RESUMO
BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral drug used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years or older at high risk of progression to severe disease (eg, hospitalization and death). Despite being the preferred option for outpatient treatment in the majority of countries worldwide, NMV/r is currently underutilized in real-world clinical practice. AREAS OF UNCERTAINTY: As numerous real-world studies have described patient outcomes following treatment with NMV/r, this systematic literature review provides a comprehensive summary of evidence on NMV/r effectiveness against hospitalization and mortality further organized by clinically meaningful categories, such as acute versus longer-term follow-up, age, underlying health conditions, and vaccination status, to help inform health care decision making. DATA SOURCES: We searched Embase and PubMed (December 22, 2021-March 31, 2023) and congress abstracts (December 1, 2021-December 31, 2022) for reports describing NMV/r effectiveness. THERAPEUTIC ADVANCES: In total, 18 real-world studies met final selection criteria. The evidence showed that NMV/r significantly reduced postinfection risk of all-cause and COVID-19-related hospitalization and mortality in both acute (≤30 days) (21%-92%) and longer-term (>30 days) (1%-61%) follow-up. The reduction in postinfection risk was higher when treatment was received within 5 days of symptom onset. Real-world effectiveness of NMV/r treatment was observed regardless of age, underlying high-risk conditions, and vaccination status. CONCLUSION: The systematic literature review findings demonstrated the effectiveness of NMV/r against hospitalization and mortality during the Omicron period among individuals at high risk of progression to severe COVID-19 disease.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Combinação de Medicamentos , Ritonavir , Humanos , Antivirais/uso terapêutico , COVID-19/mortalidade , COVID-19/prevenção & controle , Hospitalização/estatística & dados numéricos , Ritonavir/uso terapêutico , SARS-CoV-2 , Resultado do TratamentoRESUMO
Aim: To report treatment patterns and quality of life (QoL) in HER2-negative advanced breast cancer patients. Methods: Data were drawn from a cross-sectional survey in Europe and USA. Results: Hormone plus targeted therapy was the most frequent first-line (1L, 62%) and second-line (2L, 45%) treatment for HR+/HER2-patients. Chemotherapy was most frequent at third-line or greater (3L+, 39%) for HR+/HER2- patients, 2L (51%) and 3L+ (48%) for triple negative breast cancer (TNBC) patients. Time to progression was 13.8 (2L) and 11.0 (3L+) months for HR+/HER2- patients. No comparisons were observed for TNBC patients. EQ-5D-5L scores were highest in patients at 1L and lowest at 3L+. Conclusion: Reduced QoL and treatment response were reported in patients at later lines of therapy.
Breast cancer is the most common cancer in women. Differences in survival are seen depending on how widespread or advanced the cancer is, how many different treatments the patient has been given, as well as whether certain receptors on the tumor are present or absent. Many new treatments are available which can target these receptors. These treatments have improved survival in patients with advanced breast cancer, but other benefits for the patient are not always clear. In addition, differences between countries are possible as official guidance can vary. This study aimed to understand these issues, by asking physicians and their patients across Europe and USA for their views on quality of life and satisfaction with their treatments. We found that, in general, physicians prescribed treatments as recommended in the treatment guidelines. As breast cancer progressed and treatment stopped working, patients were switched on to different treatments. Survival, quality of life and treatment satisfaction were all worse in patients who had switched treatments. It appears that the patients lose confidence that their new treatment will work to improve their quality of life. We also saw differences in some of these outcomes between Europe and USA, which were likely due to differences in the treatment guidelines between countries. Both quality of life and treatment satisfaction are important for the well-being of patients with advanced breast cancer as they now live longer with these new treatments. This should be considered by physicians and taken into account for future work.
RESUMO
STUDY OBJECTIVE: The objective of this study was to define and characterize the unmet needs in the pharmacological management of insomnia. METHODS: A systematic literature review was conducted to identify relevant literature reporting real-world evidence in insomnia, published from January 2009 to April 2020. Pharmacological treatments - both prescription (benzodiazepines, 'Z-drugs' and suvorexant) and off-label (antidepressants, antipsychotics, and antihistamines) - were considered. RESULTS: Overall, 108 publications describing the humanistic (n = 59) and economic burden (n = 20) of insomnia, off-label treatment patterns (n = 28) and factors influencing treatment adherence or persistence (n = 8) were identified. A high prevalence of comorbid conditions was reported in patients with insomnia resulting in significantly lower health-related QoL compared to those with insomnia or a comorbidity alone. Current treatment options were associated with adverse events, including reduced sleep quality and next-day somnolence. An increased risk of accidents/injuries was also associated with insomnia and its treatment. Furthermore, safety concerns and perceived lack of efficacy for approved treatments have led to frequent off-label prescribing, despite a lack of clinical evidence of risk/benefit ratios. Safety concerns associated with benzodiazepines include risk of dependence, leading to prolonged treatment persistence and exacerbated adverse events, making them unsuitable for use in patients with chronic insomnia. Finally, the substantial economic burden of insomnia was evident, with reduced work productivity demonstrated in patients with insomnia compared to the general population. CONCLUSIONS: This review highlights a clear unmet need for insomnia therapies that improve sleep quality without resulting in next-day impairment and/or dependence.
