Inclusion of Safety-Related Issues in Economic Evaluations for Seasonal Influenza Vaccines:A Systematic Review

(1) Background: Vaccines for seasonal influenza are a good preventive and cost-effective strategy. However, it is unknown if and how these economic evaluations include the adverse events following immunization (AEFI), and what the impact of such inclusion is on the health economic outcomes. (2) Methods: We searched the literature, up to January 2020, to identify economic evaluations of seasonal influenza vaccines that considered AEFIs. The review protocol was published in PROSPERO (CDR42017058523). (3) Results: A total of 52 economic evaluations considered AEFI-related parameters in their analyses, reflecting 16% of the economic evaluations on seasonal influenza vaccines in the initial study selection. Most studies used the societal perspective (64%) and evaluated vaccination of children (37%). Where considered, studies included direct medical costs of AEFIs (90%), indirect costs (27%), and disutilities/quality-adjusted life years loss due to AEFIs (37%). The majority of these studies accounted for the effects of the costs of AEFI on cost-effectiveness for Guillain–Barré syndrome. In those papers allowing cost share estimation, direct medical cost of AFEIs was less than 2% of total direct costs. (4) Conclusions: Although the overall impact of AEFIs on the cost-effectiveness outcomes was found to be low, we urge their inclusion in economic evaluations of seasonal influenza vaccines to reflect comprehensive reports for the decision makers and end-users of the vaccination strategies

The Effect of Individual Movements and Interventions on the Spread of Influenza in Long-Term Care Facilities

Background. Nosocomial influenza poses a serious risk among residents of long-term care facilities (LTCFs). Objective. We sought to evaluate the effect of resident and staff movements and contact patterns on the outcomes of various intervention strategies for influenza control in an LTCF. Methods. We collected contact frequency data in Canada's largest veterans' LTCF by enroling residents and staff into a study that tracked their movements through wireless tags and signal receivers. We analyzed and fitted the data to an agent-based simulation model of influenza infection, and performed Monte-Carlo simulations to evaluate the benefit of antiviral prophylaxis and patient isolation added to standard (baseline) infection control practice (i.e., vaccination of residents and staff, plus antiviral treatment of residents with symptomatic infection). Results. We calibrated the model to attack rates of 20%, 40%, and 60% for the baseline scenario. For data-driven movements, we found that the largest reduction in attack rates (12.5% to 27%; ANOVA P 0.2) among residents. In contrast, parameterizing the model with random movements yielded different results, suggesting that the highest benefit was achieved through patient isolation (69.6% to 79.6%; ANOVA P <0.001) while the additional benefit of prophylaxis was negligible in reducing the cumulative number of infections. Conclusions. Our study revealed a highly structured contact and movement patterns within the LTCF. Accounting for this structureinstead of assuming randomnessin decision analytic methods can result in substantially different predictions

Cost-Effectiveness of Pediatric Influenza Vaccination in The Netherlands

Objective: This study evaluates the cost-effectiveness of extending the Dutch influenza vaccination program for elderly and medical high-risk groups to include pediatric influenza vaccination, taking indirect protection into account. Methods: An age-structured dynamic transmission model was used that was calibrated to influenza-associated GP visits over 4 seasons (2010-2011 to 2013-2014). The clinical and economic impact of different pediatric vaccination strategies were compared over 20 years, varying the targeted age range, the vaccine type for children or elderly and high-risk groups. Outcome measures include averted symptomatic infections and deaths, societal costs and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Costs and QALYs were discounted at 4% and 1.5% annually. Results: At an assumed coverage of 50%, adding pediatric vaccination for 2to 17-year-olds with quadrivalent live-attenuated vaccine to the current vaccination program for elderly and medical high-groups with quadrivalent inactivated vaccine was estimated to avert, on average, 401 820 symptomatic cases and 72 deaths per year. Approximately half of averted symptomatic cases and 99% of averted deaths were prevented in other age groups than 2to 17-year-olds due to herd immunity. The cumulative discounted 20-year economic impact was 35 068 QALYs gained and V1687 million saved, that is, the intervention was cost-saving. This vaccination strategy had the highest probability of being the most cost-effective strategy considered, dominating pediatric strategies targeting 2to 6-year-olds or 2to 12-year-olds or strategies with trivalent inactivated vaccine. Conclusion: Modeling indicates that introducing pediatric influenza vaccination in The Netherlands is cost-saving, reducing the influenza-related disease burden substantially

