono, and Genentech-Roche; and has received research support from NIH, National Multiple Sclerosis Society, Peabody Foundation, Consortium for MS Centers, Guthy Jackson Charitable Foundation, EMD-Serono, Novartis Biogen, and Verily. Desai reports receiving a research grant from Merck for unrelated work. Gagne is principal investigator of a research grant from Novartis Pharmaceuticals Corporation to the Brigham and Women's Hospital and has received grant support from Eli Lilly, all for unrelated work. He is also a consultant to Aetion and Optum. Minden reports grants from Biogen and other fees from Genentech, EMD Serano, Avanir, and Novartis, unrelated to this study. The other authors have no conflicts to report. This study was presented as a poster at the International Society for Pharmacoepidemiology 32nd Annual Meeting; August 25-28, 2016; Dublin, Ireland.
2018
Panozzo CA, Welch EC, Woodworth TS, Huang T-Y, Her QL, Gagne JJ, Sun JW, Rogers C, Menzin TJ, Ehrmann M, et al. Assessing the impact of the new ICD-10-CM coding system on pharmacoepidemiologic studies-An application to the known association between angiotensin-converting enzyme inhibitors and angioedema. Pharmacoepidemiol Drug Saf. 2018;27 (8) :829-838.Abstract
PURPOSE: To replicate the well-established association between angiotensin-converting enzyme inhibitors versus beta blockers and angioedema in the International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) era. METHODS: We conducted a retrospective, inception cohort study in a large insurance database formatted to the Sentinel Common Data Model. We defined study periods spanning the ICD-9-CM era only, ICD-10-CM era only, and ICD-9-CM and ICD-10-CM era and conducted simple-forward mapping (SFM), simple-backward mapping (SBM), and forward-backward mapping (FBM) referencing the General Equivalence Mappings to translate the outcome (angioedema) and covariates from ICD-9-CM to ICD-10-CM. We performed propensity score (PS)-matched and PS-stratified Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: In the ICD-9-CM and ICD-10-CM eras spanning April 1 to September 30 of 2015 and 2016, there were 152 017 and 145 232 angiotensin-converting enzyme inhibitor initiators and 115 073 and 116 652 beta-blocker initiators, respectively. The PS-matched HR was 4.19 (95% CI, 2.82-6.23) in the ICD-9-CM era, 4.37 (2.92-6.52) in the ICD-10-CM era using SFM, and 4.64 (3.05-7.07) in the ICD-10-CM era using SBM and FBM. The PS-matched HRs from the mixed ICD-9-CM and ICD-10-CM eras ranged from 3.91 (2.69-5.68) to 4.35 (3.33-5.70). CONCLUSION: The adjusted HRs across different diagnostic coding eras and the use of SFM versus SBM and FBM produced numerically different but clinically similar results. Additional investigations as ICD-10-CM data accumulate are warranted.
Frosch ZAK, Cronin AM, Gagne JJ, Teschke MP, Gray SW, Abel GA. Cancer drug shortages: Awareness and perspectives from a representative sample of the US population. Cancer. 2018;124 (10) :2205-2211.Abstract
BACKGROUND: Although cancer drug shortages are a persistent problem in oncology, little is known about the awareness and perspectives of the US population with respect to shortages. METHODS: In 2016, we administered a 13-item cross-sectional survey to 420 respondents who were randomly selected from an online, probability-based sample demographically representative of the adult US population with respect to sex, age, race/ethnicity, education, geography, and income. Analyses applied poststratification sampling weights to draw national inferences. RESULTS: Overall, 16% of respondents reported being aware of drug shortages. Those with a personal history of cancer were more likely to be aware (31% vs 14% [P = .03]). In the overall cohort, most reported wanting to be informed about a substitution due to shortage: 87% and 82% for major or minor differences in efficacy, and 87% and 83% for major or minor differences in side effects. Most also reported they would transfer care to avoid a substitution: 72% for major differences in efficacy, and 61% for major differences in side effects. Black respondents, the uninsured, the unemployed, those with lower income, and the less well-educated were all less likely to report that they would transfer care to avoid major differences in efficacy (all P < .05). CONCLUSION: These data suggest that the US population is largely unaware of cancer drug shortages. Moreover, if being treated for cancer, most people would want to know about drug substitutions, even if it were to result in only minor differences in efficacy or side effects. With more significant differences, many would transfer care. Cancer 2018;124:2205-11. © 2018 American Cancer Society.
