A Pilot Study of Value of Information Analysis to Support Research Recommendations for the National Institute for Health and Clinical Excellence

Background - This project developed as a result of the activities of the Research Teams at the Centre for Health Economics, University of York, and ScHARR at the University of Sheffield in the methods and application of decision analysis and value of information analysis as a means of informing the research recommendations made by NICE, as part of its Guidance to the NHS in England and Wales, and informing the deliberations of the NICE Research and Development Committee. Objectives - The specific objectives of the pilot study were to: • Demonstrate the benefits of using appropriate decision analytic methods and value of information analysis to inform research recommendations. • Establish the feasibility and resource implications of applying these methods in a timely way, to inform NICE. • Identify critical issues and methodological challenges to the use of value of information methods for research recommendations (with particular regard to the new reference case as a suitable basis for this type of analysis).

Cost-effectiveness of 4 mg dibotermin alfa/absorbable collagen sponge versus iliac crest bone graft for lumbar degenerative disc disease in the United Kingdom

Aims: To develop a model to evaluate the cost-effectiveness of 4 mg dibotermin alfa/absorbable collagen sponge (ACS) versus iliac crest bone graft (ICBG) in patients with lumbar degenerative disc disease in the United Kingdom. Materials & methods: A Markov decision-analytic model was constructed to calculate costs and quality-adjusted life-years over a 4-year time horizon in each treatment group, from a United Kingdom National Health Service perspective. An individual patient data meta-analysis was undertaken to synthesize data from four randomized controlled trials and two single-arm studies concerning health-related quality of life and procedural resource use. Current cost data from the United Kingdom were then applied to determine the overall mean cost per patient in each group. One-way and probabilistic sensitivity analyses were undertaken to explore the impact of parameter uncertainty. Results: The model predicted 4-year discounted cost savings of £192 per patient treated with dibotermin alfa/ACS, compared with ICBG, and a gain of 0.0114 QALYs per patient over the same time period. Sensitivity analyses indicated that the results were most sensitive to variability in the differences in health-related quality of life and secondary surgery rate, with dibotermin alfa/ACS having a 60% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained. Limitations: There is uncertainty in the difference in cost and QALYs between the two groups. However, comprehensive sensitivity analyses were undertaken to explore this and present the results in a transparent manner. Conclusions: Our results provide an economic case for the use of 4 mg dibotermin alfa/ACS versus iliac crest bone graft, with additional health benefits predicted at reduced overall cost

Mutator Suppression and Escape from Replication Error–Induced Extinction in Yeast

Cells rely on a network of conserved pathways to govern DNA replication fidelity. Loss of polymerase proofreading or mismatch repair elevates spontaneous mutation and facilitates cellular adaptation. However, double mutants are inviable, suggesting that extreme mutation rates exceed an error threshold. Here we combine alleles that affect DNA polymerase δ (Pol δ) proofreading and mismatch repair to define the maximal error rate in haploid yeast and to characterize genetic suppressors of mutator phenotypes. We show that populations tolerate mutation rates 1,000-fold above wild-type levels but collapse when the rate exceeds 10−3 inactivating mutations per gene per cell division. Variants that escape this error-induced extinction (eex) rapidly emerge from mutator clones. One-third of the escape mutants result from second-site changes in Pol δ that suppress the proofreading-deficient phenotype, while two-thirds are extragenic. The structural locations of the Pol δ changes suggest multiple antimutator mechanisms. Our studies reveal the transient nature of eukaryotic mutators and show that mutator phenotypes are readily suppressed by genetic adaptation. This has implications for the role of mutator phenotypes in cancer

The cost-effectiveness of deep brain stimulation in combination with best medical therapy, versus best medical therapy alone, in advanced Parkinson's disease

Parkinson’s disease (PD) is a complex progressive movement disorder leading to motor and non-motor symptoms that become increasingly debilitating as the disease advances, considerably reducing quality of life. Advanced treatment options include deep brain stimulation (DBS). While clinical effectiveness of DBS has been demonstrated in a number of randomised controlled trials (RCT), evidence on cost-effectiveness is limited. The cost-effectiveness of DBS combined with BMT, versus BMT alone, was evaluated from a UK payer perspective. Individual patient-level data on the effect of DBS on PD symptom progression from a large 6-month RCT were used to develop a Markov model representing clinical progression and capture treatment effect and costs. A 5-year time horizon was used, and an incremental cost-effectiveness ratio (ICER) was calculated in terms of cost per quality-adjusted life-years (QALY) and uncertainty assessed in deterministic sensitivity analyses. Total discounted costs in the DBS and BMT groups over 5 years were £68,970 and £48,243, respectively, with QALYs of 2.21 and 1.21, giving an incremental cost-effectiveness ratio of £20,678 per QALY gained. Utility weights in each health state and costs of on-going medication appear to be the key drivers of uncertainty in the model. The results suggest that DBS is a cost-effective intervention in patients with advanced PD who are eligible for surgery, providing good value for money to health care payers