Resistance to diet-induced adiposity in cannabinoid receptor-1 deficient mice is not due to impaired adipocyte function

Background: Overactivity and/or dysregulation of the endocannabinoid system (ECS) contribute to development of obesity. In vitro studies indicate a regulatory role for the cannabinoid receptor 1 (CB1) in adipocyte function and CB1-receptor deficient (CB1-/-) mice are resistant to high fat diet-induced obesity. Whether this phenotype of CB1-/- mice is related to altered fat metabolism in adipose tissue is unknown. Methods: We evaluated adipose tissue differentiation/proliferation markers and quantified lipogenic and lipolytic activities in fat tissues of CB1-/- and CB1+/+ mice fed a high-fat (HF) or a high-fat/fish oil (HF/FO) diet as compared to animals receiving a low-fat chow diet. Comparison between HF diet and HF/FO diet allowed to investigate the influence of dietary fat quality on adipose tissue biology in relation to CB1 functioning. Results: The adiposity-resistant phenotype of the CB1-/- mice was characterized by reduced fat mass and adipocyte size in HF and HF/FO-fed CB1-/- mice in parallel to a significant increase in energy expenditure as compared to CB1+/+ mice. The expression levels of adipocyte differentiation and proliferation markers were however maintained in these animals. Consistent with unaltered lipogenic gene expression, the fatty acid synthesis rates in adipose tissues from CB1-/- and CB1+/+ mice were unchanged. Whole-body and adipose-specific lipoprotein lipase (LPL) activities were also not altered in CB1-/- mice. Conclusions: These findings indicate that protection against diet-induced adiposity in CB1-deficient mice is not related to changes in adipocyte function per se, but rather results from increased energy dissipation by oxidative and non-oxidative pathways.

Use of glitazones and the risk of elective HIP or knee replacement: A population based case-control study

Background: Osteoarthritis (OA) is the most common musculoskeletal condition in the elderly population. However, to date, no disease modifying drug exists for this disease. In vivo studies have shown that glitazones may be used as anti-arthritic drugs. (Kobayashi, 2005; Boileau, 2007). Objectives: To determine the risk of total joint replacement (TJR) with the use of glitazones. Methods: A population based case-control study was performed using the Clinical Practice Research Datalink (CPRD). Cases (n=94,609) were defined as patients >18 years of age who had undergone TJR surgery between 2000 and 2012. Controls were matched by age, gender and general practice. Conditional logistic regression was used to estimate the risk of total knee (TKR) and total hip replacement (THR) associated with use of glitazones. We additionally evaluated risk of TJR in current glitazone users compared to DM patients using other antidiabetic drugs (ADs). In order to determine a dose effect relationship, we also stratified glitazone users by total number of prescriptions prior to surgery. Results: There is no difference in risk of TKR (OR=1.11 (95% CI=0.95-1.29)) or THR (OR=0.87 (95% CI=0.74-1.02)) between glitazone users and patients not using glitazones. Furthermore, there is no difference in risk of TKR (OR=1.03 (95% CI=0.88-1.22)) and THR (OR=0.90 (95% CI=0.75-1.08)) when glitazones users are compared to other AD users. Finally, we did not find a dose response effect with increasing number of prescriptions. Conclusions: This study did not find any evidence for an anti-arthritic effect of glitazones

The cost-effectiveness of trivalent and quadrivalent influenza vaccination in communities in South Africa, Vietnam and Australia

BACKGROUND: To inform national healthcare authorities whether quadrivalent influenza vaccines (QIVs) provide better value for money than trivalent influenza vaccines (TIVs), we assessed the cost-effectiveness of TIV and QIV in low-and-middle income communities based in South Africa and Vietnam and contrasted these findings with those from a high-income community in Australia. METHODS: Individual based dynamic simulation models were interfaced with a health economic analysis model to estimate the cost-effectiveness of vaccinating 15% of the population with QIV or TIV in each community over the period 2003-2013. Vaccination was prioritized for HIV-infected individuals, before elderly aged 65+ years and young children. Country or region-specific data on influenza-strain circulation, clinical outcomes and costs were obtained from published sources. The societal perspective was used and outcomes were expressed in International$(I$) per quality-adjusted life-year (QALY) gained. RESULTS: When compared with TIV, we found that QIV would provide a greater reduction in influenza-related morbidity in communities in South Africa and Vietnam as compared with Australia. The incremental cost-effectiveness ratio of QIV versus TIV was estimated at I$4183/QALY in South Africa, I$1505/QALY in Vietnam and I$80,966/QALY in Australia. CONCLUSIONS: The cost-effectiveness of QIV varied between communities due to differences in influenza epidemiology, comorbidities, and unit costs. Whether TIV or QIV is the most cost-effective alternative heavily depends on influenza B burden among subpopulations targeted forvaccination in addition to country-specific willingness-to-pay thresholds and budgetary impact

