Low Molecular Weight Heparin Treatment Patterns and Outcomes in Cancer Patients with Acute Venous Thromboembolism: A Nationwide Cohort Study in France.

Patients with cancer have an increased risk of developing venous thromboembolism (VTE) and an increased risk of death from VTE. Until recently, the standard of care for treatment of VTE in cancer patients was low molecular weight heparins (LMWH). To determine treatment patterns and outcomes, we performed an observational study using a nationwide health database. Treatment patterns, rates of bleeding, and VTE recurrence at 6 and 12 months were assessed in cancer patients with VTE in France prescribed LMWH in 2013-2018. Of 31,771 patients administered LMWH (mean age 66.3 years), 51.0% were male, 58.7% had pulmonary embolism, and 70.9% had metastatic disease. At 6 months LMWH persistence was 81.6%, VTE recurrence had occurred in 1256 patients (4.0%) at a crude rate per 100 person-months (PM) of 0.90, and bleeding had occurred in 1124 patients (3.5%) at a crude rate per 100 PM of 0.81. At 12 months, VTE recurrence had occurred in 1546 patients (4.9%) at a crude rate per 100 PM of 0.71 and bleeding had occurred in 1438 patients (4.5%) at a crude rate per 100 PM of 0.66. Overall, VTE-related clinical event rates were high among patients administered LMWH, suggesting an unmet medical need.

Cost-effectiveness of targeted screening for non-valvular atrial fibrillation in the United Kingdom in older patients using digital approaches.

AIM: Screening for non-valvular atrial fibrillation (NVAF) is key in identifying patients with undiagnosed disease who may be eligible for anticoagulation therapy. Understanding the economic value of screening is necessary to assess optimal strategies for payers and healthcare systems. We evaluated the cost effectiveness of opportunistic screening with handheld digital devices and pulse palpation, as well as targeted screening predictive algorithms for UK patients ≥75 years of age. METHODS: A previously developed Markov cohort model was adapted to evaluate clinical and economic outcomes of opportunistic screening including pulse palpation, Zenicor (extended 14 days), KardiaMobile (extended), and two algorithms compared to no screening. Key model inputs including epidemiology estimates, screening effectiveness, and risks for medical events were derived from the STROKESTOP, ARISTOTLE studies, and published literature, and cost inputs were obtained from a UK national cost database. Health and cost outcomes, annually discounted at 3.5%, were reported for a cohort of 10,000 patients vs. no screening over a time horizon equivalent to a patient's lifetime, Analyses were performed from a UK National Health Services and personal social services perspective. RESULTS: Zenicor, pulse palpation, and KardiaMobile were dominant (providing better health outcomes at lower costs) vs. no screening; both algorithms were cost-effective vs. no screening, with incremental cost-effectiveness ratios per quality-adjusted life-year (QALY) of £1,040 and £1,166. Zenicor, pulse palpation, and KardiaMobile remained dominant options vs. no screening in all scenarios explored. Deterministic sensitivity analyses indicated long-term stroke care costs, prevalence of undiagnosed NVAF in patients 75-79 years of age, and clinical efficacy of anticoagulant on stroke prevention were the main drivers of the cost-effectiveness results. CONCLUSIONS: Screening for NVAF at ≥75 years of age could result in fewer NVAF-related strokes. NVAF screening is cost-effective and may be cost-saving depending on the program chosen.

Performance of an electronic health record-based predictive model to identify patients with atrial fibrillation across countries.

BACKGROUND: Atrial fibrillation (AF) burden on patients and healthcare systems warrants innovative strategies for screening asymptomatic individuals. OBJECTIVE: We sought to externally validate a predictive model originally developed in a German population to detect unidentified incident AF utilising real-world primary healthcare databases from countries in Europe and Australia. METHODS: This retrospective cohort study used anonymized, longitudinal patient data from 5 country-level primary care databases, including Australia, Belgium, France, Germany, and the UK. The study eligibility included adult patients (≥45 years) with either an AF diagnosis (cases) or no diagnosis (controls) who had continuous enrolment in the respective database prior to the study period. Logistic regression was fitted to a binary response (yes/no) for AF diagnosis using pre-determined risk factors. RESULTS: AF patients were from Germany (n = 63,562), the UK (n = 42,652), France (n = 7,213), Australia (n = 2,753), and Belgium (n = 1,371). Cases were more likely to have hypertension or other cardiac conditions than controls in all validation datasets compared to the model development data. The area under the receiver operating characteristic (ROC) curve in the validation datasets ranged from 0.79 (Belgium) to 0.84 (Germany), comparable to the German study model, which had an area under the curve of 0.83. Most validation sets reported similar specificity at approximately 80% sensitivity, ranging from 67% (France) to 71% (United Kingdom). The positive predictive value (PPV) ranged from 2% (Belgium) to 16% (Germany), and the number needed to be screened was 50 in Belgium and 6 in Germany. The prevalence of AF varied widely between these datasets, which may be related to different coding practices. Low prevalence affected PPV, but not sensitivity, specificity, and ROC curves. CONCLUSIONS: AF risk prediction algorithms offer targeted ways to identify patients using electronic health records, which could improve screening number and the cost-effectiveness of AF screening if implemented in clinical practice.