Assuntos
Antipsicóticos , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Qualidade de Vida , Antidepressivos , Benzodiazepinas/efeitos adversosRESUMO
RATIONALE: Study 311 (E2007-G000-311; NCT02849626) was a Phase 3, multicenter, open-label single-arm study of adjunctive perampanel oral suspension in pediatric patients (aged 4 to <12â¯years) with partial-onset seizures (POS) (with/without secondarily generalized tonic-clonic seizures [SGTCS]) or primary generalized tonic-clonic seizures (PGTCS). Health-related quality of life (HRQoL) was an exploratory endpoint initially analyzed through simple descriptive summaries. The aim of this post hoc analysis was to provide a more thorough assessment of HRQoL. METHODS: This analysis focused on EQ-5D-Y data collected at Baseline, Week 23, and Week 52. Individual dimensions, visual analog scale (VAS) and summed misery index (MI) were evaluated at all visits and compared by seizure type (POS versus SGTCS versus PGTCS), age (4 to <7 versus 7 to <12), and use of concomitant enzyme-inducing antiepileptic drugs (EIAEDs) (yes versus no). Paretian Classification of Health Change (PCHC) analysis summarized the proportion of patients who showed improvement or deterioration in HRQoL. Waterfall plots assessed changes in EQ-5D-Y scores by treatment-emergent adverse events (TEAEs) and by reduction in seizure frequency. Health state utility values associated with differing seizure frequency states were estimated using a linear mixed model. RESULTS: One hundred and fifteen patients completed EQ-5D-Y at relevant study visits (Seizure type: POS nâ¯=â¯84 [of which 21 had SGTCS], PGTCS nâ¯=â¯31; Age: 4 to <7â¯years nâ¯=â¯30, 7 to <12â¯years nâ¯=â¯85; Concomitant EIAEDs: Yes nâ¯=â¯35, No nâ¯=â¯80). Completion rates out of those expected to complete EQ-5D-Y were high at both timepoints (84.4% at Week 23 and 97.2% at Week 52). Overall, VAS/MI remained stable over time (did not exceed minimal important difference); this was similar according to seizure type, age, and EIAED usage. In patients with 'no problems' on any EQ-5D-Y dimension at Baseline, nearly all retained their full health at Week 23 (94.7%), and all retained it at Week 52 (100.0%). PCHC analysis showed fewer patients with POS experienced deterioration in EQ-5D-Y than patients with PGTCS at Week 23 (24.1% versus 42.1%). Not experiencing a TEAE, or remaining seizure-free, was associated with improvements in VAS score at Week 23 compared to those experiencing TEAEs or seizures, respectively. Health state utility values (HSUVs) were estimated as follows: seizure free (LS Mean 0.914 [95% CIs 0.587, 1.240]), ≥1 seizure per year (0.620 [0.506, 0.734]), ≥1 seizure per month (0.596 [0.338, 0.855]), ≥1 seizure per week (0.284 [-0.014, 0.582]). CONCLUSIONS: An in-depth analysis of EQ-5D-Y data allowed for a more nuanced exploration of HRQoL than previous descriptive summaries. Our findings provide evidence that perampanel as adjunctive therapy did not result in deterioration of patient HRQoL. The association between TEAEs or remaining seizure-free and HRQoL warrants further exploration. Increasing seizure frequency was associated with decreasing HSUVs; these can inform cost-effectiveness modeling of perampanel and other therapies aiming to reduce seizure frequency in pediatric patients.
Assuntos
Qualidade de Vida , Convulsões , Anticonvulsivantes/uso terapêutico , Criança , Pré-Escolar , Quimioterapia Combinada , Humanos , Nitrilas , Piridonas , Convulsões/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND: The adoption of quadrivalent influenza vaccine (QIV) to replace trivalent influenza vaccine (TIV) in immunization programs is growing worldwide, thus helping to address the problem of influenza B lineage mismatch. However, the price per dose of QIV is higher than that of TIV. In such circumstances, cost-effectiveness analyses provide important and relevant information to inform national health recommendations and implementation decisions. This analysis assessed potential vaccine impacts and cost-effectiveness of a country-wide switch from TIV to QIV, in Canada and the UK, from a third-party payer perspective. METHODS: An age-stratified, dynamic four-strain transmission model which incorporates strain interaction, transmission-rate seasonality and age-specific mixing in the population was used. Model input data were obtained from published literature and online databases. In Canada, we evaluated a switch from TIV to QIV in the entire population. For the UK, we considered two strategies: Children aged 2-17 years who receive the live-attenuated influenza vaccine (LAIV) switch to the quadrivalent formulation (QLAIV), while individuals aged > 18 years switch from TIV to QIV. Two different vaccination uptake scenarios in children (UK1 and UK2, which differ in the vaccine uptake level) were considered. Health and cost outcomes for both vaccination strategies, and the cost-effectiveness of switching from TIV/LAIV to QIV/QLAIV, were estimated from the payer perspective. For Canada and the UK, cost and outcomes were discounted using 5 % and 3.5 % per year, respectively. RESULTS: Overall, in an average influenza season, our model predicts that a nationwide switch from TIV to QIV would prevent 4.6 % influenza cases, 4.9 % general practitioner (GP) visits, 5.7 % each of emergency room (ER) visits and hospitalizations, and 6.8 % deaths in Canada. In the UK (UK1/UK2), implementing QIV would prevent 1.4 %/1.8 % of influenza cases, 1.6 %/2.0 % each of GP and ER visits, 1.5 %/1.9 % of hospitalizations and 4.3 %/4.9 % of deaths. Discounted incremental cost-utility ratios of $7,961 and £7,989/£7,234 per quality-adjusted life-year (QALY) gained are estimated for Canada and the UK (UK1/UK2), both of which are well within their respective cost-effectiveness threshold values. CONCLUSIONS: Switching from TIV to QIV is expected to be a cost-effective strategy to further reduce the burden of influenza in both countries.
