OBJECTIVES: Bone marrow transplantation (BMT) is currently the only curative therapy available for patients with sickle cell disease (SCD), but clinical outcomes in routine care are not well understood. We describe the rates of vaso-occlusive crises (VOCs), transplant complications, and mortality in SCD patients after BMT.
METHODS: A cohort study of SCD patients who underwent BMT was designed using US Medicaid claims data (2000-2013).
RESULTS: A total of 204 SCD patients undergoing BMT were identified with a mean (SD) age of 10.6 (7.3) years, with 52.9% male and 67.6% African American. The overall VOC rate was 0.99 per person-year (95% CI: 0.91-1.07) over a median follow-up time of 2.1 years (IQR: 0.8-4.3 years). A total of 138 (67.6%) remained free of VOCs. The mortality rate was 1.7 (95% CI: 0.9-3.1) per 100 person-years, transplant-related complications occurred among 113 (55.4%) patients with an incidence rate of 38.2 (95% CI: 31.7-45.9) per 100 person-years, while 47 (23%) patients had GvHD with an incidence rate of 8.0 (95% CI: 6.0-10.7) per 100 person-years.
CONCLUSION: Two thirds of the BMT recipients remained VOC-free over 2 years of follow-up, but transplant-related complications, including GvHD occurred with high frequency. This highlights a continuing unmet need for alternative curative interventions in SCD.
BACKGROUND: Regulators are evaluating the use of noninterventional real-world evidence (RWE) studies to assess the effectiveness of medical products. The RCT DUPLICATE initiative (Randomized, Controlled Trials Duplicated Using Prospective Longitudinal Insurance Claims: Applying Techniques of Epidemiology) uses a structured process to design RWE studies emulating randomized, controlled trials (RCTs) and compare results. We report findings of the first 10 trial emulations, evaluating cardiovascular outcomes of antidiabetic or antiplatelet medications.
METHODS: We selected 3 active-controlled and 7 placebo-controlled RCTs for replication. Using patient-level claims data from US commercial and Medicare payers, we implemented inclusion and exclusion criteria, selected primary end points, and comparator populations to emulate those of each corresponding RCT. Within the trial-mimicking populations, we conducted propensity score matching to control for >120 preexposure confounders. All study measures were prospectively defined and protocols registered before hazard ratios and 95% CIs were computed. Success criteria for the primary analysis were prespecified for each replication.
RESULTS: Despite attempts to emulate RCT design as closely as possible, differences between the RCT and corresponding RWE study populations remained. The regulatory conclusions were equivalent in 6 of 10. The RWE emulations achieved a hazard ratio estimate that was within the 95% CI from the corresponding RCT in 8 of 10 studies. In 9 of 10, either the regulatory or estimate agreement success criteria were fulfilled. The largest differences in effect estimates were found for RCTs where second-generation sulfonylureas were used as a proxy for placebo regarding cardiovascular effects. Nine of 10 replications had a standardized difference between effect estimates of <2, which suggests differences within expected random variation.
CONCLUSIONS: Agreement between RCT and RWE findings varies depending on which agreement metric is used. Interim findings indicate that selection of active comparator therapies with similar indications and use patterns enhances the validity of RWE. Even in the context of active comparators, concordance between RCT and RWE findings is not guaranteed, partially because trials are not emulated exactly. More trial emulations are needed to understand how often and in what contexts RWE findings match RCTs. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03936049, NCT04215523, NCT04215536, NCT03936010, NCT03936036, NCT03936062, NCT03936023, NCT03648424, NCT04237935, NCT04237922.
BACKGROUND: Administrative claims do not contain ejection fraction information for heart failure patients. We recently developed and validated a claims-based model to predict ejection fraction subtype.
METHODS: Heart failure patients aged 65 years or above from US Medicare fee-for-service claims were identified using diagnoses recorded after a 6-month baseline period of continuous enrollment, which was used to identify predictors and to apply the claims-based model to distinguish heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Patients were followed for the composite outcome of time to first worsening heart failure event (heart failure hospitalization or outpatient intravenous diuretic treatment) or all-cause mortality.