Financial impact of adopting implantable loop recorder diagnostic for unexplained syncope compared with conventional diagnostic pathway in Portugal

Background: To estimate the short- and long-term financial impact of early referral for implantable loop recorder diagnostic (ILR) versus conventional diagnostic pathway (CDP) in the management of unexplained syncope (US) in the Portuguese National Health Service (PNHS). Methods: A Markov model was developed to estimate the expected number of hospital admissions due to US and its respective financial impact in patients implanted with ILR versus CDP. The average cost of a syncope episode admission was estimated based on Portuguese cost data and landmark papers. The financial impact of ILR adoption was estimated for a total of 197 patients with US, based on the number of syncope admissions per year in the PNHS. Sensitivity analysis was performed to take into account the effect of uncertainty in the input parameters (hazard ratio of death; number of syncope events per year; probabilities and unit costs of each diagnostic test; probability of trauma and yield of diagnosis) over three-year and lifetime horizons. Results: The average cost of a syncope event was estimated to be between 1,760€ and 2,800€. Over a lifetime horizon, the total discounted costs of hospital admissions and syncope diagnosis for the entire cohort were 23% lower amongst patients in the ILR group compared with the CDP group (1,204,621€ for ILR, versus 1,571,332€ for CDP). Conclusion: The utilization of ILR leads to an earlier diagnosis and lower number of syncope hospital admissions and investigations, thus allowing significant cost offsets in the Portuguese setting. The result is robust to changes in the input parameter values, and cost savings become more pronounced over time

Cost-effectiveness of TYRX absorbable antibacterial envelope for prevention of cardiovascular implantable electronic device infection

<p><b>Aims:</b> Infection is a major complication of cardiovascular implantable electronic device (CIED) therapy that usually requires device extraction and is associated with increased morbidity and mortality. The TYRX Antibacterial Envelope is a polypropylene mesh that stabilizes the CIED and elutes minocycline and rifampin to reduce the risk of post-operative infection.</p> <p><b>Methods:</b> A decision tree was developed to assess the cost-effectiveness of TYRX vs standard of care (SOC) following implantation of four CIED device types. The model was parameterized for a UK National Health Service perspective. Probabilities were derived from the literature. Resource use included drug acquisition and administration, hospitalization, adverse events, device extraction, and replacement. Incremental cost-effectiveness ratios (ICERs) were calculated from costs and quality-adjusted life-years (QALYs).</p> <p><b>Results:</b> Over a 12-month time horizon, TYRX was less costly and more effective than SOC when utilized in patients with an ICD or CRT-D. TYRX was associated with ICERs of £46,548 and £21,768 per QALY gained in patients with an IPG or CRT-P, respectively. TYRX was cost-effective at a £30,000 threshold at baseline probabilities of infection exceeding 1.65% (CRT-D), 1.95% (CRT-P), 1.87% (IPG), and 1.38% (ICD).</p> <p><b>Limitations and conclusions:</b> Device-specific infection rates for high-risk patients were not available in the literature and not used in this analysis, potentially under-estimating the impact of TYRX in certain devices. Nevertheless, TYRX is associated with a reduction in post-operative infection risk relative to SOC, resulting in reduced healthcare resource utilization at an initial cost. The ICERs are below the accepted willingness-to-pay thresholds used by UK decision-makers. TYRX, therefore, represents a cost-effective prevention option for CIED patients at high-risk of post-operative infection.</p

Predicted clinical and economic burden associated with reduction in access to acute coronary interventional care during the COVID-19 lockdown in two European countries

Aims As a consequence of untimely or missed revascularization of ST-elevation myocardial infarction (STEMI) patients during the COVID-19 pandemic, many patients died at home or survived with serious sequelae, resulting in potential long-term worse prognosis and related health-economic implications. This analysis sought to predict long-term health outcomes [survival and quality-adjusted life-years (QALYs)] and cost of reduced treatment of STEMIs occurring during the first COVID-19 lockdown. Methods and results Using a Markov decision-analytic model, we incorporated probability of hospitalization, timeliness of PCI, and projected long-term survival and cost (including societal costs) of mortality and morbidity, for STEMI occurring during the first UK and Spanish lockdowns, comparing them with expected pre-lockdown outcomes for an equivalent patient group. STEMI patients during the first UK lockdown were predicted to lose an average of 1.55 life-years and 1.17 QALYs compared with patients presenting with a STEMI pre-pandemic. Based on an annual STEMI incidence of 49 332 cases, the total additional lifetime costs calculated at the population level were 36.6 pound million (euro41.3 million), mainly driven by costs of work absenteeism. Similarly in Spain, STEMI patients during the lockdown were expected to survive 2.03 years less than pre-pandemic patients, with a corresponding reduction in projected QALYs (-1.63). At the population level, reduced PCI access would lead to additional costs of euro88.6 million. Conclusion The effect of a 1-month lockdown on STEMI treatment led to a reduction in survival and QALYs compared to the pre-pandemic era. Moreover, in working-age patients, untimely revascularization led to adverse prognosis, affecting societal productivity and therefore considerably increasing societal costs