Publications by Year: 2018

Desai RJ, Mahesri M, Abdia Y, Barberio J, Tong A, Zhang D, Mavros P, Kim SC, Franklin JM. Association of Osteoporosis Medication Use After Hip Fracture With Prevention of Subsequent Nonvertebral Fractures: An Instrumental Variable Analysis. JAMA Netw Open 2018;1(3):e180826.Abstract
Importance: Osteoporosis medication treatment is recommended after hip fracture, yet contemporary estimates of rates of initiation and clinical benefit in the patient population receiving routine care are not well documented. Objectives: To report osteoporosis treatment initiation rates between January 1, 2004, and September 30, 2015, and to estimate the risk reduction in subsequent nonvertebral fractures associated with treatment initiation in patients with hip fracture. Design, Setting, and Participants: In this cohort study, data from a commercial insurance claims database from the United States were analyzed. Patients 50 years and older who had a hip fracture and were not receiving treatment with osteoporosis medications before their fracture were included. Exposure: Prescription dispensing of an osteoporosis medication within 180 days of a hip fracture hospitalization. Main Outcomes and Measures: Each initiation episode was matched with 10 nonuse episodes on person-time after the index hip fracture event to preclude immortal time bias and followed up for the outcome of nonvertebral fracture until change in exposure or a censoring event. An instrumental variable analysis using 2-stage residual inclusion method was conducted using calendar year, specialist access, geographical variation in prescribing patterns, and hospital preference. Results: Among 97 169 patients with a hip fracture identified, the mean (SD) age was 80.2 (10.8) years, and 64 164 (66.0%) were women. A continuous decline over the study years was observed in osteoporosis medication initiation rates from 9.8% (95% CI, 9.0%-10.6%) in 2004 to 3.3% (95% CI, 2.9%-3.8%) in 2015. In the effectiveness analyses, the hospital preference instrumental variable had a stronger association with treatment (pseudo R2 = 0.20) than the other 3 instrumental variables (specialist access: pseudo R2 = 0.04; calendar year: pseudo R2 = 0.05; and geographic variation: pseudo R2 = 0.07). Instrumental variable analysis with hospital preference suggested a rate difference of 4.2 events (95% CI, 1.1-7.3) per 100 person-years in subsequent fractures associated with osteoporosis treatment initiation compared with nonuse in an additive hazard model. Conclusions and Relevance: Low rates of osteoporosis treatment initiation after a hip fracture in recent years were observed. Clinically meaningful reduction in subsequent nonvertebral fracture rates associated with treatment suggests that improving prescriber adherence to guidelines and patient adherence to prescribed regimens may result in notable public health benefit.
Panchaud A, Cohen JM, Patorno E, Huybrechts KF, Desai RJ, Gray KJ, Mogun H, Hernandez-Diaz S, Bateman BT. Anticonvulsants and the risk of perinatal bleeding complications: A pregnancy cohort study. Neurology 2018;91(6):e533-e542.Abstract
OBJECTIVE: To examine the risk of postpartum hemorrhage (PPH) and neonatal bleeding complications associated with late-pregnancy exposure to anticonvulsant drugs (ACDs) that induce cytochrome P450 enzymes (ACDi) and alter the metabolism of vitamin K compared to other ACDs. METHODS: We used a population-based cohort study stemming from a nationwide sample of publicly insured pregnant women with a liveborn infant from the 2000 to 2010 Medicaid Analytic eXtract. ACDi (carbamazepine, phenobarbital, phenytoin, oxcarbazepine, topiramate) were compared to other ACDs dispensed during the last month of pregnancy. Relative risks (RRs) and 95% confidence intervals (CIs) of PPH and neonatal bleeding complications were estimated using generalized linear models with fine stratification on the propensity score to control for indication and other potential confounders. RESULTS: Among 11,572 women with an ACD prescription overlapping delivery, 2.6% (135/5,109) in the ACDi group and 3.6% (231/6,463) in the other ACDs group had a diagnosis of PPH: unadjusted RR 0.74 (95% CI 0.60-0.91), adjusted RR 0.77 (95% CI 0.58-1.00). The prevalence of neonatal bleeding complications was 3.1% (157/5,109) in the ACDi group and 3.5% (229/6,463) in the other ACDs group: unadjusted RR 0.87 (95% CI 0.71-1.06), adjusted RR 0.83 (95% CI 0.64-1.08). CONCLUSIONS: Evidence from this large observational study suggests that use of ACDi near delivery does not increase the risk of bleeding complications compared to other ACDs in clinical settings where neonatal intramuscular or oral vitamin K administration is considered standard of care. These findings provide reassurance for clinicians and pregnant women successfully treated with ACDi.
