Safety and clinical effectiveness of peginterferon beta-1a for relapsing multiple sclerosis in a real-world setting: Final results from the Plegridy Observational Program.

Background: Interferon beta-1a remains an important treatment option for multiple sclerosis, particularly when safety or tolerability concerns may outweigh the benefits of higher-efficacy disease-modifying therapies. The five-year phase 4 Plegridy Observational Program (POP) study (NCT02230969) collected data on real-world safety and effectiveness of Plegridy® (peginterferon beta-1a) treatment in patients with relapsing multiple sclerosis. Objective: To explore the real-world safety and effectiveness of peginterferon beta-1a in patients with relapsing multiple sclerosis, including factors influencing treatment discontinuation. Methods: Data were collected prospectively from patients ≥ 18 years old with relapsing multiple sclerosis for overall population analysis and for subpopulations including newly/previously diagnosed patients, age, and experience with peginterferon beta-1a. Outcome measures included annualized relapse rates, adverse events, and predictors of time to treatment discontinuation. Results: Mean (SD) treatment duration in the overall population (N = 1172) was 896.0 (733.15) days. Incidence of adverse events was higher in new than experienced users (79.4% vs. 57.0%). New users were more likely than experienced users to discontinue (hazard ratio = 1.60; P < 0.0001). The adjusted annualized relapse rate was 0.09, and at the end of 5 years, 77.1% of patients were relapse-free. Conclusions: Peginterferon beta-1a is an effective therapy for managing relapsing multiple sclerosis. The identification of predictors of discontinuation can help inform strategies to enhance treatment persistence.

Comparative effectiveness of dimethyl fumarate versus non-specific immunosuppressants: Real-world evidence from MSBase.

Background: The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations. Objective: To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022. Methods: Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2). Results: After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; p = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; p = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; p = 0.001) and CDP (HR: 0.53; p = 0.001), and shorter time to CDI (HR: 1.99; p < 0.008), versus the NSIS cohort. Conclusion: This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.

Temporal Relationship Between Serum Neurofilament Light Chain and Radiologic Disease Activity in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Serum neurofilament light chain (sNfL) levels correlate with multiple sclerosis (MS) disease activity, but the dynamics of this correlation are unknown. We evaluated the relationship between sNfL levels and radiologic MS disease activity through monthly assessments during the 24-week natalizumab treatment interruption period in RESTORE (NCT01071083). METHODS: In the RESTORE trial, participants with relapsing forms of MS who had received natalizumab for ≥12 months were randomized to either continue or stop natalizumab and followed with MRI and blood draws every 4 weeks to week 28 and again at week 52 The sNfL was measured, and its dynamics were correlated with the development of gadolinium-enhancing (Gd+) lesions. Log-linear trend in sNfL levels were modeled longitudinally using generalized estimating equations with robust variance estimator from baseline to week 28. RESULTS: Of 175 patients enrolled in RESTORE, 166 had serum samples for analysis. Participants with Gd+ lesions were younger (37.7 vs 43.1, p = 0.001) and had lower Expanded Disability Status Scale scores at baseline (2.7 vs 3.4, p = 0.017) than participants without Gd+ lesions. sNfL levels increased in participants with Gd+ lesions (n = 65) compared with those without (n = 101, mean change from baseline to maximum sNfL value, 12.1 vs 3.2 pg/mL, respectively; p = 0.003). As the number of Gd+ lesions increased, peak median sNfL change also increased by 1.4, 3.0, 4.3, and 19.6 pg/mL in the Gd+ lesion groups of 1 (n = 12), 2-3 (n = 18), 4-9 (n = 21), and ≥10 (n = 14) lesions, respectively. However, 46 of 65 (71%) participants with Gd+ lesions did not increase above the 95th percentile threshold of the group without Gd+ lesions. The initial increase of sNfL typically trailed the first observation of Gd+ lesions, and the peak increase in sNfL was a median [interquartile range] of 8 [0, 12] weeks after the first appearance of the Gd+ lesion. DISCUSSION: Although sNfL correlated with the presence of Gd+ lesions, most participants with Gd+ lesions did not have elevations in sNfL levels. These observations have implications for the use and interpretation of sNfL as a biomarker for monitoring MS disease activity in controlled trials and clinical practice.

