Assessment of Days Alive Out of Hospital as a Possible End Point in Trials of Stroke Prevention for Atrial Fibrillation: A ROCKET AF Analysis.

BACKGROUND: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations. METHODS AND RESULTS: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin (P=0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P=0.88). CONCLUSIONS: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Cost-effectiveness analysis of aprepitant-based anti-emetic regimen for children receiving highly emetogenic chemotherapy: Individual patient data analysis of a randomized trial.

BACKGROUND: Aprepitant has been shown to reduce chemotherapy-induced nausea and vomiting in children receiving highly emetogenic chemotherapy (HEC). In this study, we assessed the cost-effectiveness of aprepitant for children receiving HEC in India, United Kingdom, and the United States. PROCEDURE: We utilized individual patient-level outcome data from a pediatric randomized trial, which demonstrated the superiority of an aprepitant-based anti-emetic prophylaxis over standard ondansetron and dexamethasone for HEC. Health state for each day of follow-up was analyzed and quality-adjusted life years (QALYs) were estimated. The incremental cost-utility ratio (ICUR), incremental cost-effectiveness ratio (ICER), and net monetary benefit (NMB) for each country were estimated. Sensitivity analyses by varying cost of aprepitant, hospitalization, and health state utility values by ±25% were conducted. RESULTS: Use of the aprepitant-based regimen resulted in gain of 0.0019 QALY per chemotherapy cycle along with cost savings of $22.25, $1335.52, and $6612.10 for India, United Kingdom, and the United States, respectively. The cost savings per QALY was estimated to be $12,355.84 for India, $734,282.90 for the United Kingdom, and $3,567,564.11 for the United States. The cost savings for 50% gain in the percentage of days without grade 3 vomiting was $124.18 for India, $7451.63 for the United Kingdom, and $36,892.76 for the United States. The NMB for gain in QALY was $33.62, $1418.60, and $6727.01 for India, United Kingdom, and the United States, respectively. The estimates remained cost-effective across all scenarios of the sensitivity analyses. CONCLUSION: Aprepitant-based anti-emetic regimen is cost-effective for children receiving HEC. It results in overall cost savings and reduced healthcare-resource utilization.

Baloxavir vs oseltamivir: reduced utilization and costs in influenza.

OBJECTIVES: To determine whether baloxavir use is associated with lower health care resource utilization (HCRU) and costs for secondary influenza complications post treatment compared with oseltamivir. STUDY DESIGN: Retrospective cohort study. METHODS: Patients filling a prescription for baloxavir or oseltamivir within 48 hours following an influenza-related outpatient visit were identified in the 2018-2019 influenza season from the US Truven MarketScan Research Databases and propensity matched 1:2 (baloxavir:oseltamivir). Outcomes were assessed 15 and 30 days after antiviral treatment and included all-cause, all respiratory-related, and select respiratory-related (influenza, asthma, chronic obstructive pulmonary disease, or infection) HCRU and costs. RESULTS: The study included 5080 baloxavir-treated and 10,160 matched oseltamivir-treated patients. All-cause emergency department (ED) visits and inpatient hospitalizations were lower in baloxavir-treated patients, with a statistically significant difference in the percentage hospitalized at 30 days (0.3% vs 0.5%; P = .04). ED visits for all or select respiratory-related conditions were significantly reduced with baloxavir (P < .01 for all comparisons). Mean per-patient cost savings at day 30 for all-cause, all respiratory-related, and select respiratory-related conditions were $79, $50, and $51, respectively, despite slightly higher prescription costs for baloxavir. In high-risk patients (baloxavir: n = 1958; oseltamivir: n = 3949), the incidence of ED visits was significantly lower for all respiratory-related and select respiratory-related conditions (P < .01); cost savings with baloxavir in the high-risk cohort were substantially greater than in the overall cohort. CONCLUSIONS: Treatment of patients with influenza with single-dose baloxavir was generally associated with lower HCRU and costs post treatment compared with oseltamivir, particularly in high-risk patients.