Zhang MA, Solomon DH, Desai RJ, Kang EH, Liu J, Neogi T, Kim SC. Assessment of Cardiovascular Risk in Older Patients With Gout Initiating Febuxostat Versus Allopurinol: Population-Based Cohort Study. Circulation 2018;138(11):1116-1126.Abstract
BACKGROUND: Hyperuricemia and gout are associated with an increased risk of cardiovascular disease. Xanthine oxidase inhibitors, allopurinol and febuxostat, are the mainstay of urate-lowering treatment for gout and may have different effects on cardiovascular risk in patients with gout. METHODS: Using US Medicare claims data (2008-2013), we conducted a cohort study for comparative cardiovascular safety of initiating febuxostat versus allopurinol among patients with gout ≥65 years of age. The primary outcome was a composite end point of hospitalization for myocardial infarction or stroke. Secondary outcomes were individual end points of hospitalization for myocardial infarction, stroke, coronary revascularization, new and recurrent heart failure, and all-cause mortality. We used propensity score matching with a ratio of 1:3 to control for confounding. We estimated incidence rates and hazard ratios for primary and secondary outcomes in the propensity score-matched cohorts of febuxostat and allopurinol initiators. RESULTS: We included 24 936 febuxostat initiators propensity score-matched to 74 808 allopurinol initiators. The median age was 76 years, 52% were male, and 12% had cardiovascular disease at baseline. The incidence rate per 100 person-years for the primary outcome was 3.43 in febuxostat and 3.36 in allopurinol initiators. The hazard ratio for the primary outcome was 1.01 (95% CI, 0.94-1.08) in the febuxostat group compared with the allopurinol group. Risk of secondary outcomes including all-cause mortality was similar in both groups, except for a modestly decreased risk of heart failure exacerbation (hazard ratio, 0.94; 95% CI, 0.91-0.99) in febuxostat initiators. The hazard ratio for all-cause mortality associated with long-term use of febuxostat (>3 years) was 1.25 (95% CI, 0.56-2.80) versus allopurinol. Subgroup and sensitivity analyses consistently showed similar cardiovascular risk in both groups. CONCLUSIONS: Among a cohort of 99 744 older Medicare patients with gout, overall there was no difference in the risk of myocardial infarction, stroke, new-onset heart failure, coronary revascularization, or all-cause mortality between patients initiating febuxostat compared with allopurinol. However, there seemed to be a trend toward an increased, albeit not statistically significant, risk for all-cause mortality in patients who used febuxostat for >3 years versus allopurinol for >3 years. The risk of heart failure exacerbation was slightly lower in febuxostat initiators.
Huybrechts KF, Hernández-Díaz S, Straub L, Gray KJ, Zhu Y, Patorno E, Desai RJ, Mogun H, Bateman BT. Association of Maternal First-Trimester Ondansetron Use With Cardiac Malformations and Oral Clefts in Offspring. JAMA 2018;320(23):2429-2437.Abstract
Importance: Evidence for the fetal safety of ondansetron, a 5-HT3 receptor antagonist that is commonly prescribed for nausea and vomiting during pregnancy, is limited and conflicting. Objective: To evaluate the association between ondansetron exposure during pregnancy and risk of congenital malformations. Design, Setting, and Participants: A retrospective cohort study nested in the 2000-2013 nationwide Medicaid Analytic eXtract. The cohort consisted of 1 816 414 pregnancies contributed by 1 502 895 women enrolled in Medicaid from 3 months before the last menstrual period through 1 month or longer after delivery; infants were enrolled in Medicaid for at least 3 months after birth. The final date of follow-up was December 31, 2013. Analyses were conducted between November 1, 2017, and June 30, 2018. Propensity score stratification was used to control for treatment indication and other confounders. Exposures: Ondansetron dispensing during the first trimester, the period of organogenesis. Main Outcomes and Measures: Primary outcomes were cardiac malformations and oral clefts diagnosed during the first 90 days after delivery. Secondary