A Cost-Effectiveness Framework for Amyotrophic Lateral Sclerosis, Applied to Riluzole.

OBJECTIVES: Reexamine cost-effectiveness of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) in light of recent advances in disease staging and understanding of stage-specific drug effect. METHODS: ALS was staged according to the "fine'til 9" (FT9) staging method. Stage-specific health utilities (EQ-5D, US valuation) were estimated from an institutional cohort, whereas literature informed costs and transition probabilities. Costs at 2018 prices were disaggregated into recurring costs (RCs) and "one-off" transition/"tollgate" costs (TCs). Five- and 10-year horizons starting in stage 1 disease were examined from healthcare sector and societal perspectives using Markov models to evaluate riluzole use, at a threshold of $100 000/quality-adjusted life year (QALY). Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: Mean EQ-5D utilities for stages 0 to 4 were 0.79, 0.74, 0.63, 0.54, and 0.46, respectively. From the healthcare sector perspective at the 5-year horizon, riluzole use contributed to 0.182 QALY gained at the cost difference of $12 348 ($5403 riluzole cost, $8870 RC and -$1925 TC differences), translating to an incremental cost-effectiveness ratio (ICER) of $67 658/QALY. Transition probability variation contributed considerably to ICER uncertainty (-30.2% to +90.0%). ICER was sensitive to drug price and RCs, whereas higher TCs modestly reduced ICER due to delayed tollgates. CONCLUSION: This study provides a framework for health economic studies of ALS treatments using FT9 staging. Prospective stage-specific and disaggregated cost measurement is warranted for accurate future cost-effectiveness analyses. Appropriate separation of TCs from RCs substantially mitigates the high burden of background cost of care on the ICER.

[Pharmacoeconomic analysis of the neuroprotective medicines in the treatment of ischemic stroke]. / Farmakoékonomicheskii analiz neiroprotektorov, primeniaemykh v terapii ishemicheskogo insul'ta.

AIM: To perform a pharmacoeconomic analysis of the most frequently prescribed neuroprotective medicines for treating patients with mild ischemic stroke in the acute and early rehabilitation periods in the Russian Federation. MATERIAL AND METHODS: Three medical technologies were compared: ethylmethylhydroxypyridine succinate (mexidol), inosine + nicotinamide + riboflavin + succinic acid (cytoflavin) and a deproteinized hemoderivate of the blood of calves (actovegin). Cost minimization analysis, budget impact analysis and sensitivity analysis were performed based on the indirect comparison results. RESULTS: Efficacy analysis shows that mentioned above medicines have the same efficacy: mean difference mexidol is 0,2 (CI min 0,25; max 0,65), cytoflavin - 0,61 (CI min 0,23; max 0,99), actovegin 0,2 (CI min 0,18; max 0,22). The cost minimization analysis for the Russian Federation shows that mexidol therapy is associated with the lowest costs, while savings are observed both in the evaluation of total costs and separate components: intravenous ampoules and tablet forms. The savings in comparison with cytoflavin and actovegin are 231 RUB and 12,872 RUB, respectively. These savings will be enough to treat five patients with ischemic stroke (IS) with mexidol. Moreover, oral mexidol therapy is cheaper than the same dosage forms of cytoflavin and actovegin by 481 RUB and 3,164 RUB, respectively. This is an advantage for the treatment of population at the outpatient stage. Budget impact analysis has shown that the budget for the medicines for treating IS at the current distribution between treatment regimens, is estimated at 1.99 BN RUB. The increase in the proportion of patients receiving mexidol by 10% reduces total costs to 1.75 BN RUB, which is 240 M RUB less than current costs. With these savings 85 thousand patients with IS could be treated. The sensitivity analysis reveals that the result of the cost minimization analysis and the budget impact analysis remain stable when both the amount of the population and the cost of 1 mg of mexidol vary from -10% to + 10%. CONCLUSIONS: Mexidol has the same efficacy as alternatives. However mexidol is superior to cytoflavin and actovegin in terms of cost minimization analysis. The savings from one course of alternatives will cover costs of treatment of five patients with IS using mexidol. The increase in the proportion of patients receiving mexidol is associated with savings, which allows us to consider mexidol therapy of mild IS as budget-saving in the Russian Federation.