Assuntos
Análise Custo-Benefício , Vacinas contra Influenza/economia , Vacinas contra Influenza/uso terapêutico , Influenza Humana/prevenção & controle , Adolescente , Adulto , Idoso , Canadá , Criança , Pré-Escolar , Comércio , Hospitalização/economia , Humanos , Programas de Imunização/economia , Lactente , Vacinas contra Influenza/administração & dosagem , Influenza Humana/economia , Influenza Humana/transmissão , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Reino Unido , Vacinas Atenuadas/economia , Adulto JovemRESUMO
BACKGROUND: The Insomnia Severity Index (ISI) is a widely used measure of insomnia severity. Various ISI research findings suggest different factor solutions and meaningful within-individual change (MWIC) to detect treatment response in patients with insomnia. This study examined an ISI factor solution and psychometric indices to define MWIC in a robust patient sample from clinical trial settings. METHODS: We endeavored to improve upon previous validation of ISI by examining structural components of confirmatory factor analysis (CFA) models using two large, placebo-controlled clinical trials of lemborexant for insomnia. Using the best-fitting two-factor solution, we evaluated anchor-based, distribution-based and receiver operating characteristic (ROC) curve methods to derive an estimate of the MWIC. RESULTS: The model structure for the 7-item scale proposed in other research did not fit the observed data from our two lemborexant clinical trials (N = 1956) as well as a two-factor solution based on 6 items did. Using triangulation of anchor-based, distribution-based, and ROC methods, we determined that a 5-point reduction using 6 items best represented a clinically meaningful improvement in individuals with insomnia in our patient sample. CONCLUSIONS: A 6-item two-factor scale had better psychometric properties than the 7-item scale in this patient sample. On the 6-item scale, a reduction of 5 points in the ISI total score represented the MWIC. Generalizability of the proposed MWIC may be limited to patient populations with similar demographic and clinical characteristics.
Assuntos
Psicometria , Índice de Gravidade de Doença , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Psicometria/métodos , Adulto , Análise Fatorial , Resultado do Tratamento , Curva ROC , Piridinas , PirimidinasRESUMO
BACKGROUND: Influenza vaccines are most effective when the antigens in the vaccine match those of circulating strains. However, antigens contained in the vaccines do not always match circulating strains. In the present work we aimed to examine the vaccine efficacy (VE) afforded by influenza vaccines when they are not well matched to circulating strains. METHODS: We identified randomized clinical trials (RCTs) through MEDLINE, EMBASE, the Cochrane Library, and references of included RCTs. RCTs reporting laboratory-confirmed influenza among healthy participants vaccinated with antigens of matching and non-matching influenza strains were included. Two independent reviewers screened citations/full-text articles, abstracted data, and appraised risk of bias. Conflicts were resolved by discussion. A random effects meta-analysis was conducted. VE was calculated using the following formula: (1 - relative risk × 100%). RESULTS: We included 34 RCTs, providing data on 47 influenza seasons and 94,821 participants. The live-attenuated influenza vaccine (LAIV) showed significant protection against mismatched (six RCTs, VE 54%, 95% confidence interval (CI) 28% to 71%) and matched (seven RCTs, VE 83%, 95% CI 75% to 88%) influenza strains among children aged 6 to 36 months. Differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 75%, 95% CI 41% to 90%) and mismatched influenza B (five RCTs, VE 42%, 95% CI 22% to 56%) estimates among children aged 6 to 36 months. The trivalent inactivated vaccine (TIV) also afforded significant protection against mismatched (nine RCTs, VE 52%, 95% CI 37% to 63%) and matched (eight RCTs, VE 65%, 95% CI 54% to 73%) influenza strains among adults. Numerical differences were observed between the point estimates for mismatched influenza A (five RCTs, VE 64%, 95% CI 23% to 82%) and mismatched influenza B (eight RCTs, VE 52%, 95% CI 19% to 72%) estimates among adults. Statistical heterogeneity was low (I2 <50%) across all meta-analyses, except for the LAIV meta-analyses among children (I2 = 79%). CONCLUSIONS: The TIV and LAIV vaccines can provide cross protection against non-matching circulating strains. The point estimates for VE were different for matching versus non-matching strains, with overlapping CIs.
