Aims: This article aimed to examine the cost-effectiveness of rivaroxaban in comparison to warfarin for stroke prevention in Japanese patients with non-valvular atrial fibrillation (NVAF), from a public healthcare payer’s perspective.Materials and methods: Baseline event risks were obtained from the J-ROCKET AF trial and the treatment effect data were taken from a network meta-analysis. The other model inputs were extracted from the literature and official Japanese sources. The outcomes included the number of ischaemic strokes, myocardial infarctions, systemic embolisms and bleedings avoided, life-years, quality-adjusted life-years (QALYs), incremental costs and incremental cost-effectiveness ratio (ICER). The scenario analysis considered treatment effect data from the same network meta-analysis.Results: In comparison with warfarin, rivaroxaban was estimated to avoid 0.284 ischaemic strokes per patient, to increase the number of QALYs by 0.535 per patient and to decrease the total costs by ¥118,892 (€1,011.11) per patient (1 JPY = 0.00850638 EUR; XE.com, 7 October 2019). Consequently, rivaroxaban treatment was found to be dominant compared to warfarin. In the scenario analysis, the ICER of rivaroxaban versus warfarin was ¥2,873,499 (€24,446.42) per QALY.Limitations: The various sources of data used resulted in the heterogeneity of the cost-effectiveness analysis results. Although, rivaroxaban was cost-effective in the majority of cases.Conclusion: Rivaroxaban is cost-effective against warfarin for stroke prevention in Japanese patients with NVAF, giving the payer WTP of 5,000,000 JPY.

BACKGROUND: Regional variations in gastric cancer incidence are not explained by prevalence of Helicobacter pylori, the main cause of the disease, with several areas presenting high H. pylori prevalence but low gastric cancer incidence. The IARC worldwide H. pylori prevalence surveys (ENIGMA) aim at systematically describing age and sex-specific prevalence of H. pylori infection around the world and generating hypotheses to explain regional variations in gastric cancer risk. METHODS: We selected age- and sex-stratified population samples in two areas with different gastric cancer incidence and mortality in Chile: Antofagasta (lower rate) and Valdivia (higher rate). Participants were 1-69 years old and provided interviews and blood for anti-H. pylori antibodies (IgG, VacA, CagA, others) and atrophy biomarkers (pepsinogens). RESULTS: H. pylori seroprevalence (Age-standardized to world population) and antibodies against CagA and VacA were similar in both sites. H. pylori seroprevalence was 20% among children <10 years old, 40% among 10-19 year olds, 60% in the 20-29 year olds and close to or above 80% in those 30+ years. The comparison of the prevalence of known and potential H. pylori cofactors in gastric carcinogenesis between the high and the low risk area showed that consumption of chili products was significantly higher in Valdivia and daily non-green vegetable consumption was more common in Antofagasta. Pepsinogen levels suggestive of gastric atrophy were significantly more common and occurred at earlier ages in Valdivia, the higher risk area. In a multivariate model combining both study sites, age, chili consumption and CagA were the main risk factors for gastric atrophy. CONCLUSIONS: The prevalence of H. pylori infection and its virulence factors was similar in the high and the low risk area, but atrophy was more common and occurred at younger ages in the higher risk area. Dietary factors could partly explain higher rates of atrophy and gastric cancer in Valdivia. IMPACT: The ENIGMA study in Chile contributes to better understanding regional variations in gastric cancer incidence and provides essential information for public health interventions.

ABSTRACTThe results of a clinical trial comparing hydroxychloroquine with or without azithromycin to the standard of care for the treatment of COVID-19 were recently published by Philippe Gautret et al. This study provides outstanding results for the combination of hydroxychloroquine and azithromycin over the standard of care, but the evidence was deemed insufficiently robust to warrant a public health decision to widen the use of hydroxychloroquine for the treatment of COVID-19. We provide a scientific critical review of the Gautret et al. publication, put the results in the context of the current knowledge, provide an evaluation of the validity of the results (from a methodologic perspective), and discuss public health implications. The study has a number of limitations, including small sample size, lack of comparability between patients in active treatment and control arms, lack of blinding, use of interim analyses without controlling for the risk of type 1 error, use of analysis in the per-protocol population instead of the intention-to-treat population, and inconsistencies between the study protocol and article. However, none of these observations is of a nature to reverse the conclusions. The study brings useful knowledge consistent with available evidence and clinical practice from China and South Korea, which could have prompted quicker policy decision-making.