outcomes included congenital malformations overall and subgroups of cardiac malformations and oral clefts. Results: Among 1 816 414 pregnancies (mean age of mothers, 24.3 [5.8] years), 88 467 (4.9%) were exposed to ondansetron during the first trimester. Overall, 14 577 of 1 727 947 unexposed and 835 of 88 467 exposed infants were diagnosed with a cardiac malformation, for an absolute risk of 84.4 (95% CI, 83.0 to 85.7) and 94.4 (95% CI, 88.0 to 100.8) per 10 000 births respectively. The absolute risk of oral clefts was 11.1 per 10 000 births (95% CI, 10.6 to 11.6; 1921 unexposed infants) and was 14.0 per 10 000 births (95% CI, 11.6 to 16.5; 124 exposed infants). The risk of any congenital malformation was 313.5 per 10 000 births (95% CI, 310.9 to 316.1; 54 174 unexposed infants) and was 370.4 (95% CI, 358.0 to 382.9; 3277 exposed infants). The adjusted relative risk (RR) for cardiac malformations was 0.99 (95% CI, 0.93 to 1.06) and the adjusted risk difference (RD) was -0.8 (95% CI, -7.3 to 5.7 per 10 000 births). For oral clefts, the adjusted RR was 1.24 (95% CI, 1.03 to 1.48) and the RD was 2.7 (95% CI, 0.2 to 5.2 per 10 000 births). The adjusted estimate for congenital malformations overall was an RR of 1.01 (95% CI, 0.98 to 1.05) and an RD of 5.4 (95% CI, -7.3 to 18.2 per 10 000 births). Conclusions and Relevance: Among offspring of mothers enrolled in Medicaid, first-trimester exposure to ondansetron was not associated with cardiac malformations or congenital malformations overall after accounting for measured confounders but was associated with a small increased risk of oral clefts.
Spoendlin J, Schneeweiss S, Tsacogianis T, Paik JM, Fischer MA, Kim SC, Desai RJ. Association of Medicare's Bundled Payment Reform With Changes in Use of Vitamin D Among Patients Receiving Maintenance Hemodialysis: An Interrupted Time-Series Analysis. Am J Kidney Dis 2018;72(2):178-187.Abstract
BACKGROUND & RATIONALE: Medicare's 2011 prospective payment system (PPS) was introduced to curb overuse of separately billable injectable drugs. After epoietin, intravenous (IV) vitamin D analogues are the biggest drug cost drivers in hemodialysis (HD) patients, but the association between PPS introduction and vitamin D therapy has been scarcely investigated. STUDY DESIGN: Interrupted time-series analyses. SETTING & PARTICIPANTS: Adult US HD patients represented in the US Renal Data System between 2008 and 2013. EXPOSURES: PPS implementation. OUTCOMES: The cumulative dose of IV vitamin D analogues (paricalcitol equivalents) per patient per calendar quarter in prevalent HD patients. The average starting dose of IV vitamin D analogues and quarterly rates of new vitamin D use (initiations/100 person-months) in incident HD patients within 90 days of beginning HD therapy. ANALYTICAL APPROACH: Segmented linear regression models of the immediate change and slope change over time of vitamin D use after PPS implementation. RESULTS: Among 359,600 prevalent HD patients, IV vitamin D analogues accounted for 99% of the total use, and this trend was unchanged over time. PPS resulted in an immediate 7% decline in the average dose of IV vitamin D analogues (average baseline dose = 186.5 μg per quarter; immediate change = -13.5 μg [P < 0.001]; slope change = 0.43 per quarter [P = 0.3]) and in the starting dose of IV vitamin D analogues in incident HD patients (average baseline starting dose = 5.22 μg; immediate change = -0.40 μg [P < 0.001]; slope change = -0.03 per quarter [P = 0.03]). The baseline rate of vitamin D therapy initiation among 99,970 incident HD patients was 44.9/100 person-months and decreased over time, even before PPS implementation (pre-PPS β = -0.46/100 person-months [P < 0.001]; slope change = -0.19/100 person-months [P = 0.2]). PPS implementation was associated with an immediate change in initiation levels (by -4.5/100 person-months; P < 0.001). LIMITATIONS: Incident HD patients were restricted to those 65 years or older. CONCLUSION: PPS implementation was associated with a 7% reduction in the average dose and starting dose of IV vitamin D analogues and a 10% reduction in the rate of vitamin D therapy initiation.