Cost-effectiveness of baloxavir marboxil compared with laninamivir for the treatment of influenza in patients at high risk for complications in Japan.

OBJECTIVE: Baloxavir marboxil (baloxavir) is a single-dose antiviral which was previously found to be a cost-effective alternative to laninamivir in otherwise healthy adults in Japan. This study aimed at investigating the cost-effectiveness of baloxavir versus laninamivir in patients with influenza at high risk for complications. METHODS: A decision tree was utilized to estimate costs and health gains associated with the use of antivirals. A lifetime horizon was applied to capture the long-term impact of influenza complications, and other events with associated costs and health outcomes were accounted for one influenza season. The study population was stratified into three categories: adolescents and non-elderly adults with high-risk conditions (HRC), elderly without other HRC, and elderly with other HRC. The cost-effectiveness was assessed from a public healthcare payer's perspective. The duration of influenza symptoms, probabilities of complications and probabilities of adverse events were obtained from a clinical trial and network meta-analysis. The costs of influenza and adverse events management were derived from the JammNet claims database. Utility values were informed by the clinical trial data and literature. Sensitivity analyses were also performed. RESULTS: The baloxavir strategy was associated with higher costs (+¥144) and higher quality-adjusted life-years (QALYs) in adults with HRC, elderly without HRC and elderly with HRC (+0.00078, +0.00183 and +0.00350 respectively). The overall incremental cost/QALY for baloxavir versus laninamivir was ¥68,855, which was below the willingness-to-pay threshold of ¥5 million/QALY gained. Key drivers of the model results were the probability of pneumonia and bronchitis. The probability of baloxavir being cost-effective was 72%. CONCLUSIONS: This study suggests that influenza treatment with baloxavir is cost-effective compared with laninamivir in the adult high-risk population in Japan.

Comparison of Hospitalization Incidence in Influenza Outpatients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is a single-dose, oral antiinfluenza drug with a novel mechanism of action. We compared the incidence of hospitalization in patients treated with baloxavir vs neuraminidase inhibitors. METHODS: In this retrospective, observational, cohort study, we used real-world patient data extracted from a Japanese health insurance claims database. The enrollment period was 1 October 2018 to 17 April 2019. On day 1, eligible patients (N = 339 007) received baloxavir, oseltamivir, zanamivir, or laninamivir. Baseline characteristics were standardized using the inverse probability of treatment weighting method. The primary end point was the incidence of hospitalization (days 2-14). Secondary end points included antibacterial use, secondary pneumonia, and additional antiinfluenza drug use. RESULTS: Compared with the baloxavir group, the incidence of hospitalization was greater in the oseltamivir group (risk ratio [RR] and 95% confidence interval [CI], 1.41 [1.00-2.00]; risk difference [RD] and 95% CI, 0.06 [.01-.12]) and zanamivir group (RR, 1.85 [1.23-2.78]; RD, 0.11 [.02-.20]). Oseltamivir-treated patients were less likely to require antibacterials than baloxavir-treated patients (RR, 0.87 [.82-.91]). However, oseltamivir-treated patients were more likely to be hospitalized with antibacterials (RR, 1.70 [1.21-2.38]) or antibacterial injection (RR, 1.67 [1.17-2.38]) than baloxavir-treated patients (post hoc analysis). Compared with baloxavir-treated patients, additional antiinfluenza drug use was greater in oseltamivir-, zanamivir-, and laninamivir-treated patients (RR, 1.51 [1.05-2.18], 2.84 [2.04-3.96], and 1.68 [1.35-2.10], respectively). CONCLUSIONS: Baloxavir is an efficacious antiinfluenza treatment that may reduce hospitalization compared with oseltamivir and zanamivir. CLINICAL TRIALS REGISTRATION: University hospital Medical Information Network Clinical Trials Registry (UMIN000038159).

Comparison of Household Transmission of Influenza Virus From Index Patients Treated With Baloxavir Marboxil or Neuraminidase Inhibitors: A Health Insurance Claims Database Study.

