Search

We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2− advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45–78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p =.002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24–2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04–1.37). The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression. [ABSTRACT FROM AUTHOR]

Background: It is crucial that the safety profiles of biosimilars are similar to those of the original biologics. A better understanding of biosimilars and their relative safety and immunogenicity profiles are required for healthcare providers to prescribe them to patients with life-threatening cancer diseases who receive chemotherapies with potentially serious adverse events (AEs). Objectives: The purpose of this study was to collate and analyze currently available safety and immunogenicity outcomes of biosimilars used in oncology and compare their safety information with those of the original biologics. Methods: The MEDLINE and Cochrane Library databases were searched as at 28 February 2022. Four anti-cancer biosimilar molecules were considered: bevacizumab, trastuzumab, rituximab, and (peg)filgrastim. Through a systematic review, we selected the randomized controlled trials (RCTs) comparing safety outcomes between the biosimilars and original biologics of the four molecules. As safety outcomes, various treatment-emergent adverse events (TEAEs) were collated, such as any TEAE, serious AE, and TEAE higher than grade 3. A risk ratio (RR) per category of TEAE was estimated through a meta-analysis. A network meta-analysis (NMA) was also conducted to compare the safety among the biosimilar brands for TEAEs over 25% with higher variability in addition to the serious AE cases. Results: Forty-nine RCTs were identified. The results from the meta-analysis showed that the safety and immunogenicity profiles of all four biosimilar molecules are comparable with that of the original biologics at the TEAE level without statistically significant differences, except for diarrhea for (peg)filgrastim. The incidence of diarrhea with (peg)filgrastim was less than that with the original biologic (RR 0.66, 95% confidence interval 0.50–0.89). The NMA results showed similar safety profiles among the biosimilar brands for all four biosimilar molecules, except for the serious adverse event of a trastuzumab biosimilar (RR 0.296, 95% credible interval 0.109–0.840). Conclusion: The meta-analysis and NMA for all four biosimilars showed that the safety and immunogenicity profiles of biosimilar products in oncology are generally comparable with that of the original biologics at the TEAE level. However, additional evidence needs to be collected since several TEAEs of specific biosimilars were out of the equivalent range. The results of this study provide comparative safety information and a better understanding of oncology biosimilars for healthcare providers to prescribe them to patients. [ABSTRACT FROM AUTHOR]

Purpose: There is a lack of real‐world data in Asian populations for brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non‐small cell lung cancer (NSCLC). This study analysed real‐world outcomes and dosing patterns for brigatinib in patients with crizotinib‐refractory ALK+ NSCLC in South Korea. Methods: This retrospective, non‐interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. Results: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3–48) months. Median follow‐up after brigatinib initiation was 18 (range 0–34) months. Overall, 88.5% of patients received full‐dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2–not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2‐year OS rate was 68.7%. Conclusions: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real‐world clinical benefit as second‐line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea. [ABSTRACT FROM AUTHOR]

Background: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon. Objectives: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective. Methods: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness. Results: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness. Conclusions: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care. [ABSTRACT FROM AUTHOR]