Jin Y, Kang EH, Brill G, Desai RJ, Kim SC. Cardiovascular (CV) Risk after Initiation of Abatacept versus TNF Inhibitors in Rheumatoid Arthritis Patients with and without Baseline CV Disease. J Rheumatol 2018;45(9):1240-1248.Abstract
OBJECTIVE: To evaluate the cardiovascular safety of abatacept (ABA) versus tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA) patients with and without underlying cardiovascular disease (CVD). METHODS: We identified RA patients with and without baseline CVD who initiated ABA or TNFi by using data from 2 large US insurance claims databases: Medicare (2008-2013) and Truven MarketScan (2006-2015). After stratifying by baseline CVD, ABA initiators were 1:1 propensity score (PS) matched to TNFi initiators to control for > 60 baseline covariates. Cox proportional hazards regression estimated the HR and 95% CI for a composite endpoint of CVD including myocardial infarction, stroke/transient ischemic stroke, or coronary revascularization in the PS-matched cohorts. HR from 2 databases were combined through an inverse variance-weighted fixed-effects model. RESULTS: We included 6102 PS-matched pairs of ABA and TNFi initiators from Medicare and 6934 pairs from MarketScan. Of these, 35.3% in Medicare and 14.0% in MarketScan had baseline CVD. HR (95% CI) for composite CVD in the overall ABA group versus TNFi was 0.67 (0.55-0.81) in Medicare and 1.08 (0.83-1.41) in MarketScan with the combined HR of 0.79 (0.67-0.92). Among patients with baseline CVD, the HR (95% CI) was 0.71 (0.55-0.92) in Medicare and 1.02 (0.68-1.51) in MarketScan, with the combined HR of 0.79 (0.64-0.98). CONCLUSION: In this large cohort of publicly or privately insured patients with RA in the United States, ABA was associated with a 20% reduced risk of CVD versus TNFi. While this observational study is subject to potential residual confounding, our results were consistent in patients with baseline CVD.
Kim SC, Neogi T, Kang EH, Liu J, Desai RJ, Zhang MA, Solomon DH. Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients With Gout. J Am Coll Cardiol 2018;71(9):994-1004.Abstract
BACKGROUND: Patients with gout are at an increased risk of cardiovascular (CV) disease including myocardial infarction (MI), stroke, and heart failure (HF). OBJECTIVES: The authors conducted a cohort study to examine comparative CV safety of the 2 gout treatments-probenecid and allopurinol-in patients with gout. METHODS: Among gout patients ≥65 years of age and enrolled in Medicare (2008 to 2013), those who initiated probenecid or allopurinol were identified. The primary outcome was a composite CV endpoint of hospitalization for MI or stroke. MI, stroke, coronary revascularization, HF, and mortality were assessed separately as secondary outcomes. The authors estimated the incidence rate and hazard ratio of the primary and secondary outcomes in the 1:3 propensity score-matched cohort of probenecid and allopurinol initiators. RESULTS: A total of 9,722 probenecid initiators propensity score-matched to 29,166 allopurinol initiators with mean age of 76 ± 7 years, and 54% males were included. The incidence rate of the primary composite endpoint of MI or stroke per 100 person-years was 2.36 in probenecid and 2.83 in allopurinol initiators with a hazard ratio of 0.80 (95% confidence interval: 0.69 to 0.93). In the secondary analyses, probenecid was associated with a decreased risk of MI, stroke, HF exacerbation, and mortality versus allopurinol. These results were consistent in the subgroup analyses of patients without baseline CV disease or those without baseline chronic kidney disease. CONCLUSIONS: In this large cohort of 38,888 elderly gout patients, treatment with probenecid appears to be associated with a modestly decreased risk of CV events including MI, stroke, and HF exacerbation compared with allopurinol.