Gagne JJ, Tsacogianis T, Bruce Wirta S, Rogers JR, Calado F, Chang C-L, Turner SJ, Schlienger RG, Balas B, Abdurrob A, et al. Characteristics of early sacubitril/valsartan patients and considerations for studies in electronic health record data. J Comp Eff Res. 2018;7 (11) :1073-1082.Abstract
AIM: We examined characteristics of early sacubitril/valsartan users in a large US electronic health records database. PATIENTS & METHODS: We identified three cohorts of patients with heart failure (HF): sacubitril/valsartan patients with a prior HF diagnosis; patients with HF with reduced ejection fraction; and patients with HF treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker and a β-blocker. RESULTS: Sacubitril/valsartan patients were younger than patients in the other cohorts; the mean age of sacubitril/valsartan patients increased by 2 years in the first 15 months of marketing. Most sacubitril/valsartan patients had prior use of HF treatment. CONCLUSION: Overall, sacubitril/valsartan patients resembled those in the HF with reduced ejection fraction cohort, and commonly used other drugs for HF.
Spoendlin J, Gagne JJ, Lewey JJ, Patorno E, Schneeweiss S, Desai RJ. Comparative effectiveness and safety of antiplatelet drugs in patients with diabetes mellitus and acute coronary syndrome. Pharmacoepidemiol Drug Saf. 2018;27 (12) :1361-1370.Abstract
PURPOSE: Comparative outcomes of treatment with antiplatelet drugs in patients with acute coronary syndrome (ACS) and co-morbid diabetes mellitus (DM) are not well studied. METHODS: We performed a cohort study using US commercial claims data (2009-2015) and conducted the following pairwise comparisons in ACS patients with DM: prasugrel vs clopidogrel, ticagrelor vs clopidogrel, and prasugrel vs ticagrelor. Outcomes of interest included (1) a composite effectiveness endpoint including myocardial infarction, ischemic stroke, or inpatient mortality; (2) a composite safety endpoint including major bleeding events requiring hospitalization; and (3) pneumonia hospitalizations as a negative control endpoint. We used calendar time-specific propensity score matching to account for confounding and applied Cox proportional hazard models to calculate hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: Comparative risk of the effectiveness endpoint was lower among prasugrel initiators compared to clopidogrel initiators (HR 0.82, 95% CI 0.68-0.99, N = 7011 matched pairs), but no different between ticagrelor and clopidogrel (HR 1.02, 95% CI 0.76-1.37, N = 3013 pairs) or prasugrel and ticagrelor (HR 0.83, 95% CI 0.58-1.18, N = 2207 pairs). Bleeding risk was higher among prasugrel initiators when compared to clopidogrel initiators within the first month of treatment (HR 1.85, 95% CI 1.03-3.35); no other comparison indicated any difference. No differences in the negative control outcomes were noted after PS matching for all comparisons, indicating adequate confounding control. CONCLUSIONS: Prasugrel was associated with superior cardiovascular outcomes and a higher risk of short-term bleeding compared to clopidogrel in patients with ACS and DM. Comparative outcomes were similar between ticagrelor and clopidogrel or prasugrel and ticagrelor.