RESULTS: A total of 3,134,414 heart failure patients with an average age of 79 years were identified, of which 200,950 (6.4%) were classified as HFrEF. Among those classified as HFrEF, men comprised a larger proportion (68% vs 41%) and the average age was lower (76 vs 79 years) compared with HFpEF. History of myocardial infarction was more common in HFrEF (32% vs 13%), while hypertension was more common in HFpEF (71% vs 77%). One-year cumulative incidence of the composite endpoint was 42.6% for HFrEF and 36.9% for HFpEF. One-year all-cause mortality incidence was similar between the groups (27.4% for HFrEF and 26.4% for HFpEF), however, cardiovascular mortality was higher for HFrEF (15.6% vs 11.3%), whereas noncardiovascular mortality was higher for HFpEF (11.8% vs 15.1%).
CONCLUSION: We replicated well-documented differences in key patient characteristics and cause-specific outcomes between HFrEF and HFpEF in populations identified based on the application of a claims-based model.
BACKGROUND: Hydroxychloroquine is generally considered safe in pregnancy for the treatment of rheumatic conditions, but studies have been too small to evaluate teratogenicity. Quantifying the risk of congenital malformations associated with early pregnancy exposure to hydroxychloroquine is important in both the context of its ongoing use for rheumatological disorders and its potential future use for coronavirus disease 2019 prophylaxis, for which a number of clinical trials are ongoing despite initial trials for coronavirus disease 2019 treatment having been negative.
OBJECTIVE: The study objective was to evaluate the risk of major congenital malformations associated with exposure to hydroxychloroquine during the first trimester of pregnancy, the period of organogenesis.
STUDY DESIGN: We performed a population-based cohort study nested in the Medicaid Analytic eXtract (MAX, 2000-2014) and IBM MarketScan Research Database (MarketScan, 2003-2015). The source cohort included 2045 hydroxychloroquine-exposed pregnancies and 3,198,589 pregnancies not exposed to hydroxychloroquine continuously enrolled in their respective insurance program for 3 months before the last menstrual period through at least 1 month after delivery; infants were enrolled for at least 3 months after birth. We compared the risk of congenital malformations in women using hydroxychloroquine during the first trimester of pregnancy with that of those not using hydroxychloroquine, restricting the cohort to women with rheumatic disorders and using propensity score matching to control for indication, demographics, medical comorbidities, and concomitant medications (1867 hydroxychloroquine-exposed pregnancies and 19,080 pregnancies not exposed to hydroxychloroquine). The outcomes considered included major congenital malformations diagnosed during the first 90 days after delivery and specific malformation types for which there were at least 5 exposed events: oral cleft, cardiac, respiratory, gastrointestinal, genital, urinary, musculoskeletal, and limb defects.
RESULTS: Overall, 54.8 per 1000 infants exposed to hydroxychloroquine were born with a major congenital malformation versus 35.3 per 1000 unexposed infants, corresponding to an unadjusted relative risk of 1.51 (95% confidence interval, 1.27-1.81). Patient characteristics were balanced in the restricted, propensity score-matched cohort. The adjusted relative risk was 1.26 (95% confidence interval, 1.04-1.54); it was 1.33 (95% confidence interval, 1.08-1.65) for a daily dose of ≥400 mg and 0.95 (95% confidence interval, 0.60-1.50) for a daily dose of <400 mg. Among the different malformation groups considered, more substantial increases in the risk of oral clefts, respiratory anomalies, and urinary defects were observed, although estimates were imprecise. No pattern of malformation was identified.
CONCLUSION: Our findings suggest a small increase in the risk of malformations associated with first-trimester hydroxychloroquine use. For most patients with autoimmune rheumatic disorders, the benefits of treatment during pregnancy will likely outweigh this risk. If hydroxychloroquine were shown to be effective for coronavirus disease 2019 prophylaxis in ongoing trials, the risk of malformations would need to be balanced against such benefits.
BACKGROUND: Vaginal delivery is the most common reason for hospitalization in the United States, and approximately 30% of women fill an opioid prescription after vaginal delivery, making this a common source of opioid exposure in women of reproductive age.