Purpose Although asthma exacerbation comprises a large burden of the total asthma-related costs, few studies have examined the frequency and cost of acute exacerbation according to asthma severity. This study investigated asthma-related health care utilization and costs according to the severity of asthma. Methods We conducted a descriptive study using the national health insurance claims database between January 1 and December 31, 2014. We included adult patients with asthma (18 years of age and older) who had ≥2 claims with for an asthma diagnosis and were prescribed ≥1 asthma medications. They were classified into 3 asthma severity levels (level 1 = mild, level 2 = moderate, and level 3 = severe), based on individual medication prescriptions. Acute exacerbation was defined as having a corticosteroid burst, an emergency department visit, or hospitalization. Health care utilization, acute exacerbation, and direct costs associated with asthma were compared according to asthma severity levels. Findings Of the 36,687 adult asthma patients, level 1 had the largest proportion of patients (81.2%), followed by level 2 (18.2%), and level 3 (0.6%). The average number of asthma-related outpatient visits was 4.5 for level 1, 7.2 for level 2, and 11.9 for level 3 ( P < 0.01). The estimated asthma-related direct cost per patient was $174 for level 1, $634 for level 2, and $1635 for level 3 ( P < 0.01). The number of patients who experienced acute exacerbation increased as asthma severity increased: level 1, 22.6%; level 2, 26.0%; and level 3, 48.7% ( P < 0.01). Direct costs associated with asthma exacerbation dramatically increased and accounted for 15.1% of the total cost in level 1 patients, 19.5% in level 2 patients, and 40.8% in level 3 patients ( P < 0.01). Implications The direct costs of acute exacerbation increased as asthma severity increased. In patients with severe asthma, acute exacerbation and the relative cost ratio in South Korea were higher than those in other countries. Proper management is required to avoid acute exacerbations and to reduce the burden of asthma, particularly in patients with severe asthma. [ABSTRACT FROM AUTHOR]

Background & Aims: The cost‐effectiveness to screen hepatic fibrosis in at‐risk population as recommended by several professional societies has been limited. This study aimed to investigate the cost‐effectiveness of this screening strategy in the expanded at‐risk population recently proposed by several societies. Methods: A combined model of the decision tree and Markov models was developed to compare expected costs, quality‐adjusted life‐years (QALYs) and incremental cost‐effectiveness ratio (ICER) between screening and no screening groups. The model included liver disease‐related health states and cardiovascular disease (CVD) states as a base‐case analysis. Screening strategy consisted of fibrosis‐4 index (FIB‐4) followed by vibration‐controlled transient elastography (VCTE) and intensive lifestyle intervention (ILI) as a treatment for diagnosed patients. Results: Cost‐effectiveness analysis showed that screening the at‐risk population entailed $298 incremental costs and an additional 0.0199 QALY per patient compared to no screening (ICER $14 949/QALY). Screening was cost‐effective based on the implicit ICER threshold of $25 000/QALY in Korea. When the effects of ILI on CVD and extrahepatic malignancy were incorporated into the cost‐effectiveness model, the ICER decreased by 0.85 times from the base‐case analysis (ICER $12 749/QALY). In contrast, when only the effects of liver disease were considered in the model, excluding cardiovascular disease effects, ICER increased from the baseline case analysis to $16 305. Even when replacing with medical costs in Japan and U.S., it remained cost‐effective with the estimate below the countries' ICER threshold. Conclusions: Our study provides compelling evidence supporting the cost‐effectiveness of FIB‐4‐based screening the at‐risk population for advanced hepatic fibrosis. [ABSTRACT FROM AUTHOR]

The paper gives an overview of the current status of the methods and methodologies which are in use for the evaluation of the structural response induced by sloshing impacts. First the overall problem (seakeeping, sloshing, impacts, statistics…) is discussed and then the accent is put on the modeling of hydro-structure interactions which occur during the severe sloshing impacts in the tanks of the Liquefied Natural Gas (LNG) Carriers of membrane type. The main conclusion is that the sloshing assessment procedures are still under investigations and there are still no fully satisfactory methods and methodologies available to solve the problem fully consistently within the so called direct calculation approach. That is why, for the time being, a relatively simplified procedures are used in practice. [ABSTRACT FROM AUTHOR]