Kang EH, Jin Y, Brill G, Lewey J, Patorno E, Desai RJ, Kim SC. Comparative Cardiovascular Risk of Abatacept and Tumor Necrosis Factor Inhibitors in Patients With Rheumatoid Arthritis With and Without Diabetes Mellitus: A Multidatabase Cohort Study. J Am Heart Assoc 2018;7(3)Abstract
BACKGROUND: We examined the cardiovascular risk of abatacept compared with tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis with and without diabetes mellitus (DM). METHODS AND RESULTS: We conducted a cohort study of patients with rheumatoid arthritis who newly started abatacept or TNF inhibitors using claims data from Medicare and MarketScan. The primary outcome was a composite cardiovascular end point of myocardial infarction (MI), stroke/transient ischemic attack, and coronary revascularization. To account for >60 baseline characteristics, abatacept initiators were 1:1 propensity score (PS) matched to TNF initiators in each database. Cox proportional hazards models estimated hazard ratio (HR) and 95% confidence interval (CI) in the PS-matched cohort per database. A fixed-effects meta-analysis pooled database-specific HRs. We included a total of 13 039 PS-matched pairs of abatacept and TNF inhibitor initiators (6103 pairs in Medicare and 6936 pairs in MarketScan). A total of 34.7% in Medicare and 19.8% in MarketScan had baseline DM. The HR (95% CI) for the primary outcome associated with abatacept use versus TNF inhibitor was 0.81 (0.66-0.99) in Medicare and 0.95 (0.74-1.23) in MarketScan, with a pooled HR of 0.86 (95% CI, 0.73-1.01; =0.3 for heterogeneity). The risk of the primary outcome was lower in abatacept initiators versus TNF inhibitors in the DM subgroup, with a pooled HR of 0.74 (95% CI, 0.57-0.96; =0.7 for heterogeneity), but not in the non-DM subgroup, with a pooled HR of 0.94 (95% CI, 0.77-1.14; =0.4 for heterogeneity). CONCLUSIONS: In this large population-based cohort of patients with rheumatoid arthritis, abatacept use appeared to be associated with a modestly reduced cardiovascular risk when compared with TNF inhibitor use, particularly in patients with DM.
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.
Park Y, Hernandez-Diaz S, Bateman BT, Cohen JM, Desai RJ, Patorno E, Glynn RJ, Cohen LS, Mogun H, Huybrechts KF. Continuation of Atypical Antipsychotic Medication During Early Pregnancy and the Risk of Gestational Diabetes. Am J Psychiatry 2018;175(6):564-574.Abstract
OBJECTIVE: Some atypical antipsychotics are associated with metabolic side effects, which are risk factors for gestational diabetes. The authors examined the risk of developing gestational diabetes associated with the continuation of treatment with aripiprazole, ziprasidone, quetiapine, risperidone, and olanzapine during pregnancy compared with discontinuation of these antipsychotic drugs. METHOD: Nondiabetic pregnant women who were linked to a live-born infant and enrolled in Medicaid (2000-2010) and who received one or more prescriptions dispensed for an antipsychotic drug during the 3 months before pregnancy were included in the analyses. Among 1,543,334 pregnancies, some expectant mothers at baseline were receiving treatment with aripiprazole (N=1,924), ziprasidone (N=673), quetiapine (N=4,533), risperidone (N=1,824), or olanzapine (N=1,425). For each antipsychotic drug, women with two or more dispensings ("continuers") were compared with women with no dispensings ("discontinuers") during the first half of pregnancy. A generalized linear model and propensity-score stratification were used to obtain absolute and relative risks of developing gestational diabetes, with adjustment for confounders. RESULTS: Women who continued antipsychotic treatment during pregnancy generally had higher comorbidity and longer baseline antipsychotic use. The crude risk of developing gestational diabetes among continuers compared with discontinuers, respectively, was 4.8% and 4.5% for aripiprazole, 4.2% and 3.8% for ziprasidone, 7.1% and 4.1% for quetiapine, 6.4% and 4.1% for risperidone, and 12.0% and 4.7% for olanzapine. The adjusted relative risks were 0.82 (95% CI=0.50-1.33) for aripiprazole, 0.76 (95% CI=0.29-2.00) for ziprasidone, 1.28 (95% CI=1.01-1.62) for quetiapine, 1.09 (95% CI=0.70-1.70) for risperidone, and 1.61 (95% CI=1.13-2.29) for olanzapine. CONCLUSIONS: Compared with women who discontinued use of an atypical antipsychotic medication before the start of pregnancy, women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs.