BACKGROUND: Baloxavir marboxil (baloxavir) is expected to reduce influenza transmission by rapid reduction of viral load. The incidence of household transmission was compared between index patients (IPs) treated with baloxavir and those treated with neuraminidase inhibitors. METHODS: Using a Japanese claims database, the first family members with influenza diagnosis during the 2018-2019 influenza season were identified as IPs, and the diagnosis date was designated day 1. According to the anti-influenza drug dispensed to the IP, their families were classified into the oral baloxavir group and 3 controls: oral oseltamivir group (a primary control), inhaled zanamivir group, and inhaled laninamivir group. A household transmission was defined as influenza diagnosed for any non-IP family members during days 3-8. The incidence of household transmission was compared between groups using a logistic regression model adjusting backgrounds of IPs. RESULTS: The proportion of families with household transmission was 17.98% (15 226 of 84 672) in the baloxavir group and 24.16% (14 983 of 62 004) in the oseltamivir group. The covariate-adjusted odds ratio (oseltamivir/baloxavir) was 1.09 (95% confidence interval [95% CI], 1.05-1.12), which indicated significantly lower incidence in the baloxavir group. The adjusted odds ratios (controls/baloxavir) against zanamivir and laninamivir were 0.93 (95% CI, .89-.97) and 0.99 (95% CI, .96-1.02), respectively. CONCLUSIONS: Baloxavir may contribute to reduction in household transmission compared with oseltamivir. In comparison between baloxavir and inhalants, a similar reduction was not shown and it might be due to unmeasured confounding by administration route differences.

Burden of influenza B virus infection and considerations for clinical management.

Influenza B viruses cause significant morbidity and mortality, particularly in children, but the awareness of their impact is often less than influenza A viruses partly due to their lack of pandemic potential. Here, we summarise the biology, epidemiology and disease burden of influenza B, and review existing data on available antivirals for its management. There has long been uncertainty surrounding the clinical efficacy of neuraminidase inhibitors (NAIs) for influenza B treatment. In this article, we bring together the existing data on NAIs and discuss these alongside recent large randomised controlled trial data for the new polymerase inhibitor baloxavir in high-risk influenza B patients. Finally, we offer considerations for the clinical management of influenza B, with a focus on children and high-risk patients where disease burden is highest.

Comprehensive assessment of amino acid substitutions in the trimeric RNA polymerase complex of influenza A virus detected in clinical trials of baloxavir marboxil.

BACKGROUND: Baloxavir marboxil (BXM) is an approved drug that selectively targets cap-dependent endonuclease on PA subunit in the RNA polymerase complex of influenza A and B viruses. Amino acid substitutions at position 38 in the PA subunit were identified as a major pathway for reduced susceptibility to baloxavir acid (BXA), the active form of BXM. Additionally, substitutions found at positions E23, A37, and E199 in the PA subunit impact BXA susceptibility by less than 10-fold. METHODS: We comprehensively evaluated the impact of novel amino acid substitutions identified in PA, PB1, and PB2 subunits in BXM clinical trials and influenza sequence databases by means of drug susceptibility and replicative capacity. RESULTS: PA/I38N in A(H1N1)pdm09 and PA/I38R in A(H3N2) were newly identified as treatment-emergent substitutions in the CAPSTONE-2 study. The I38N substitution conferred reduced susceptibility by 24-fold, whereas replicative capacity of the I38N-substituted virus was impaired compared with the wild-type. The I38R-substituted virus was not viable in cell culture. All other mutations assessed in this extensive study did not significantly affect BXA susceptibility (< 2.4-fold change). CONCLUSION: These results provide additional information on the impact of amino acid substitutions in the trimeric viral polymerase complex to BXA susceptibility and will further support influenza surveillance.

Best Practice Approach to Successful Conversion of Fosaprepitant to Aprepitant IV in a Large Multisite Community Oncology Infusion Center: A Retrospective Analysis.

PURPOSE: To evaluate the impact on cost, time, resource use, and clinic workflow of converting the route of drug administration from a neurokinin-1 receptor antagonist (NK-1 RA) 30-min intravenous (IV) infusion to aprepitant IV, and more specifically to IV push, within a multicenter community oncology practice. METHODS: This was a retrospective, multicenter time, motion, and resource/cost evaluation study. Conversion to aprepitant IV was determined by calculating number of doses of aprepitant IV versus fosaprepitant administered in patients receiving moderately or highly emetogenic chemotherapy regimens. Operational advantages (i.e., supply costs, time saved) of switching from fosaprepitant IV infusion to aprepitant administered as a 2-min IV push were assessed. RESULTS: A total of 12,908 doses of aprepitant IV 130 mg were administered at 13 Rocky Mountain Cancer Centers clinics over an 18-month period. Conversion from fosaprepitant to aprepitant IV reached 90% after 9 months of aprepitant IV initiation. Supply costs per administration were reduced ($2.51 to $0.52) when aprepitant was prepared as an IV push versus an NK-1 RA infusion. The overall time savings per administration of aprepitant was reduced by 90% (from 36.5 to 3.5 min, 33 min saved) as an IV push rather than an infusion. Most of the time saved per administration (30 min) pertained to the infusion nurse, and 3 min was saved by the pharmacy technician. CONCLUSION: Successful conversion to aprepitant, and specifically to a 2-min IV push, provides time, cost, and resource savings, improves operational efficiency, and avoids the negative impact of potential future IV fluid shortages.

Chemotherapy-induced nausea and vomiting (CINV) can have a major impact on quality of life for patients receiving chemotherapy. Intravenous (IV) aprepitant is an approved neurokinin-1 receptor antagonist (NK-1 RA) that has been effective and safe when administered as part of a guideline-recommended regimen in patients receiving chemotherapy. In addition to being approved as a 30-min infusion, aprepitant IV is the only NK-1 RA approved for administration as a 2-min injection. These factors contributed to Rocky Mountain Cancer Centers (RMCC), which is a physician-owned community oncology practice, evaluating the impact on cost, time, and resource use of converting from a 30-min infusion of fosaprepitant to aprepitant IV, and more specifically a 2-min injection. Within 9 months of implementing aprepitant IV at RMCC, the percent utilization compared to fosaprepitant reached over 90%, signifying a successful conversion within the practice. Furthermore, a 2-min injection of aprepitant IV resulted in several operational advantages compared to a 30-min infusion. When accounting for all 13 clinics within RMCC, total monthly time savings to the practice would be over 28,000 min, or approximately 60 workdays per month of saved time. This new workflow is more efficient and allows for pharmacy technicians to complete other necessary tasks in the pharmacy such as cleaning, organizing, managing inventory, drug ordering, and charge/documentation corrections. Time saved by the nurses could be used for enhanced patient care, thoroughly reviewing chemotherapy or other orders, and assisting other nurses.

Cost-minimization analysis of GSTP1c.313A>G genotyping for the prevention of cisplatin-induced nausea and vomiting: A Bayesian inference approach.

BACKGROUND: Chemotherapy-induced nausea and vomiting are concerning adverse events resulting from cancer treatment, and current guidelines recommend the use of neurokinin-1-selective antagonists, such as fosaprepitant, in highly emetogenic schemes. However, the implementation of this strategy may be limited by the cost of treatment. GSTP1 c.313A>G genotype was recently described as a predictor of vomiting related to high-dose cisplatin. We hypothesized that the inclusion of routine GSTP1 c.313A>G screening may be promising in financial terms, in contrast to the wide-spread use of fosaprepitant. METHODS: A cost-minimization analysis was planned to compare GSTP1 c.313A>G genotyping versus overall fosaprepitant implementation for patients with head and neck cancer under chemoradiation therapy with high-dose cisplatin. A decision analytic tree was designed, and conditional probabilities were calculated under Markov chain Monte Carlo simulations using the Metropolis-Hastings algorithm. The observed data included patients under treatment without fosaprepitant, while priors were derived from published studies. RESULTS: To introduce screening with real-time polymerase chain reaction, an initial investment of U$ 39,379.97 would be required, with an amortization cost of U$ 7,272.97 per year. The mean cost of standard therapy with fosaprepitant is U$ 243.24 per patient, and although the initial cost of routine genotyping is higher, there is a tendency of progressive minimization at a threshold of 155 patients (Credible interval-CI: 119 to 216), provided more than one sample is incorporated for simultaneous analysis. A resulting reduction of 35.83% (CI: 30.31 to 41.74%) in fosaprepitant expenditures is then expected with the implementation of GSTP1 c.313A>G genotyping. CONCLUSION: GSTP1 c.313A>G genotyping may reduce the use of preventive support for chemotherapy induced nausea and lower the overall cost of treatment. Despite the results of this simulation, randomized, interventional studies are required to control for known and unknown confounders as well as unexpected expenses.

Cost-effectiveness of aprepitant in Japanese patients treated with cisplatin-containing highly emetogenic chemotherapy.

Chemotherapy-induced nausea and vomiting (CINV) remains a major adverse event in cancer chemotherapy. Although aprepitant is effective in preventing CINV, an increment in financial burden for uniform use of aprepitant is a concern. The aim of the present study was to define the cost-effectiveness of aprepitant from the perspective of the Japanese National Health Insurance system. Based on the results of a randomized phase II trial comparing an aprepitant-containing regimen versus a nonaprepitant regimen in Japanese patients who received cisplatin-containing highly emetogenic chemotherapy, a decision analytic model was developed. The incremental cost-effectiveness ratio (ICER) was calculated both in the outpatient care setting (OCS) and in the inpatient care setting (ICS). The use of the aprepitant-containing regimen was associated with improved quality of life compared with the nonaprepitant regimen, with an increment in quality-adjusted life years (QALY) of 0.0016. The incremental total medical costs associated with the use of the aprepitant regimen were lower in the OCS than in the ICS, 6192 JPY (56.92 USD) and 9820 JPY (90.27 USD), respectively. The ICER was calculated as 3 906 698 JPY (35 910 USD) per QALY gained in the OCS and 6 195 781 JPY (56 952 USD) per QALY gained in the ICS. Cost-effectiveness of the aprepitant-containing antiemetic therapy was limited to the OCS, considering the threshold of willingness-to-pay commonly accepted (5 million JPY [45 960 USD] in Japan and 50 000 USD in the USA). The efficacy of aprepitant offsets the costs for revisiting clinics or rehospitalization added with rescue medications in the OCS.

Comparison of three preclinical models for nausea and vomiting assessment.

INTRODUCTION: Nausea is a subjective sensation often preceding emesis in humans. Drug-induced nausea remains difficult to predict in preclinical tests. The aim of this study was to compare the effects of emetic agents in rats (pica behavior), ferrets (acute and delayed phases of emesis) or dogs (emesis and cardiovascular endpoints). METHODS: Rats and ferrets were administered cisplatin (±aprepitant/ondansetron or aprepitant) or apomorphine (±domperidone). Telemetered dogs were administered apomorphine (±domperidone). Food and kaolin intake was measured in rats whereas the number of emetic events was counted in ferrets and dogs. Cardiovascular changes were also monitored in dogs. RESULTS: In rats, cisplatin (6mg/kg, i.p.) increased kaolin intake (+2257%, p<0.001). The cisplatin effects were not reversed by the combination of aprepitant/ondansetron (2mg/kg, p.o./2mg/kg, i.p.) or by aprepitant (30mg/kg, p.o.). Apomorphine (10mg/kg, i.p.) did not induce pica behavior. In ferrets, cisplatin (8mg/kg, i.p.) induced acute and delayed emesis (371.8±47.8 emetic events over 72h) which was antagonized by aprepitant (1mg/kg, p.o.). Apomorphine (0.25mg/kg, s.c.) induced acute emesis (38.8±8.7 emetic events over 2h) which was abolished by domperidone (0.1mg/kg, s.c.). In dogs, apomorphine (100µg/kg, s.c.) induced emesis and tachycardia which were decreased by domperidone (0.2mg/kg, i.v.). CONCLUSIONS: The assessment of emesis in the ferret or in the dog displays a strong predictive value. In contrast, assessing nausea remains challenging in all animal species and the use of pica behavior remains questionable in the context of antiemetic drug development.

Assessment of Drug-Drug Interaction between Warfarin and Aprepitant and Its Effects on PT-INR of Patients Receiving Anticancer Chemotherapy.

Aprepitant is a known inducer of CYP2C9, the main warfarin-metabolizing enzyme. Consequently, co-administration of these two drugs may result in reduction of the anticoagulation activity of warfarin. However, the nature and degree of time-dependent changes in prothrombin time international normalized ratio (PT-INR) after aprepitant and warfarin co-treatment in patients receiving anticancer chemotherapy has not been elucidated. We retrospectively examined the changes in warfarin dose, PT-INR, and warfarin sensitivity index (WSI; average of PT-INR value/average of daily warfarin dose) during four weeks, i.e., one week before and three weeks after aprepitant administration. The mean and standard deviation values of WSI for one week before and one, two, and three weeks after the beginning of aprepitant administration were 0.51±0.22 (1.00, n=34), 0.74±0.30 (1.53±0.59, n=30), 0.38±0.15 (0.82±0.22, n=28), and 0.46±0.29 (0.87±0.23, n=24), respectively. Values in parentheses represent relative changes versus WSI of one week before and number of subjects. Although the mean value of WSI significantly increased one week after aprepitant administration compared to that at one week before the administration, it in turn significantly decreased two weeks after compared to one week before (paired t-test, p<0.05 after Bonferoni correction). In patients taking warfarin, PT-INR should be carefully monitored for at least two weeks after the beginning of aprepitant administration because it may fluctuate with both aprepitant and chemotherapy during this period.

Comparison of user-friendliness and treatment cost of Loceryl® vs. Ciclopoli®--a patient's perspective.

Topical monotherapy is a valid therapeutic approach in onychomycosis. Due to its lengthy course and its non-reimbursed product status, cost and compliance are important issues and non-pharmacological properties such as over-the-counter price and ease of use should be considered when deciding which product to recommend. We investigated surrogate parameters for patient-friendliness and treatment cost in Germany in a questionnaire-based prospective, comparative, intra-individual, open-label trial of the two common topical antifungal nail lacquers Loceryl(®) (amorolfine 5%) and Ciclopoli(®) (ciclopirox 8%) in eight patients with clinically diagnosed onychomycosis. The 2.5 ml bottle of Loceryl(®) covered a treatment period of 308 days, resulting in treatment costs of €0.10 per day in comparison to the 3.3 ml bottle of Ciclopoli(®), covering 127 days at €0.21 per day, given once-daily application for Ciclopoli(®) and once-weekly application for Loceryl(®) in accordance with regulatory approval. Six out of eight patients favoured the Loceryl(®) treatment regimen. Furthermore, four out of eight patients found Loceryl(®) easier to apply, whereas three preferred Ciclopoli(®). In total, seven out of eight stated a clear preference for Loceryl(®) over Ciclopoli(®). Loceryl(®) therapy is less expensive and less time-consuming. The therapeutic period that can be covered is longer and more patients stated a clear preference for Loceryl(®) in comparison to Ciclopoli(®). The differences are statistically significant, underlining probable clinical relevance.

Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.

BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.

Novel oral anticoagulants in non-valvular atrial fibrillation.