Secondary adherence to non-vitamin-K antagonist oral anticoagulants in patients with atrial fibrillation in Sweden and the Netherlands

Objective: There is limited evidence on patients' adherence and the impact of the prescribed dosing regimen in non-vitamin-K oral anticoagulants (NOACs). We aimed to assess secondary adherence to NOACs and to determine the impact of the dosing regimen in patients with atrial fibrillation. Methods: Patients using a NOAC between 2009 and 2013 were identified from the nation-wide Swedish Prescribed Drug Register and the Dutch regional IADB.nl database. Patients using a consistent dosage for at least 180 consecutive days were included. Adherence was calculated using the medication possession ratio (MPR) and adjusted for overlapping dates. Adherence was defined as a MPR >= 0.8. Sensitivity analyses were performed using a MPR >= 0.9. Logistic regression was performed to compare secondary adherence and to explore the influence of the dosing regimen. Results: A total of 5254 Swedish and 430 Dutch NOAC users were included. The mean MPR was 96.0% (SD 7.8%) in Sweden and 95.1% (SD 10.1%) in the Netherlands. Multivariable logistic regression analysis showed that a twice daily regimen had a lower likelihood of being secondary adherent compared to a once daily regimen in Sweden (odds ratio [OR] 0.21 [95% CI 0.12-0.35]). Limitations: The influence of selection bias introduced by the inclusion criterion of >= 2 dispensations covering at least 180 days could not be excluded. Conclusions: This study demonstrated that secondary adherence was high in this specific setting among patients with at least two initial dispensations of a NOAC covering a minimum of 180 days. The use of NOACs in a once daily regimen showed higher adherence compared to a twice daily regimen

Cost-effectiveness of vaccination of immunocompetent older adults against herpes zoster in the Netherlands: a comparison between the adjuvanted subunit and live-attenuated vaccines.

BACKGROUND: The newly registered adjuvanted herpes zoster subunit vaccine (HZ/su) has a higher efficacy than the available live-attenuated vaccine (ZVL). National decision-makers soon need to decide whether to introduce HZ/su or to prefer HZ/su above ZVL. METHODS: Using a Markov model with a decision tree, we conducted a cost-effectiveness analysis of vaccination with HZ/su (two doses within 2 months) or zoster vaccine live (ZVL) (single dose, or single dose with a booster after 10 years) for cohorts of 50-, 60-, 70- or 80-year-olds in the Netherlands. The model was parameterized using vaccine efficacy data from randomized clinical trials and up-to-date incidence, costs and health-related quality of life data from national datasets. We used a time horizon of 15 years, and the analysis was conducted from the societal perspective. RESULTS: At a coverage of 50%, vaccination with two doses of HZ/su was estimated to prevent 4335 to 10,896 HZ cases, depending on the cohort age. In comparison, this reduction was estimated at 400-4877 for ZVL and 427-6466 for ZVL with a booster. The maximum vaccine cost per series of HZ/su to remain cost-effective to a willingness-to-pay threshold of €20,000 per quality-adjusted life year (QALY) gained ranged from €109.09 for 70-year-olds to €63.68 for 50-year-olds. The cost-effectiveness of ZVL changed considerably by age, with corresponding maximum vaccine cost per dose ranging from €51.37 for 60-year-olds to €0.73 for 80-year-olds. Adding a ZVL booster after 10 years would require a substantial reduction of the maximum cost per dose to remain cost-effective as compared to ZVL single dose. Sensitivity analyses on the vaccine cost demonstrated that there were scenarios in which vaccination with either HZ/su (two doses), ZVL single dose or ZVL + booster could be the most cost-effective strategy. CONCLUSIONS: A strategy with two doses of HZ/su was superior in reducing the burden of HZ as compared to a single dose or single dose + booster of ZVL. Both vaccines could potentially be cost-effective to a conventional Dutch willingness-to-pay threshold for preventive interventions. However, whether HZ/su or ZVL would be the most cost-effective alternative depends largely on the vaccine cost

Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype

INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving