A Canadian cost-effectiveness analysis of SAPIEN 3 transcatheter aortic valve implantation compared with surgery, in intermediate and high-risk severe aortic stenosis patients.

Background and objectives: The treatment of severe aortic stenosis requires replacement of the defective native valve. Traditionally, this has been done via surgery, but in the last 10 years, transcatheter techniques have emerged. Transcatheter aortic valve implantation (TAVI) is a less invasive option compared to surgical aortic valve replacement (SAVR), and this study evaluates the cost-effectiveness of TAVI versus SAVR in intermediate and high surgical risk patients in Canada. Methods: A Markov model was used to project the costs and quality-adjusted life years (QALYs) gained for TAVI using the SAPIEN 3 valve and SAVR over a 15-year time horizon. The PARTNER I and II studies were used to populate the model in terms of survival, clinical event rates and quality of life over time. The costs of TAVI with SAPIEN 3 and SAVR as well as the costs associated with events included in the model were derived from Canadian administrative and literature data. Costs were expressed in 2018 Canadian dollars and all future costs and QALYs were discounted at a rate of 1.5% annually. Probabilistic and one-way sensitivity analyses were conducted. Results: The incremental cost-effectiveness ratios of TAVI using the SAPIEN 3 valve compared to surgery were $28,154 per QALY gained in intermediate risk patients and $17,237 per QALY gained in high-risk patients. The results of the probabilistic analyses indicated that at willingness-to-pay threshold of $50,000 per QALY gained, the probability of TAVI to be cost-effective was greater than 0.9 in both intermediate-risk and high-risk patients. Sensitivity analyses showed the results were most sensitive to the time horizon used. Conclusion: TAVI using the SAPIEN 3 valve is highly likely to be cost-effective in Canadian patients with severe aortic stenosis who are at intermediate and high surgical risk.

Cost-effectiveness analysis of the SAPIEN 3 TAVI valve compared with surgery in intermediate-risk patients.

OBJECTIVE: Transcatheter aortic valve implantation (TAVI) has become the therapy of choice for treating severe aortic stenosis in patients at high-risk for surgery or where it is considered too risky to attempt. This uptake varies across geographies however, and its cost or value has frequently been cited as the reason for this. We sought to evaluate the potential cost and clinical impact of TAVI in intermediate risk patients from a French collective perspective. MATERIALS AND METHODS: The analysis was performed using a novel Markov model with data derived from the PARTNER II randomized controlled trial for survival, clinical event rates, and quality-of-life. The simulated time horizon was 15 years, costs were from French sources and presented in 2016 Euros. Discounting of all outcomes was at 4% annually and the effect of uncertainty in model parameters was explored by deterministic and probabilistic sensitivity analysis (PSA). RESULTS: In comparison to surgery, TAVI resulted in improved clinical outcomes (life expectancy and quality-adjusted life expectancy) and lower costs over a lifetime time horizon. The base case results showed increases of 0.42 years and 0.41 QALYs with lifetime cost savings of €439 for TAVI compared to surgery. PSA results showed a >50% likelihood of cost-effectiveness at €0 willingness-to-pay and a 100% likelihood at ∼€15,000. LIMITATIONS: Clinically, survival projections are based on limited follow-up data and introduce uncertainty into the outcomes from the model. Economically, procedure costs are derived from a heterogeneous mix of patient risk groups, although this is much more likely to bias against TAVI and under-estimate overall cost savings. CONCLUSIONS: In our analyses of intermediate risk patients, TAVI is associated with superior clinical outcomes compared to surgery and is cost saving. It could be expected that cost savings are conservative and likely to increase over time.

The Burden and Impact of Vertigo: Findings from the REVERT Patient Registry.