Leonard CE, Brensinger CM, Aquilante CL, Bilker WB, Boudreau DM, Deo R, Flory JH, Gagne JJ, Mangaali MJ, Hennessy S. Comparative Safety of Sulfonylureas and the Risk of Sudden Cardiac Arrest and Ventricular Arrhythmia. Diabetes Care. 2018;41 (4) :713-722.Abstract
OBJECTIVE: To examine the association between individual antidiabetic sulfonylureas and outpatient-originating sudden cardiac arrest and ventricular arrhythmia (SCA/VA). RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using 1999-2010 U.S. Medicaid claims from five large states. Exposures were determined by incident use of glyburide, glimepiride, or glipizide. Glipizide served as the reference exposure, as its effects are believed to be highly pancreas specific. Outcomes were ascertained by a validated ICD-9-based algorithm indicative of SCA/VA (positive predictive value ∼85%). Potential confounding was addressed by adjustment for multinomial high-dimensional propensity scores included as continuous variables in a Cox proportional hazards model. RESULTS: Of sulfonylurea users under study ( = 519,272), 60.3% were female and 34.9% non-Hispanic Caucasian, and the median age was 58.0 years. In 176,889 person-years of sulfonylurea exposure, we identified 632 SCA/VA events (50.5% were immediately fatal) for a crude incidence rate of 3.6 per 1,000 person-years. Compared with glipizide, propensity score-adjusted hazard ratios for SCA/VA were 0.82 (95% CI 0.69-0.98) for glyburide and 1.10 (0.89-1.36) for glimepiride. Numerous secondary analyses showed a very similar effect estimate for glyburide; yet, not all CIs excluded the null. CONCLUSIONS: Glyburide may be associated with a lower risk of SCA/VA than glipizide, consistent with a very small clinical trial suggesting that glyburide may reduce ventricular tachycardia and isolated ventricular premature complexes. This potential benefit must be contextualized by considering putative effects of different sulfonylureas on other cardiovascular end points, cerebrovascular end points, all-cause death, and hypoglycemia.
Maura G, Billionnet C, Alla F, Gagne JJ, Pariente A. Comparison of Treatment Persistence with Dabigatran or Rivaroxaban versus Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients: A Competing Risk Analysis in the French National Health Care Databases. Pharmacotherapy. 2018;38 (1) :6-18.Abstract
BACKGROUND: Direct oral anticoagulants (DOACs) have been proposed as a more convenient alternative to vitamin K antagonists (VKAs), which are commonly associated with poor treatment persistence in non-valvular atrial fibrillation (nv-AF). METHODS: Using data from the French national health care databases (Régime Général, 50 million beneficiaries), a cohort study was conducted to compare the 1-year non-persistence rates in nv-AF patients initiating dabigatran (N=11,141) or rivaroxaban (N=11,126) versus VKA (N=11,998). Treatment discontinuation was defined as a switch between oral anticoagulant (OAC) classes or a 60-day gap with no medication coverage, with the additional criterion of no reimbursement for international normalized ratio monitoring during this gap for VKA patients. Considering death as a competing risk, differences between 1-year discontinuation rates were used to compare each DOAC versus VKA. The 95% confidence intervals (CIs) were estimated via bootstrapping. Baseline patient characteristics were adjusted using inverse probability of treatment weighting. Subgroup analyses considered DOAC dose at initiation, age, risk of stroke, and bleeding. RESULTS: Adjusted 1-year discontinuation rates were higher for dabigatran than for VKA new users (36.8% vs 30.2%; difference: 6.6% [95% CI, 5.5-7.6]) and for rivaroxaban versus VKA new users (33.4% vs 30.4%; 3.0% [1.9-4.1]). Similar differences were found in all subgroup analyses, except in dabigatran and rivaroxaban patients <75 years (dabigatran vs VKA: 0.3% [-1.4 to 1.8]; rivaroxaban vs VKA: -2.6% [-4.3 to -0.9]) and dabigatran 150 mg new users (-1.1% [-3.1 to 0.7]). Consistent results were obtained when considering both switches between OAC classes and death as competing risks of treatment discontinuation. CONCLUSION: Results from this nationwide cohort study showed high non-persistence levels with all OACs and suggest that persistence with both dabigatran and rivaroxaban therapy is not better than persistence with VKA therapy. Hospitalizations for bleeding among non-persistent patients were unlikely to explain these high non-persistence rates.
Gagne JJ, Polinski JM, Jiang W, Dutcher SK, Xie J, Lii J, Fulchino LA, Kesselheim AS. Correction to: Outcomes Associated with Generic Drugs Approved Using Product-Specific Determinations of Therapeutic Equivalence. Drugs. 2018;78 (4) :523-524.Abstract
Page 432, Fig. 2 Plots of model-based outcome incidence rates (per 100 person-years of exposure) before and after introduction of first generic versions of study and control drugs.
