A Systematic Review and Statistical Analysis of Factors Influencing the Cost-Effectiveness of Transcatheter Aortic Valve Implantation for Symptomatic Severe Aortic Stenosis.

Objective: Transcatheter aortic valve implantation (TAVI) is a disruptive technology recommended for patients with symptomatic severe aortic stenosis (sSAS). Despite being available for over 15 years in Europe, with an extensive volume of clinical and economic evaluations across all surgical risk groups, there is little evidence on the identification of the key drivers of TAVI's cost-effectiveness. This study sought to identify these factors and quantify their role. Methods: A systematic literature review was conducted to identify published economic evaluations of TAVI. This was supplemented by health technology assessment reports. The primary outcome was the likelihood of TAVI being found cost-effective. Secondary outcomes of TAVI being dominant, and the incremental health benefits of TAVI were also explored. Results: Forty-two studies, reporting 65 unique analyses, were identified. TAVI was found to be cost-effective and dominant in 74% and 20% of analyses, respectively. The latest generation balloon-expandable TAVI device (SAPIEN 3) was more likely to be found cost-effective, as was TAVI use in low-risk populations and when performed via transfemoral access route. There was heterogeneity in the approach taken to economic modelling, which may also influence estimates of cost-effectiveness. Analyses that found TAVI to be dominant always compared it to surgery and usually considered the latest generation balloon-expandable TAVI device. Largest health benefits were observed for the inoperable risk group. Conclusion: For patients with sSAS, TAVI is typically a cost-effective treatment option. There are important differences by device generation, risk group and access route. It is crucial to consider these differences when appraising the health economic evidence-base for TAVI.

Living Health Technology Assessment: Issues, Challenges and Opportunities.

Health technology assessments (HTAs) are typically performed as one-off evaluations and can potentially become out-of-date due to the availability of new data, new comparators, or other factors. Recently, living approaches have been applied to systematic reviews and network meta-analyses to enable evidence syntheses to be updated more easily. In this paper, we provide a definition for 'Living HTA' where such a living approach could be applied to the entire HTA process. Living HTA could involve performing regular or scheduled updates using a traditional manual approach, or indeed in a semi-automated manner leveraging recent technological innovations that automate parts of the HTA process. The practical implementation of living HTA using both approaches (i.e., manual approach and using semi-automation) is described along with the likely issues and challenges with planning and implementing a living HTA process. The time, resources and additional considerations outlined may prohibit living HTA from becoming the norm for every evaluation; however, scenarios where living HTA would be particularly beneficial are discussed.

Droplet Impact and Spreading on Inclined Surfaces.

Introducing surface inclination in the case of droplet impact on solid substrates results in complicated dynamics post impact. The present work investigates the dynamics involved in the spreading phase of the droplet on inclined substrates. Experiments are conducted with water droplets impinging on inclined dry solid substrates with varying wettability values. The results reveal the presence of three phases in the droplet spread behavior. In the first phase, the droplet is observed to depict a close radial symmetry and is dominated by inertia forces. Phase 1 ends when the upstream droplet lamella post impact gets pinned to the surface or starts retracting as a consequence of surface forces becoming dominant. A scaling analysis developed to predict the pinning time of the droplet shows that the pinning time is independent of impact velocity, which is also observed during experiments. The asymmetries in the radial evolution of the droplet appear in phase 2 and become dominant in phase 3. Phase 2 terminates when the droplet attains the maximum lateral spread, which is established as a function of the normal component of the Weber number. Phase 3 is initiated when the droplet starts retracting in the lateral direction while the longitudinal expansion continues. Using an energy-based model constructed to predict the maximum spread, we show that the impact inertia of the droplet controls the longitudinal droplet spread in phases 1 and 2, while the gravity forces are primarily responsible for the droplet spread in phase 3. The model results were validated with the experiments conducted in-house and were found to be in good agreement.

Estimation of Transition Probabilities for State-Transition Models: A Review of NICE Appraisals.

State transition models are used to inform health technology reimbursement decisions. Within state transition models, the movement of patients between the model health states over discrete time intervals is determined by transition probabilities (TPs). Estimating TPs presents numerous issues, including missing data for specific transitions, data incongruence and uncertainty around extrapolation. Inappropriately estimated TPs could result in biased models. There is limited guidance on how to address common issues associated with TP estimation. To assess current methods for estimating TPs and to identify issues that may introduce bias, we reviewed National Institute for Health and Care Excellence Technology Appraisals published from 1 January, 2019 to 27 May, 2020. Twenty-eight models (from 26 Technology Appraisals) were included in the review. Several methods for estimating TPs were identified: survival analysis (n = 11); count method (n = 9); multi-state modelling (n = 7); logistic regression (n = 2); negative binomial regression (n = 2); Poisson regression (n = 1); and calibration (n = 1). Evidence Review Groups identified several issues relating to TP estimation within these models, including important transitions being excluded (n = 5); potential selection bias when estimating TPs for post-randomisation health states (n = 2); issues concerning the use of multiple data sources (n = 4); potential biases resulting from the use of data from different populations (n = 2), and inappropriate assumptions around extrapolation (n = 3). These issues remained unresolved in almost every instance. Failing to address these issues may bias model results and lead to sub-optimal decision making. Further research is recommended to address these methodological problems.

Electronic clinical decision support tool for assessing stomach symptoms in primary care (ECASS): a feasibility study.

OBJECTIVE: To determine the feasibility of a definitive trial in primary care of electronic clinical decision support (eCDS) for possible oesophago-gastric (O-G) cancer. DESIGN AND SETTING: Feasibility study in 42 general practices in two regions of England, cluster randomised controlled trial design without blinding, nested qualitative and health economic evaluation. PARTICIPANTS: Patients aged 55 years or older, presenting to their general practitioner (GP) with symptoms associated with O-G cancer. 530 patients (mean age 68 years, 58% female) participated. INTERVENTION: Practices randomised 1:1 to usual care (control) or to receive a previously piloted eCDS tool for suspected cancer (intervention), for use at the discretion of the GPs, supported by a theory-based implementation package and ongoing support. We conducted semistructured interviews with GPs in intervention practices. Recruitment lasted 22 months. OUTCOMES: Patient participation rate, use of eCDS, referrals and route to diagnosis, O-G cancer diagnoses; acceptability to GPs; cost-effectiveness. Participants followed up 6 months after index encounter. RESULTS: From control and intervention practices, we screened 3841 and 1303 patients, respectively; 1189 and 434 were eligible, 392 and 138 consented to participate. Ten patients (1.9%) had O-G cancer. eCDS was used eight times in total by five unique users. GPs experienced interoperability problems between the eCDS tool and their clinical system and also found it did not fit with their workflow. Unexpected restrictions on software installation caused major problems with implementation. CONCLUSIONS: The conduct of this study was hampered by technical limitations not evident during an earlier pilot of the eCDS tool, and by regulatory controls on software installation introduced by primary care trusts early in the study. This eCDS tool needed to integrate better with clinical workflow; even then, its use for suspected cancer may be infrequent. Any definitive trial of eCDS for cancer diagnosis should only proceed after addressing these constraints. TRIAL REGISTRATION NUMBER: ISRCTN125595588.

Cost-Effectiveness of Lenvatinib Compared with Sorafenib for the First-Line Treatment of Advanced Hepatocellular Carcinoma in Australia.

BACKGROUND AND OBJECTIVE: In the REFLECT trial, lenvatinib showed superior clinical benefits to sorafenib in terms of progression-free survival and was non-inferior for overall survival in the treatment of advanced hepatocellular carcinoma (HCC). We assessed the cost-effectiveness of lenvatinib compared with sorafenib for patients with advanced HCC in Australia. METHOD: A partitioned-survival model was built to perform a cost-effectiveness analysis comparing lenvatinib and sorafenib from an Australian health-system perspective. Survival curves were obtained from the REFLECT trial and fitted with parametric survival functions for extrapolation purposes beyond the trial follow-up. Cost and quality-adjusted life-years (QALYs) were accrued over the 10-year time horizon of the model. Deterministic and probability sensitivity analysis (PSA) were carried out to verify the validity of the model. RESULTS: Lenvatinib incurred higher costs (A$96,325) and superior health outcomes (QALYs: 1.205), while sorafenib had lower costs (A$92,394) and inferior health outcomes (QALYs: 1.086). Thus, lenvatinib yielded an incremental cost-utility ratio of A$33,028/QALY gained. Further, the results of the PSA found that the probability of lenvatinib being cost-effective at a willingness-to-pay threshold of A$50,000/QALY was 64%. CONCLUSION: Our study found that, at current prices, lenvatinib is a cost-effective treatment option compared with sorafenib for the first-line treatment of patients with advanced HCC.

Role of Culture, Values, and Politics in the Implementation of Health Technology Assessment in India: A Commentary.

India is a diverse land with different cultures, social norms, castes, religions, faiths, languages, politics, and a complex healthcare system. As a step to enhance healthcare, the government of India announced a move toward universal health coverage to increase accessibility and affordability of health-related services. Recently, there has been an introduction of health technology assessment (HTA) in India to help inform evidence-based decision making in cases of limited resources and budgets. Nevertheless, there are challenges related to biased decision making, an unregulated healthcare framework, and the lack of data and capacity that will (directly or indirectly) affect the use of HTA in India. For HTA to be successful in India and in similar low- and middle-income countries, it is important that the decision makers acknowledge these challenges and embrace differences in ideologies, cultures, and politics instead of ignoring them. Drawing lessons from countries with well-developed HTA bodies may help, but these need to be modified for the country-specific context. Ensuring quality and transparency is key to building trust in medical decision making. Improved coordination at all levels of healthcare is vital to ensure the long-term success of HTA in India. This is challenging but achievable by spreading awareness among stakeholders and achieving moderate health-sector regulation that can combat corruption. HTA will prosper in India if it incorporates cultural and institutional diversity, alongside tackling socioeconomic inequalities.

Cost-effectiveness of Pembrolizumab as Second-line Therapy for the Treatment of Locally Advanced or Metastatic Urothelial Carcinoma in Sweden.

BACKGROUND: Urothelial carcinoma (UC) is the most common subtype of bladder cancer. The randomized phase 3 KEYNOTE-045 trial showed that pembrolizumab, used as second-line therapy significantly prolonged overall survival with fewer treatment-related adverse events than chemotherapy for advanced UC. Pembrolizumab has been approved by the European Medicines Agency for the treatment of locally advanced or metastatic UC in adults who have received platinum-containing chemotherapy. Many European countries use cost-effectiveness analysis to inform reimbursement decisions. OBJECTIVE: To assess the cost-effectiveness of pembrolizumab as second-line therapy for the treatment of advanced UC from a Swedish health care perspective. DESIGN, SETTING, AND PARTICIPANTS: We developed a partitioned-survival model to assess the costs and effectiveness of pembrolizumab compared with vinflunine (base case), paclitaxel, or docetaxel monotherapy in patients with advanced UC over a 15-yr time horizon. We obtained Kaplan-Meier estimates for survival endpoints, adverse events, and utility data from KEYNOTE-045. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We performed parametric extrapolations to estimate overall and progression-free survival beyond the clinical trial period. Swedish costs and utility weights were used to estimate total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). We performed deterministic and probabilistic sensitivity analyses to assess the robustness of the model results. RESULTS AND LIMITATIONS: In the base-case analysis, pembrolizumab resulted in a mean survival gain of 1.66 years (1.38 QALYs) at an incremental cost of €69852 and an ICER of €50529/QALY gained versus vinflunine monotherapy. ICERs for other chemotherapies were €81356/QALY for pembrolizumab versus paclitaxel or docetaxel monotherapy, and €71924/QALY for pembrolizumab versus paclitaxel, docetaxel, or vinflunine monotherapy. Long-term follow-up from KEYNOTE-045 and real-world data are needed to validate the extrapolations. CONCLUSIONS: The results indicate that pembrolizumab improves survival, increases QALYs, and is cost-effective as second-line therapy at a willingness-to-pay threshold of €100000/QALY for the treatment of advanced UC. PATIENT SUMMARY: To date, pembrolizumab is the only treatment associated with a significant overall survival benefit compared with chemotherapy in a randomized controlled trial as second-line therapy for advanced urothelial carcinoma. Our trial-based cost-effectiveness analysis suggests that pembrolizumab is a cost-effective option over chemotherapy in patients with advanced urothelial carcinoma after platinum-based therapy in Sweden.

Early Discharge From Intensive Care After Cardiac Surgery is Feasible With an Adequate Fast Track, Stepdown Unit: Waikato Experience.

BACKGROUND: Enhanced recovery programs within cardiothoracic surgery are a well described benefit to patient postoperative outcomes. We describe our Australasian unit's experience of a day zero discharge enhanced recovery unit from the intensive care department. METHODS: A retrospective study was conducted on a prospectively maintained database at Waikato Cardiothoracic Unit from September 2014 till October 2017 with 1,739 patients undergoing cardiac surgery. Twenty-two (22) patients were excluded as deaths either intraoperative or in the intensive care unit (ICU) and therefore never discharged. Total population of the study was 1,717 patients. The primary endpoint of this study was to determine if there is no survival disadvantage for the day zero discharge unit compared to standard treatment in ICU at follow-up. The secondary endpoint of the study was to highlight the association between pre and postoperative variables and the impact on discharge from the ICU. RESULTS: One hundred sixty-eight (168) patients were discharged to the enhanced recovery unit (ERU) day zero. Mean number of hours spent in ICU for the day zero cohort was 7.18 (±1.59. Mean Age 62.5 (±11.22), M:F 4.25:1. Patients were more likely to be discharged day zero if they had a lower EuroSCORE II 1.57 (±1.67) and lower preoperative creatinine 89.4 (±27.5). Those admitted to the ERU on day zero postoperatively were more likely to be discharged with a lower creatinine level, a higher haemoglobin level and have less readmissions per 30days (p<0.05). Survival analysis demonstrated that the patients who were discharged early from ICU had significantly better follow-up survival compared to those who were discharged after 24hours (p<0.05). CONCLUSIONS: A fast track unit increases the efficiency of an ICU and cardiac surgical department. With the advancements of cardiac surgery a higher number of patients will be suitable for a fast track method. Our unit has demonstrated that a day zero fast track unit in New Zealand can perform with adequate patient safety with no increased risk of mortality and with low rates of failure of the day zero discharge fast track therapy.

A Three-Locus, PCR-based Method for Forensic Identification of Plant Material.

Plant residue is currently an underutilized resource in forensic investigations despite the fact that many crime scenes, as well as suspects and victims, harbor plant-derived residue that could be recovered and analyzed. Notwithstanding the considerable skill of forensic botanists, current methods of species determination could benefit from tools for DNA-based species identification. However, DNA barcoding in plants has been hampered by sequence complications in the plant genome. Following a database search for usable barcodes, broad-spectrum primers were designed and utilized to amplify and sequence the rbcL, trnL-F, and rrn18 genetic loci from a variety of household plants. Once obtained, these DNA sequences were used to design species-targeted primers that could successfully discriminate the source of plant residue from among the 21 species tested.

Importance of phosphate contacts for sequence recognition by EcoRI restriction enzyme.

We have studied the importance of charge and hydrogen-bonding potential of the phosphodiester backbone for binding and cleavage by EcoRI restriction endonuclease. We used 12-mer oligodeoxynucleotide substrates with single substitutions of phosphates by chiral methylphosphonates at each position of the recognition sequence -pGpApApTpTpCp-. Binding was moderately reduced between 4- and 400-fold more or less equally for the R(P) and S(P)-analogues mainly caused by missing charge interaction. The range of cleavage effects was much wider. Four substrates were not cleaved at all. At both flanking positions and in the purine half of the sequence up to the central position, cleavage was more impaired than binding and differences between R(P) and S(P) diastereomeres were more pronounced. These effects are easily interpreted by direct phosphate contacts seen in the crystal structure. For the effects of substitutions in the pyrimidine half of the recognition sequence, more indirect effects have to be discussed.