OBJECTIVE: Despite the high prevalence of vertigo globally and an acknowledged, but under-reported, effect on an individual's wellbeing, few studies have evaluated the burden on healthcare systems and society. This study was aimed to quantitatively determine the impact of vertigo on healthcare resource use and work productivity. METHODS: The economic burden of vertigo was assessed through a multi-country, non-interventional, observational registry of vertigo patients: the Registry to Evaluate the Burden of Disease in Vertigo. Patients included were those with a new diagnosis of Meniere's disease, benign paroxysmal positional vertigo, other vertigo of peripheral vestibular origin, or peripheral vestibular vertigo of unknown origin. RESULTS: A total of 4,294 patients at 618 centers in 13 countries were included during the registry. Of the 4,105 patients analyzed, only half were in employment. Among this working patient population, 69.8% had reduced their workload, 63.3% had lost working days, and 4.6% had changed and 5.7% had quit their jobs, due to vertigo symptoms. Use of healthcare services among patients was high. In the 3 months preceding Visit 1, patients used emergency services 0.4 ± 0.9 times, primary care consultations 1.6 ± 1.8 times, and specialist consultations 1.4 ± 2.0 times (all mean ± SD). A mean of 2.0 ± 5.4 days/patient was also spent in hospital due to vertigo. CONCLUSION: In addition to the negative impact on the patient from a humanistic perspective, vertigo has considerable impact on work productivity and healthcare resource use.

Coste-efectividad de exenatida en comparación con insulina glargina en pacientes con obesidad y diabetes mellitus tipo 2 en España / Cost-effectiveness of exenatide versus insulin glargine in Spanish patients with obesity and type 2 diabetes mellitus

Antecedentes y objetivos Exenatida es un agonista del receptor de GLP-1 empleado como tratamiento adyuvante en la diabetes mellitus tipo 2 (DM2), que ha demostrado ser tan eficaz como insulina glargina (IG) reduciendo la concentración de hemoglobina glucosilada, cuando se administra en combinación con metformina o/y sulfonilureas. Exenatida se asocia a una reducción de peso y a una mayor incidencia de acontecimientos adversos de tipo gastrointestinal. El objetivo de este estudio fue evaluar el coste-efectividad de exenatida frente a IG en pacientes obesos con DM2, que no alcanzan un control glucémico adecuado, desde la perspectiva del sistema nacional de salud. Material y métodos Se utilizó un modelo farmacoeconómico que incluyó información procedente de un ensayo clínico internacional, aleatorizado y controlado, que comparaba exenatida con IG, en pacientes con un inadecuado control de la glucosa, en concreto de la subpoblación de pacientes obesos (IMC ≥ 30 k/m2), y de datos específicos del país. Resultados Exenatida se asocia con un incremento de años de vida ganados y años de vida ajustados por calidad (AVAC) (0,11 y 0,62, respectivamente), frente a IG. Los costes directos se incrementaron 9.306 € en comparación con IG (47.010 frente a 37.704 €) siendo los costes farmacológicos los más importantes. Esto se tradujo en un coste-efectividad incremental de 15.068 €/AVAC de exenatida frente a IG. Conclusiones En pacientes obesos con DM2, exenatida se asocia con mayores beneficios clínicos y mayores costes que IG. Considerando el umbral de disposición a pagar de 30.000 € /AVAC para España, exenatida representa una opción eficiente en comparación con IG (AU)

Background and objectives: Exenatide, a GLP-1 receptor agonist for adjuvant treatment of type2 diabetes mellitus (T2DM), has been shown to be as effective as insulin glargine (IG) for reducingglycated hemoglobin levels combined with metformin or/and sulphonylureas. Exenatide isassociated to weight reduction and a higher incidence of gastrointestinal adverse events. The objective of this study was to assess the cost-effectiveness of exenatide as comparedto IG in obese patients with T2DM not achieving an adequate blood glucose control from the perspective of the Spanish healthcare system. Methods: Pharmacoeconomic model inputs were obtained from an obese subpopulation (BMI ≥30 k/m2) of an international, randomized, controlled clinical trial comparing exenatide with IGin poorly controlled T2DM patients, and were supplemented with country-specific data.Results: Exenatide was associated to improvements in life-years gained and quality-adjusted life years (QALYs) by 0.11 and 0.62 respectively versus IG. Direct costs were D 9,306 higher as compared to IG (D 47,010 versus D 37,704, with increased pharmacy costs as the main driver).Exenatideís incremental cost-effectiveness ratio was D 15,068 per QALY gained versus IG. Conclusions: Exenatide was associated to greater clinical benefits and higher costs in obeseT2DM patients as compared to IG. Considering a willingness-to-pay threshold of D 30,000 perQALY gained in the Spanish setting, exenatide represents an efficient option in comparison withIG (AU)