INTRODUCTION: Human papillomavirus (HPV) testing is replacing cytology in primary screening. Its limited specificity demands using a second (triage) test to better identify women at high-risk of cervical disease. Cytology represents the immediate triage but its low sensitivity might hamper HPV testing sensitivity, particularly in low-income and middle-income countries (LMICs), where cytology performance has been suboptimal. The ESTAMPA (EStudio multicéntrico de TAMizaje y triaje de cáncer de cuello uterino con pruebas del virus del PApiloma humano; Spanish acronym) study will: (1) evaluate the performance of different triage techniques to detect cervical precancer and (2) inform on how to implement HPV-based screening programmes in LMIC. METHODS AND ANALYSIS: Women aged 30-64 years are screened with HPV testing and Pap across 12 study centres in Latin America. Screened positives have colposcopy with biopsy and treatment of lesions. Women with no evident disease are recalled 18 months later for another HPV test; those HPV-positive undergo colposcopy with biopsy and treatment as needed. Biological specimens are collected in different visits for triage testing, which is not used for clinical management. The study outcome is histological high-grade squamous intraepithelial or worse lesions (HSIL+) under the lower anogenital squamous terminology. About 50 000 women will be screened and 500 HSIL+ cases detected (at initial and 18 months screening). Performance measures (sensitivity, specificity and predictive values) of triage techniques to detect HSIL+ will be estimated and compared with adjustment by age and study centre. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of the International Agency for Research on Cancer (IARC), of the Pan American Health Organisation (PAHO) and by those in each participating centre. A Data and Safety Monitoring Board (DSMB) has been established to monitor progress of the study, assure participant safety, advice on scientific conduct and analysis and suggest protocol improvements. Study findings will be published in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: NCT01881659.

BACKGROUND: The cost of treating Clostridioides difficile infection (CDI), particularly recurrent disease, is high. In clinical trials, fidaxomicin has been associated with significantly lower recurrence rates and higher sustained cure rates versus vancomycin. The high acquisition cost of fidaxomicin has limited its acceptance into clinical practice. OBJECTIVE: To evaluate the cost-effectiveness of fidaxomicin versus vancomycin in patients with CDI after failure of metronidazole in the Japanese healthcare setting. METHODS: Clinical results from three phase III trials and inputs based on assumptions validated by clinical experts in Japan were used in a semi-Markov model with 1-year time horizon. Incremental cost-effectiveness ratios (ICERs) for fidaxomicin versus vancomycin were expressed as cost per quality-adjusted life year (QALY) and interpreted using willingness-to-pay thresholds of JPY 5,000,000 (primary) and JPY 7,500,000 (secondary) per QALY gained in Japan. Probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Higher drug acquisition costs for fidaxomicin were partially offset by lower hospitalization costs driven by fewer recurrences, lower costs of complications, and fewer general practitioner visits versus vancomycin. The ICER for fidaxomicin versus vancomycin was estimated at JPY 5,715,183 per QALY gained. Sensitivity analyses showed a 46% probability of fidaxomicin being cost-effective versus vancomycin at a willingness-to-pay threshold of JPY 5,000,000 per QALY gained. At a threshold of JPY 7,500,000, there was a 54% probability of fidaxomicin being cost-effective. CONCLUSIONS: Fidaxomicin treatment in patients with CDI following failure of metronidazole improves health outcomes with partial offset of higher drug acquisition costs versus vancomycin.