Atrial fibrillation is the most frequent arrhythmia in clinical practice, reaching 2% of the people in the world and is associated with systemic embolism. Thus, the use of anticoagulants is indicated if CHA2DS2-VASc score ≥ 2 or in patients with previous transient ischemic attack or stroke. For decades, warfarin, a vitamin K antagonist, was the only choice for chronic oral anticoagulation. Recently, novel oral anticoagulants (NOACs) have been introduced, offering similar (or better) effectiveness, safety, and convenience to the vitamin K antagonists. Dabigatran was the first NOAC approved and is a direct thrombin inhibitor. Rivaroxaban and apixaban are factor Xa inhibitors. They display rapid onset of action, more predictable of pharmacological profile, less interactions with other drugs, lack of significant effects in the diet, and less risk of intracranial hemorrhage than warfarin. Despite that dose adjustment is necessary for patients with chronic kidney disease or according to body weight, these new drugs do not require regular monitoring. There are recommendations for the start and follow-up therapy with NOACs, planning for cardioversion, ablation and surgical interventions and the management of bleeding. This article is a review of the major studies of the NOACs. The clinical use of these drugs in patients with non-valvular atrial fibrillation is presented.

Cost effectiveness of new oral anticoagulants for stroke prevention in patients with atrial fibrillation in two different European healthcare settings.

OBJECTIVES: Our objectives were to investigate the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives for stroke prevention in patients with atrial fibrillation in a country with specialized anticoagulation clinics (the Netherlands) and in a country without these clinics (the UK). METHODS: A decision-analytic Markov model was used to analyse the cost effectiveness of apixaban, rivaroxaban, and dabigatran compared with coumarin derivatives in the Netherlands and the UK over a lifetime horizon. RESULTS: In the Netherlands, the use of rivaroxaban, apixaban, or dabigatran increased health by 0.166, 0.365, and 0.374 quality-adjusted life-years (QALYs) compared with coumarin derivatives, but also increased costs by 5,681, 4,754, and 5,465, respectively. The incremental cost-effectiveness ratios (ICERs) were 34,248, 13,024, and 14,626 per QALY gained. In the UK, health was increased by 0.302, 0.455, and 0.461 QALYs, and the incremental costs were similar for all three new oral anticoagulants (5,118-5,217). The ICERs varied from 11,172 to 16,949 per QALY gained. In the Netherlands, apixaban had the highest chance (37 %) of being cost effective at a threshold of 20,000; in the UK, this chance was 41 % for dabigatran. The quality of care, reflected in time in therapeutic range, had an important influence on the ICER. CONCLUSIONS: Apixaban, rivaroxaban, and dabigatran are cost-effective alternatives to coumarin derivatives in the UK, while in the Netherlands, only apixaban and dabigatran could be considered cost effective. The cost effectiveness of the new oral anticoagulants is largely dependent on the setting and quality of local anticoagulant care facilities.

Cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for stroke prevention in patients with atrial fibrillation.

PURPOSE: This study aimed to evaluate the cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for the prevention of stroke in patients with atrial fibrillation (AF) in Singapore. METHODS: A Markov model was constructed to compare the lifetime costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) of dabigatran 110 and 150 mg, rivaroxaban 20 mg and adjusted-dose warfarin from the perspective of the Singapore healthcare system, using clinical data from published studies, utilities from a patient-reported survey and costs from hospital databases. The target population was a hypothetical cohort of 65-year-old AF patients with no contraindications to anticoagulation. RESULTS: In the base-case analysis, the QALYs were 8.75 with warfarin, 8.73 with dabigatran 110 mg, 8.82 with dabigatran 150 mg, and 9.33 with rivaroxaban. The costs were Singapore dollar (SG$) 34,648 for warfarin, SG$54,919 for dabigatran 110 mg, SG$50,484 for dabigatran 150 mg and SG$51,975 for rivaroxaban. The ICER of rivaroxaban versus warfarin was SG$29,697 (US$26,727) per QALY. Rivaroxaban and warfarin had extended dominance over the high-dose dabigatran. The low-dose dabigatran was dominated by warfarin. Deterministic sensitivity analyses showed that the ICER of rivaroxaban versus warfarin was sensitive to cost of rivaroxaban and utilities for rivaroxaban and warfarin. Probability sensitivity analysis demonstrated that the probability of rivaroxaban being the optimal choice was 97.8% and 99.5% at a willingness-to-pay threshold of SG$65,000 (US$58,500) and SG$130,000 (US$117,000) per QALY, respectively. CONCLUSION: Rivaroxaban may be a cost-effective alternative to warfarin for the prevention of stroke in patients with AF in Singapore.