[Cost-effectiveness of exenatide versus insulin glargine in Spanish patients with obesity and type 2 diabetes mellitus]. / Coste-efectividad de exenatida en comparación con insulina glargina en pacientes con obesidad y diabetes mellitus tipo 2 en España.

BACKGROUND AND OBJECTIVES: Exenatide, a GLP-1 receptor agonist for adjuvant treatment of type 2 diabetes mellitus (T2DM), has been shown to be as effective as insulin glargine (IG) for reducing glycated hemoglobin levels combined with metformin or/and sulphonylureas. Exenatide is associated to weight reduction and a higher incidence of gastrointestinal adverse events. The objective of this study was to assess the cost-effectiveness of exenatide as compared to IG in obese patients with T2DM not achieving an adequate blood glucose control from the perspective of the Spanish healthcare system. METHODS: Pharmacoeconomic model inputs were obtained from an obese subpopulation (BMI ≥ 30 k/m(2)) of an international, randomized, controlled clinical trial comparing exenatide with IG in poorly controlled T2DM patients, and were supplemented with country-specific data. RESULTS: Exenatide was associated to improvements in life-years gained and quality-adjusted life years (QALYs) by 0.11 and 0.62 respectively versus IG. Direct costs were € 9,306 higher as compared to IG (€ 47,010 versus € 37,704, with increased pharmacy costs as the main driver). Exenatideís incremental cost-effectiveness ratio was € 15,068 per QALY gained versus IG. CONCLUSIONS: Exenatide was associated to greater clinical benefits and higher costs in obese T2DM patients as compared to IG. Considering a willingness-to-pay threshold of € 30,000 per QALY gained in the Spanish setting, exenatide represents an efficient option in comparison with IG.

Cost-effectiveness of highly purified omega-3 polyunsaturated fatty acid ethyl esters in the treatment of chronic heart failure: results of Markov modelling in a UK setting.

AIMS: A recent randomized placebo-controlled clinical trial has reported reductions in mortality and hospitalizations in patients with chronic heart failure (CHF) who were prescribed highly purified omega-3 polyunsaturated fatty acid ethyl esters (n-3 PUFA). This study aimed at evaluating the cost and benefits associated with their use in the treatment of CHF in a UK setting. METHODS AND RESULTS: Results from a recent clinical trial were used to develop a Markov model to project clinical outcomes while capturing relevant costs and patient quality of life. The model captured outcomes over a lifetime horizon from a UK National Health Service perspective, with direct costs accounted in 2009 GBP (£) and discounted at 3.5% together with clinical benefits. Results are presented in terms of life expectancy, quality-adjusted life expectancy, direct costs, and incremental cost-effectiveness ratios. In addition to standard therapy, n-3 PUFA vs. placebo increased lifetime direct costs by £993 (≈€1150), with additional quality-adjusted life expectancy of 0.079 quality-adjusted life years (QALYs), and mean lifetime costs of £12,636 (≈€14,600) per QALY gained. Probabilistic sensitivity analyses suggested a 60% likelihood of n-3 PUFA being regarded as cost-effective versus placebo at a willingness-to-pay threshold of £30,000 (≈€34,600) per QALY gained. CONCLUSIONS: By currently accepted standards of value for money in the UK; the addition of n-3 PUFA to optimal medical therapy for patients with heart failure is likely to be cost-effective.

Evaluating the cost-effectiveness of self-monitoring of blood glucose in type 2 diabetes patients on oral anti-diabetic agents.

