Screening for liver fibrosis: lessons from colorectal and lung cancer screening.

Many countries have incorporated population screening programmes for cancer, such as colorectal and lung cancer, into their health-care systems. Cirrhosis is more prevalent than colorectal cancer and has a comparable age-standardized mortality rate to lung cancer. Despite this fact, there are no screening programmes in place for early detection of liver fibrosis, the precursor of cirrhosis. In this Perspective, we use insights from colorectal and lung cancer screening to explore the benefits, challenges, implementation strategies and pathways for future liver fibrosis screening initiatives. Several non-invasive methods and referral pathways for early identification of liver fibrosis exist, but in addition to accurate detection, screening programmes must also be cost-effective and demonstrate benefit through a reduction in liver-related mortality. Randomized controlled trials are needed to confirm this. Future randomized screening trials should evaluate not only the screening tests, but also interventions used to halt disease progression in individuals identified through screening.

Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort.

AIMS: Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment. METHODS: The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment. RESULTS: 228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained. CONCLUSIONS: Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.

Longitudinal Changes in Health-Related Quality of Life in Patients With Atrial Fibrillation.

Background Optimizing health-related quality of life (HRQoL) is an important aim of atrial fibrillation (AF) treatment. Little is known about patients' long-term HRQoL trajectories and the impact of patient and disease characteristics. The aim of this study was to describe HRQoL trajectories in an observational AF study population and in clusters of patients with similar patient and disease characteristics. Methods and Results We used 5-year follow-up data from the Swiss-Atrial Fibrillation prospective cohort, which enrolled 2415 patients with prevalent AF from 2014 to 2017. HRQoL data, collected yearly, comprised EuroQoL-5 dimension utilities and EuroQoL visual analog scale scores. Patient clusters with similar characteristics at enrollment were identified using hierarchical clustering. HRQoL trajectories were analyzed descriptively and with inverse probability-weighted regressions. Effects of postbaseline clinical events were additionally assessed using time-shifted event variables. Among 2412 (99.9%) patients with available baseline HRQoL, 3 clusters of patients with AF were identified, which we characterized as follows: "cardiovascular dominated," "isolated symptomatic," and "severely morbid without cardiovascular disease." Utilities and EuroQoL visual analog scale scores remained stable over time for the full population and the clusters; isolated symptomatic patients showed higher levels of HRQoL. Utilities were reduced after occurrences of stroke, hospitalization for heart failure, and bleeding, by -0.12 (95% CI, -0.18 to -0.06), -0.10 (95% CI, -0.13 to -0.08), and -0.06 (95% CI, -0.08 to -0.04), respectively, on a 0 to 1 utility scale. Utility of surviving patients returned to preevent levels 4 years after heart failure hospitalization; 3 years after bleeding; and 1 year after stroke. Conclusions In patients with prevalent AF, HRQoL was stable over time, irrespective of baseline patient characteristics. Clinical events of hospitalization for heart failure, stroke, and bleeding had only a temporary effect on HRQoL.

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Regulatory Review Duration and Differences in Submission Times of Drugs in the United States and Europe, 2011 to 2020.

The speed of drug regulatory agencies in the United States and Europe is often a source of discussion. The objective of this research was to assess regulatory review duration of first and supplementary indications approved between 2011 and 2020 in the United States and Europe (European Union [EU] and Switzerland) and differences in submission times between the United States and Europe. Descriptive statistics were applied to review times between the jurisdictions and across the therapeutic areas. A regression analysis was done to estimate the association between approval agency and review times. The primary analysis cohort included 241 drugs approved in the United States, the EU, and Switzerland. Of these, 128 drugs had supplemental indications (331 in total) in the United States and 87 had supplemental indications (206 in total) in the EU. Overall median review duration from submission to approval subtracting the clock stop period was 39 weeks in the United States, 44 weeks in the EU, and 44 weeks in Switzerland. When review times within each drug were compared, the European Medicines Agency took a median of 3.7 weeks (IQR, -6.7 to 14.9 weeks) longer than the U.S. Food and Drug Administration and Swissmedic a median of 0.3 weeks (IQR, -10.6 to 15.3 weeks) longer. Median total review duration for supplemental indications was 26 weeks in the United States and 40 weeks in the EU. Applications were submitted a median of 1.3 and 17.9 weeks later in the EU and Switzerland, respectively, than in the United States. The regression analysis showed small differences in submission times between the United States and the EU (-2.1 weeks [95% CI, -11.7 to 7.6 weeks]) and larger differences between the United States and Switzerland (33.0 weeks [CI, 23.1 to 42.8 weeks]). It would be beneficial for patients if differences in submission times between the United States and Europe continue to be minimized.