BACKGROUND: Mounting pressures on the healthcare system, such as budget constraints and new, costly health technologies reaching the market, have pushed payers and manufacturers to engage in managed entry agreements (MEAs) to address uncertainty and facilitate market access. OBJECTIVES: This study was conducted to illustrate the current landscape of MEAs in Europe and to analyze the main hurdles they face in implementation, providing a policy perspective. METHODS: We conducted a health policy analysis based on a literature review and described the emergence, classification, current use, and implementation obstacles of MEAs in Europe. RESULTS: Throughout Europe, uncertainty and high prices of health technologies have pushed stakeholders towards MEAs. Two main types of MEAs were applied heavily, finance-based agreements (FBAs) and performance-based agreements, including individual performance-based agreements and coverage with evidence development (CED). Service-based agreements have not been as heavily considered so far, yet are increasingly used. Many European countries are turning to CEDs to address uncertainty and facilitate market access while negotiating the pricing and reimbursement rates of products. Despite the interest in CEDs, European countries have moved toward FBAs due to the complexities and burdens associated with PBAs. CONCLUSIONS: Ultimately, in Europe, with the exception of Italy, where MEAs have proven to be inefficient, MEAs are predominantly FBAs dedicated to addressing cost containment from payers’ perspective and external reference pricing from the manufacturers’ perspective. It has been speculated that MEAs will disappear in the medium-term as they are counterproductive for extending patient access and emergence of innovation. To inform value-based decision making and allow early access to innovative medicines, CEDs should be revisited.

ABSTRACT Purpose A international registry analysis led by Mehra et al. to investigate the use of hydroxychloroquine (HCQ) and chloroquine (CQ) with or without a macrolide in 96,032 hospitalised COVID-19 patients were published on Lancet, which has raised considerable discussions in the public health community. This study aimed to critically review the quality and limitations of the Mehra et al. publication and discuss the potential influences on the use of HCQ/CQ worldwide. Method A critical review of this publication was conducted to examine the potential study bias in the study objectives, methodology, confounding factors and outcomes and summarise the external reviews. Results The very high homogeneity of the patients? characteristics at baseline was inconsistent with region specific epidemiology and several critical confounding factors. The results indicated that angiotensin converting enzyme inhibitors were associated with a hazard ratio of 0.5, which suggested a technical problem in the estimation of the propensity scores. Several major risk factors for mortality identified in the analysis were treated as a minor risk or neutral or even protective factors. Antiviral treatments were recognised as an effective method to reduce mortality and were neither further studied nor integrated in the multivariate Cox model. Conclusion This research appeared to carry multiple biases. An extensive audit of the study, conditions of review and acceptance for publication in the Lancet of that study are requested to avoid damage to the publics? trust on the scientific community at this critical time of COVID-19 pandemic.

ABSTRACTBackground: Dementia has become a growing health-care problem in the rapidly ageing Japanese population. This study assesses the impact of dementia on quality of life, economic burden, and productivity loss.Objective: The objective of this study was to assess the impact of dementia on the Quality of Life (QoL), economic burden, and productivity loss among families living with dementia.Methods: An online survey was conducted among families who lived with relatives with dementia. Demographic data and information about health condition and costs of long-term care and treatment were collected. Participants were asked to answer the EuroQol (EQ-5D-5L) questionnaire, Zarit Burden Interview (ZARIT-8), and Work Productivity and Activity Impairment Questionnaire (WPAI). Multivariate analyses were conducted to assess factors associated with burden by families living with dementia.Results: Six hundred and thirty-five participants completed the survey. Of these participants, 50.5% were primary caregivers. Overall, 78.7% of dementia patients suffered from Alzheimer, and 43.9% needed long-term care. Compared to non-primary caregivers, primary caregivers had lower health utility scores (0.896 vs 0.873; p = 0.02), higher burden of caregiving (ZARIT-8: 21.1 vs 24.5; p < 0.0001), and higher overall work impairment (40.2% vs 20.8%; p < 0.0001), absenteeism (15.3% vs 5.7%; p < 0.0001), and presenteeism-related impairment (33.2% vs 17.3%; p < 0.0001).Conclusion: Families living with dementia caring for a person with dementia experience increased burden. Health policies related to dementia need to be considered not only for patients, but also for their families living with dementia to improve their QoL.

BackgroundBaloxavir marboxil (baloxavir) is a new oral antiviral for influenza types A and B.

PURPOSE: To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS: A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS: Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION: Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.