OBJECTIVES: To evaluate the cost-effectiveness of self-monitoring of blood glucose (SMBG) in patients with type 2 diabetes treated with oral anti-diabetic agents (OADs) in Switzerland. METHODS: A validated computer model of diabetes was used to project outcomes reported from a published longitudinal study of SMBG in type 2 diabetes patients, treated with OADs and with no history of SMBG, over a 30-year time horizon and cost-effectiveness was assessed from the perspective of a third party healthcare payer. Costs and clinical outcomes were discounted at 3% annually in line with recommended practice. Sensitivity analyses were performed. RESULTS: Once, twice or three times daily SMBG was associated with improvements in HbA1c which led to increased life expectancy and quality-adjusted life expectancy, and reduced incidence of diabetes complications compared with no SMBG in type 2 diabetes patients on OADs. Direct medical costs increased by CHF 528, CHF 1'650 and CHF 2'899 in patients performing SMBG once, twice or three times daily compared to those not using SMBG, respectively. Incremental cost-effectiveness ratios were well below commonly quoted willingness-to-pay thresholds at CHF 9'177, CHF 12'928 and CHF 17'342 per quality-adjusted life year (QALY) gained respectively. CONCLUSIONS: Based on data from a large observational study, SMBG is likely to be cost-effective by generally accepted standards in SMBG-naïve patients on oral anti-diabetic agents in the Swiss setting.

The consequences of delaying insulin initiation in UK type 2 diabetes patients failing oral hyperglycaemic agents: a modelling study.

BACKGROUND: Recent data have shown that type 2 diabetes patients in the UK delay initiating insulin on average for over 11 years after first being prescribed an oral medication. Using a published computer simulation model of diabetes we used UK-specific data to estimate the clinical consequences of immediately initiating insulin versus delaying initiation for periods in line with published estimates. METHODS: In the base case scenario simulated patients, with characteristics based on published UK data, were modelled as either initiating insulin immediately or delaying for 8 years. Clinical outcomes in terms of both life expectancy and quality-adjusted life expectancy and also diabetes-related complications (cumulative incidence and time to onset) were projected over a 35 year time horizon. Treatment effects associated with insulin use were taken from published studies and sensitivity analyses were performed around time to initiation of insulin, insulin efficacies and hypoglycaemia utilities. RESULTS: For patients immediately initiating insulin there were increases in (undiscounted) life expectancy of 0.61 years and quality-adjusted life expectancy of 0.34 quality-adjusted life years versus delaying initiation for 8 years. There were also substantial reductions in cumulative incidence and time to onset of all diabetes-related complications with immediate versus delayed insulin initiation. Sensitivity analyses showed that a reduced delay in insulin initiation or change in insulin efficacy still demonstrated clinical benefits for immediate versus delayed initiation. CONCLUSION: UK type 2 diabetes patients are at increased risk of a large number of diabetes-related complications due to an unnecessary delay in insulin initiation. Despite clear guidelines recommending tight glycaemic control this failure to begin insulin therapy promptly is likely to result in needlessly reduced life expectancy and compromised quality of life.

Cost-effectiveness of pioglitazone in type 2 diabetes patients with a history of macrovascular disease: a German perspective.

BACKGROUND: The aim of this study was to project health-economic outcomes relevant to the German setting for the addition of pioglitazone to existing treatment regimens in patients with type 2 diabetes, evidence of macrovascular disease and at high risk of cardiovascular events. METHODS: Event rates corresponding to macrovascular outcomes from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study of pioglitazone were used with a modified version of the CORE Diabetes Model to simulate outcomes over a 35-year time horizon. Direct medical costs were accounted from a healthcare payer perspective in year 2005 values. Germany specific costs were applied for patient treatment, hospitalization and management. Both costs and clinical benefits were discounted at 5.0% per annum. RESULTS: Over patient lifetimes pioglitazone treatment improved undiscounted life expectancy by 0.406 years and improved quality-adjusted life expectancy by 0.120 quality-adjusted life years (QALYs) compared to placebo. Direct medical costs (treatment plus complication costs) were marginally higher for pioglitazone treatment and calculation of the incremental cost-effectiveness ratio (ICER) produced a value of euro13,294 per QALY gained with the pioglitazone regimen versus placebo. Acceptability curve analysis showed that there was a 78.2% likelihood that pioglitazone would be considered cost-effective in Germany, using a "good value for money" threshold of euro50,000 per QALY gained. Sensitivity analyses showed that the results were most sensitive to changes in the simulation time horizon. After adjustment for the potential stabilization of pancreatic beta-cell function with pioglitazone treatment, the ICER was euro6,667 per QALY gained for pioglitazone versus placebo. CONCLUSION: The findings of this modelling analysis indicated that, for patients with a history of macrovascular disease, addition of pioglitazone to existing therapy reduces the long-term cumulative incidence of diabetes-complications at a cost that would be considered to represent good value for money in the German setting.

Evaluating the cost-effectiveness of therapy conversion to insulin detemir in patients with type 2 diabetes in Germany: a modelling study of long-term clinical and cost outcomes.

OBJECTIVES: To evaluate the long-term cost-effectiveness of transferring type 2 diabetes patients to an insulin detemir regimen after failure to achieve adequate control with oral antidiabetic agents (OADs) alone, or in combination with neutral protamine hagedorn (NPH) insulin, or with insulin glargine in Germany. METHODS: A computer simulation model of diabetes was used to make long-term projections of future clinical outcomes and direct medical costs based on findings from a German subanalysis of the PREDICTIVE trial. The study analysed the impact of converting patients failing their current treatments to an insulin detemir regimen. Therapy conversion to insulin detemir +/- OADs was associated with a significant reduction in glycosylated haemoglobin (HbA(1)c) compared with OADs alone, NPH insulin +/- OADs, and insulin glargine +/- OADs. Across all three groups, hypoglycaemia rates decreased by 80% and patients lost an average of 0.9 kg of body weight during treatment with insulin detemir +/- OADs. RESULTS: Therapy conversion to insulin detemir +/- OADs was projected to improve life expectancy by 0.28 years compared with OADs alone, and by 0.13 years compared with the NPH and glargine regimens. Transfer to insulin detemir was associated with improvements in quality-adjusted life expectancy of 0.21 quality-adjusted life years (QALYs) over OADs alone, 0.28 QALYs over NPH +/- OADs, and 0.29 QALYs over glargine +/- OADs. Insulin detemir was associated with savings over patient lifetimes due to reduced diabetes-related complications in all three comparisons. CONCLUSIONS: Therapy conversion to insulin detemir +/- OADs in type 2 diabetes patients failing OADs alone, NPH or insulin glargine regimens was associated with improvements in life expectancy, quality-adjusted life expectancy and cost savings in all three scenarios evaluated.

Cost-effectiveness of insulin aspart versus human soluble insulin in type 2 diabetes in four European countries: subgroup analyses from the PREDICTIVE study.

OBJECTIVES: To evaluate the long-term health economic outcomes associated with insulin aspart (IAsp) compared to human soluble insulin (HI) in type 2 diabetes patients on basal-bolus therapy in Sweden, Spain, Italy and Poland. METHODS: A published computer simulation model of diabetes was used to predict life expectancy, quality-adjusted life expectancy and incidence of diabetes-related complications. Baseline cohort characteristics (age 61.6 years, duration of diabetes 13.2 years, 45.1% male, HbA(1c) 8.2%, BMI 29.8 kg/m(2)) and treatment effects were derived from the PREDICTIVE observational study. Country-specific complication costs were derived from published sources. The analyses were run over 35-year time horizons from third-party payer perspectives in Spain, Italy and Poland and from a societal perspective in Sweden. Future costs and clinical benefits were discounted at country-specific discount rates. Sensitivity analyses were performed. RESULTS: IAsp was associated with improvements in discounted life expectancy and quality-adjusted life expectancy, and a reduced incidence of most diabetes-related complications versus HI in all four settings. IAsp was associated with societal cost-savings in Sweden (SEK 2470), direct medical cost-savings in Sweden and Spain (SEK 8248 and euro 1382, respectively), but increased direct costs in Italy (euro 2235) and Poland (euro 743). IAsp was associated with improved quality-adjusted life expectancy in Sweden (0.077 QALYs), Spain (0.080 QALYs), Italy (0.120 QALYs) and Poland (0.003 QALYs). CONCLUSIONS: IAsp was dominant versus HI in both Sweden and Spain, would be considered cost-effective in Italy with an incremental cost-effectiveness ratio of euro 18,597 per QALY gained, but would not be considered cost-effective in Poland.