Background: We aimed to examine whether patients with de novo and relapsed/progressed stage IIIB–IV non-small cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations have different prognoses. Methods: This retrospective study analyzed the Health Insurance Review and Assessment claims data in South Korea from 2013 to 2020. Patients with stage IIIB–IV NSCLC without EGFR or ALK mutations who received first-line palliative therapy between 2015 and 2019 were identified. Overall survival (OS), time to first subsequent therapy (TFST), and time to second subsequent therapy (TSST) were estimated using the Kaplan–Meier method. Multivariate Cox regression analysis was used to reveal the impact of de novo versus relapsed/progressed disease on OS. Treatment patterns, including treatment sequence, top five most frequent regimens, and time to treatment discontinuation, were described in both groups. Results: Of 14,505 patients, 12,811 (88.3%) were de novo, and 1,694 (11.7%) were relapsed/progressed. The median OS in the de novo group was 11.0 versus 11.5 months in the relapsed/progressed group (P = 0.002). The ongoing treatment probability was higher in relapsed/progressed patients than in de novo patients from 6.4 months since the initiation of first-line treatment (P < 0.001). Median TSST was shorter in the de novo group than in the relapsed/progressed group (9.5 vs. 9.9 months, P < 0.001). In multivariate analysis, de novo disease was associated with shorter OS (hazard ratio 1.07; 95% confidence interval 1.01–1.14). The overall treatment patterns for de novo and relapsed/progressed patients were similar. Conclusions: De novo patients had poorer OS and TSST after the initiation of palliative therapy than relapsed/progressed patients. These findings suggest that the stage of the disease at the time of initial diagnosis should be considered in observational studies and clinical trials as a prognostic factor. [ABSTRACT FROM AUTHOR]

Post-transplant infections are associated with high mortality rates. This retrospective nationwide cohort study examined the incidence and risk factors of infections requiring hospitalization after heart transplantation and the associated economic burden. The entire heart transplant recipients' data from the Korean Health Insurance Review and Assessment Service between 2013 and 2020 was used. We estimated the annual incidence of post-transplant infections and adjusted incidence rate ratios (aIRR) of risk factors for reported infections using the poisson generalized linear model. Among 1,030 heart transplant recipients (324 with and 706 without post-transplant infections), 0.45 post-transplant infections were reported annually, with respiratory tract infections constituting the highest proportion (0.16). The risk of post-transplant infections was high in recipients with renal failure (aIRR = 1.35; 95% confidence interval [CI], 1.05–1.75) or nosocomial infection (aIRR = 1.47; 95% CI, 1.15–1.87). Combination regimens, including mammalian target of rapamycin inhibitor (mTORi), did not differ significantly from the standard 3 drug regimen (aIRR = 1.16; 95% CI, 0.80–1.67). The risk of death was higher among recipients with post-transplant infections than in uninfected recipients (adjusted hazard ratio = 4.59; 95% CI, 2.19–9.65). The mean follow-up cost per patient per month was 2-fold higher in recipients with post-transplant infections than in uninfected recipients ($5,096 and $2,532, respectively; p <.001). mTORi combination, which reportedly maintains renal function, can be considered, as it does not increase the infection risk. Post-transplant infections present clinical and economic burdens, warranting careful observation of at-risk patients. [ABSTRACT FROM AUTHOR]