Efficacy of Dimethyl Fumarate in Young Adults with Relapsing-Remitting Multiple Sclerosis: Analysis of the DEFINE, CONFIRM, and ENDORSE Studies.

INTRODUCTION: Dimethyl fumarate (DMF) showed favorable benefit-risk in patients with relapsing-remitting multiple sclerosis (MS) in phase 3 DEFINE and CONFIRM trials and in the ENDORSE extension study. Disease activity can differ in younger patients with MS compared with the overall population. METHODS: Randomized patients received DMF 240 mg twice daily or placebo (PBO; years 0-2 DEFINE/CONFIRM), then DMF (years 3-10; continuous DMF/DMF or PBO/DMF; ENDORSE); maximum follow-up (combined studies) was 13 years. This integrated post hoc analysis evaluated safety and efficacy of DMF in a subgroup of young adults aged 18-29 years. RESULTS: Of 1736 patients enrolled in ENDORSE, 125 were young adults, 86 treated continuously with DMF (DMF/DMF) and 39 received delayed DMF (PBO/DMF) in DEFINE/CONFIRM. Most (n = 116 [93%]) young adults completed DMF treatment in DEFINE/CONFIRM. Median (range) follow-up time in ENDORSE was 6.5 (2.0-10.0) years. Young adults entering ENDORSE who had been treated with DMF in DEFINE/CONFIRM had a model-based Annualized Relapse Rate (ARR; 95% CI) of 0.24 (0.16-0.35) vs. 0.56 (0.35-0.88) in PBO patients. ARR remained low in ENDORSE: 0.07 (0.01-0.47) at years 9-10 (DMF/DMF group). At year 10 of ENDORSE, EDSS scores were low in young adults: DMF/DMF, 1.9 (1.4); PBO/DMF, 2.4 (1.6). At ~ 7 years, the proportion of young adults with no confirmed disability progresion was 81% for DMF/DMF and 72% for PBO/DMF. Patient-reported outcomes (PROs) (SF-36 and EQ-5D) generally remained stable during ENDORSE. The most common adverse events (AEs) in young adults during ENDORSE were MS relapse (n = 53 [42%]). Most AEs were mild (n = 20 [23.3%], n = 7 [17.9%]) to moderate (n = 45 [52.3%], n = 23 [59.0%]) in the DMF/DMF and PBO/DMF groups, respectively. The most common serious AE (SAE) was MS relapse (n = 19 [15%]). CONCLUSION: The data support a favorable benefit-risk profile of DMF in young adults, as evidenced by well-characterized safety, sustained efficacy, and stable PROs. CLINICAL TRIAL INFORMATION: Clinical trials.gov, DEFINE (NCT00420212), CONFIRM (NCT00451451), and ENDORSE (NCT00835770).

Dimethyl fumarate is associated with lower rates of infection and lower infection-related healthcare costs when compared with ocrelizumab.