Assuntos
Vacinas contra Influenza/genética , Vacinas contra Influenza/uso terapêutico , Influenza Humana/genética , Influenza Humana/prevenção & controle , Proteção Cruzada/genética , Humanos , Influenza Humana/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Especificidade da Espécie , Resultado do Tratamento , Vacinas Atenuadas/genética , Vacinas Atenuadas/uso terapêuticoRESUMO
BACKGROUND: Indirect herd effect from vaccination of children offers potential for improving the effectiveness of influenza prevention in the remaining unvaccinated population. Static models used in cost-effectiveness analyses cannot dynamically capture herd effects. The objective of this study was to develop a methodology to allow herd effect associated with vaccinating children against seasonal influenza to be incorporated into static models evaluating the cost-effectiveness of influenza vaccination. METHODS: Two previously published linear equations for approximation of herd effects in general were compared with the results of a structured literature review undertaken using PubMed searches to identify data on herd effects specific to influenza vaccination. A linear function was fitted to point estimates from the literature using the sum of squared residuals. RESULTS: The literature review identified 21 publications on 20 studies for inclusion. Six studies provided data on a mathematical relationship between effective vaccine coverage in subgroups and reduction of influenza infection in a larger unvaccinated population. These supported a linear relationship when effective vaccine coverage in a subgroup population was between 20% and 80%. Three studies evaluating herd effect at a community level, specifically induced by vaccinating children, provided point estimates for fitting linear equations. The fitted linear equation for herd protection in the target population for vaccination (children) was slightly less conservative than a previously published equation for herd effects in general. The fitted linear equation for herd protection in the non-target population was considerably less conservative than the previously published equation. CONCLUSIONS: This method of approximating herd effect requires simple adjustments to the annual baseline risk of influenza in static models: (1) for the age group targeted by the childhood vaccination strategy (i.e. children); and (2) for other age groups not targeted (e.g. adults and/or elderly). Two approximations provide a linear relationship between effective coverage and reduction in the risk of infection. The first is a conservative approximation, recommended as a base-case for cost-effectiveness evaluations. The second, fitted to data extracted from a structured literature review, provides a less conservative estimate of herd effect, recommended for sensitivity analyses.
Assuntos
Influenza Humana/economia , Influenza Humana/prevenção & controle , Modelos Teóricos , Vacinação , Adolescente , Adulto , Análise Custo-Benefício , Humanos , Risco , Vacinação/economia , Adulto JovemRESUMO
Study Objectives: This systematic literature review and meta-analysis explored the impact of lemborexant and other insomnia treatments on next-day driving performance. Methods: Searches were conducted in MEDLINE and Embase on May 16, 2019, supplemented by clinical trial registries. Randomized controlled trials in healthy volunteers or people with insomnia were included if they reported a standardized on-road driving test, were published in English and included ≥1 group receiving a recommended dose of flunitrazepam, estazolam, triazolam, temazepam, brotizolam, etizolam, alprazolam, lorazepam, zolpidem, eszopiclone, zaleplon, zopiclone, trazodone, ramelteon, lemborexant, or suvorexant. Pairwise random-effects meta-analyses used the difference between each active treatment and placebo in standard deviation of lateral position (ΔSDLP). ΔSDLP of +2.4 cm, established as equivalent to a blood alcohol concentration of 0.05%, was considered clinically significant. Results: Fourteen studies were included. Clinically significant differences in ΔSDLP were shown in healthy volunteers for zopiclone (10/10 studies) and ramelteon (1/1 study), and in people with insomnia for flunitrazepam (2/3 studies). Premature test termination was reported most frequently for zopiclone (5/10 studies) and was reported in two subjects for suvorexant (1/2 studies), one for flunitrazepam (1/3 studies), and one for placebo (1/12 studies). Lemborexant had no statistically or clinically significant ΔSDLP, and no premature driving test terminations. Conclusions: Zopiclone, flunitrazepam, and ramelteon were associated with impaired driving performance, similar to driving under the influence of alcohol. Premature test termination was reported most frequently for zopiclone, and also for suvorexant, flunitrazepam and placebo. Lemborexant had no statistically or clinically significant effect on driving performance.