Background: Transthyretin cardiac amyloidosis, also known as transthyretin cardiomyopathy (ATTR-CM) is a poorly-recognized disease with delayed diagnosis and poor prognosis. This nationwide population-based study aimed to identify disease manifestations, economic burden, and mortality of patients with ATTR-CM.Methods: Data of newly diagnosed patients with ATTR-CM between 2013 and 2018 from the Korean National Health Insurance Service were used, covering the entire population. Patient characteristics included comorbidities, medical procedures, and medication. Healthcare resource utilization and medical costs were observed as measures of the economic burden. The Kaplan-Meier survival curve and years of potential life lost (YPLL) from the general population were estimated for disease burden with ATTR CM.Results: A total of 175 newly diagnosed patients with ATTR-CM were identified. The most common cardiac manifestation was hypertension (51.3%), while the most common non-cardiac manifestation was musculoskeletal disease (68.0%). Mean medical costs at the post-cohort entry date were significantly higher than those at the pre-cohort entry date ($1,864 vs. $400 per patient per month (PPPM), p < 0.001). Of the total medical costs during the study period, the proportion of inpatients cost was 12.9 times higher than the outpatients cost ($1,730 and $134 PPPM, respectively). The median survival time was 3.53 years from the first diagnosis of ATTR-CM, and the mean (SD) YPLL was 13.0 (7.7).Conclusions: Patients with ATTR-CM had short survival and high medical costs. To reduce the clinical and economic burdens, carefully examining manifestations of disease in patients can help with early diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Few studies assessed the association between major adverse cardiovascular events and adherence to warfarin and direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF). Therefore, we aimed to evaluate the effects of adherence to oral anticoagulants (OACs) in patients with AF using claims data (July 2014–April 2019). Using the initial 3-month medication possession rate (MPR), patients were categorized into adherent (MPR ≥ 0.8) or non-adherent (MPR < 0.8) groups. Propensity score matching of non-adherent group to adherent group was conducted for warfarin (1:1) and DOAC (1:3), respectively. Incidence of ischemic stroke, myocardial infarction (MI), intracranial hemorrhage, and all-cause death was assessed in the matched cohort (67,147 patients). The hazard ratio (HR) for adherence to OAC was estimated using the Cox proportional hazard model with adjusting covariate including age and sex. The risk for ischemic stroke, MI, and all-cause death was lower in the DOAC adherent group than in the DOAC non-adherent group (HR: 0.78; 95% confidence intervals: 0.73–0.84; 0.75, 0.60–0.94; 0.54, 0.51–0.57, respectively). Adherence to OAC was not associated with the risk of intracranial hemorrhage (1.01, 0.85–1.20). Commitment programs to improve adherence in patients with AF could maximize drug effectiveness and safety. [ABSTRACT FROM AUTHOR]

Asides from the influence of incoming waves, ships can experience steady motions, such as rigid-body sinkage and trim motions, and flexible-body vertical bending motions, due to a constant forward speed even under calm water conditions. In this paper, a novel approach to analyze steady-ship hydroelasticity, particularly for the steady-ship motions and surrounding steady-wave disturbances, is proposed using a three-dimensional (3D) direct coupling method, based on a higher-order boundary element method (HOBEM) and a higher-order shell finite element method (FEM). Within the linearized framework, a solution method is proposed based on a two-step procedure, using two types of Neumann–Kelvin (NK) linear flow models for the fluid part and a virtual work equilibrium equation for the structural part. The first step is to compute a mean position wave-resistance problem using the modified NK equation, the second step is to solve a perturbed position wave-resistance problem, by employing a classical NK model and a virtual work equation based on the first step's solution. Detailed mathematical formulation and numerical procedures are described, and a few numerical results are illustrated. These include both rigid and flexible steady-ship motions, Von-Mises stress distributions, and wave-resistance coefficients for Froude numbers ranging from 0.15 to 0.5. Furthermore, the numerical results obtained using the present direct coupling method and a modal-based one are compared. [ABSTRACT FROM AUTHOR]

Aims: We aimed to assess treatment persistence of tumor necrosis factor (TNF) inhibitors and non-TNF inhibitors in two groups of rheumatoid arthritis (RA) patients: biologic disease-modifying antirheumatic drug (bDMARD) initiators and switchers.Patients and methods: This retrospective cohort study utilized a national health insurance claims database. Patients aged ≥18 years initiating/switching bDMARD between 1 December 2013 and 31 December 2014, the index period, were followed for 12 months. Initiators who began treatment with a bDMARD during the index period were defined as having no bDMARD prescriptions for the previous year. Switchers who changed treatment from the previous bDMARD to the index bDMARD were defined as having different bDMARDs during the index period. Treatment persistence rates during the follow-up period were measured, and factors associated with non-persistence were assessed with the Cox proportional hazard model.Results: Of 2684 patients, treatment persistence rates were the highest for abatacept in initiators (69.3%) and tocilizumab in switchers (77.0%), while adalimumab showed the lowest persistence rates for both initiators and switchers (48.2%, 28.8%), followed by etanercept (51.3%, 41.0%). Adalimumab and etanercept were significantly more likely to show non-persistence (HR 1.58, 95% CI 1.27-1.96; HR 1.42, 95% CI 1.14-1.76) compared to infliximab for initiators, while tocilizumab was significantly more likely to show persistence (HR 0.411, 95% CI 0.206-0.819) in switchers.Conclusions: Non-TNF inhibitors showed higher persistence rates than TNF inhibitors in South Korean RA patients, and tocilizumab especially was associated with higher persistence in patients with inadequate response to TNF inhibitors. Good persistence with non-TNF inhibitors indicates the potential for long-term efficacy as first-line treatment. [ABSTRACT FROM AUTHOR]