BACKGROUND: Infections in people with multiple sclerosis (PwMS) may have a detrimental effect on disease progression, risk of hospitalization, and healthcare resource utilization (HRU). The infection risk and HRU costs may vary between disease-modifying therapies (DMTs); however, the individual risks and differences associated with DMTs are not well characterized. Some DMTs may increase the risk for infections in PwMS; however, previous studies have reported an intact humoral immune response in dimethyl fumarate (DMF)-treated patients. The objective was to compare infection-related HRU and healthcare costs (HCCs) between PwMS treated with DMF or ocrelizumab (OCR). METHODS: Eligible patients were identified from the Optum US claims database between April 2017 and September 2020 (DMF n = 1429; OCR n = 3170). Patients were followed from index date to first occurrence of: (1) end of study, (2) end of insurance eligibility, (3) discontinuation of index DMT, or (4) switch from index DMT to another DMT. Outcomes were annualized rate of infection encounters (defined as infection encounters [n] during follow-up window / days followed [n] × 365); annualized infection-related HCCs (defined as aggregated costs of infection encounters during follow-up window / days followed [n] × 365); location-specific infections, and overall infection-related events. Propensity score matching (PSM) 1:1 method was used; PS was calculated via logistic regression for probability of DMF treatment conditional on demographics and comorbidities. Mean differences (MD) were reported for infection encounter measures. RESULTS: After PSM, DMF and OCR cohorts (n = 1094 in each cohort) were balanced based on baseline characteristics (standardized MD of adjusted baseline characteristics <0.1). Mean (standard deviation) follow-up was 296 (244) days for DMF patients and 297 (243) for OCR patients. DMF patients experienced lower annualized rates of overall infection encounters vs OCR patients (MD -0.51 [95% confidence interval (CI): -0.92 to -0.11], p = 0.01). When stratified by type of infection encounter, DMF patients experienced significantly lower annualized rates of outpatient (MD [95% CI]: -0.44 [-0.80 to -0.08], p = 0.02) and inpatient/hospitalization infection encounters (-0.08 [-0.14 to -0.02], p<0.01) vs OCR patients. A trend towards a shorter duration of infection-related hospitalization in the DMF vs the OCR group was observed (MD [95% CI]: -2.20 [-4.73 to 0.26] days, p = 0.08). The most common infection types in both DMT groups were urinary tract infections, sepsis, and pneumonia. DMF patients experienced lower annualized infection-related HCCs (MD [95% CI]: -$3642 [-$6380 to -$904], p < 0.01) vs OCR patients, which were driven largely by infection-related hospitalization costs (-$3639 [-$6019 to -$1259], p < 0.01). CONCLUSION: DMF-treated patients PS-matched with OCR patients experienced lower annualized rates of infection encounters and lower infection-related HCCs.

Real-world effectiveness of dimethyl fumarate versus fingolimod in a cohort of patients with multiple sclerosis using standardized, quantitative outcome metrics.

BACKGROUND: Prior studies suggest comparable effectiveness of dimethyl fumarate (DMF) and fingolimod (FTY) in multiple sclerosis (MS) using relapse, Expanded Disability Status Score (EDSS), and magnetic resonance imaging (MRI) lesion metrics. OBJECTIVE: Compare the real-world effectiveness of DMF versus FTY using quantitative, validated neuroperformance tests, MRI, and serum neurofilament light chain (sNfL) outcomes while controlling for between-group differences. METHODS: Patients were eligible if on DMF or FTY when first enrolled in the MS Partners Advancing Technology and Health Solutions (MS PATHS) network and had ≥1-year follow-up in MS PATHS. Sensitivity analysis included a subgroup who started DMF/FTY ≤2 years from enrolment. After propensity score weighting, differences in means and in mean 1-year change of neuroperformance and MRI outcomes were compared. sNfL levels were assessed. This was a non-randomized comparison. RESULTS: In the overall cohort, no significant differences were observed between DMF (n = 702) and FTY (n = 600) in neuroperformance or MRI outcomes including brain volume loss; mean time (SD) since treatment initiation was 1.98 (0.68) years for DMF and 2.02 (0.75) years for FTY. A sensitivity analysis controlling for DMF and FTY treatment duration yielded similar results. CONCLUSION: In this study, DMF and FTY demonstrated similar effects on physical and cognitive neuroperformance and MRI outcomes. Direct comparisons to other fumarates and S1P receptor modulators were not conducted.

Addressing Posttreatment Selection Bias in Comparative Effectiveness Research, Using Real-World Data and Simulation.