RESUMO
BACKGROUND: Insomnia is a common disorder associated with a substantial burden of illness, particularly in older adults. OBJECTIVE: To compare the efficacy and safety of lemborexant with specified other insomnia treatments through a systematic literature review and network meta-analysis (NMA). METHODS: Medline and Embase were systematically searched from inception to February 2019 and updated with a targeted search of PubMed for pivotal trials in March 2021. Randomized controlled trials in adults with primary insomnia were included if they reported results following at least 1 week of treatment. Interventions of interest were specified as lemborexant, suvorexant, benzodiazepines, benzodiazepine receptor agonists (also called Z-drugs [zolpidem, eszopiclone, zaleplon, zopiclone]), trazodone, and ramelteon. Efficacy outcomes included wake after sleep onset (WASO), sleep efficiency (SE), latency to persistent sleep (LPS)/sleep onset latency (SOL), total sleep time (TST) and Insomnia Severity Index (ISI). Bayesian NMA were performed at predetermined time intervals approximating 4 weeks, 3 months, and 6 months. Safety outcomes included serious adverse events (SAEs), withdrawals due to adverse events (AEs), and specified AEs (dizziness, somnolence, and falls). Subgroup analysis was conducted in the older population. RESULTS: 45 studies were included in the NMA. At 4 weeks, lemborexant had the highest probability of being the best treatment for 3 of the 4 outcomes measured objectively by polysomnography-TST, LPS, and SE-and was ranked second to suvorexant on WASO. Eszopiclone was highly ranked for subjectively measured SOL and ISI at 4 weeks, 3 months, and 6 months. Lemborexant was rated more highly than suvorexant in subjective measures of WASO, TST, and SOL at 4 weeks (the differences were not statistically significant). No statistically significant interactions between treatment effect and older subpopulations were found, indicating that the treatment effect was similar in older and adult populations. The safety profile of lemborexant was broadly similar to the other treatments for SAEs and withdrawals due to AEs. A limitation is the age of some of the included studies (3 were published in 1990 or earlier). A further limitation is the lack of stratification of recommended doses. If the doses used in the study publications do not reflect doses used in clinical practice, this could potentially bias the results. CONCLUSIONS: Lemborexant was ranked highest of the treatments studied on 3 out of the 4 objectively measured insomnia efficacy outcomes, with a safety profile broadly similar to other insomnia treatments. DISCLOSURES: This work was funded by Eisai Inc., which was involved with all stages of the study and analysis. McElroy, O'Leary, and Adena are consultants with Datalytics Pty Ltd., which was paid by Eisai Inc. for conducting the literature review and analysis. They were not financially compensated for collaborative efforts on publication-related activities. Campbell, Tahami Monfared, and Meier are employed by Eisai Inc. This study was presented as a poster at AMCP Nexus Virtual, October 20-23, 2020 and at the AGS Virtual Annual Scientific Meeting 2021, May 13-15, 2021.
Assuntos
Antagonistas dos Receptores de Orexina/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Humanos , Resultado do TratamentoRESUMO
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality in Japan. Prognosis is poor, and until recently sorafenib was the only treatment option available for patients with unresectable disease. Lenvatinib is the first therapy to demonstrate noninferiority to sorafenib. An analysis was conducted using clinical data from Japanese patients in the phase III REFLECT trial to assess the cost-effectiveness of lenvatinib versus sorafenib for first-line treatment of unresectable HCC in Japan. METHODS: A partitioned survival model was implemented adopting the perspective of the Japanese healthcare system, with costs and outcomes modeled over a lifetime horizon and using a discount rate of 2%, as per Japanese guidelines. Population data from the Japanese subpopulation of REFLECT were used to extrapolate outcomes, and costs and resource use were based on Japanese sources. The Japanese tariff was applied to EQ-5D data collected during the REFLECT clinical trial to obtain utility values reflecting the preferences of the Japanese population. RESULTS: Compared with sorafenib, lenvatinib is dominant because it is associated with a reduction in incremental costs of ¥156 799 and incremental quality-adjusted life-years of 0.31. These results were robust to changes in key assumptions, and probabilistic outcomes aligned with deterministic outcomes. CONCLUSION: Given the use of Japan-specific data in the cost-effectiveness model, it is expected that the use of lenvatinib as a first-line treatment in Japan will be associated with cost savings and improved clinical outcomes versus sorafenib for patients with unresectable HCC.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Análise Custo-Benefício , Humanos , Japão , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia , QuinolinasRESUMO
BACKGROUND: Hepatocellular carcinoma is the third-leading cause of cancer-related death worldwide. Preservation of health-related quality of life (HRQOL) during treatment is an important therapeutic goal. The aim of this study was to evaluate the effect of treatment with lenvatinib versus sorafenib on HRQOL. METHODS: REFLECT was a previously published multicentre, randomised, open-label, non-inferiority phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib as a first-line systemic treatment for unresectable hepatocellular carcinoma. Eligible patients were aged 18 years or older with unresectable hepatocellular carcinoma and one or more measurable target lesion per modified Response Evaluation Criteria in Solid Tumors criteria, Barcelona Clinic Liver Cancer stage B or C categorisation, Child-Pugh class A, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or lower, and adequate organ function. Patients were randomly assigned (1:1) via an interactive voice-web response system; stratification factors for treatment allocation included region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG performance status; and bodyweight. Patient-reported outcomes (PROs), collected at baseline, on day 1 of each subsequent cycle, and at the end of treatment, were evaluated in post-hoc analyses of secondary and exploratory endpoints in the analysis population, which was the subpopulation of patients with a PRO assessment at baseline. A linear mixed-effects model evaluated change from baseline in PROs, including European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and hepatocellular carcinoma-specific QLQ-HCC18 scales (both secondary endpoints of the REFLECT trial). Time-to-definitive-deterioration analyses were done based on established thresholds for minimum differences for worsening in PROs. Responder analyses explored associations between HRQOL and clinical response. This study is registered with ClinicalTrials.gov, NCT01761266. FINDINGS: Of 954 eligible patients randomly assigned to lenvatinib (n=478) or sorafenib (n=476) between March 14, 2013, and July 30, 2015, 931 patients (n=468 for lenvatinib; n=463 for sorafenib) were included in this analysis. Baseline PRO scores reflected impaired HRQOL and functioning and considerable symptom burden relative to full HRQOL. Differences in overall mean change from baseline estimates in most PRO scales generally favoured the lenvatinib over the sorafenib group, although the differences were not nominally statistically or clinically significant. Patients treated with lenvatinib experienced nominally statistically significant delays in definitive, meaningful deterioration on the QLQ-C30 fatigue (hazard ratio [HR] 0·83, 95% CI 0·69-0·99), pain (0·80, 0·66-0·96), and diarrhoea (0·52, 0·42-0·65) domains versus patients treated with sorafenib. Significant differences in time to definitive deterioration were not observed for other QLQ-C30 domains, and there was no difference in time to definitive deterioration on the global health status/QOL score (0·89, 0·73-1·09). For most PRO scales, differences in overall mean change from baseline estimates favoured responders versus non-responders. Across all scales, HRs for time to definitive deterioration were in favour of responders; median time to definitive deterioration for responders exceeded those for non-responders by a range of 4·8 to 14·6 months. INTERPRETATION: HRQOL for patients undergoing treatment for unresectable hepatocellular carcinoma is an important therapeutic consideration. The evidence of HRQOL benefits in clinically relevant domains support the use of lenvatinib compared with sorafenib to delay functional deterioration in advanced hepatocellular carcinoma. FUNDING: Eisai and Merck Sharp & Dohme.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Sorafenibe/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/diagnóstico , Humanos , Neoplasias Hepáticas/diagnóstico , Resultado do TratamentoRESUMO
BACKGROUND: Previous studies have shown that influenza is associated with a substantial healthcare burden in the United Kingdom (UK), but more studies are needed to evaluate the resource use and direct medical costs of influenza in primary care and secondary care. METHODS: A retrospective observational database study in the UK to describe the primary care and directly-associated secondary care resource use, and direct medical costs of acute respiratory illness (ARI), according to age, and risk status (NCT Number: 01521416). Patients with influenza, ARI or influenza-related respiratory infections during 9 consecutive pre-pandemic influenza peak seasons were identified by READ codes in the linked Clinical Practice Research Datalink (CPRD) and Hospital Episodes Statistics (HES) dataset. The study period was from 21st January 2001 to 31st March 2009. RESULTS: A total of 156,193 patients had ≥1 general practitioner (GP) episode of ARI, and a total of 82,204 patients received ≥1 GP prescription, at a mean of 2.5 (standard deviation [SD]: 3.0) prescriptions per patient. The total cost of GP consultations and prescriptions equated to £462,827 per year per 100,000 patients. The yearly cost of prescribed medication for ARI was £319,732, at an estimated cost of £11,596,350 per year extrapolated to the UK, with 40% attributable to antibiotics. The mean cost of hospital admissions equated to a yearly cost of £981,808 per 100,000 patients. The total mean direct medical cost of ARI over 9 influenza seasons was £21,343,445 (SD: £10,441,364), at £136.65 (SD: £66.85) per case. CONCLUSIONS: Extrapolating to the UK population, for pre-pandemic influenza seasons from 2001 to 2009, the direct medical cost of ARI equated to £86 million each year. More studies are needed to assess the costs of influenza disease to help guide public health decision-making for seasonal influenza in the UK.
Assuntos
Custos e Análise de Custo , Recursos em Saúde/provisão & distribuição , Atenção Primária à Saúde/economia , Infecções Respiratórias , Atenção Secundária à Saúde/economia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos Transversais , Bases de Dados Factuais , Humanos , Pessoa de Meia-Idade , Infecções Respiratórias/economia , Infecções Respiratórias/epidemiologia , Estudos Retrospectivos , Reino Unido , Adulto JovemRESUMO
INTRODUCTION: Metastatic renal cell carcinoma is a complex cancer for which several drugs have been developed over the years. More recently, drugs that target the specific cancer cell mutations have been developed for metastatic cell carcinoma. However, even with the recent influx of targeted therapy options, significant unmet needs exist in around half of treated renal cell carcinoma patients following the failure of first-line therapy. The aim of this study was to review the health technology appraisals of renal cell carcinoma treatments in several countries to establish what factors might affect the reimbursement decisions. METHODS: The reimbursement data for 10 drugs in several countries were collated from the health technology assessment bodies for each country. The data included information on clinical trials used in the submission documents for the health technology assessment, the reimbursement decisions and the reasons for those decisions, as well as any specific restrictions for use of any of the included drugs. RESULTS: Of the 10 drugs reviewed, only everolimus received a positive reimbursement decision by all the health technology assessment bodies included in the study. The most common reason for a negative reimbursement decision was lack of demonstration of cost-effectiveness of the drugs. Another frequently cited reason was unproven clinical efficacy and poor impact on overall survival. CONCLUSION: Despite the many treatment guidelines and current treatment options that are available for renal cell carcinoma, there remains an unmet need in patients with metastatic renal cell carcinoma. On the basis of this analysis, the key reason for a drug not obtaining a positive reimbursement decision is due to poor efficacy or uncertainty of the drug's efficacy. FUNDING: Eisai, Inc.
Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/economia , Análise Custo-Benefício , Everolimo/economia , Everolimo/uso terapêutico , Reembolso de Seguro de Saúde/estatística & dados numéricos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/economia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológicoRESUMO
INTRODUCTION: A significant proportion of dementia is concretely estimated to be attributable to dementia with Lewy bodies (DLB)-one of the most common types of progressive dementia; however, there is a paucity of literature on this disease. We aimed to examine available evidence to gain a better understanding of its treatment landscape, clinical management, and disease burden. METHODS: A systematic literature review captured any DLB studies that report on randomised controlled trials (RCTs), epidemiology, disease progression, and economic data. An additional targeted literature review captured studies reporting on clinical management and quality of life (QoL) in this disease. Publication date was limited to 1 January 2007-26 March 2018, with the exception for RCTs, where no time restrictions were applied. FINDINGS: Of the 3486 studies initially identified, 55 studies were eligible for inclusion. The studies were mainly from Europe (n = 29), the USA (n = 9), and Japan (n = 8). Mini-Mental State Examination and Neuropsychiatric Inventory scores were the most commonly reported clinical outcomes in RCTs (n = 14). The most frequently identified interventions reported in RCTs were donepezil and memantine. Patients with DLB typically reported worse outcomes in relation to efficacy and safety, cognitive impairment, survival, and QoL compared with those with Alzheimer's disease (AD). Additionally, patients with DLB were associated with higher hospitalisation rates and cost of care. Furthermore, there is a reliance on a small number of consensus guidelines. Of these, only one set of guidelines (DLB Consortium) was developed specifically for DLB. CONCLUSION: The paucity of data indicates an unmet need in this therapy area. Although several studies look into the clinical and pathological aspects of DLB, consensus guidelines and studies on healthcare utilisation in patients with dementia have largely focused on AD. Additionally, most of the findings were made in comparison with AD. FUNDING: Eisai Inc.
RESUMO
BACKGROUND: In the absence of clinical trials providing direct efficacy results, this study compares different methods of indirect treatment comparison (ITC), and their respective impacts on efficacy estimates for lenvatinib (LEN) plus everolimus (EVE) combination therapy compared to other second-line treatments for advanced/metastatic renal cell carcinoma (a/mRCC). METHODS: Using EVE alone as the common comparator, the Bucher method for ITC compared LEN + EVE with cabozantinib (CAB), nivolumab (NIV), placebo (PBO) and axitinib (AXI). Hazard ratios (HR) for overall survival (OS) and progression-free survival (PFS) estimated the impact of applying three versions of the LEN+EVE trial data in separate ITCs. Last, to overcome exchangeability bias and potential violations to the proportional hazards assumption, a network meta-analysis using fractional polynomials was performed. RESULTS: Bucher ITCs demonstrated LEN + EVE superiority over EVE for PFS, indirect superiority to NIV, AXI, and PBO, and no difference to CAB. For OS, LEN + EVE was superior to EVE and indirectly superior to PBO, applying original HOPE 205 data. Using European Medicines Agency data, LEN + EVE was directly superior to EVE for OS. Fractional polynomial HRs for PFS and OS substantially overlapped with Bucher estimates, demonstrating LEN+EVE superiority over EVE, alone, NIV, and CAB. However, there were no statistically significant results as the credible intervals for HR crossed 1.0. CONCLUSIONS: Comparing three Bucher ITCs, LEN + EVE demonstrated superior PFS when indirectly compared to NIV, AXI, and PBO, and mixed results for OS. While fractional polynomial modelling for PFS and OS failed to find statistically significant differences in LEN + EVE efficacy, the overall HR trends were comparable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Quinolinas/uso terapêutico , Carcinoma de Células Renais/patologia , Humanos , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Lenvatinib demonstrated a treatment effect on overall survival by the statistical confirmation of non-inferiority to sorafenib for the first-line treatment of uHCC. The objective of this study was to evaluate the cost-effectiveness of lenvatinib compared with sorafenib for patients with uHCC in Japan. METHODS: A partitioned-survival model was developed to estimate the cost-effectiveness of lenvatinib versus sorafenib when treating uHCC patients over a lifetime horizon and considering total public healthcare expenditure. Efficacy and safety data were extracted from the REFLECT trial. Utility values were derived from the European Quality-of-Life 5-Dimension Questionnaire, conducted with patients enrolled in the REFLECT trial. Direct medical costs, such as primary drug therapy, outpatient visits, diagnostic tests, hospitalization, post-progression therapy, and adverse-event treatments, were included. Cost parameters unavailable in the clinical trial or publications were obtained based on the consolidated clinical standards from a Delphi panel of four Japanese medical experts. RESULTS: For lenvatinib versus sorafenib, the incremental cost was - 406,307 Japanese Yen (JPY), and the incremental life years and quality-adjusted life years (QALYs) were 0.27 and 0.23, respectively. Thus, lenvatinib dominated sorafenib, due to the mean incremental cost-effectiveness ratio falling in the fourth quadrant, conferring more benefit at lower costs compared with sorafenib. The probabilistic sensitivity analysis showed that 81.3% of the simulations were favorable to lenvatinib compared with sorafenib, with a payer's willingness-to-pay-per-QALY of 5 million JPY. CONCLUSIONS: Lenvatinib was cost-effective compared with sorafenib for the first-line treatment of uHCC in Japan.
Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Sorafenibe/administração & dosagem , Antineoplásicos/administração & dosagem , Antineoplásicos/economia , Carcinoma Hepatocelular/economia , Análise Custo-Benefício , Humanos , Japão , Neoplasias Hepáticas/economia , Modelos Econômicos , Compostos de Fenilureia/economia , Anos de Vida Ajustados por Qualidade de Vida , Quinolinas/economia , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorafenibe/economia , Análise de SobrevidaRESUMO
Trivalent inactivated influenza vaccines (IIV3s) protect against 2 A strains and one B lineage; quadrivalent versions (IIV4s) protect against an additional B lineage. The objective was to assess projected health and economic outcomes associated with IIV4 versus IIV3 for preventing seasonal influenza in the US. A cost-effectiveness model was developed to interact with a dynamic transmission model. The transmission model tracked vaccination, influenza cases, infection-spreading interactions, and recovery over 10 y (2012-2022). The cost-effectiveness model estimated influenza-related complications, direct and indirect costs (2013-2014 US$), health outcomes, and cost-effectiveness. Inputs were taken from published/public sources or estimated using regression or calibration. Outcomes were discounted at 3% per year. Scenario analyses tested the reliability of the results. Seasonal vaccination with IIV4 versus IIV3 is predicted to reduce annual influenza cases by 1,973,849 (discounted; 2,325,644 undiscounted), resulting in 12-13% fewer cases and influenza-related complications and deaths. These reductions are predicted to translate into 18,485 more quality-adjusted life years (QALYs) accrued annually for IIV4 versus IIV3. Increased vaccine-related costs ($599 million; 5.7%) are predicted to be more than offset by reduced influenza treatment costs ($699 million; 12.2%), resulting in direct medical cost saving annually ($100 million; 0.6%). Including indirect costs, savings with IIV4 are predicted to be $7.1 billion (5.6%). Scenario analyses predict IIV4 to be cost-saving in all scenarios tested apart from low infectivity, where IIV4 is predicted to be cost-effective. In summary, seasonal influenza vaccination in the US with IIV4 versus IIV3 is predicted to improve health outcomes and reduce costs.
Assuntos
Análise Custo-Benefício , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/economia , Influenza Humana/prevenção & controle , Vacinação/economia , Vacinação/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Vacinas contra Influenza/imunologia , Masculino , Pessoa de Meia-Idade , Estados Unidos , Adulto JovemRESUMO
BACKGROUND: Acute otitis media (AOM) affects both child and parental quality of life (QoL). Data on QoL associated with AOM in Malaysia is sparse, and the burden of indirect costs have not been previously reported. OBJECTIVE: To determine the effect of pediatric AOM on child and parental QoL in Malaysia and its economic impact (indirect costs). METHODS: We utilized a set of QoL questionnaires (PAR-AOM-QOL, OM-6, and EQ-5D) combined with questions addressing work/productivity loss and financial costs associated with caring for a child during his or her illness in an observational, multicenter, prospective study. RESULTS: One hundred and ten AOM patients aged ≤5 years were included in the analysis. The majority of respondents were the patient's mother. Parental QoL was negatively affected for both emotional and daily disturbance scales, but the level of disturbance was low. Using OM-6, the greatest negative impact was on the child's QoL, followed by caregiver concerns, physical suffering, and emotional distress. Using EQ-5D, a moderately positive relationship between parents' emotional disturbance and daily disturbance, and a weak, negative correlation between parental emotional disturbance and parental health status was found. Parents with paid employment took an average of 21 h from work to care for their child, at an average cost of 321.8 Malaysian ringgit (US$97) in addition to their contribution to direct medical costs. Productivity losses whilst at work, uncompensated wage losses, and leisure time losses are also reported. CONCLUSIONS: This study found that AOM is associated with some negative impact on parental QoL and significant economic impact at both patient and societal levels. The findings provide useful data on healthcare resource utilization and disease burden of AOM in Malaysia.
RESUMO
On 17 and 18 July 2015, a meeting in Siena jointly sponsored by ADITEC and GlaxoSmithKline (GSK) was held to review the goals of the Global Health 2035 Grand Convergence, to discuss current vaccine evaluation methods, and to determine the feasibility of reaching consensus on an assessment framework for comprehensively and accurately capturing the full benefits of vaccines. Through lectures and workshops, participants reached a consensus that Multi-Criteria-Decision-Analysis is a method suited to systematically account for the many variables needed to evaluate the broad benefits of vaccination, which include not only health system savings, but also societal benefits, including benefits to the family and increased productivity. Participants also agreed on a set of "core values" to be used in future assessments of vaccines for development and introduction. These values include measures of vaccine efficacy and safety, incident cases prevented per year, the results of cost-benefit analyses, preventable mortality, and the severity of the target disease. Agreement on this set of core assessment parameters has the potential to increase alignment between manufacturers, public health agencies, non-governmental organizations (NGOs), and policy makers (see Global Health 2035 Mission Grand Convergence [1]). The following sections capture the deliberations of a workshop (Working Group 4) chartered to: (1) review the list of 24 parameters selected from SMART vaccines (see the companion papers by Timmis et al. and Madhavan et al., respectively) to determine which represent factors (see Table 1) that should be taken into account when evaluating the role of vaccines in maximizing the success of the Global Health 2035 Grand Convergence; (2) develop 3-5 "core values" that should be taken into account when evaluating vaccines at various stages of development; and (3) determine how vaccines can best contribute to the Global Health 2035 Grand Convergence effort.