Comparative Analysis of All-Cause Health Care Resource Utilization and Costs Among Venous Thrombosis Patients Without Cancer Prescribed Apixaban or VKAs in France.

INTRODUCTION: The direct oral anticoagulant (DOAC) apixaban has shown to have non-inferior efficacy and better safety than vitamin K antagonists (VKAs) in patients with venous thromboembolism (VTE). We determined whether healthcare resource use (HCRU) and direct all-cause medical and non-medical costs in patients with VTE in France differed between VKAs and apixaban. METHODS: A retrospective cohort study was conducted using French national health data from January 2013-June 2018 for anticoagulant-naïve adults hospitalized with VTE. All-cause costs and HCRU per patient per month (PPPM) were compared between apixaban and VKA cohorts created by 1:1 propensity score matching. Two-part models with bootstrapping were used to calculate marginal effects for costs and HCRU. RESULTS: The matched VKA and apixaban cohorts each comprised 7503 patients. Compared to VKAs, patients prescribed apixaban had significantly lower (P < 0.0001) mean all-cause costs PPPM for outpatient visits (€438.54 vs. €455.58), overall laboratory tests (€21.26 vs. €83.73), and hospitalizations (€249.48 vs. €343.82), but significantly higher (P < 0.0001) mean all-cause costs PPPM for overall drugs (€97.06 vs. €69.56) and medical procedures (€42.12 vs. €35.50). Mean total all-cause direct medical costs (€687.93 vs. €798.70) and total all-cause direct medical and non-medical costs (€771.60 vs. €883.66) were significantly lower (P < 0.0001) for apixaban. Mean HCRU PPPM showed similar trends. Subgroup analyses showed that, among patients with recurrent VTE, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€17.26 vs. €18.12) and total all-cause direct medical and non-medical costs (€18.37 vs. €19.20) than patients prescribed VKAs. Similarly, among patients with bleeding, patients prescribed apixaban had significantly lower (P < 0.0001) all-cause costs PPPM for total medical costs (€15.34 vs. €32.61) and total all-cause direct medical and non-medical costs (€16.23 vs. €34.63) than patients prescribed VKAs. CONCLUSION: Compared to VKAs, apixaban may be cost-saving in the treatment of patients hospitalized for acute VTE.

Effectiveness and Safety of Oral Anticoagulants in the Treatment of Acute Venous Thromboembolism: A Nationwide Comparative Cohort Study in France.

INTRODUCTION: Data from clinical trials indicate that direct oral anticoagulants (DOACs) are noninferior and safer than conventional therapy (low-molecular-weight heparin followed by a vitamin K antagonist [VKA]) for treating venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism (PE). This study compared the effectiveness and safety of DOACs and conventional therapy in a real-world setting. METHODS: This observational study used French national claims data of adult, treatment-naïve patients diagnosed with VTE (majority PE) who were hospitalized and treated for VTE with a DOAC (apixaban or rivaroxaban) or VKAs during 2013 to 2018. Patients with active cancer were excluded. After propensity score matching for each DOAC-VKA comparison, risks of bleeding, recurrent VTE, and all-cause mortality were compared at 6 months. Cox proportional hazards regression was used to estimate adjusted hazard ratios of the endpoints. RESULTS: A total of 58,137 patients were included (10,775 VKAs, 10,440 apixaban, 36,922 rivaroxaban). Propensity score-matched cohort sizes were 7,503 for apixaban and 9,179 for rivaroxaban. The hazard ratio (95% confidence interval) was significantly lower for apixaban than VKAs for bleeding requiring hospitalization (0.43 [0.32-0.59]), all-cause death (0.61 [0.51-0.74]), and first recurrent VTE (0.67 [0.52-0.85]). The hazard ratio was also significantly lower for rivaroxaban than VKAs for all-cause death (0.63 [0.53-0.74]) but not for bleeding requiring hospitalization (0.86 [0.69-1.07]) or first recurrent VTE (0.91 [0.74-1.13]). CONCLUSION: Apixaban was associated with superior safety and effectiveness than VKAs. All-cause mortality was lower in both DOACs than VKAs. Our results support recommendations to use DOACs over VKAs for the treatment of VTE.