To examine methodologies that address imbalanced treatment switching and censoring, 6 different analytical approaches were evaluated under a comparative effectiveness framework: intention-to-treat, as-treated, intention-to-treat with censor-weighting, as-treated with censor-weighting, time-varying exposure, and time-varying exposure with censor-weighting. Marginal structural models were employed to address time-varying exposure, confounding, and possibly informative censoring in an administrative data set of adult patients who were hospitalized with acute coronary syndrome and treated with either clopidogrel or ticagrelor. The effectiveness endpoint included first occurrence of death, myocardial infarction, or stroke. These methodologies were then applied across simulated data sets with varying frequencies of treatment switching and censoring to compare the effect estimate of each analysis. The findings suggest that implementing different analytical approaches has an impact on the point estimate and interpretation of analyses, especially when censoring is highly unbalanced.

Association Between Prenatal Opioid Exposure and Neurodevelopmental Outcomes in Early Childhood: A Retrospective Cohort Study.

INTRODUCTION: Several studies have reported increasing prevalence of prescription opioid use among pregnant women. However, little is known regarding the effects of maternal opioid use on neurodevelopmental disorders in early childhood in pregnant women with no evidence of opioid use disorders or drug dependence. OBJECTIVE: The aim of this study was to quantify the association between prenatal opioid exposure from maternal prescription use and neurodevelopmental outcomes in early childhood. METHODS: This retrospective study included pregnant women aged 12-55 years and their live-birth infants born from 2010 to 2012 present in Optum's deidentified Clinformatics® Data Mart database. Eligible infants born to mothers without opioid use disorders or drug dependence were followed till occurrence of neurodevelopmental disorders, loss to follow-up, or study end (December 31, 2017), whichever came first. Propensity score by fine stratification was applied to adjust for confounding by demographic characteristics, obstetric characteristics, maternal comorbid mental and pain conditions, and measures of burden of illnesses and to obtain adjusted hazard ratios (HR) and 95% confidence intervals (CI). Exposed and unexposed infants were compared on the incidence of neurodevelopmental disorders. RESULTS: Of 24,910 newborns, 7.6% (1899) were prenatally exposed to prescription opioids. Overall, 1562 children were diagnosed with neurodevelopmental disorders, with crude incidence rates of 2.9 per 100 person-years in exposed children versus 2.5 per 100 person-years in unexposed children. After adjustment, we observed no association between fetal opioid exposure and the risk of neurodevelopmental disorders (HR 1.10; 95% CI 0.92-1.32). However, increased risk of neurodevelopmental disorders were observed in children with longer cumulative exposure duration (HR 1.70; 95% CI 1.05-2.96) or high cumulative opioid doses (HR 1.22; 95% CI 1.01-1.54). CONCLUSION AND RELEVANCE: In pregnant women without opioid use disorders or drug dependence, maternal opioid use was not associated with increased risk of neurodevelopmental disorders in early childhood. However, increased risks of early neurodevelopmental disorders were observed in children born to women receiving prescription opioids for longer duration and at higher doses during pregnancy.

Comparative effectiveness and safety of prasugrel versus ticagrelor following percutaneous coronary intervention: An observational study.

BACKGROUND: Observational studies comparing ticagrelor and prasugrel in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) have yielded contradictory results, but these studies often did not consider differential censoring (eg, for treatment switching or insurance disenrollment) or confounding by time-dependent factors. OBJECTIVE: Our objective was to conduct a comparative effectiveness and safety analysis of ticagrelor and prasugrel in patients who underwent PCI after being hospitalized for an ACS. METHODS: This study used the Optum's de-identified Clinformatics® Data Mart Database and included patients aged 18 years or older with an index hospital admission between May 2012 and September 2015, a diagnosis of ACS managed with PCI, and treatment with either ticagrelor or prasugrel. The primary composite outcome was defined as the first occurrence of all-cause death, myocardial infarction (MI), or ischemic stroke. The secondary composite outcome included the first occurrence of gastrointestinal (GI) bleed, intracranial hemorrhage (ICH), or other major bleeds requiring hospitalization. Weighted Cox proportional hazard models and robust variance estimation were implemented to adjust for baseline comorbidities, time-varying exposure, time-dependent confounders, and differential censoring. RESULTS: Included in the analysis were 2559 patients initiated on ticagrelor and 4456 patients initiated on prasugrel following PCI. Patients initiated on ticagrelor were 10% more likely to have eligibility disenrollment (Ticagrelor: 57%, Prasugrel: 47%, p < 0.01) and 7 percentage-points more likely to switch medication (Ticagrelor: 35%, Prasugrel: 28%, p < 0.01). After adjusting for multiple factors, including time-varying exposure and censoring imbalance, ticagrelor was associated with a higher risk of all-cause death, MI, or stroke when compared to prasugrel (Hazard ratio (HR): 1.33; 95% CI: 1.04-1.68). Similarly, ticagrelor was associated with a higher risk in bleeding events when compared with prasugrel (HR: 1.61; 95% CI: 1.19-2.17). CONCLUSION: When compared with ticagrelor, prasugrel use following PCI for ACS was associated with a lower risk of death, MI, or stroke, as well as a reduced risk of major bleeding.

Association of Gestational Opioid Exposure and Risk of Major and Minor Congenital Malformations.

Importance: The rapid increase of opioid-related overdoses and deaths has become a public health concern in the US. Use of prescription opioids in pregnant women has increased; results from teratogenicity studies remain controversial. Objective: To evaluate the association between maternal prescription opioid use (excluding opioid use disorders) during pregnancy and the incidence of congenital malformations. Design, Setting, and Participants: This retrospective population-based cohort study evaluated linked Rhode Island Medicaid claims and vital statistics data of live births from January 1, 2008, to December 31, 2016. Data analysis was conducted from May 1, 2019, to May 31, 2020. Women who had a live birth during the study period, but no cancer or opioid use disorder, were followed up from 3 months before pregnancy to the end of pregnancy. Exposures: Data on the mother's prescription opioid exposure were obtained through pharmacy claims and exposure was defined as dispensing of at least 1 prescription opioid during the first, second, or third trimester. Main Outcomes and Measures: The primary outcome was overall major or minor congenital malformations, defined as 1 or more major or minor congenital malformation. Secondary outcomes were defined as 10 specific categories of congenital malformations classified by organ systems using International Classification of Diseases diagnosis codes. Results: Of 12 424 included pregnancies, 891 mothers (7.2%) received prescription opioids during pregnancy and 3153 infants (25.4%) were diagnosed with major or minor congenital malformations. Comparing prescription opioid exposure vs nonexposure, no excess risk was observed for major birth defects in infants with opioid exposure in trimester 1 (adjusted relative risk [aRR], 1.40; 95% CI, 0.84-2.34), and higher risks were found for overall minor birth defects in trimester 3 (aRR, 1.26; 95% CI, 1.04-1.53) and minor birth defects in the musculoskeletal system in trimester 2 (aRR, 1.50; 95% CI, 1.10-2.03) and trimester 3 (aRR, 1.65; 95% CI, 1.23-2.22). Significant dose responses in selected minor malformations and effects of specific opioids were also identified. Hydrocodone in trimester 2 (aRR, 3.01; 95% CI, 1.80-5.03) and oxycodone in trimester 3 (aRR, 2.43; 95% CI, 1.37-4.02) were associated with plagiocephaly, polydactyly, and other specified congenital deformities of the hip. Conclusions and Relevance: The findings of this study suggest a higher risk of minor congenital malformations associated with use of prenatal prescription opioids in trimester 3, which seems to be dose-dependent. Further investigation is needed to establish causality and explore the physiologic plausibility of the association.

Development and Application of a Measurement Framework to Evaluate Safe, Effective and Efficient Medication Use Among Older Adults.

BACKGROUND: A majority of older adults in the United States (US) use prescription medications. Comprehensive population-level approaches to examine medication safety, effectiveness, and costs among older adults are needed. OBJECTIVES: The objectives of this study were to develop a framework of quality measures spanning the domains of safety, effectiveness, and efficiency of prescription medication use among older adults, and to apply those measures using pharmacy claims data. METHODS: We performed a retrospective study among adults age 65 years and older of a US East Coast state who filled at least one prescription from a particular pharmacy chain during 2016 (N = 99,056). Firstly, we performed an environmental scan to identify quality measures and potentially relevant measures addressing prescription medication use. These measures were reviewed and rated by local geriatric pharmacotherapy experts. After evaluating feasibility, evidence, and relevance, a total of 19 measures representing the domains of safety (n = 7), effectiveness (n = 7), and efficiency (n = 5) were identified. These measures were then applied to an older adult population using prescription data for the year 2016 provided by a national pharmacy chain. All measures were configured such that a score of 100% corresponded to optimal performance. RESULTS: For the domain of safety, 12.8% of patients received a benzodiazepine chronically, 23.6% received central nervous system depressants, 16.7% received fluoroquinolones as first-line antibiotic therapy, and 21.9% of those who were prescribed opioids received them in excessive quantities. For the domain of effectiveness, one-fourth of the diabetes patients did not receive statins and angiotensin-acting medications, while 18.0% were not adherent to oral anticoagulant medications and 54% were not adherent to respiratory inhalers. For the domain of efficiency, 12.0% of the patients received prescriptions from five or more unique prescribers. Overall, 85.7%, 76.1%, and 87.9% of the older adults showed safe, effective, and efficient prescription medication use, respectively. CONCLUSION: A novel approach to comprehensively examine the quality of medication use among older adults using prescription claims data is provided in our study. A considerable proportion of the older adults in our study received safe, effective, and efficient prescription medications. However, within each domain, several opportunities for improving the alignment of prescription medication use with current recommendations were identified.

Prescription Opioid Use among Pregnant Women Enrolled in Rhode Island Medicaid.

OBJECTIVE: Our objective was to identify patterns of opioid use among pregnant women enrolled in RI Medicaid. METHODS: This study used linked RI Medicaid and RI Birth Certificate data from 01/01/2006 to 12/31/2016. We examined temporal trends of prescription opioid dispensings and identified risk factors associated with opioids use during pregnancy. RESULTS: Among 25,500 RI Medicaid enrolled pregnant women who delivered a live baby from 2008 to 2016, 1,914 (7.5%) received at least one prescription for an opioid medication during pregnancy, 810 (3.2%) were during the first trimester, 633 (2.5%) during the second trimester, and 866 (3.4%) during the third trimester. Of these, 213 (0.8%) women received 3 or more opioids during pregnancy. The prevalence of prescription opioids dispensed in pregnant women increased from 4.9% in 2008 to 9.6% in 2015 (ß±SD: 0.66±0.28, P=0.05). CONCLUSIONS: Prescription opioid use during pregnancy has increased among women enrolled in RI Medicaid.

Outcomes in human immunodeficiency virus-infected recipients of heart transplants.

BACKGROUND: With the advent of combined antiretroviral therapy (cART), growing evidence has shown human immunodeficiency virus (HIV) may no longer be an absolute contraindication for solid organ transplantation. This study compares outcomes of heart transplantations between HIV-positive and HIV-negative recipients using SRTR transplant registry data. METHODS: Patient survival, overall graft survival and death-censored graft survival were compared between HIV-positive and HIV-negative recipients. Multivariate Cox regression and Cox regression with a disease risk score (DRS) methodology were used to estimate the adjusted hazard ratios among heart transplant recipients (HTRs). RESULTS: In total, 35 HTRs with HIV+ status were identified. No significant differences were found in patient survival (88% vs 77%; P = 0.1493), overall graft survival (85% vs 76%; P = 0.2758), and death-censored graft survival (91% vs 91%; P = 0.9871) between HIV-positive and HIV-negative HTRs in 5-year follow-up. No significant differences were found after adjusting for confounders. CONCLUSIONS: This study supports the use of heart transplant procedures in selected HIV-positive patients. This study suggests that HIV-positive status is not a contraindication for life-saving heart transplant as there were no differences in graft, patient survival.