Estimating the cost impact of atrial fibrillation using a prospective cohort study and population-based controls.

AIMS: Atrial fibrillation (AF) costs are expected to be substantial, but cost comparisons with the general population are scarce. Using data from the prospective Swiss-AF cohort study and population-based controls, we estimated the impact of AF on direct healthcare costs from the Swiss statutory health insurance perspective. METHODS: Swiss-AF patients, enrolled from 2014 to 2017, had documented, prevalent AF. We analysed 5 years of follow-up, where clinical data, and health insurance claims in 42% of the patients were collected on a yearly basis. Controls from a health insurance claims database were matched for demographics and region. The cost impact of AF was estimated using five different methods: (1) ordinary least square regression (OLS), (2) OLS-based two-part modelling, (3) generalised linear model-based two-part modelling, (4) 1:1 nearest neighbour propensity score matching and (5) a cost adjudication algorithm using Swiss-AF data non-comparatively and considering clinical data. Cost of illness at the Swiss national level was modelled using obtained cost estimates, prevalence from the Global Burden of Disease Project, and Swiss population data. RESULTS: The 1024 Swiss-AF patients with available claims data were compared with 16 556 controls without known AF. AF patients accrued CHF5600 (EUR5091) of AF-related direct healthcare costs per year, in addition to non-AF-related healthcare costs of CHF11100 (EUR10 091) per year accrued by AF patients and controls. All five methods yielded comparable results. AF-related costs at the national level were estimated to amount to 1% of Swiss healthcare expenditure. CONCLUSIONS: We robustly found direct medical costs of AF patients were 50% higher than those of population-based controls. Such information on the incremental cost burden of AF may support healthcare capacity planning.

Real-World Cost-Effectiveness of Pulmonary Vein Isolation for Atrial Fibrillation: A Target Trial Approach.

OBJECTIVES: Randomized controlled trials of pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have proven the procedure's efficacy. Studies assessing its empirical cost-effectiveness outside randomized trial settings are lacking. We aimed to evaluate the effectiveness and cost-effectiveness of PVI versus medical therapy for AF. METHODS: We followed a target trial approach using the Swiss-AF cohort, a prospective observational cohort study that enrolled patients with AF between 2014 and 2017. Resource utilization and cost information were collected through claims data. Quality of life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios (ICERs) from the perspective of the Swiss statutory health insurance system. RESULTS: Patients undergoing PVI compared with medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95% CI 0.46-1.21; P = .69) and a 19.8% SD improvement in quality of life (95% CI 15.5-22.9; P < .001), at an incremental cost of 29 604 Swiss francs (CHF) (95% CI 16 354-42 855; P < .001). The estimated ICER was CHF 158 612 per quality-adjusted life-year (QALY) gained within a 5-year time horizon. Assuming similar health effects and costs over 5 additional years changed the ICER to CHF 82 195 per QALY gained. Results were robust to the sensitivity analyses performed. CONCLUSIONS: Our results show that PVI might be a cost-effective intervention within the Swiss healthcare context in a 10-year time horizon, but unlikely to be so at 5 years, if a willingness-to-pay threshold of CHF 100 000 per QALY gained is assumed. Given data availability, we find target trial designs are a valuable tool for assessing the cost-effectiveness of healthcare interventions outside of randomized controlled trial settings.

Development, validation, and prognostic evaluation of a risk score for long-term liver-related outcomes in the general population: a multicohort study.

BACKGROUND: Liver cirrhosis is a major cause of death worldwide. Cirrhosis develops after a long asymptomatic period of fibrosis progression, with the diagnosis frequently occurring late, when major complications or cancer develop. Few reliable tools exist for timely identification of individuals at risk of cirrhosis to allow for early intervention. We aimed to develop a novel score to identify individuals at risk for future liver-related outcomes. METHODS: We derived the LiverRisk score from an international prospective cohort of individuals from six countries without known liver disease from the general population, who underwent liver fibrosis assessment by transient elastography. The score included age, sex, and six standard laboratory variables. We created four groups: minimal risk, low risk, medium risk, and high risk according to selected cutoff values of the LiverRisk score (6, 10, and 15). The model's discriminatory accuracy and calibration were externally validated in two prospective cohorts from the general population. Moreover, we ascertained the prognostic value of the score in the prediction of liver-related outcomes in participants without known liver disease with median follow-up of 12 years (UK Biobank cohort). FINDINGS: We included 14 726 participants: 6357 (43·2%) in the derivation cohort, 4370 (29·7%) in the first external validation cohort, and 3999 (27·2%) in the second external validation cohort. The score accurately predicted liver stiffness in the development and external validation cohorts, and was superior to conventional serum biomarkers of fibrosis, as measured by area under the receiver-operating characteristics curve (AUC; 0·83 [95% CI [0·78-0·89]) versus the fibrosis-4 index (FIB-4; 0·68 [0·61-0·75] at 10 kPa). The score was effective in identifying individuals at risk of liver-related mortality, liver-related hospitalisation, and liver cancer, thereby allowing stratification to different risk groups for liver-related outcomes. The hazard ratio for liver-related mortality in the high-risk group was 471 (95% CI 347-641) compared with the minimal risk group, and the overall AUC of the score in predicting 10-year liver-related mortality was 0·90 (0·88-0·91) versus 0.84 (0·82-0·86) for FIB-4. INTERPRETATION: The LiverRisk score, based on simple parameters, predicted liver fibrosis and future development of liver-related outcomes in the general population. The score might allow for stratification of individuals according to liver risk and thus guide preventive care. FUNDING: European Commission under the H20/20 programme; Fondo de Investigación Sanitaria de Salud; Instituto de Salud Carlos III; Spanish Ministry of Economy, Industry, and Competitiveness; the European Regional Development Fund; and the German Ministry of Education and Research (BMBF).

Therapeutic value of first versus supplemental indications of drugs in US and Europe (2011-20): retrospective cohort study.

OBJECTIVE: To analyze the therapeutic value of supplemental indications compared with first indications for drugs approved in the US and Europe. DESIGN: Retrospective cohort study. SETTING: New and supplemental indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) between 2011 and 2020. MAIN OUTCOME MEASURES: Proportion of first and supplemental indications rated as having high therapeutic value using ratings from the French and German national, independent health authorities. RESULTS: The cohort study included 124 first and 335 supplemental indications approved by the FDA and 88 first and 215 supplemental indications approved by the EMA between 2011 and 2020; the largest subset was for cancer disorders. Therapeutic ratings were available for 107 (86%) first and 179 (53%) supplemental indications in the US and for 87 (99%) first and 184 (86%) supplemental indications in Europe. Among FDA approved indications with available ratings, 41% (44/107) had high therapeutic value ratings for first indications compared with 34% (61/179) for supplemental indications. In Europe, 47% (41/87) of first and 36% (67/184) of supplemental indications had high therapeutic value ratings. Among FDA approvals, when the sample was restricted to the first three approved indications, second indication approvals were 36% less likely to have a high value rating (relative ratio 0.64, 95% confidence interval 0.43 to 0.96) and third indication approvals were 45% less likely (0.55, 0.29 to 1.01) compared with the first indication approval. Similar findings were observed for Europe and when weighting by the inverse number of indications for each drug. CONCLUSIONS: The proportion of supplemental indications rated as having high therapeutic value was substantially lower than for first indications. When first or supplemental indications do not offer added therapeutic value over other available treatments, that information should be clearly communicated to patients and physicians and reflected in the price of the drugs.

The cancer premium - explaining differences in prices for cancer vs non-cancer drugs with efficacy and epidemiological endpoints in the US, Germany, and Switzerland: a cross sectional study.