OBJECTIVE: This study aimed to evaluate the effect of receiving an opioid prescription after vaginal delivery on the risk of subsequent persistent opioid use, opioid use disorders, and overdose.
STUDY DESIGN: We assembled a nationwide cohort of Medicaid beneficiaries in the United States using the Medicaid Analytic eXtract 2009-2014. The study population included pregnant women who delivered vaginally between 2009 and 2013 and were continuously enrolled in Medicaid from 90 days before to 365 days after delivery. We identified patients with prescription opioids dispensed within 7 days of the date of vaginal delivery. Persistent opioid use was defined as ≥10 opioid fills or >120 days' supply dispensed from 30 to 365 days after delivery. Incident diagnoses of opioid use disorder and overdose were ascertained during the same interval. Propensity score matching was used to control for potential confounding factors.
RESULTS: Among 459,829 pregnancies ending in vaginal deliveries, 140,807 (30.62%) had an opioid dispensed within 7 days of delivery. Overall, 5770 of 140,807 (4.10%) women who filled an opioid prescription vs 2668 of 319,022 (0.84%) unexposed women had subsequent persistent opioid use, with an unadjusted relative risk of 4.90 (95% confidence interval, 4.68-5.13) and a risk difference of 3.26% (95% confidence interval, 3.15-3.37). After propensity score matching, the risk remained higher among pregnancies with an opioid prescription dispensed, with a relative risk of 2.57 (95% confidence interval, 2.43-2.72) and a risk difference of 2.21% (95% confidence interval, 2.08-2.33), which was confirmed by the instrumental variable analysis with a risk difference of 1.31% (95% confidence interval, 1.06-1.56) by using the rate of opioid prescribing at the delivery facility in a given geographic region as the instrument. The adjusted relative risk of newly diagnosed opioid use disorder and overdose was 1.48 (95% confidence interval, 1.40-1.57) and 1.92 (95% confidence interval, 1.20-3.09), respectively.
CONCLUSION: Opioid dispensing following vaginal delivery is associated with future persistent opioid use and misuse, independent of confounding factors. Opioid prescriptions to women after vaginal delivery should be avoided, except in rare circumstances.
BACKGROUND: Population-level data spanning different countries describing oral and parenteral treatment in pregnant women with inflammatory bowel disease (IBD) are scarce. We studied treatment with sulfasalazine/5-aminosalicylates, corticosteroids, thiopurines/immunomodulators, and tumor necrosis factor (TNF)-inhibitors in the United States (Optum Clinformatics Data Mart and the Medicaid Analytics Extract [MAX]) and in the Swedish national health registers.
METHODS: We identified 2975 pregnant women in Optum (2004-2013), 3219 women in MAX (2001-2013), and 1713 women in Sweden (2006-2015) with a recorded diagnosis of IBD. We assessed patterns of use for each drug class according to filled prescriptions, assessing frequency of treatment continuation in those that were treated in the prepregnancy period.
RESULTS: The proportion of women with Crohn's disease and ulcerative colitis on any treatment during pregnancy was 56.1% and 56.3% in Optum, 47.5% and 49.3% in MAX, and 61.3% and 64.7% in Sweden, respectively, and remained stable over time. Sulfasalazine/5-aminosalicylates was the most commonly used treatment in Crohn's disease, ranging from 25.1% in MAX to 31.8% in Optum, and in ulcerative colitis, ranging from 34.9% in MAX to 53.6% in Sweden. From 2006 to 2012, the TNF-inhibitor use increased from 5.0% to 15.5% in Optum, from 3.6% to 8.5% in MAX, and from 0.7% to 8.3% in Sweden. Continuing TNF-inhibitor treatment throughout pregnancy was more common in Optum (55.8%) and in MAX (43.0%) than in Sweden (11.8%).
CONCLUSIONS: In this population-based study from 2 countries, the proportion of women with IBD treatment in pregnancy remained relatively constant. TNF-inhibitor use increased substantially in both countries.
Background The bias implications of outcome misclassification arising from imperfect capture of mortality in claims-based studies are not well understood. Methods and Results We identified 2 cohorts of patients: (1) type 2 diabetes mellitus (n=8.6 million), and (2) heart failure (n=3.1 million), from Medicare claims (2012-2016). Within the 2 cohorts, mortality was identified from claims using the following approaches: (1) all-place all-cause mortality, (2) in-hospital all-cause mortality, (3) all-place cardiovascular mortality (based on diagnosis codes for a major cardiovascular event within 30 days of death date), or (4) in-hospital cardiovascular mortality, and compared against National Death Index identified mortality. Empirically identified sensitivity and specificity based on observed values in the 2 cohorts were used to conduct Monte Carlo simulations for treatment effect estimation under differential and nondifferential misclassification scenarios. From National Death Index, 1 544 805 deaths (549 996 [35.6%] cardiovascular deaths) in the type 2 diabetes mellitus cohort and 1 175 202 deaths (523 430 [44.5%] cardiovascular deaths) in the heart failure cohort were included. Sensitivity was 99.997% and 99.207% for the all-place all-cause mortality approach, whereas it was 27.71% and 33.71% for the in-hospital all-cause mortality approach in the type 2 diabetes mellitus and heart failure cohorts, respectively, with perfect positive predicted values. For all-place cardiovascular mortality, sensitivity was 52.01% in the type 2 diabetes mellitus cohort and 53.83% in the heart failure cohort with positive predicted values of 49.98% and 54.45%, respectively. Simulations suggested a possibility for substantial bias in treatment effects. Conclusions Approaches to identify mortality from claims had variable performance compared with the National Death Index. Investigators should anticipate the potential for bias from outcome misclassification when using administrative claims to capture mortality.
To add to the limited existing evidence on clinical outcomes and healthcare use in sickle cell disease (SCD) among beneficiaries of the US Medicaid program, we conducted a cohort study using nationwide Medicaid claims data (2000-2013). Patients were included based on HbSS SCD diagnosis and followed until Medicaid disenrollment, death, bone marrow transplant, or end of data availability to assess vasoocclusive crises (VOC), emergency room (ER) visits, hospitalizations, outpatient visits, and blood transfusions. Annualized event rates (with 95% confidence intervals [CI]) were reported. The impact of VOCs on the risk of mortality was analyzed using a multivariable Cox model with VOC modeled as time-varying and updated annually. In a total of 44,033 SCD patients included with a mean (SD) age of 15.7 (13.6) years, the VOC rate (95% CI) was 3.71 (3.70-3.72) per person-year, with highest rate among patients 19-35 years who had ≥ 5 VOCs at baseline (13.20 [13.15-13.26]). Event rates (95% CI) per person per year for other outcomes were 2.97 (2.97-2.98) ER visits, 2.39 (2.38-2.40) hospitalizations, 5.80 (5.79-5.81) outpatient visits, and 0.91 (0.90-0.91) blood transfusions. A higher VOC burden in the preceding year was associated with an increased risk of mortality, with a hazard ratio (95% CI) of 1.26 (1.14-1.40) for 2-4 VOC vs. < 2 and 1.57 (1.41-1.74) for ≥ 5 VOC vs < 2. In conclusion, we documented a substantial burden of SCD in US Medicaid enrollees, especially during early adulthood and noted that ongoing burden of VOC is associated with mortality in these patients.
BACKGROUND: Despite the widespread use, only sparse information is available on the safety of gabapentin during pregnancy. We sought to evaluate the association between gabapentin exposure during pregnancy and risk of adverse neonatal and maternal outcomes.
