Initiation of Oral Endocrine Therapy and Survival Benefit Among Women with Early-Stage Breast Cancer.

Introduction: Endocrine therapy (ET) is the cornerstone of systemic treatment for patients with estrogen receptor positive breast cancer, but its uptake and adherence need further improvement. This observational study assessed ET initiation and 1-year adherence and its survival benefit among female Medicare beneficiaries with early-stage breast cancer. Materials and Methods: This retrospective cohort study analyzed the linked 2011-2019 Surveillance, Epidemiology, and End Results-Medicare data. Female beneficiaries newly diagnosed with hormone receptor positive, stage I-III breast cancer were included. Beneficiaries who initiated tamoxifen, anastrozole, letrozole, or exemestane within 3 months after cancer diagnosis were defined as initiators (n = 24,289), and those who never initiated these treatments were noninitiators (n = 8,899). Adherence was measured using proportion of days covered (PDC) in the continuous 12 months follow-up period. Multivariable logistic regression models were used to assess factors associated with ET initiation and adherence (PDC ≥ 80%), controlling for covariates. Weighted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause and breast cancer related mortality between initiators and noninitiators and by adherence status. Results: Among eligible female beneficiaries (n = 55,893), 43% initiated ET within 3 months of cancer diagnosis. Among initiators, 77% had PDC ≥ 80% during the first year. Patient's demographics (e.g., older age, race/ethnicity) and baseline health services utilization (e.g., mammography) were associated with ET initiation and adherence. ET initiation and adherence was associated with reduced risk of all-cause (adjusted HR = 0.62, 0.59-0.66; HR = 0.55, 0.53-0.59; respectively) and breast cancer related (adjusted HR = 0.57, 0.50-0.64; HR = 0.41, 0.36-0.47; respectively) mortality compared with noninitiators. Conclusion: Women with early-stage breast cancer who initiate ET and are adherent to treatment may achieve survival benefits compared with noninitiators.

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients with Atrial Fibrillation and Cancer: A Target Trial Emulation from SEER-Medicare Database.

BACKGROUND: Direct oral anticoagulants (DOACs) are preferred over warfarin in patients with atrial fibrillation (AFib). However, their safety and effectiveness in patients with AFib and cancer are inconclusive. METHODS: We conducted a retrospective cohort study by emulating a target trial. Patients with a record of cancer (breast, prostate, or lung), newly diagnosed with AFib initiated DOACs or warfarin within 3 months after AFib diagnosis from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database were included. We compared the risk of ischemic stroke, major bleeding, and secondary outcomes (venous thromboembolism, intracranial bleeding, gastrointestinal bleeding, and non-critical site bleeding) between patients who initiated DOACs and warfarin. Inverse probability treatment weights and inverse probability censoring weights were used to adjust imbalanced patient and disease characteristics and loss to follow-up between the two groups. Weighted pooled logistic regression were used to estimate treatment effect with hazard ratios (HRs) with 95% confidence interval (95% CIs). RESULTS: The incidence rates of stroke and major bleeding between DOAC and warfarin initiators were 9.97 vs. 9.91 and 7.74 vs. 9.24 cases per 1000 person-years, respectively. In adjusted intention-to-treat analysis, patients initiated DOACs had no statistically significant difference in risk of ischemic stroke (HR = 0.87, 95% CI 0.52-1.44) and major bleeding (HR = 1.14, 95% CI 0.77-1.68) compared to those initiated warfarin. In adjusted per-protocol analysis, there was no statistical difference in risk of ischemic stroke (HR = 1.81, 95% CI 0.75-4.36) and lower risk for major bleeding, but the 95% CI was wide (HR = 0.35, 95% CI 0.12-0.99) among DOAC initiators compared to warfarin initiators. The benefits in secondary outcomes were in favor of DOACs. The findings remained consistent across subgroups and sensitivity analyses. CONCLUSION: DOACs are safe and effective alternatives to warfarin in the management of patients with AFib and cancer.

Real-World Long-Term Effectiveness of Risankizumab Among Patients with Moderate-to-Severe Psoriasis: Analysis from an International Medical Chart Review (RAPID) Study.

INTRODUCTION: Real-world data on the efficacy of risankizumab (RZB) in clinical moderate-to-severe plaque psoriasis (PsO) are limited. The RAPID study assessed real-world clinical and patient-reported outcomes in RZB-treated PsO patients using data collected from dermatologists in Canada, the Czech Republic, Germany, Japan, and Poland. METHODS: This ongoing, retrospective chart review collected data from medical records of RZB-treated adults with moderate-to-severe PsO (09/2022-06/2023). Eligible patients received RZB, had ≥ 12 months of medical records after RZB initiation (index date), and had Psoriasis Area and Severity Index (PASI), Investigator Global Assessment (IGA), or static Physician's Global Assessment (sPGA) scores ≥ 3 months before and up to 18 months after the index date. The proportion of patients achieving a clear/almost clear PsO (IGA/sPGA = 0/1), PASI ≤ 1, Dermatology Life Quality Index (DLQI) = 0/1, and a 90%/100% improvement from baseline in PASI as well as the mean changes in PASI, DLQI, itch, and skin pain scores at 12 and 18 months were reported for patients with non-missing assessments at baseline and 12 months. RESULTS: Most patients (66.4%) were male, 74.0% were biologic naïve, and 73.0% had scalp PsO. Mean baseline IGA/sPGA was 3.7 ± 0.5, with a mean PASI of 23.3 ± 11.8. After 12 months, 86.1% of patients reported IGA/sPGA ≤ 1, and 75.7% achieved PASI90; these further increased to 91.1% and 80.5% at 18 months. DLQI, itch, and skin pain scores improved over time. CONCLUSIONS: These data demonstrated the durable, real-world effectiveness of RZB in patients with moderate-to-severe PsO through continued improvement in disease and symptom severity over 18 months, with most of the patients reporting clear/almost clear skin.

Benefit and risk of oral anticoagulant initiation strategies in patients with atrial fibrillation and cancer: a target trial emulation using the SEER-Medicare database.

Oral anticoagulants (OACs) are recommended for patients with atrial fibrillation (AFib) having CHA2DS2-VASc score ≥ 2. However, the benefits of OAC initiation in patients with AFib and cancer at different levels of CHA2DS2-VASc is unknown. We included patients with new AFib diagnosis and a record of cancer (breast, prostate, or lung) from the 2012-2019 Surveillance, Epidemiology, and End Results (SEER)-Medicare database (n = 39,915). Risks of stroke and bleeding were compared between 5 treatment strategies: (1) initiated OAC when CHA2DS2-VASc ≥ 1 (n = 6008), (2) CHA2DS2-VASc ≥ 2 (n = 8694), (3) CHA2DS2-VASc ≥ 4 (n = 20,286), (4) CHA2DS2-VASc ≥ 6 (n = 30,944), and (5) never initiated OAC (reference group, n = 33,907). Confounders were adjusted using inverse probability weighting through cloning-censoring-weighting approach. Weighted pooled logistic regressions were used to estimate treatment effect [hazard ratios (HRs) and 95% confidence interval (95% CIs)]. We found that only patients who initiated OACs at CHA2DS2-VASc ≥ 6 had lower risk of stroke compared without OAC initiation (HR 0.64, 95% CI 0.54-0.75). All 4 active treatment strategies had reduced risk of bleeding compared to non-initiators, with OAC initiation at CHA2DS2-VASc ≥ 6 being the most beneficial strategy (HR = 0.49, 95% CI 0.44-0.55). In patients with lung cancer or regional/metastatic cancer, OAC initiation at any CHA2DS2-VASc level increased risk of stroke and did not reduce risk of bleeding (except for Regimen 4). In conclusion, among cancer patients with new AFib diagnosis, OAC initiation at higher risk of stroke (CHA2DS2-VASc score ≥ 6) is more beneficial in preventing ischemic stroke and bleeding. Patients with advanced cancer or low life-expectancy may initiate OACs when CHA2DS2-VASc score ≥ 6.

Development and Validation of Machine Learning Algorithms to Predict 1-Year Ischemic Stroke and Bleeding Events in Patients with Atrial Fibrillation and Cancer.

In this study, we leveraged machine learning (ML) approach to develop and validate new assessment tools for predicting stroke and bleeding among patients with atrial fibrillation (AFib) and cancer. We conducted a retrospective cohort study including patients who were newly diagnosed with AFib with a record of cancer from the 2012-2018 Surveillance, Epidemiology, and End Results (SEER)-Medicare database. The ML algorithms were developed and validated separately for each outcome by fitting elastic net, random forest (RF), extreme gradient boosting (XGBoost), support vector machine (SVM), and neural network models with tenfold cross-validation (train:test = 7:3). We obtained area under the curve (AUC), sensitivity, specificity, and F2 score as performance metrics. Model calibration was assessed using Brier score. In sensitivity analysis, we resampled data using Synthetic Minority Oversampling Technique (SMOTE). Among 18,388 patients with AFib and cancer, 523 (2.84%) had ischemic stroke and 221 (1.20%) had major bleeding within one year after AFib diagnosis. In prediction of ischemic stroke, RF significantly outperformed other ML models [AUC (0.916, 95% CI 0.887-0.945), sensitivity 0.868, specificity 0.801, F2 score 0.375, Brier score = 0.035]. However, the performance of ML algorithms in prediction of major bleeding was low with highest AUC achieved by RF (0.623, 95% CI 0.554-0.692). RF models performed better than CHA2DS2-VASc and HAS-BLED scores. SMOTE did not improve the performance of the ML algorithms. Our study demonstrated a promising application of ML in stroke prediction among patients with AFib and cancer. This tool may be leveraged in assisting clinicians to identify patients at high risk of stroke and optimize treatment decisions.

Factors associated with adherence to medications for lowering breast cancer risk between female Medicare beneficiaries in Alabama and nationwide.

PURPOSE: The U.S. Preventive Services Task Force recommends use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) for breast cancer (BC) prevention. We examined factors associated with adherence to SERMs/AI treatments among female Medicare beneficiaries in Alabama and those nationwide. METHODS: This retrospective new user cohort study analyzed the 2013-2016 Medicare administrative claims data files (100% Alabama and random 5% national samples). Female Medicare beneficiaries without invasive BC and osteoporosis, continuously enrolled in Medicare Parts A, B, and D for at least 18 months (with a 6-month washout and a 12-month follow-up period) in 2013-2016. Among beneficiaries who initiated (6-month washout) any of the SERMs/AIs (tamoxifen, raloxifene, anastrozole, and exemestane), we examined their 1-year treatment adherence using proportion of days covered (PDC) and operationalized as both continuous (0-1) and dichotomized (≥ 80% as adherent and < 80% as non-adherent) outcomes. Multivariable logistic models were used to identify factors associated with adherence (PDC ≥ 80%) among Alabama and national samples, respectively. RESULTS: A total of 885 women in Alabama and 1,213 women in national sample initiated these SERMs/AI treatments. Among those with ≥ 2 prescriptions (n = 479 in Alabama and n = 870 in national sample), Mean PDC was 0.74 [standard deviation (SD) = 0.30] among Alabamian women, similar to those in the national sample [0.71 (SD = 0.31), p = 0.09]. Use of mammography prior to treatment initiation was associated with higher likelihood of adherence to treatments in both samples. CONCLUSION: Our findings highlight the importance of access to preventive services such as mammography to better adherence to BC preventive treatments among female Medicare beneficiaries.

Use of second-generation antidiabetic medication among a nationally representative sample.

OBJECTIVES: Existing studies have shown the benefits of second-generation antidiabetic medications in patients with type 2 diabetes (T2D). However, the medications' real-world utilization was not well understood. Our study assessed patient factors associated with the use of second-generation antidiabetic medications in a nationally representative sample of patients with T2D. STUDY DESIGN: This retrospective, cross-sectional analysis used the 2005 to 2018 National Health and Nutrition Examination Survey (NHANES) data. METHODS: Survey participants 18 years and older who had a diagnosis of T2D and had used antidiabetic medications in the past 30 days were included. The primary outcome was the prescription of any second-generation antidiabetic medication. Weighted stepwise multivariable logistic regression models were used to assess the associations between the use of second-generation antidiabetic medications and patients' characteristics. RESULTS: Among 4493 patients with T2D, 533 (weighted %, 13.67%) reported using at least 1 second-generation antidiabetic drug. In multivariable analyses, patients with incomes at least 400% of the federal poverty level (adjusted odds ratio [AOR], 2.30; 95% CI, 1.58-3.34), with higher hemoglobin A1c levels (AOR, 1.10; 95% CI, 1.02-1.18), and taking more medications (AOR, 1.14; 95% CI, 1.09-1.20) were more likely to use second-generation antidiabetic drugs compared with their counterparts. CONCLUSIONS: The uptake of second-generation antidiabetic medications was 14% among patients with T2D in the United States. Prescription benefit design that targets lower out-of-pocket payments for these newer drugs may improve patient access and clinical outcomes for patients with T2D.

Screening for clinically relevant drug-drug interactions between direct oral anticoagulants and antineoplastic agents: a pharmacovigilance approach.

BACKGROUND: Use of direct oral anticoagulants (DOACs) in patients with cancer remains suboptimal due to the concern regarding potential drug-drug interactions (DDIs) with antineoplastic treatments. However, the clinical relevance of these DDIs is unknown. METHODS: We conducted a pharmacovigilance study of adverse event (AE) reports from the US Food and Drug Administration Adverse Event Reporting System from 1/1/2004 to 12/31/2021. AE reports containing DOACs and antineoplastic agents with CYP3A4/P-gp inhibitory or inducing activity suggested by published pharmacokinetic studies were included (n = 36,066). The outcomes of interest were bleeding or stroke, identified by MedDRA dictionary version 25.0. We used disproportionality analyses (DPA), logistic regression models (LR), and Multi-item Gamma-Poisson Shrinker (MGPS) (Empirical Bayes Geometric Means (EBGM) and 90% credible intervals (90% CIs)) algorithms to identify the safety signal of DDIs. RESULTS: The highest bleeding reporting rates for each drug class were the combination of DOACs with neratinib (39.08%, n = 34), tamoxifen (21.22%, n = 104), irinotecan (20.54%, n = 83), and cyclosporine (19.17%, n = 227). The highest rate of stroke was found for prednisolone (2.43%, n = 113). In the primary analysis, no signal of DDIs by the antineoplastic therapeutic class was detected by MGPS, DPA, and LR approaches. By individual antineoplastic drug, DOACs-neratinib was the only signal detected [EBGM (EB05-EB95) = 2.71 (2.03-3.54)]. CONCLUSION: No signal of DDIs between DOACs and antineoplastic agents was detected, except for DOAC-neratinib. Most DDIs between DOACs and antineoplastic agents may not be clinically relevant. The DDIs between DOACs and neratinib should be further examined in future research.

Population adjusted-indirect comparisons in health technology assessment: A methodological systematic review.

In health technology assessment (HTA), population-adjusted indirect comparisons (PAICs) are increasingly considered to adjust for the difference in the target population between studies. We aim to assess the conduct and reporting of PAICs in recent HTA practice, by performing, a methodological systematic review of studies implementing PAICs from PubMed, EMBASE Classic, Embase/Ovid Medline All, and Cochrane databases from January 1, 2010 to Feb 13, 2023. Four independent researchers screened the titles, abstracts, and full-texts of the identified records, then extracted data on methodological and reporting characteristics of 106 eligible articles. Most PAIC analyses (96.9%, n = 157) were conducted by (or received funding from) pharmaceutical companies. Prior to adjustment, 44.5% of analyses (n = 72) (partially) aligned the eligibility criteria of different studies to enhance the similarity of their target populations. In 37.0% of analyses (n = 60), the clinical and methodological heterogeneity across studies were extensively assessed. In 9.3% of analyses (n = 15), the quality (or bias) of individual studies was evaluated. Among 18 analyses using methods that required an outcome model specification, results of the model fitting procedure were adequately reported in three analyses (16.7%). These findings suggest that the conduct and reporting of PAICs are remarkably heterogeneous and suboptimal in current practice. More recommendations and guidelines on PAICs are thus warranted to enhance the quality of these analyses in the future.

Adverse event reporting of marketed biosimilar and biological monoclonal antibody cancer treatments in the United States.

BACKGROUND: By 8 September 2022, 10 biological monoclonal antibody (mAb) biosimilar products for cancer treatment had been approved and marketed in the United States (US). This study examined adverse event (AE) reporting patterns and disproportionate reporting signals for mAb biosimilars in the US compared to their originator biologics. RESEARCH DESIGN AND METHODS: The US Food and Drug Adverse Event Reporting System database was used to identify AE reports for biological rituximab, bevacizumab, trastuzumab, and their marketed biosimilars. Proportions of patient age, sex and type of reporters of AEs were described for these reports. Reporting odds ratios (RORs) with 95% confidence intervals were calculated to compare reporting disproportionality in serious, death, and specific AEs between mAb biologics/biosimilars (index) and all other drugs. Breslow-Day statistic was used to determine homogeneity in RORs between each mAb biologic-biosimilar pair at p < 0.05. RESULTS: We observed no risk signals of serious or death AE reporting for all three mAb biosimilars. A signal of disproportionate reporting of death was detected between biological and biosimilar bevacizumab (p < 0.05). CONCLUSIONS: Our findings support the similarity in signals of disproportionate AE reporting between mAb originator biologics and biosimilars, except for death between biological and biosimilar bevacizumab.

Novel Enzyme Actions for Sulphated Galactofucan Depolymerisation and a New Engineering Strategy for Molecular Stabilisation of Fucoidan Degrading Enzymes.

Fucoidans from brown macroalgae have beneficial biomedical properties but their use as pharma products requires homogenous oligomeric products. In this study, the action of five recombinant microbial fucoidan degrading enzymes were evaluated on fucoidans from brown macroalgae: Sargassum mcclurei, Fucus evanescens, Fucus vesiculosus, Turbinaria ornata, Saccharina cichorioides, and Undaria pinnatifida. The enzymes included three endo-fucoidanases (EC 3.2.1.-GH 107), FcnA2, Fda1, and Fda2, and two unclassified endo-fucoglucuronomannan lyases, FdlA and FdlB. The oligosaccharide product profiles were assessed by carbohydrate-polyacrylamide gel electrophoresis and size exclusion chromatography. The recombinant enzymes FcnA2, Fda1, and Fda2 were unstable but were stabilised by truncation of the C-terminal end (removing up to 40% of the enzyme sequence). All five enzymes catalysed degradation of fucoidans containing α(1→4)-linked l-fucosyls. Fda2 also degraded S. cichorioides and U. pinnatifida fucoidans that have α(1→3)-linked l-fucosyls in their backbone. In the stabilised form, Fda1 also cleaved α(1→3) bonds. For the first time, we also show that several enzymes catalyse degradation of S. mcclurei galactofucan-fucoidan, known to contain α(1→4) and α(1→3) linked l-fucosyls and galactosyl-ß(1→3) bonds in the backbone. These data enhance our understanding of fucoidan degrading enzymes and their substrate preferences and may assist development of enzyme-assisted production of defined fuco-oligosaccharides from fucoidan substrates.