Background: High treatment prices of new cancer drugs are a global public health challenge to patients and healthcare systems. Policymakers in the US and Europe are debating reforms to drug pricing. The objective of this study was to assess whether drug efficacy or epidemiological characteristics (prevalence, incidence, mortality) explain the gap in treatment prices between cancer and non-cancer drugs in the US, Germany, and Switzerland. Methods: This cross-sectional study identified all new drugs approved in the US, Germany, and Switzerland between 2011 and 2020. Drug efficacy was extracted from pivotal trials, drug prices from public and commercial databases, and epidemiological characteristics from the Global Burden of Disease (GBD) 2019 study. We used regression models to explain drug prices with drug efficacy and epidemiological characteristics (prevalence, incidence, mortality). Findings: The cohort included 181 drugs, including 68 (37.5%) drugs approved for treatment of cancer. A significant negative correlation was found between incidence/prevalence and treatment prices, and a significant positive correlation was observed between mortality and treatment prices for both, cancer and non-cancer drugs. A significant association between relative drug efficacy and treatment prices of drugs was observed, however, less pronounced for cancer drugs. Our regression estimates indicated that after adjusting for efficacy and epidemiological characteristics, cancer drugs were on average approximately three times more expensive compared to non-cancer drugs in all three countries, indicating a cancer premium; i.e., treatment prices of cancer drugs were on average USD 74,412 (95% CI [62,810; 86,015]) more expensive in the US compared to non-cancer drugs, USD 37,770 (95% CI [26,175; 49,367]) more expensive in Germany, and USD 32,801 (95% CI [27,048; 38,555]) more expensive in Switzerland. Our model explained 72% of the variance in observed prices (R2). Interpretation: Drug pricing reforms should target the cancer premium to improve access of patients to cancer drugs as well as to achieve equity across the different therapeutic areas and sustainability in the health care systems. Funding: This study was funded by the Swiss National Science Foundation (SNSF, grant number PCEGP1_194607) and the Swiss Cancer Research Foundation (Krebsforschung Schweiz).

Delivering Safe Surgical Care While Simultaneously Caring for Patients With COVID-19; Assessment of Patient Selection, Volume and Outcomes in a Tertiary Care Hospital.

Objectives: Compare patient selection and postoperative outcomes after surgical treatment for gastrointestinal disorders before and during the SARS-CoV-2 pandemic. Methods: We assessed gastrointestinal surgeries conducted at a tertiary center from 2017-2021 for differences in patient populations and procedures before (up to February 2020) and during the pandemic (March 2020 to December 2021). We analyzed mortality, Intensive Care Unit (ICU) length of stay, admission to ICU and postoperative complications for complex procedures using descriptive statistics and regression models. Results: 7309 procedures were analyzed, showing a caseload reduction in March and October 2020, but no statistical evidence for fewer overall procedures overall. Population characteristics differed with lower Body Mass Indices in 2020 and 2021, more patients smoking and with diabetes treated in 2020. There was no increased mortality, ICU length of stay and in 1,144 complex procedures assessed low overall morbidity at 90 days postoperative. Conclusion: Delivering surgical care while treating patients for COVID-19 in the same hospital was safe. Healthcare officials should consider continuing surgical care during future health crises as consequences of limiting surgical treatment for gastrointestinal disorders may be fatal for patients.

Patient clusters and cost trajectories in the Swiss Atrial Fibrillation cohort.

OBJECTIVE: Evidence on long-term costs of atrial fibrillation (AF) and associated factors is scarce. As part of the Swiss-AF prospective cohort study, we aimed to characterise AF costs and their development over time, and to assess specific patient clusters and their cost trajectories. METHODS: Swiss-AF enrolled 2415 patients with variable duration of AF between 2014 and 2017. Patient clusters were identified using hierarchical cluster analysis of baseline characteristics. Ongoing yearly follow-ups include health insurance clinical and claims data. An algorithm was developed to adjudicate costs to AF and related complications. RESULTS: A subpopulation of 1024 Swiss-AF patients with available claims data was followed up for a median (IQR) of 3.24 (1.09) years. Average yearly AF-adjudicated costs amounted to SFr5679 (€5163), remaining stable across the observation period. AF-adjudicated costs consisted mainly of inpatient and outpatient AF treatment costs (SFr4078; €3707), followed by costs of bleeding (SFr696; €633) and heart failure (SFr494; €449). Hierarchical analysis identified three patient clusters: cardiovascular (CV; N=253 with claims), isolated-symptomatic (IS; N=586) and severely morbid without cardiovascular disease (SM; N=185). The CV cluster and SM cluster depicted similarly high costs across all cost outcomes; IS patients accrued the lowest costs. CONCLUSION: Our results highlight three well-defined patient clusters with specific costs that could be used for stratification in both clinical and economic studies. Patient characteristics associated with adjudicated costs as well as cost trajectories may enable an early understanding of the magnitude of upcoming AF-related healthcare costs.

Validation of Adult Spinal Deformity Surgical Outcome Prediction Tools in Adult Symptomatic Lumbar Scoliosis.