METHODS AND FINDINGS: Using the United States Medicaid Analytic eXtract (MAX) dataset, we conducted a population-based study of 1,753,865 Medicaid-eligible pregnancies between January 2000 and December 2013. We examined the risk of major congenital malformations and cardiac defects associated with gabapentin exposure during the first trimester (T1), and the risk of preeclampsia (PE), preterm birth (PTB), small for gestational age (SGA), and neonatal intensive care unit admission (NICUa) associated with gabapentin exposure early, late, or both early and late in pregnancy. Gabapentin-unexposed pregnancies served as the reference. We estimated relative risks (RRs) and 95% confidence intervals (CIs) using fine stratification on the propensity score (PS) to control for over 70 confounders (e.g., maternal age, race/ethnicity, indications for gabapentin, other pain conditions, hypertension, diabetes, use of opioids, and specific morphine equivalents). We identified 4,642 pregnancies exposed in T1 (mean age = 28 years; 69% white), 3,745 exposed in early pregnancy only (28 years; 67% white), 556 exposed in late pregnancy only (27 years; 60% white), and 1,275 exposed in both early and late pregnancy (29 years; 75% white). The reference group consisted of 1,744,447 unexposed pregnancies (24 years; 40% white). The adjusted RR for major malformations was 1.07 (95% CI 0.94-1.21, p = 0.33) and for cardiac defects 1.12 (0.89-1.40, p = 0.35). Requiring ≥2 gabapentin dispensings moved the RR to 1.40 (1.03-1.90, p = 0.03) for cardiac defects. There was a higher risk of preterm birth among women exposed to gabapentin either late (RR, 1.28 [1.08-1.52], p < 0.01) or both early and late in pregnancy (RR, 1.22 [1.09-1.36], p < 0.001), SGA among women exposed to gabapentin early (1.17 [1.02-1.33], p = 0.02), late (1.39 [1.01-1.91], p = 0.05), or both early and late in pregnancy (RR, 1.32 [1.08-1.60], p < 0.01), and NICU admission among women exposed to gabapentin both early and late in pregnancy (RR, 1.35 [1.20-1.52], p < 0.001). There was no higher risk of preeclampsia among women exposed to gabapentin after adjustment. Study limitations include the potential for residual confounding and exposure misclassification.
CONCLUSIONS: In this large population-based study, we did not find evidence for an association between gabapentin exposure during early pregnancy and major malformations overall, although there was some evidence of a higher risk of cardiac malformations. Maternal use of gabapentin, particularly late in pregnancy, was associated with a higher risk of PTB, SGA, and NICUa.
OBJECTIVE: Certain antihyperglycemic therapies modify cardiovascular and kidney outcomes among patients with type 2 diabetes, but early uptake in practice appears restricted to particular demographics. We examine the association of Medicaid expansion with use of and expenditures related to antihyperglycemic therapies among Medicaid beneficiaries.
RESEARCH DESIGN AND METHODS: We employed a difference-in-difference design to analyze the association of Medicaid expansion on prescription of noninsulin antihyperglycemic therapies. We used 2012-2017 national and state Medicaid data to compare prescription claims and costs between states that did (n = 25) and did not expand (n = 26) Medicaid by January 2014.
RESULTS: Following Medicaid expansion in 2014, average noninsulin antihyperglycemic therapies per state/1,000 enrollees increased by 4.2%/quarter in expansion states and 1.6%/quarter in nonexpansion states. For sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA), quarterly growth rates per 1,000 enrollees were 125.3% and 20.7% for expansion states and 87.6% and 16.0% for nonexpansion states, respectively. Expansion states had faster utilization of SGLT2i and GLP-1RA than nonexpansion states. Difference-in-difference estimates for change in volume of prescriptions after Medicaid expansion between expansion versus nonexpansion states was 1.68 (95% CI 1.09-2.26; P < 0.001) for all noninsulin therapies, 0.125 (-0.003 to 0.25; P = 0.056) for SGLT2i, and 0.12 (0.055-0.18; P < 0.001) for GLP-1RA.
CONCLUSIONS: Use of noninsulin antihyperglycemic therapies, including SGLT2i and GLP-1RA, increased among low-income adults in both Medicaid expansion and nonexpansion states, with a significantly greater increase in overall use and in GLP-1RA use in expansion states. Future evaluation of the population-level health impact of expanded access to these therapies is needed.
INTRODUCTION: With increasing rates of opioid overdoses in the US, a surveillance tool to identify high-risk patients may help facilitate early intervention.
OBJECTIVE: To develop an algorithm to predict overdose using routinely-collected healthcare databases.
