Real-World Treatment Patterns and Survival Outcomes for Patients with Non-Metastatic Non-Small-Cell Lung Cancer in Sweden: A Nationwide Registry Analysis from the I-O Optimise Initiative.

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide, with ~40-50% of patients diagnosed with non-metastatic disease (stages IA-IIIC). The treatment landscape is evolving rapidly as immunotherapies and targeted therapy are introduced in the non-metastatic setting, creating a need to assess patient outcomes prior to their introduction. This real-world study using Swedish National Lung Cancer Registry data examined outcomes (overall survival (OS) and time to next treatment or death (TTNTD)) and treatment patterns for adults diagnosed with non-metastatic NSCLC. Baseline characteristics and OS from diagnosis were described for all patients; OS, treatment patterns, and TTNTD from treatment start were described for the treatment subgroup (patients diagnosed from 2014 onwards), stratified by disease stage and initial treatment. OS and TTNTD were described using the Kaplan-Meier estimator. The overall population (2008-2019) included 17,433 patients; the treatment subgroup included 5147 patients. Median OS (interquartile range) overall ranged from 83.3 (31.6-165.3) months (stage I patients) to 10.4 (4.3-24.2) months (stage IIIB patients). Among the treatment subgroup, median OS and TTNTD were longest among patients receiving surgery versus other anticancer treatments. These findings provide a baseline upon which to evaluate the epidemiology of non-metastatic NSCLC as newer treatments are introduced.

Changes in primary care management of atrial fibrillation patients following the shift from warfarin to non-vitamin K antagonist oral anticoagulants: a Norwegian population based study.

BACKGROUND: To assess baseline characteristics, drug utilisation and healthcare use for oral anticoagulants (OACs) following the introduction of non-vitamin K antagonist oral anticoagulants among patients with atrial fibrillation in primary care in Norway. METHODS: In this retrospective longitudinal cohort study, 92,936 patients with atrial fibrillation were identified from the Norwegian Primary Care Registry between 2010 and 2018. Linking to the Norwegian Prescription Database, we identified 64,112 patients (69.0%) treated with OACs and 28,824 (31%) who were untreated. Participants were followed until 15 May 2019, death, or loss to follow-up, whichever came first. For each OAC, predictors of initiation were assessed by modelling the probability of initiating the OAC using logistic regression, and predictors of the first switch after index date were assessed using multivariable Cox proportional hazards models. The numbers of primary care visits per quarter by index OAC were plotted and analysed with negative binomial regression analyses offset for the log of days at risk. RESULTS: Patients treated with OACs were older, had more comorbidities, and higher CHA2DS2-VASc scores than untreated patients. However, the mean CHA2DS2-VASc in the non-OAC group was 1.58 for men and 3.13 for women, suggesting an indication for OAC therapy. The percentage of patients with atrial fibrillation initiating OACs increased from 59% in 2010 to 79% in 2018. Non-vitamin K antagonist oral anticoagulant use increased throughout the study period to 95% of new OAC-treated patients in 2018, and switches from warfarin to non-vitamin K antagonist oral anticoagulants were common. The persistence of OAC treatment was > 60% after four years, with greatest persistence for apixaban. Patients treated with non-vitamin K antagonist oral anticoagulants had fewer primary care visits compared with those treated with warfarin (incidence rate ratio: 0.73, 95% confidence interval 0.71 to 0.75). CONCLUSION: In this Norwegian primary care study, we found that the shift from warfarin to non-vitamin K antagonist oral anticoagulants was successful with 95% use in patients initiating OACs in 2018, and associated with fewer general practitioner visits. Persistence with OACs was high, particularly for apixaban. However, many patients eligible for treatment with OACs remained untreated.

Oral Anticoagulation Therapy for Venous Thromboembolism in Norway: Time Trends and Treatment Patterns.