STUDY DESIGN: A post hoc analysis. OBJECTIVE: Advances in machine learning (ML) have led to tools offering individualized outcome predictions for adult spinal deformity (ASD). Our objective is to examine the properties of these ASD models in a cohort of adult symptomatic lumbar scoliosis (ASLS) patients. SUMMARY OF BACKGROUND DATA: ML algorithms produce patient-specific probabilities of outcomes, including major complication (MC), reoperation (RO), and readmission (RA) in ASD. External validation of these models is needed. METHODS: Thirty-nine predictive factors (12 demographic, 9 radiographic, 4 health-related quality of life, 14 surgical) were retrieved and entered into web-based prediction models for MC, unplanned RO, and hospital RA. Calculated probabilities were compared with actual event rates. Discrimination and calibration were analyzed using receiver operative characteristic area under the curve (where 0.5=chance, 1=perfect) and calibration curves (Brier scores, where 0.25=chance, 0=perfect). Ninety-five percent confidence intervals are reported. RESULTS: A total of 169 of 187 (90%) surgical patients completed 2-year follow up. The observed rate of MCs was 41.4% with model predictions ranging from 13% to 68% (mean: 38.7%). RO was 20.7% with model predictions ranging from 9% to 54% (mean: 30.1%). Hospital RA was 17.2% with model predictions ranging from 13% to 50% (mean: 28.5%). Model classification for all three outcome measures was better than chance for all [area under the curve=MC 0.6 (0.5-0.7), RA 0.6 (0.5-0.7), RO 0.6 (0.5-0.7)]. Calibration was better than chance for all, though best for RA and RO (Brier Score=MC 0.22, RA 0.16, RO 0.17). CONCLUSIONS: ASD prediction models for MC, RA, and RO performed better than chance in a cohort of adult lumbar scoliosis patients, though the homogeneity of ASLS affected calibration and accuracy. Optimization of models require samples with the breadth of outcomes (0%-100%), supporting the need for continued data collection as personalized prediction models may improve decision-making for the patient and surgeon alike.

Nationwide indoor smoking ban and impact on smoking behaviour and lung function: a two-population natural experiment.

INTRODUCTION: Many countries have implemented indoor smoking bans over the past two decades. Although smoking bans have been shown to reduce cardiovascular outcomes, little is known about their impact on respiratory health. This study investigated the impact of a nationwide indoor smoking ban on smoking behaviour and lung function. METHODS: We used repeated cross-sectional data from two large cohorts of the general population comprising 31 807 Swiss and 62 093 Danish adults. We compared associations between smoking ban and smoking prevalence and prebronchodilator lung function trends in Denmark (indoor smoking ban introduced in 2007) and Switzerland (indoor smoking ban introduced in 2010) from 2005 to 2010 using a quasi-experimental study design. We performed difference-in-difference analyses with linear regression models adjusted for age, sex, weight and height. RESULTS: Denmark had a stronger decrease in active smokers compared with Switzerland. Also, forced expiratory volume in the first second was higher in Danish adults than in Swiss adults: 26 mL (95% CI 2.4 to 49) 1 year, 88 mL (65 to 112) 2 years, and 74 mL (51 to 98) 3 years after smoking ban implementation. Correspondingly, forced vital capacity was higher in Danish adults compared with Swiss adults (80 mL (50 to 109) after 1 year and 126 mL (97 to 155) after two and 3 years). Improvements were observed in both never-smokers and ever-smokers, most pronounced in ever-smokers. CONCLUSIONS: Nationwide indoor smoking ban is associated with less smoking and improved lung function in the general population. Implementing an indoor smoking ban can improve lung function by influencing smoking behaviour and reducing secondhand smoke.

A discrete choice experiment on price and flavour effects on the appeal of nicotine products: a pilot study among young adults in Switzerland.

AIMS: To explore the effects of prices and flavour availability on the appeal of different tobacco and nicotine products, including conventional cigarettes, Electronic Nicotine Delivery Systems (ENDS) and Heated Tobacco Systems (HTS) among an adult population in Switzerland. METHODS: We performed a Discrete Choice Experiment among a group of Swiss aged ≥18 years via the online recruiting platform Prolific in a convenience sample. Our sample included both non-smokers and smokers. We used a within-subject, alternative-specific block design in a series of choice sets including different smoking products. We fixed the attributes of nicotine content (high or medium) and harmfulness (in years of life lost) for each product. Attributes of interest included price (ranging from CHF 5 to 25 in increments of 5) and flavour (fruity/menthol vs none/tobacco flavour). We performed a conditional logistic regression on the attributes' influence on the appeal of cigarettes, ENDS and HTS. RESULTS: A total of 108 out of 153 participants (n = 25 smokers and n = 83 non-smokers, completion rate = 71%) successfully completed our pilot survey experiment. We found that, in general, increasing the price of combustible cigarettes, ENDS and HTS by one standard deviation (around CHF 7) reduced their appeal by approximately 66% (relative risk [RR]: 0.34; 95% CI: 0.28-0.42). Unflavoured alternative nicotine products were found to be less appealing than flavoured products, especially for non-smokers, with a 86% decrease in appeal (RR: 0.14; 95% CI: 0.13-0.16). For non-smokers, an increase in price by one standard deviation was associated with a decrease in the appeal of any product by approximately 19% (RR: 0.81; 95% CI: 0.72-0.92). For smokers, the effect sizes were smaller, but overall, the appeal of all products decreased with increasing prices and reduced flavours. CONCLUSIONS: Our Discrete Choice Experiment suggests that, for the Swiss context, limiting the availability of flavours for alternative smoking products has the potential to reduce their appeal to non-smokers by 86% and that a small but significant increase in prices to CHF 15 for cigarettes, ENDS and HTS could lead to a major (around 66%) decrease in their appeal.