Comparing cure rates for gemtuzumab ozogamicin plus standard chemotherapy vs standard chemotherapy alone in acute myeloid leukemia patients.

Aim: Assess the suitability of standard parametric, piecewise and mixture cure models (MCMs) for modeling long-term survival of acute myeloid leukemia patients achieving remission following treatment with gemtuzumab ozogamicin (GO) + standard chemotherapy (SC) or SC alone. MCMs can model survival data comprising of statistically cured (patients in long-term remission) and uncured patients. Materials & methods: Models were fit to patient-level data corresponding to individual treatment arms. Results: Visual inspection showed that MCMs fit the clinical data best. Survival modeling with MCMs showed that treatment with GO + SC versus SC alone results in higher statistical cure rates for event-free survival (rates: 26-35% vs 21-23%) and overall survival (rates: 48-52% vs 38-44%). Conclusion: MCMs are well suited to modeling long-term survival in acute myeloid leukemia patients. Clinical trial registration: NCT00927498 (ClinicalTrials.gov).

Lay abstract To assess the effectiveness of acute myeloid leukemia (AML) treatments, researchers use statistical models to estimate the survival rate of patients who receive a particular treatment. Some patients receiving certain AML treatments can achieve long-term remission and are often considered 'cured'. Standard statistical models cannot differentiate between cured and uncured patients and so tend to underestimate the survival rates of cured patients. Mixture cure models (MCMs) can account separately for the survival of cured versus uncured patients. We tested MCMs and standard statistical models using data from a clinical trial comparing gemtuzumab ozogamicin (GO) + standard chemotherapy against standard chemotherapy alone in AML patients. Of all the models tested, MCMs generated survival extrapolations over time that most closely resembled the data from the clinical trial. Through our analyses, we demonstrated that GO + standard chemotherapy can result in higher survival rates than standard chemotherapy alone.

Real-world persistence to direct oral anticoagulants in patients with atrial fibrillation: a systematic review and network meta-analysis.

OBJECTIVE: To conduct a systematic review and network meta-analysis of real-world evidence comparing adherence, persistence, cost, and utilization between oral anticoagulant (OAC) in non-valvular atrial fibrillation (NVAF) patients. METHODS: A systematic search of MEDLINE and Embase (inception-July 2019) was conducted for published observational cohort studies comparing outcomes between ≥2 OACs. A network meta-analysis was performed to estimate odds ratios for non-persistence using a random-effects model. RESULTS: There were 80 studies evaluating the outcomes of interest. However, due to a paucity in adherence studies and heterogeneity in adherence, cost, and utilization definitions, persistence was the focus of this network meta-analysis. There were 36 studies evaluating non-persistence in 395,593 participants, 24 of which used 3 gap definitions (30-, 60-, and 90-days); 18 unique studies evaluating non-persistence at 12 months were included in the network meta-analysis. Using 30- and 90-day gaps, all NOACs, when compared with VKAs, had lower odds of non-persistence (30-day OR (95%CI): apixaban: 0.63 (0.58, 0.69); rivaroxaban: 0.69 (0.62, 0.76); dabigatran: 0.89 (0.82, 0.97); 90-day OR (95%CI): apixaban: 0.33 (0.22, 0.47); rivaroxaban: 0.47 (0.36, 0.61); dabigatran 0.61 (0.44, 0.85)). When using a 60-day gap, dabigatran had higher odds of non-persistence vs VKAs (OR: 1.35; 95%CI: 1.12, 1.61), but there were no significant differences for apixaban and rivaroxaban. Apixaban had the lowest probability of non-persistence across the 3-gap definitions (95.7% with 30-day gap, 76.9% with 60-day gap, 98.4% with 90-day gap). CONCLUSIONS: The current findings, despite multiple limitations, can raise awareness and understanding of real-world persistence associated with OAC therapy in NVAF patients.

Living with Ulcerative Colitis Study (LUCY) in England: a retrospective study evaluating healthcare resource utilisation and direct healthcare costs of postoperative care in ulcerative colitis.

OBJECTIVE: Ulcerative colitis (UC) is a lifelong, relapsing-remitting disease. Patients non-responsive to pharmacological treatment may require a colectomy. We estimated pre-colectomy and post-colectomy healthcare resource utilisation (HCRU) and costs in England. DESIGN/METHOD: A retrospective, longitudinal cohort study indexing adult patients with UC undergoing colectomy (2009-2015), using linked Clinical Practice Research Datalink/Hospital Episode Statistics data, was conducted. HCRU, healthcare costs and pharmacological treatments were evaluated during 12 months prior to and including colectomy (baseline) and 24 months post-colectomy (follow-up; F-U), comparing baseline/F-U, emergency/elective colectomy and subtotal/full colectomy using descriptive statistics and paired/unpaired tests. RESULTS: 249 patients from 26 165 identified were analysed including 145 (58%) elective and 184 (74%) full colectomies. Number/cost of general practitioner consultations increased post-colectomy (p<0.001), and then decreased at 13-24 months (p<0.05). From baseline to F-U, the number of outpatient visits, number/cost of hospitalisations and total direct healthcare costs decreased (all p<0.01). Postoperative HCRU was similar between elective and emergency colectomies, except for the costs of colectomy-related hospitalisations and medication, which were lower in the elective group (p<0.05). Postoperative costs were higher for subtotal versus full colectomies (p<0.001). At 1-12 month F-U, 30%, 19% and 5% of patients received aminosalicylates, steroids and immunosuppressants, respectively. CONCLUSION: HCRU/costs increased for primary care in the first year post-colectomy but decreased for secondary care, and varied according to the colectomy type. Ongoing and potentially unnecessary pharmacological therapy was seen in up to 30% of patients. These findings can inform patients and decision-makers of potential benefits and burdens of colectomy in UC.

Cost-effectiveness of targeted screening for the identification of patients with atrial fibrillation: evaluation of a machine learning risk prediction algorithm.

Aims: As many cases of atrial fibrillation (AF) are asymptomatic, patients often remain undiagnosed until complications (e.g. stroke) manifest. Risk-prediction algorithms may help to efficiently identify people with undiagnosed AF. However, the cost-effectiveness of targeted screening remains uncertain. This study aimed to assess the cost-effectiveness of targeted screening, informed by a machine learning (ML) risk prediction algorithm, to identify patients with AF.Methods: Cost-effectiveness analyses were undertaken utilizing a hybrid screening decision tree and Markov disease progression model. Costs and outcomes associated with the detection of AF compared traditional systematic and opportunistic AF screening strategies to targeted screening informed by a ML risk prediction algorithm. Model analyses were based on adults ≥50 years and adopted the UK NHS perspective.Results: Targeted screening using the ML risk prediction algorithm required fewer patients to be screened (61 per 1,000 patients, compared to 534 and 687 patients in the systematic and opportunistic strategies) and detected more AF cases (11 per 1,000 patients, compared to 6 and 8 AF cases in the systematic and opportunistic screening strategies). The targeted approach demonstrated cost-effectiveness under base case settings (cost per QALY gained of £4,847 and £5,544 against systematic and opportunistic screening respectively). The targeted screening strategy was predicted to provide an additional 3.40 and 2.05 QALYs per 1,000 patients screened versus systematic and opportunistic strategies. The targeted screening strategy remained cost-effective in all scenarios evaluated.Limitations: The analysis relied on assumptions that include the extended period of patient life span and the lack of consideration for treatment discontinuations/switching, as well as the assumption that the ML risk-prediction algorithm will identify asymptomatic AF.Conclusions: Targeted screening using a ML risk prediction algorithm has the potential to enhance the clinical and cost-effectiveness of AF screening, improving health outcomes through efficient use of limited healthcare resources.

A comparative evaluation of gemtuzumab ozogamicin + daunorubicin-cytarabine and other treatments for newly diagnosed acute myeloid leukemia.

AIM: To evaluate the comparative efficacy and safety of gemtuzumab ozogamicin + daunorubicin-cytarabine (GO + DA) versus common induction therapies for newly diagnosed acute myeloid leukemia. Materials & methods: A network meta-analysis following a systematic literature review. RESULTS: In base-case analyses, GO + DA was associated with significantly greater overall survival and relapse-free survival versus most comparators, and similar rates of complete remission versus all evaluated comparators. Similar findings were seen in the subgroup analyses. Grade 3+ bleeding and hepatic events were higher with GO + DA versus some comparators, consistent with GO's profile. No differences were found for other evaluated outcomes. CONCLUSION: GO + DA provides significant overall survival and relapse-free survival benefit versus evaluated induction regimens for newly diagnosed acute myeloid leukemia.

Social preferences for health states associated with acute myeloid leukemia for patients undergoing treatment in the United Kingdom.

BACKGROUND: Health state (HS) utility values for patients with acute myeloid leukemia (AML), a hematological malignancy, are not available in the United Kingdom (UK). This study aims to develop clinically sound HSs for previously untreated patients with AML and to assign utility values based on preferences of the general UK population. METHODS: This study was conducted in the UK and comprised 2 stages. During the first stage, AML HSs were drafted based on evidence from a literature review of AML clinical and health-related quality-of-life studies (published January 2000-June 2016) and patient-reported outcome measures previously used in this population. A panel of UK hematologists with AML experience validated the clinical relevance and accuracy of the HSs. During the second stage, validated HSs were valued in an elicitation survey with a representative UK population sample using the time trade-off (TTO) method. Descriptive statistics and bivariate tests were obtained and performed. RESULTS: A total of eight HSs were developed and clinically validated, including treatment with chemotherapy, consolidation therapy, transplant, graft-vs-host disease (GvHD), remission, relapse, refractory, and functionally cured. In total, 125 adults participated (mean age, 49.6 years [range, 18-87 years], 52.8% female). Mean (95% confidence interval [CI]) TTO preference values (n = 120), ranked from lowest (worst HS) to highest (best HS) were as follows: refractory - 0.11 (- 0.21 to - 0.01), relapse 0.10 (0.00-0.20), transplant 0.28 (0.20-0.37), treatment with chemotherapy 0.36 (0.28-0.43), GvHD 0.43 (0.36-0.50), consolidation 0.46 (0.40-0.53), remission 0.62 (0.57-0.67), and functionally cured 0.76 (0.72-0.79). Mean (95% CI) visual analog scale preference values followed the same rank order, ranging from 0.15 (0.13-0.17) for refractory to 0.71 (0.68-0.73) for functionally cured. CONCLUSIONS: To our knowledge, this is the first study to report utility values for AML from the UK societal perspective. Participants were able to distinguish differences in severity among AML HSs, and preference values were consistent with clinical perception of HS severity. HS preference values observed in this study may be useful in future evaluations of treatment benefit, including cost-effectiveness analyses and improved patient well-being.

Ion transporters in brain endothelial cells that contribute to formation of brain interstitial fluid.

Ions and water transported across the endothelium lining the blood­brain barrier contribute to the fluid secreted into the brain and are important in maintaining appropriate volume and ionic composition of brain interstitial fluid. Changes in this secretion process may occur after stroke. The present study identifies at transcript and protein level ion transporters involved in the movement of key ions and examines how levels of certain of these alter following oxidative stress. Immunohistochemistry provides evidence for Cl−/HCO3− exchanger, AE2, and Na+, HCO3− cotransporters, NBCe1 and NBCn1, on brain microvessels. mRNA analysis by RT-PCR reveals expression of these transporters in cultured rat brain microvascular endothelial cells (both primary and immortalized GPNT cells) and also Na+/H+ exchangers, NHE1 (primary and immortalized) and NHE2 (primary cells only). Knock-down using siRNA in immortalized GPNT cells identifies AE2 as responsible for much of the Cl−/HCO3− exchange following extracellular chloride removal and NHE1 as the transporter that accounts for most of the Na+/H+ exchange following intracellular acidification. Transcript levels of both AE2 and NHE1 are increased following hypoxia/reoxygenation. Further work is now required to determine the localization of the bicarbonate transporters to luminal or abluminal membranes of the endothelial cells as well as to identify and localize additional transport mechanisms that must exist for K+ and Cl−.

Nitric oxide contributes to hypoxia-reoxygenation-induced P-glycoprotein expression in rat brain endothelial cells.

Ischemia-reperfusion leads to increased levels at the blood-brain barrier of the multidrug efflux transporter, P-glycoprotein that provides protection to the brain by limiting access of unwanted substances. This is coincident with the production of nitric oxide. This present study using immortalized rat brain endothelial cells (GPNTs) examines whether following hypoxia-reoxygenation, nitric oxide contributes to the alterations in P-glycoprotein levels. After 6 h of hypoxia, both nitric oxide and reactive oxygen species, detected intracellularly using fluorescent monitoring dyes, were produced in the subsequent reoxygenation phase coincident with increased P-glycoprotein. The evidence that nitric oxide can directly affect P-glycoprotein expression was sought by applying S-nitroso-N-acetyl-DL: -penicillamine that as shown increased the nitric oxide generation. Sodium nitroprusside, though more effective at increasing P-glycoprotein expression, appeared to produce different reactive species. Real time RT-PCR analysis revealed the predominant form of nitric oxide synthase in these cells to be endothelial, inhibition of which partially prevented the increase in P-glycoprotein during reoxygenation. These data indicate that the production of nitric oxide by endothelial nitric oxide synthase during reoxygenation can influence P-glycoprotein expression in cells of the blood-rat brain barrier, highlighting another route by which nitric oxide may protect the brain.