Wang SV, Maro JC, Baro E, Izem R, Dashevsky I, Rogers JR, Nguyen M, Gagne JJ, Patorno E, Huybrechts KF, et al. Data Mining for Adverse Drug Events With a Propensity Score-matched Tree-based Scan Statistic. Epidemiology. 2018;29 (6) :895-903.Abstract
The tree-based scan statistic is a statistical data mining tool that has been used for signal detection with a self-controlled design in vaccine safety studies. This disproportionality statistic adjusts for multiple testing in evaluation of thousands of potential adverse events. However, many drug safety questions are not well suited for self-controlled analysis. We propose a method that combines tree-based scan statistics with propensity score-matched analysis of new initiator cohorts, a robust design for investigations of drug safety. We conducted plasmode simulations to evaluate performance. In multiple realistic scenarios, tree-based scan statistics in cohorts that were propensity score matched to adjust for confounding outperformed tree-based scan statistics in unmatched cohorts. In scenarios where confounding moved point estimates away from the null, adjusted analyses recovered the prespecified type 1 error while unadjusted analyses inflated type 1 error. In scenarios where confounding moved point estimates toward the null, adjusted analyses preserved power, whereas unadjusted analyses greatly reduced power. Although complete adjustment of true confounders had the best performance, matching on a moderately mis-specified propensity score substantially improved type 1 error and power compared with no adjustment. When there was true elevation in risk of an adverse event, there were often co-occurring signals for clinically related concepts. TreeScan with propensity score matching shows promise as a method for screening and prioritization of potential adverse events. It should be followed by clinical review and safety studies specifically designed to quantify the magnitude of effect, with confounding control targeted to the outcome of interest.
Krumme AA, Glynn RJ, Schneeweiss S, Choudhry NK, Tong AY, Gagne JJ. Defining Exposure in Observational Studies Comparing Outcomes of Treatment Discontinuation. Circ Cardiovasc Qual Outcomes. 2018;11 (7) :e004684.Abstract
BACKGROUND: Continuation of antiplatelet therapy beyond 12 months after a drug-eluting stent procedure reduced the risk of a major adverse cardiovascular and cerebrovascular event (MACCE) in the DAPT trial (Dual Antiplatelet Therapy). Observational studies have evaluated outcomes related to different durations of therapy but are susceptible to bias. METHODS AND RESULTS: Using deidentified claims from commercially insured and Medicare populations in the United States, we compared how increasingly stringent definitions of exposure affect associations between antiplatelet continuation versus discontinuation and MACCE, myocardial infarction, and intracerebral hemorrhage or gastrointestinal bleeding in patients meeting DAPT trial inclusion criteria between 2004 and 2013. Therapy continuation at 12 months was defined as (1) having antiplatelet supply on hand versus not (landmark time); (2) refilling within 30 days versus not among individuals with antiplatelet supply; (3) criteria 2 plus continuous prior antiplatelet use; and (4) criteria 2 and 3 plus a cardiologist visit in months 10 to 12. Propensity score-adjusted hazard ratios were compared. Cohort sizes were 53 679, 27 524, 16 971, and 7948, respectively, of which 20% were discontinuers on average. Increasing restriction led to progressively larger associations with continued treatment: cohort 1 MACCE hazard ratio, 0.79 (0.73, 0.87); myocardial infarction, 0.74 (0.65, 0.83); bleed, 1.03 (0.96, 1.11) versus cohort 4 MACCE hazard ratio, 0.66 (0.48, 0.91); myocardial infarction, 0.56 (0.37, 0.86); bleed, 1.24 (0.95, 1.61). Estimates trended toward DAPT trial estimates and were associated with reduced levels of exposure misclassification. CONCLUSIONS: In an example of long-term antiplatelet use, increasing restrictions on the definition of therapy continuation yielded results consistent with trial estimates by reducing exposure misclassification.
Smith DH, Shetterly S, Flory J, Haynes K, Lu CY, Gagne JJ, Herrinton L, Nyirenda C, Patorno E, Shoaibi A, et al. Diagnosis-based cohort augmentation using laboratory results data: The case of chronic kidney disease. Pharmacoepidemiol Drug Saf. 2018;27 (8) :872-877.Abstract
PURPOSE: In this report, we use data from FDA's Sentinel System to focus on how augmenting a diagnosis-based chronic kidney disease cohort with patients identified through laboratory results impacts cohort characteristics and outcomes. METHODS: We used data from 2 Data Partners. Patients were eligible if they were health plan members on January 1, 2012. We classified chronic kidney disease patients into mutually exclusive categories according to the hierarchy of (1) ICD-9-CM diagnosis (DXGroup), or (2) two estimated glomerular filtration rates <60 mL/min/1.73m , separated by at least 90 days (2-LabGroup), or (3) a single estimated glomerular filtration rates <60 mL/min/1.73m (1-LabGroup). We compared the groups on demographic, clinical, and health care utilization characteristics using pairwise standardized differences. We used Cox regression to compare the groups on mortality, adjusting for baseline covariates. RESULTS: We identified 209 864 patients: 107 607 in DxGroup (51%) and 102 257 (49%) from laboratory data alone. For every characteristic, the DxGroup was the sickest, followed by the 2-LabGroup and then the 1-LabGroup. The DxGroup was more likely to die than 2-LabGroup (hazard ratio [HR], 1.47; 95% CI, 1.22-1.77) at Site 1; that effect was observed, but attenuated, at Site 2 (HR, 1.16; 95% CI, 1.07-1.25). The DxGroup was more likely to die than the 1-LabGroup at Site 1 (HR, 1.36; 95% CI, 1.20-1.55), but not at Site 2 (HR, 0.94; 95% CI, 0.89-1.00). CONCLUSIONS: We suggest that drug safety researchers consider whether the method of cohort identification contributes to generalizability of safety findings.
Desai RJ, Sarpatwari A, Dejene S, Khan NF, Lii J, Rogers JR, Dutcher SK, Raofi S, Bohn J, Connolly J, et al. Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study. BMJ. 2018;361 :k1180.Abstract
OBJECTIVES: To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. DESIGN: Observational cohort study. SETTING: Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. PARTICIPANTS: Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). MAIN OUTCOME MEASURES: Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine-benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. RESULTS: A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. CONCLUSION: Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products.
Dommasch ED, Lee MP, Joyce CJ, Garry EM, Gagne JJ. Drug utilization patterns and adherence in patients on systemic medications for the treatment of psoriasis: A retrospective, comparative cohort study. J Am Acad Dermatol. 2018;79 (6) :1061-1068.e1.Abstract
BACKGROUND: Nonadherence to systemic treatments for psoriasis leads to treatment failure and increased health care utilization. OBJECTIVE: Examine drug utilization patterns and adherence of new users of systemic medications for psoriasis. METHODS: We conducted a retrospective, comparative cohort study using a large US health insurance claims database including psoriasis patients who were new users of acitretin, adalimumab, etanercept, methotrexate, or ustekinumab. Adherence was measured by using proportion of days covered dichotomized as adherent (≥0.80) or nonadherent (<0.80). Odds ratios (ORs) and 95% confidence intervals (CIs) comparing adherence to each exposure (acitretin, adalimumab, etanercept, or ustekinumab) to the referent (methotrexate) were estimated via logistic regression, with pairwise 1:1 propensity score matching to adjust for potential confounders. RESULTS: In total, 22,742 patients were new users of systemic medications. Among these patients, adherence to adalimumab (OR 2.24, 95% CI 2.05-2.45); etanercept (OR 1.77, 95% CI 1.63-1.92); and ustekinumab (OR 2.54, 95% CI 2.24-2.87) was greater and acitretin (OR 0.57, 95% CI 0.50-0.63) lower compared with methotrexate. LIMITATIONS: Unable to evaluate reasons for discontinuation. CONCLUSION: We report greater adherence to biologics than methotrexate in new users. Further research is needed to understand overall low adherence to systemic medications for psoriasis.
Choudhry NK, Isaac T, Lauffenburger JC, Gopalakrishnan C, Lee M, Vachon A, Iliadis TL, Hollands W, Elman S, Kraft JM, et al. Effect of a Remotely Delivered Tailored Multicomponent Approach to Enhance Medication Taking for Patients With Hyperlipidemia, Hypertension, and Diabetes: The STIC2IT Cluster Randomized Clinical Trial. JAMA Intern Med. 2018;178 (9) :1182-1189.Abstract
Importance: Approximately half of patients with chronic conditions are nonadherent to prescribed medications, and interventions have been only modestly effective. Objective: To evaluate the effect of a remotely delivered multicomponent behaviorally tailored intervention on adherence to medications for hyperlipidemia, hypertension, and diabetes. Design, Setting, and Participants: Two-arm pragmatic cluster randomized controlled trial at a multispecialty group practice including participants 18 to 85 years old with suboptimal hyperlipidemia, hypertension, or diabetes disease control, and who were nonadherent to prescribed medications for these conditions. Interventions: Usual care or a multicomponent intervention using telephone-delivered behavioral interviewing by trained clinical pharmacists, text messaging, pillboxes, and mailed progress reports. The intervention was tailored to individual barriers and level of activation. Main Outcomes and Measures: The primary outcome was medication adherence from pharmacy claims data. Secondary outcomes were disease control based on achieved levels of low-density lipoprotein cholesterol, systolic blood pressure, and hemoglobin A1c from electronic health records, and health care resource use from claims data. Outcomes were evaluated using intention-to-treat principles and multiple imputation for missing values. Results: Fourteen practice sites with 4078 participants had a mean (SD) age of 59.8 (11.6) years; 45.1% were female. Seven sites were each randomized to intervention or usual care. The intervention resulted in a 4.7% (95% CI, 3.0%-6.4%) improvement in adherence vs usual care but no difference in the odds of achieving good disease control for at least 1 (odds ratio [OR], 1.10; 95% CI, 0.94-1.28) or all eligible conditions (OR, 1.05; 95% CI, 0.91-1.22), hospitalization (OR, 1.02; 95% CI, 0.78-1.34), or having a physician office visit (OR, 1.11; 95% CI, 0.91-1.36). However, intervention participants were significantly less likely to have an emergency department visit (OR, 0.62; 95% CI, 0.45-0.85). In as-treated analyses, the intervention was associated with a 10.4% (95% CI, 8.2%-12.5%) increase in adherence, a significant increase in patients achieving disease control for at least 1 eligible condition (OR, 1.24; 95% CI, 1.03-1.50), and nonsignificantly improved disease control for all eligible conditions (OR, 1.18; 95% CI, 0.99-1.41). Conclusions and Relevance: A remotely delivered multicomponent behaviorally tailored intervention resulted in a statistically significant increase in medication adherence but did not change clinical outcomes. Future work should focus on identifying which groups derive the most clinical benefit from adherence improvement efforts. Trial Registration: ClinicalTrials.gov identifier: NCT02512276.
Gagne JJ, Popovic JR, Nguyen M, Sandhu SK, Greene P, Izem R, Jiang W, Wang Z, Zhao Y, Petrone AB, et al. Evaluation of Switching Patterns in FDA's Sentinel System: A New Tool to Assess Generic Drugs. Drug Saf. 2018;41 (12) :1313-1323.Abstract
INTRODUCTION: Nearly 90% of drugs dispensed in the US are generic products. OBJECTIVE: The aim of this study was to develop and implement a tool for analyzing manufacturer-level drug utilization and switching patterns within the US Food and Drug Administration's Sentinel system. METHODS: A descriptive tool was designed to analyze data in the Sentinel common data model and was tested with two case studies-metoprolol extended release (ER) and lamotrigine ER-using claims data from four Sentinel data partners. We plotted initiators of each brand and generic product over time. For metoprolol ER, we evaluated rates of switching from generics around the time of manufacturing issues. For lamotrigine ER, we examined rates of switching back to the brand among those who switched from brand to generic. RESULTS: We identified 1,651,285 initiators of metoprolol ER products between July 2008 and September 2015. We observed a large decrease in monthly metoprolol ER initiators (from 25,465 in December 2008 to 13,128 in February 2009), corresponding to recalls by generic manufacturers. We observed simultaneous increases in utilization of the authorized generic and brand products. We identified 4266 initiators of lamotrigine ER with an epilepsy diagnosis between January 2012 and September 2015. Among those who switched from brand to generic, the cumulative incidence of switching back was close to 20% at 2 years. Switchback rates were higher for the first available generic products. CONCLUSIONS: This developed tool was able to elucidate novel utilization and switching patterns in two case studies. Such information can be used to support surveillance of generic drugs and biosimilars.

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