Evaluation of medical costs associated with use of new oral anticoagulants compared with standard therapy among venous thromboembolism patients.

OBJECTIVE: This study evaluated differences in medical costs associated with clinical end-points from randomized clinical trials that compared the new oral anticoagulants (NOACs), dabigatran, rivaroxaban, apixaban, and edoxaban, to standard therapy for treatment of patients with venous thromboembolism (VTE). RESEARCH DESIGN AND METHODS: Event rates of efficacy and safety end-points from the clinical trials (RE-COVER, RE-COVER II, EINSTEIN-Pooled, AMPLIFY, Hokusai-VTE trial) were obtained from published literature. Incremental annual medical costs among patients with clinical events from a US payer perspective were obtained from the literature or healthcare claims databases and inflation adjusted to 2013 costs. Differences in total medical costs associated with clinical end-points for the NOACs vs standard therapy were then estimated. One-way and Monte Carlo sensitivity analyses were carried out. RESULTS: A lower rate of major bleedings was associated with use of any of the NOACs vs standard therapy. Except for dabigatran, use of NOACs was also associated with a lower rate of recurrent VTE/death. As a result of the reduction in clinical event rates, the overall medical cost differences were -$146, -$482, -$918, and -$344 for VTE patients treated with dabigatran, rivaroxaban, apixaban, and edoxaban, respectively, vs patients treated with standard therapy. CONCLUSIONS: When any of the four NOACs are used instead of standard therapy for acute VTE, treatment medical costs are reduced. Apixaban is associated with the greatest reduction in medical costs, which is driven by medical cost reductions associated with both efficacy and safety end-points. Further evaluation may be needed to validate these results in the real-world setting.

Estimated medical cost reductions associated with use of novel oral anticoagulants vs warfarin in a real-world non-valvular atrial fibrillation patient population.

OBJECTIVE: RESULTS of randomized clinical trials (RCT) demonstrate that novel oral anticoagulants (NOAC) are effective therapies for reducing the risk of stroke in non-valvular atrial fibrillation (NVAF). Prior medical cost avoidance studies have used warfarin event rates from RCTs, which may differ from patients receiving treatment in a real-world (RW) setting, where the quality of care may not be the same as in a RCT. The purpose of this study was to estimate the change in medical costs related to stroke and major bleeding for each NOAC (apixaban, dabigatran, and rivoraxaban) relative to warfarin in a RW NVAF population. METHODS: Patients (n = 23,525) with a diagnosis of NVAF during 2007-2010 were selected from a Medco population of US health plans. Stroke and major bleeding excluding intracranial hemorrhage (MBEIH) events were identified using diagnosis codes on medical claims. RW reference event rates were calculated during periods of warfarin exposure. RW event rates for NOACs were estimated by multiplying the corresponding relative risk (RR) from the RCTs by each reference rate. Absolute risk reductions (ARR) or number of events avoided per patient year were then estimated. Changes in medical costs associated with each NOAC were calculated by applying the ARR to the 1-year cost for each event. Costs for stroke and MBEIH were obtained from the literature. Drug and international normalized ratio monitoring costs were not considered in this analysis. RESULTS: Compared to RW warfarin, use of apixaban and dabigatran resulted in total (stroke plus MBEIH) medical cost reductions of $1245 and $555, respectively, during a patient year. Rivaroxaban resulted in a medical cost increase of $144. CONCLUSIONS: If relative risk reductions demonstrated in RCTs persist in a RW setting, apixaban would confer the greatest medical cost savings vs warfarin, resulting from significantly lower rates of both stroke and MBEIH.