Comparison of Uptake and Prices of Biosimilars in the US, Germany, and Switzerland.

Importance: Biologics account for a substantial proportion of health care expenditures. Their costs have been projected to reach US $452 billion in global spending by 2022. Given recent expiration of patent protection of biologics, a shift toward greater follow-on competition among biosimilars would be expected that would allow greater uptake and lower drug costs. Objective: To assess uptake and prices of biosimilars in the US compared with 2 European countries (Germany and Switzerland) with national mechanisms for drug price negotiation. Design, Setting, and Participants: In this cohort study, biologics and biosimilars that were approved in the US, Germany, and Switzerland until August 2020 were identified. Prices and sales data were extracted from public and commercial databases for the years 2011 to 2020. Data were analyzed from August 1, 2021, to February 28, 2022. Main Outcomes and Measures: Descriptive statistics were used to show temporal trends in the uptake of biosimilars and relative prices compared with those of reference products (ie, biologic agents) for each country. Descriptive analysis was also performed to compare the uptake of biosimilars between the 3 countries limited to biologics that have biosimilars on the market in all countries. To test if biosimilar awareness in each country increased over the last decade, a linear least squares regression was applied. Results: The study cohort included 15 biosimilars and 6 biologics for the US, 52 biosimilars and 15 biologics for Germany, and 28 biosimilars and 13 biologics for Switzerland. Uptake of biosimilars increased over time in all countries. On average, the biosimilar market share at launch was highest in Germany; however, it increased at the fastest rate in the US. Monthly treatment costs of biosimilars in the US were a median of 1.94 (IQR, 1.78-2.44) and 2.74 (IQR, 1.91-3.46) higher than corresponding costs in Germany and Switzerland, respectively. Conclusions and Relevance: The findings of this cohort study suggest that more biosimilars have been marketed in Germany and Switzerland than in the US. Policies that counter anticompetitive practices in the US could allow biosimilars to enter the market sooner and could also lower health care costs with improved access. Awareness of biosimilars should be promoted to increase uptake of biosimilars globally.

High frequency of acute decompensation and cancer in patients with compensated cirrhosis due to nonalcoholic fatty liver disease: A retrospective cohort study.

The natural history of compensated cirrhosis due to nonalcoholic fatty liver disease (NAFLD) has not been completely characterized. The aim of the present study was to assess the incidence and risk factors of acute decompensation of cirrhosis, hepatocellular carcinoma, and extrahepatic cancers. This was a multicenter, retrospective, cohort study including 449 patients with compensated cirrhosis due to NAFLD. We calculated cumulative incidences and used competitive risk analysis to determine the risk factors associated with decompensation and cancer development. Over a median of 39 months of follow-up, 124 patients (28%) presented acute decompensation. The most frequent decompensation was ascites (21%) followed by hepatic encephalopathy (15%), variceal bleeding (9%), and spontaneous bacterial peritonitis (3%). Acute-on-chronic liver failure was diagnosed in 6% of patients during follow-up. Liver function parameters and specifically an albumin level below 40 g/L were independently associated with an increased risk of decompensation. The presence of ischemic heart disease was independently associated with acute decompensation. Seventy-eight patients (18%) developed hepatocellular carcinoma or extrahepatic cancers during follow-up (51 and 27, respectively). Conclusion: Patients with compensated cirrhosis due to NAFLD are at high risk of severe liver complications, such as the development of acute decompensation, in a relative short follow-up time. This population is at high risk of hepatic and extrahepatic cancers.