An experimental study was performed on the piston- and sloshing-mode moonpool resonances of offshore structures. Two different geometries were considered to investigate the flow characteristics in a plain moonpool and a moonpool with a cofferdam. To examine the efficiency of a cofferdam for reducing the flow in a moonpool, three cofferdam geometries were tested. The plain moonpool presented violent flows as a result of the piston- and sloshing-mode resonances. However, the moonpool with the cofferdam introduced violent sloshing waves instead of the ascent and descent of the water column in the piston-mode moonpool resonance. Among three different cofferdam geometries, the model with a right triangle facing to the left on the top of the cofferdam was most effective in reducing the flow in the moonpool when compared with the other models. [ABSTRACT FROM AUTHOR]

Purpose: The benefit-risk balance for drugs can alter post approval owing to additional data on efficacy or adverse events. This study developed a quantitative benefit-risk assessment (BRA) model for statins using multicriteria decision analysis with discrete choice experiments and compared a recent BRA with that at the time of approval.Patients and Methods: Following a systematic review of the literature, the benefit criteria within the statin BRA model were defined as a reduction in the plasma low-density lipoprotein cholesterol level and a reduction in myocardial infarction incidence; the risk criteria were hepatotoxicity (Liv) and fatal rhabdomyolysis (Rha). The scores for these criteria were estimated using mixed treatment comparison methods. Weighting was calculated from a discrete choice experiment involving 203 Korean patients. The scores and weights were integrated to produce an overall value representing the benefit-risk balance, and sensitivity analyses were conducted.Results: In this BRA model, low-density lipoprotein (relative importance [RI]: 37.50%) was found to be a more important benefit criterion than myocardial infarction (RI: 35.43%), and Liv (RI: 16.28%) was a more important risk criterion than Rha (RI: 10.79%). Patients preferred atorvastatin, and the preference ranking of cerivastatin and simvastatin was switched post approval because of the emergence of additional risk information related to cerivastatin.Conclusion: A quantitative statin BRA model confirmed that the preference ranking of statins changed post approval because of the identification of additional benefits or risks. [ABSTRACT FROM AUTHOR]

Highlights: [•] We synthesized self-healable polyurethane (SPU)/modified graphene (MG) nanocomposites. [•] MG gave dual effects of reinforcing filler and light absorption medium. [•] SPU/MG nanocomposite showed significantly enhanced Young’s modulus and NIR absorption. [•] NIR absorbed by MG is dissipated into heat and actuate self healing. [Copyright &y& Elsevier]

Observability properties of errors in an integrated navigation system are studied with a control-theoretic approach in this paper. A navigation system with a low-grade inertial measurement unit and an accurate single-antenna Global Positioning System (GPS) measurement system is considered for observability analysis. Uncertainties in attitude, gyro bias, and GPS antenna Lever arm were shown to determine unobservable errors in the position, veIocity, and accelerometer bias. It was proved that all the errors can be made observable by maneuvering. Acceleration changes improve the estimates of attitude and gyro bias. Changes in angular velocity enhance the lever arm estimate. However, both the motions of translation and constant angular velocity have no influence on the estimation of the lever arm. A covariance simulation with an extended Kalman filter was performed to confirm the observability analysis. [ABSTRACT FROM AUTHOR]