PURPOSE: Data describing treatment patterns of patients with venous thromboembolism (VTE) patients in Scandinavia are scarce. This study sought to address this scarcity by describing demographic and clinical characteristics, trends in the use of oral anticoagulants (OACs), and treatment patterns in patients treated for VTE in Norway between 2013 and 2017. METHODS: Using data from Norway's nationwide registries, a cohort study included patients newly (after 2008) treated OACs who were diagnosed with VTE between January 2013 and December 2017 and were dispensed an OAC (warfarin, apixaban, rivaroxaban, dabigatran, or edoxaban) within 30 days. Patient characteristics and the percentage of patients with VTE who initiated treatment with each OAC for each calendar year were reported. Initial therapy persistence was assessed using Kaplan-Meier curves and compared between the OAC groups using the log-rank test. FINDINGS: The comorbidity burden was similar between patients taking warfarin and those taking apixaban but lower among patients taking rivaroxaban. Direct oral anticoagulant (DOAC) use increased from 33.2% to 93.6% during the study period, whereas warfarin use decreased. Persistence was higher in the apixaban cohort compared with the warfarin cohort, with the difference mostly apparent after 6 months, whereas persistence was similar between the patients taking rivaroxaban and those taking warfarin. IMPLICATIONS: Between 2013 and 2017, DOAC use among patients with VTEs increased markedly in Norway, whereas the use of warfarin decreased. Patients taking apixaban had higher persistence compared with those taking warfarin, whereas patients taking warfarin and those taking rivaroxaban had similar persistence. Further studies with longer follow-up are required to examine the use of extended OAC treatment for VTE.

CHA2DS2-VASc and HAS-BLED risk scores and real-world oral anticoagulant prescribing decisions in atrial fibrillation.

Background: Guidelines indicate that oral anticoagulant (OAC) treatment decisions in atrial fibrillation should be based on a balanced consideration of thromboembolic and bleeding risk. Materials & methods: A retrospective cohort of nonvalvular atrial fibrillation patients were identified. Univariate logistic regression and conditional inference trees were used to quantify the importance of the CHA2DS2-VASc and modified HAS-BLED scores and their individual components on OAC treatment decisions. Results: The individual components of these risk scores provided more distinguishability between treated and untreated patients than the risk scores themselves, with bleeding risk factors strongly associated with nontreatment. Conclusion: While individual components of risk scores drive OAC treatment decisions according to guidelines, the relationship between bleeding risk factors and nontreatment warrants further consideration.

The changing face of venous thromboembolism management in England.

Aim: Venous thromboembolism (VTE), which comprises deep vein thrombosis and pulmonary embolism, poses a global disease burden. Vitamin K antagonists have traditionally been the mainstay of treatment; however, the non-vitamin K oral anticoagulants (NOACs) are emerging as an alternative. The relative use of these treatment classes in the real world is unknown. Patients & methods: We performed a retrospective study using data from the UK Clinical Practice Research Datalink to understand VTE treatment patterns. Results: NOACs have unseated vitamin K antagonist as the main form of VTE patient treatment in England. Conclusion: The data highlight how comfortable physicians have become in using NOACs to treat VTE in England and it is likely that the increasing use of NOACs will continue.

Drug metabolizing enzyme and transporter protein profiles of hepatocytes derived from human embryonic and induced pluripotent stem cells.

Human embryonic and induced pluripotent stem cell-derived hepatocytes (hESC-Hep and hiPSC-Hep) have the potential to provide relevant human in vitro model systems for toxicity testing and drug discovery studies. In this study, the expression and function of important drug metabolizing cytochrome P450 (CYP) enzymes and transporter proteins in hESC-Hep and hiPSC-Hep were compared to cryopreserved human primary hepatocytes (hphep) and HepG2 cells. Overall, CYP activities in hESC-Hep and hiPSC-Hep were much lower than in hphep cultured for 4 h, but CYP1A and 3A activities were comparable to levels in hphep cultured for 48h (CYP1A: 35% and 26% of 48 h hphep, respectively; CYP3A: 80% and 440% of 48 h hphep, respectively). Importantly, in hESC-Hep and hiPSC-Hep, CYP activities were stable or increasing for at least one week in culture which was in contrast to the rapid loss of CYP activities in cultured hphep between 4 and 48 h after plating. With regard to transporters, in hESC-Hep and hiPSC-Hep, pronounced NTCP activity (17% and 29% of 4 h hphep, respectively) and moderate BSEP activity (6% and 8% of 4 h hphep, respectively) were observed. Analyses of mRNA expression and immunocytochemistry supported the observed CYP and transporter activities and showed expression of additional CYPs and transporters. In conclusion, the stable expression and function of CYPs and transporters in hESC-Hep and hiPSC-Hep for at least one week opens up the possibility to reproducibly perform long term and extensive studies, e.g. chronic toxicity testing, in a stem cell-derived hepatic system.

In vitro evaluation of major in vivo drug metabolic pathways using primary human hepatocytes and HepaRG cells in suspension and a dynamic three-dimensional bioreactor system.