Desai RJ, Lin KJ, Patorno E, Barberio J, Lee M, Levin R, Evers T, Wang SV, Schneeweiss S. Development and Preliminary Validation of a Medicare Claims-Based Model to Predict Left Ventricular Ejection Fraction Class in Patients With Heart Failure. Circ Cardiovasc Qual Outcomes 2018;11(12):e004700.Abstract
BACKGROUND: Ejection fraction (EF) class is an important predictor of treatment response in heart failure (HF); however, administrative claims databases lack information on EF, limiting their usefulness in clinical and health services research of HF. METHODS AND RESULTS: We linked Medicare claims data to electronic medical records containing EF measurements for a cohort of 11 073 patients with HF from 2 academic medical centers. A a claims-based model predicting EF class was constructed using data from center 1 ("training sample") and validated using data from center 2 ("testing sample). Linear and logistic regression models with least absolute square shrinkage operator and Bayesian information criteria were developed to select the relevant predictor variables out of the total 57 candidate variables in the training sample. Higher accuracy was noted in the testing sample with models classifying patients into 2 EF classes (reduced EF <0.45) versus preserved EF (≥0.45) when compared with classifying patients into 3 EF classes (reduced, <0.40, moderately reduced, 0.40-0.49, or preserved, ≥0.50). In the testing sample, the most efficient model had 35 predictors and resulted in 83% of patients being correctly classified (95% CI, 82%-84%). The model had positive predictive value of 0.73 (95% CI, 0.68-0.78) and 0.84 (95% CI, 0.83-0.86) and sensitivity of 0.29 (95% CI, 0.25-0.32) and 0.97 (95% CI, 0.97-0.98) for reduced and preserved EF, respectively. In addition to HF-specific diagnosis codes, other factors including age, sex, medication use, and comorbidities, such as myocardial infarction and valve disorders, were important discriminators between EF classes. CONCLUSIONS: The claims-based model developed in this study may be used to identify patient subgroups with specific EF class in studies evaluating the health outcomes, utilization patterns, and cost, of HF patients in routine care when EF measurements are not available.
Desai RJ, Sarpatwari A, Dejene S, Khan NF, Lii J, Rogers JR, Dutcher SK, Raofi S, Bohn J, Connolly J, Fischer MA, Kesselheim AS, Gagne JJ. 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.
Desai RJ, Franklin JM, Spoendlin-Allen J, Solomon DH, Danaei G, Kim SC. An evaluation of longitudinal changes in serum uric acid levels and associated risk of cardio-metabolic events and renal function decline in gout. PLoS One 2018;13(2):e0193622.Abstract
OBJECTIVE: Gout patients have a high burden of co-morbid conditions including diabetes mellitus (DM), chronic kidney disease (CKD), and cardiovascular disease (CVD). We sought to evaluate the association between changes in serum uric acid (SUA) levels over time and the risk of incident DM, CVD, and renal function decline in gout patients. METHODS: An observational cohort study was conducted among enrollees of private health insurance programs in the US between 2004 and 2015. Gout patients were included on the index date of a SUA measurement ≥6.8 mg/dl. The exposure of interest was cumulative change in SUA levels from baseline. Hazard ratios (HR) and 95% confidence intervals (CI) for incident DM, incident CVD, and renal function decline (≥30% reduction in glomerular filtration rate) were derived using marginal structural models with stabilized inverse probability weights accounting for baseline confounders (age, gender, co-morbidities, co-medications) and time-varying confounders (serum creatinine, blood urea nitrogen, glycated hemoglobin). RESULTS: Among 26,341 patients with gout, the average age was 62, 75% were men, and the median baseline SUA was 8.6 mg/dl (interquartile range 7.7 to 9.5). The incidence rates/100 person-years (95% CI) were 1.63 (1.51-1.75) for DM, 0.77 (0.70-0.84) for CVD, and 4.32 (4.14-4.49) for renal function decline. The adjusted HR (95% CI) per 3 mg/dl reduction in SUA, corresponding on average to achieving the target level of <6 mg/dl in this population, was 1.04 (0.92-1.17) for DM, 1.07 (0.89-1.29) for CVD, and 0.85 (0.78-0.92) for renal function decline. CONCLUSIONS: Reduction in SUA in patients with gout may be associated with a reduced risk of renal function decline, but not with DM or CVD.
Desai RJ, Wyss R, Jin Y, Bohn J, Toh S, Cosgrove A, Kennedy A, Kim J, Kim C, Ouellet-Hellstrom R, Karami S, Major JM, Niman A, Wang SV, Gagne JJ. Extension of Disease Risk Score-Based Confounding Adjustments for Multiple Outcomes of Interest: An Empirical Evaluation. Am J Epidemiol 2018;187(11):2439-2448.Abstract
Use of disease risk score (DRS)-based confounding adjustment when estimating treatment effects on multiple outcomes is not well studied. We designed an empirical cohort study to compare dabigatran initiators and warfarin initiators with respect to risks of ischemic stroke and major bleeding in 12 sequential monitoring periods (90 days each), using data from the Truven Marketscan database (Truven Health Analytics, Ann Arbor, Michigan). We implemented 2 approaches to combine DRS for multiple outcomes: 1) 1:1 matching on prognostic propensity scores (PPS), created using DRS for bleeding and stroke as independent variables in a propensity score (PS) model; and 2) simultaneous 1:1 matching on DRS for bleeding and stroke using Mahalanobis distance (M-distance), and compared their performance with that of traditional PS matching. M-distance matching appeared to produce more stable results in the early marketing period than both PPS and traditional PS matching; hazard ratios from unadjusted analysis, traditional PS matching, PPS matching, and M-distance matching after 4 periods were 0.72 (95% confidence interval (CI): 0.51, 1.03), 0.61 (95% CI: 0.31, 1.09), 0.55 (95% CI: 0.33, 0.91), and 0.78 (95% CI: 0.45, 1.34), respectively, for stroke and 0.65 (95% CI: 0.53, 0.80), 0.78 (95% CI: 0.60, 1.01), 0.75 (95% CI: 0.59, 0.96), and 0.78 (95% CI: 0.64, 0.95), respectively, for bleeding. In later periods, estimates were similar for traditional PS matching and M-distance matching but suggested potential residual confounding with PPS matching. These results suggest that M-distance matching may be a valid approach for extension of DRS-based confounding adjustments for multiple outcomes of interest.
Cheng F, Desai RJ, Handy DE, Wang R, Schneeweiss S, Barabási A-L, Loscalzo J. Network-based approach to prediction and population-based validation of in silico drug repurposing. Nat Commun 2018;9(1):2691.Abstract
Here we identify hundreds of new drug-disease associations for over 900 FDA-approved drugs by quantifying the network proximity of disease genes and drug targets in the human (protein-protein) interactome. We select four network-predicted associations to test their causal relationship using large healthcare databases with over 220 million patients and state-of-the-art pharmacoepidemiologic analyses. Using propensity score matching, two of four network-based predictions are validated in patient-level data: carbamazepine is associated with an increased risk of coronary artery disease (CAD) [hazard ratio (HR) 1.56, 95% confidence interval (CI) 1.12-2.18], and hydroxychloroquine is associated with a decreased risk of CAD (HR 0.76, 95% CI 0.59-0.97). In vitro experiments show that hydroxychloroquine attenuates pro-inflammatory cytokine-mediated activation in human aortic endothelial cells, supporting mechanistically its potential beneficial effect in CAD. In summary, we demonstrate that a unique integration of protein-protein interaction network proximity and large-scale patient-level longitudinal data complemented by mechanistic in vitro studies can facilitate drug repurposing.
Mundkur ML, Rough K, Huybrechts KF, Levin R, Gagne JJ, Desai RJ, Patorno E, Choudhry NK, Bateman BT. Patterns of opioid initiation at first visits for pain in United States primary care settings. Pharmacoepidemiol Drug Saf 2018;27(5):495-503.Abstract
PURPOSE: The primary objective of this study was to characterize variation in patterns of opioid prescribing within primary care settings at first visits for pain, and to describe variation by condition, geography, and patient characteristics. METHODS: 2014 healthcare utilization data from Optum's Clinformatics™ DataMart were used to evaluate individuals 18 years or older with an initial presentation to primary care for 1 of 10 common pain conditions. The main outcomes assessed were (1) the proportion of first visits for pain associated with an opioid prescription fill and (2) the proportion of opioid prescriptions with >7 days' supply. RESULTS: We identified 205 560 individuals who met inclusion criteria; 9.1% of all visits were associated with an opioid fill, ranging from 4.1% (headache) to 28.2% (dental pain). Approximately half (46%) of all opioid prescriptions supplied more than 7 days, and 10% of prescriptions supplied ≥30 days. We observed a 4-fold variation in rates of opioid initiation by state, with highest rates of prescribing in Alabama (16.6%) and lowest rates in New York (3.7%). CONCLUSIONS: In 2014, nearly half of all patients filling opioid prescriptions received more than 7 days' of opioids in an initial prescription. Policies limiting initial supplies have the potential to substantially impact opioid prescribing in the primary care setting.
Lee MP, Lii J, Jin Y, Desai RJ, Solomon DH, Merola JF, Kim SC. Patterns of Systemic Treatment for Psoriatic Arthritis in the US: 2004-2015. Arthritis Care Res (Hoboken) 2018;70(5):791-796.Abstract
OBJECTIVE: To examine trends in the use of systemic disease-modifying antirheumatic drugs (DMARDs) among patients with psoriatic arthritis (PsA) in the US. METHODS: Using claims data (2004-2015) from a large US commercial health plan, we identified patients with PsA who initiated DMARD therapy. We examined baseline patient characteristics and initial treatment patterns. We then assessed changes in the DMARD regimen over the 12-month period after the first DMARD initiation date. Using Poisson regression, we estimated age- and sex-adjusted incidence rates of treatment changes in each calendar year. RESULTS: We identified 9,222 PsA patients who initiated DMARD therapy (42.8% biologic DMARDs [bDMARDs] and 57.2% conventional synthetic DMARDs [csDMARDs]). Initiators of bDMARDs were younger than those initiating csDMARDs (mean ± SD age 48 ± 13 versus 52 ± 14 years) and generally had fewer comorbidities, but a higher proportion of bDMARD initiators received nonsystemic treatments for psoriasis at baseline. Methotrexate was the most frequently used DMARD, constituting 80.6% of csDMARD initiations. Etanercept (49.1%) was the most commonly prescribed bDMARD, followed by adalimumab (34.4%). During the 12-month followup after the first DMARD initiation, 20.1% of bDMARD initiators and 31.1% of csDMARD initiators had their initial DMARD regimen modified, with an increasing trend in treatment modifications over the 11-year study period (P = 0.03). Overall, 5.3% of patients discontinued treatment, but the rates of discontinuation decreased over time (P < 0.001). CONCLUSION: In this large cohort of PsA patients with DMARD initiation, more than 40% were treated with a bDMARD. We found an increasing trend in treatment modification after use of the initial DMARD and a decreasing trend in complete DMARD discontinuation over the past decade.
Hernandez-Diaz S, Huybrechts KF, Desai RJ, Cohen JM, Mogun H, Pennell PB, Bateman BT, Patorno E. Topiramate use early in pregnancy and the risk of oral clefts: A pregnancy cohort study. Neurology 2018;90(4):e342-e351.Abstract
OBJECTIVE: To assess the relative risk of oral clefts associated with maternal use of high and low doses of topiramate during the first trimester for epilepsy and nonepilepsy indications. METHODS: This population-based study nested in the US 2000-2010 Medicaid Analytic eXtract included a cohort of 1,360,101 pregnant women with a live-born infant enrolled in Medicaid from 3 months before conception through 1 month after delivery. Oral clefts were defined as the presence of a recorded diagnosis in claims during the first 90 days after birth. Women with a topiramate dispensing during the first trimester were compared with those without any dispensing and with an active reference group of women with a lamotrigine dispensing during the first trimester. Risk ratios (RRs) were estimated with generalized linear models with fine stratification on the propensity score of treatment to control for potential confounders. Stratified analyses by indication of use and dose were conducted. RESULTS: The risk of oral clefts at birth was 4.1 per 1,000 in the 2,425 infants born to women exposed to topiramate compared with 1.1 per 1,000 in the unexposed group (RR 2.90, 95% confidence interval [CI] 1.56-5.40). The RR among women with epilepsy was 8.30 (95% CI 2.65-26.07); among women with other indications such as bipolar disorder, it was 1.45 (95% CI 0.54-3.86). The median daily dose for the first prescription filled during the first trimester was 200 mg for women with epilepsy and 100 mg for women without epilepsy. For topiramate monotherapy, the RR for oral clefts associated with doses ≤100 mg was 1.64 (95% CI 0.53-5.07) and for doses >100 mg it was 5.16 (95% CI 1.94-13.73). Results were similar when lamotrigine was used as a reference group. CONCLUSION: The increased risk of oral clefts associated with use of topiramate early in pregnancy was more pronounced in women with epilepsy, who used higher doses.