METHODS: Within a US commercial claims database (2011-2015), patients with ≥1 opioid prescription were identified. Patients were randomly allocated into the training (50%), validation (25%), or test set (25%). For each month of follow-up, pooled logistic regression was used to predict the odds of incident overdose in the next month based on patient history from the preceding 3-6 months (time-updated), using elastic net for variable selection. As secondary analyses, we explored whether using simpler models (few predictors, baseline only) or different analytic methods (random forest, traditional regression) influenced performance.
RESULTS: We identified 5,293,880 individuals prescribed opioids; 2,682 patients (0.05%) had an overdose during follow-up (mean: 17.1 months). On average, patients who overdosed were younger and had more diagnoses and prescriptions. The elastic net model achieved good performance (c-statistic 0.887, 95% CI 0.872-0.902; sensitivity 80.2, specificity 80.1, PPV 0.21, NPV 99.9 at optimal cutpoint). It outperformed simpler models based on few predictors (c-statistic 0.825, 95% CI 0.808-0.843) and baseline predictors only (c-statistic 0.806, 95% CI 0.787-0.26). Different analytic techniques did not substantially influence performance. In the final algorithm based on elastic net, the strongest predictors were age 18-25 years (OR: 2.21), prior suicide attempt (OR: 3.68), opioid dependence (OR: 3.14).
CONCLUSIONS: We demonstrate that sophisticated algorithms using healthcare databases can be predictive of overdose, creating opportunities for active monitoring and early intervention.
Background: The differential impact of various demographic characteristics and comorbid conditions on development of heart failure (HF) with preserved (pEF) and reduced ejection fraction (rEF) is not well studied among the elderly.
Methods: Using Medicare claims data linked to electronic health records, we conducted an observational cohort study of individuals ≥65 years of age without HF. A Cox proportional hazards model accounting for competing risk of HFrEF and HFpEF incidence was constructed. A gradient-boosted model (GBM) assessed the relative influence (RI) of each predictor in the development of HFrEF and HFpEF.
Results: Among 138,388 included individuals, 9701 developed HF (incidence rate = 20.9 per 1000 person-years). Males were more likely to develop HFrEF than HFpEF (HR = 2.07, 95% CI: 1.81-2.37 vs. 1.11, 95% CI: 1.02-1.20, P for heterogeneity <0.01). Atrial fibrillation and pulmonary hypertension had stronger associations with the risk of HFpEF (HR = 2.02, 95% CI: 1.80-2.26 and 1.66, 95% CI: 1.23-2.22) while cardiomyopathy and myocardial infarction were more strongly associated with HFrEF (HR = 4.37, 95% CI: 3.21-5.97 and 1.94, 95% CI: 1.23-3.07). Age was the strongest predictor across all HF subtypes with RI from GBM >35%. Atrial fibrillation was the most influential comorbidity for the development of HFpEF (RI = 8.4%) while cardiomyopathy was the most influential comorbidity for the development of HFrEF (RI = 20.7%).
Conclusion: These findings of heterogeneous relationships between several important risk factors and heart failure types underline the potential differences in the etiology of HFpEF and HFrEF.
Drug discovery for disease-modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population-based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease-modifying therapies for evaluation in randomized controlled trials.
OBJECTIVE: The objective of this study is to compare the risk of incident diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) treated with biologic or targeted synthetic disease-modifying antirheumatic drugs.
METHODS: A new-user observational cohort study was conducted using data from a US commercial (Truven MarketScan, 2005-2016) claims database and a public insurance (Medicare, 2010-2014) claims database. Patients with RA who did not have DM were selected into one of eight exposure groups (abatacept, infliximab, adalimumab, golimumab, certolizumab, etanercept, tocilizumab, or tofacitinib) and observed for the outcome of incident DM, defined as a combination of a diagnosis code and initiation of a hypoglycemic treatment. A stabilized inverse probability-weighted Cox proportional hazards model was used to account for 56 confounding variables and estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were conducted separately in two databases, and estimates were combined using inverse variance meta-analysis.
RESULTS: Among a total of 50 505 patients with RA from Truven and 17 251 patients with RA from Medicare, incidence rates (95% CI) for DM were 6.8 (6.1-7.6) and 6.6 (5.4-7.9) per 1000 person-years, respectively. After confounding adjustment, the pooled HRs (95% CI) indicated a significantly higher risk of DM among adalimumab (2.00 [1.11-3.03]) and infliximab initiators (2.34 [1.38-3.98]) compared with abatacept initiators. The pooled HR (95% CI) for the etanercept versus abatacept comparison was elevated but not statistically significant (1.65 [0.91-2.98]). The effect estimates for certolizumab, golimumab, tocilizumab, and tofacitinib, compared with abatacept, were highly imprecise because of a limited sample size.
CONCLUSION: Initiation of abatacept was associated with a lower risk of incident DM in patients with RA compared with infliximab or adalimumab.
BACKGROUND: To compare the risk of incident heart failure (HF) between initiators of hydrophilic and lipophilic statins.
METHODS: Using claims data for commercial health insurance program enrollees in the USA (2005-2014), we identified new initiators of hydrophilic or lipophilic statins. Follow-up for the primary outcome of incident HF began after a lag period of 1 year after statin initiation. The outcome was defined as 1 inpatient or 2 outpatient diagnosis codes for HF and the use of loop diuretics. Propensity scores (PS) were used to account for confounding. Hazard ratios (HR) for incident HF were computed separately for low and high-intensity statin users, and then pooled to provide dose-adjusted effect estimates.
RESULTS: A total of 7,820,204 patients met all our inclusion criteria for statin initiation (hydrophilic and lipophilic statins). Mean age was 58 years, 40% had hypertension, and 23% had diabetes mellitus. After PS matching, there were 691,584 patients in the low-intensity statin group and 807,370 patients in the high-intensity statin group. After a median follow-up of 725 days (IQR 500-1,153),there were 8,389 cases of incident HF (incidence rate 4.5/1,000 person years, 95% confidence interval [CI] 4.4-4.6). The unadjusted HR for the risk of HF was 0.77 (95% CI 0.76-0.79) and the pooled adjusted HR for incident HF after PS matching was 0.94 (95% CI 0.90-0.98) for hydrophilic versus lipophilic statins. The HR for incident HF was 1.06 (95% CI 1.00-1.12) for hydrophilic versus lipophilic statins for the low-intensity statin group and 0.82 (95% CI 0.78-0.87) for the high-intensity statin group. In subgroup analyses, a similar trend persisted for those younger and older than 65 years and when comparing rosuvastatin with atorvastatin.
CONCLUSION: In this observational cohort study, hydrophilic statins were associated with a modest risk reduction in incident HF as compared to lipophilic statins. Future research replicating these findings in different populations is recommended.
Regulators wish to understand whether real world evidence can be used for secondary indications of biologics. Using the secondary indication of adalimumab for ulcerative colitis (UC) as an example, we aimed to replicate the ULTRA-2 randomized controlled trial finding on the effectiveness of adalimumab in patients with UC using realworld data analyses. Adalimumab, a TNF-alpha receptor inhibitor initially approved for Crohn's disease, was approved for moderate to severe UC in 2012. The ULTRA-2 trial had shown improved remission against placebo in patients with UC. Using claims data (2006-2012), we conducted a cohort study of patients with UC who initiated adalimumab and compared them with (i) nonusers and (ii) new users of infliximab using propensity score matching. The coprimary end points were corticosteroid (CS) discontinuation within 8 weeks and 1 year of treatment. We computed hazard ratios (HRs) and 95% confidence intervals (CIs). We identified 398 matched pairs of adalimumab users vs. nonusers and 326 pairs of adalimumab vs. infliximab users. Adalimumab users were 28% more likely to achieve CS-discontinuation compared with nonusers over 1 year (HR = 1.28; 95% CI 0.94-1.73). However, unlike in ULTRA-2, this effect was not observed in the first 8 weeks (HR = 0.79; 95% CI 0.65-0.97). Compared with infliximab, adalimumab initiators showed no incremental benefit over 1 year (HR = 1.08; 95% CI 0.80-1.04), but showed a 22% reduction (HR = 0.78; 95% CI 0.64-0.95) during the first 8 weeks of treatment. In summary, our results highlight opportunities and some limitations of database analysis to identify treatment effects for secondary indications.