Major human specific metabolites, not detected during in vivo and in vitro preclinical studies, may cause unexpected drug interactions and toxicity in human and delays in clinical programs. Thus, reliable preclinical tools for the detection of major human metabolites are of high importance. The aim of this study was to compare major drug metabolic pathways in HepaRG cells, a human hepatoma cell line, to fresh human hepatocytes, cryopreserved human hepatocytes, and human in vivo data. Furthermore, the maintenance of cytochrome P450 (P450) and UDP-glucuronosyltransferase (UGT) activities in a dynamic three-dimensional (3D) bioreactor were evaluated over time by using HepaRG cells and human hepatocytes. (14)C-diclofenac and a candidate from AstraZeneca's drug development program, (14)C-AZD6610, which are metabolized by P450 and UGT in vivo, were used as model substrates. The proportion of relevant biotransformation pathways of the investigated drug was clearly different in the various cell systems. The hydroxylation route was favored in primary human hepatocytes, whereas the glucuronidation route was favored in HepaRG cells. The human in vivo metabolite profile of AZD6610 was best represented by human hepatocytes, whereas all major diclofenac metabolites were detected in HepaRG cells. Moreover, the metabolite profiles in cryopreserved and fresh human hepatocytes were essentially the same. The liver bioreactor using both fresh human hepatocytes and HepaRG cells retained biotransformation capacity over 1 week. Thus, the incubation time can be increased from a few hours in suspension to several days in 3D cultures, which opens up for detection of metabolites from slowly metabolized drugs.

Evaluation of organic anion-transporting polypeptide 1B1 and CYP3A4 activities in primary human hepatocytes and HepaRG cells cultured in a dynamic three-dimensional bioreactor system.

The long-term stability of liver cell functions is a major challenge when studying hepatic drug transport, metabolism, and toxicity in vitro. The aim of the present study was to investigate organic anion-transporting polypeptide (OATP) 1B1 and CYP3A4 activities in fresh primary human hepatocytes and differentiated cryopreserved HepaRG cells when cultured in a three-dimensional (3D) bioreactor system. OATP1B1 activity was determined by loss from media experiments of [(3)H]estradiol-17ß-D-glucuronide and atorvastatin acid (ATA) for up to 7 days in culture. ATA metabolite formation was determined at days 3 to 4 to evaluate CYP3A4 activity. Overall, the results showed that freshly isolated human hepatocytes inoculated in the bioreactor retained OATP1B1 activity for at least 7 days, whereas in HepaRG cells no OATP1B1 activity was observed beyond day 2. The activity data were in agreement with immunohistochemical stainings, which showed that OATP1B1 protein expression was preserved for at least 9 days in fresh human hepatocytes, whereas OATP1B1 was expressed markedly lower in HepaRG cells after 9 days in culture. Fresh human hepatocytes and HepaRG cells exhibited similar CYP3A4 activity in bioreactor culture, and immunohistochemical stainings supported these findings. Activity and mRNA expression of OATP1B1 and CYP3A4 in primary human hepatocytes compared with HepaRG cells in fresh suspensions were in agreement with data obtained in bioreactor culture. In conclusion, freshly isolated human hepatocytes cultured in a 3D bioreactor system preserve both OATP1B1 and CYP3A4 activities, allowing long-term in vitro studies on drug disposition and toxicity.

OATP1B1/1B3 activity in plated primary human hepatocytes over time in culture.

Primary human hepatocytes are widely used as an in vitro model for evaluation of drug metabolism and transport. However, it has been shown that the gene expression of many drug-metabolizing enzymes and transporters change in culture. The aim of the present study was to evaluate the activity of organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3) in plated primary human hepatocytes over time in culture. The uptake kinetics of the OATP1B1/1B3 substrate [(3)H]-estradiol-17ß-d-glucuronide was determined in cells from five donors. An extensive and variable decrease in OATP1B1/1B3 activity and/or increase in passive diffusion was observed over time. Already after 6h in culture, the OATP1B1/1B3 activity was not possible to determine in liver cells from one donor, while after 24h, the uptake activity was not measurable in one additional donor. In the other three, the decrease in CL(int) (V(max)/K(m)) values ranged from 15% to 86% after 24h in culture compared to the values measured at 2h. Visual examination of OATP1B1 protein expression by confocal microscopy showed localization to the plasma membrane as expected, and an extensive decrease in OATP1B1 expression over time in culture supported the decline in activity. The significant reduction in SLCO1B1 and SLCO1B3 gene expression over time determined by RT-PCR also supported the loss of OATP1B1/1B3 activity. In conclusion, plated primary human hepatocytes are useful as an in vitro model for OATP1B1/1B3-mediated uptake studies, but the culture time may substantially change the uptake kinetics.