Cysteine biosynthesis in Trichomonas vaginalis involves cysteine synthase utilizing O-phosphoserine.

Trichomonas vaginalis is an early divergent eukaryote with many unusual biochemical features. It is an anaerobic protozoan parasite of humans that is thought to rely heavily on cysteine as a major redox buffer, because it lacks glutathione. We report here that for synthesis of cysteine from sulfide, T. vaginalis relies upon cysteine synthase. The enzyme (TvCS1) can use either O-acetylserine or O-phosphoserine as substrates. The K(m) values of the enzyme for sulfide are very low (0.02 mm), suggesting that the enzyme may be a means of ensuring that sulfide in the parasite is maintained at a low level. T. vaginalis appears to lack serine acetyltransferase, the source of O-acetylserine in many cells, but has a functional 3-phosphoglycerate dehydrogenase and an O-phosphoserine aminotransferase that together result in the production of O-phosphoserine, suggesting that this is the physiological substrate. TvCS1 can also use thiosulfate as substrate. Overall, TvCS1 has substrate specificities similar to those reported for cysteine synthases of Aeropyrum pernix and Escherichia coli, and this is reflected by sequence similarities around the active site. We suggest that these enzymes are classified together as type B cysteine synthases, and we hypothesize that the use of O-phosphoserine is a common characteristic of these cysteine synthases. The level of cysteine synthase in T. vaginalis is regulated according to need, such that parasites growing in an environment rich in cysteine have low activity, whereas exposure to propargylglycine results in elevated cysteine synthase activity. Humans lack cysteine synthase; therefore, this parasite enzyme could be an exploitable drug target.

Light and scanning electron microscopy of the cardiac gland region of the stomach of the babirusa (Babyrousa babyrussa--Suidae, Mammalia).

Previous studies have indicated that the gross anatomical structure of the stomach of the babirusa (Babyrousa babyrussa) differs markedly from that of all other pigs. This light and scanning electron microscopic study revealed a previously unknown, microscopic structure characterised by a 'honeycomb' pattern at the luminal surface of the tunica mucosa. The walls of the 'honeycomb' were about 0.20-0.25 mm high and appeared almost entirely composed of various types of bacteria. Underneath the bacteria the walls were formed by thin tubes composed of non-glandular squamous epithelial-like cells, extending from the tops of the ridges between each glandular pit. There is as yet no evidence of a comparable structure in the stomach of any other pig, or to our knowledge any other forestomach-fermenting mammal.

Freezing survival and cryoprotective dehydration as cold tolerance mechanisms in the Antarctic nematode Panagrolaimus davidi.

The relative importance of freezing tolerance and cryoprotective dehydration in the Antarctic nematode Panagrolaimus davidi has been investigated. If nucleation of the medium is initiated at a high subzero temperature (-1 degree C), the nematodes do not freeze but dehydrate. This effect occurs in deionised water, indicating that the loss of water is driven by the difference in vapour pressure of ice and supercooled water at the same temperature. If the nematodes are held above their nucleation temperature for a sufficient time, or are cooled slowly, enough water is lost to prevent freezing (cryoprotective dehydration). However, if the medium is nucleated at lower temperatures or if the sample is cooled at a faster cooling rate, the nematodes freeze and can survive intracellular ice formation. P. davidi thus has a variety of mechanisms that ensure its survival in its harsh terrestrial Antarctic habitat.