High-dose methylprednisolone for acute traumatic spinal cord injury: A meta-analysis.

OBJECTIVE: Due to the continuing debates on the utility of high-dose methylprednisolone (MP) early after acute spinal cord injury (ASCI), we aimed to evaluate the therapeutic and adverse effects of high-dose MP according to the second National Acute Spinal Cord Injury Study (NASCIS-2) dosing protocol in comparison to no steroids in patients with ASCI by performing a meta-analysis on the basis of the current available clinical trials. METHODS: We searched PubMed and Cochrane Library (to May 22, 2018) for studies comparing neurologic recoveries, adverse events, and in-hospital costs between ASCI patients who underwent high-dose MP treatment or not. Data were synthesized with corresponding statistical models according to the degree of heterogeneity. RESULTS: We enrolled 16 studies (1,863 participants) including 3 randomized controlled trials (RCTs) and 13 observational studies. Pooled results indicated that MP was not associated with an increase in motor score improvement (RCTs: p = 0.84; observational studies: p = 0.44) and incidence of recovery by at least one grade on the American Spinal Injury Association Impairment Scale or Frankel (p = 0.53). Meanwhile, MP did not lead to better sensory recovery (p = 0.07). However, MP was associated with a significantly higher incidence of gastrointestinal hemorrhage (p = 0.04) and respiratory tract infection (p = 0.01). The difference in the overall in-hospital costs between MP and control groups was not statistically significant (p = 0.78). CONCLUSIONS: Based on the current evidence, high-dose MP treatment, in comparison to controls, does not contribute to better neurologic recoveries but may increase the risk of adverse events in patients with ASCI. Therefore, we recommend against routine use of high-dose MP early after ASCI.

Cost-Effectiveness of Erythropoietin in Traumatic Brain Injury: A Multinational Trial-Based Economic Analysis.

The EPO-TBI multi-national randomized controlled trial found that erythropoietin (EPO), when compared to placebo, did not affect 6-month neurological outcome, but reduced illness severity-adjusted mortality in patients with traumatic brain injury (TBI), making the cost-effectiveness of EPO in TBI uncertain. The current study uses patient-level data from the EPO-TBI trial to evaluate the cost-effectiveness of EPO in patients with moderate or severe TBI from the healthcare payers' perspective. We addressed the issue of transferability in multi-national trials by estimating costs and effects for specific geographical regions of the study (Australia/New Zealand, Europe, and Saudi Arabia). Unadjusted mean quality-adjusted life-years (QALYs; 95% confidence interval [CI]) at 6 months were 0.027 (0.020-0.034; p < 0.001) higher in the EPO group, with an adjusted QALY increment of 0.014 (0.000-0.028; p = 0.04). Mean unadjusted costs (95% CI) were $US5668 (-9191 to -2144; p = 0.002) lower in the treatment group; controlling for baseline IMPACT-TBI score and regional heterogeneity reduced this difference to $2377 (-12,446 to 7693; p = 0.64). For a willingness-to-pay threshold of $US50,000 per QALY, 71.8% of replications were considered cost-effective. Therefore, we did not find evidence that EPO was significantly cost-effective in the treatment of moderate or severe TBI at 6-month follow-up.

The cost-effectiveness of medication, laser trabeculoplasty, and trabeculectomy for treatment of open-angle glaucoma in South Korea.

OBJECTIVES: Open-angle glaucoma (OAG) imposes high disease burden in South Korea. Although various effective interventions are available to manage the progression of OAG, there is limited data on the cost-effectiveness of these treatment strategies in South Korea. METHODS: Using a Markov cohort model, we evaluated the cost-effectiveness of 3 major treatment strategies (medication, laser trabeculoplasty, and trabeculectomy) for South Korean patients with OAG. We projected a 25-year time horizon to study a hypothetical cohort of 10,000 patients of age 40 with mild OAG. The outcome measures were quality-adjusted life-years (QALYs) gained, cost from the societal perspective, and the incremental cost-effectiveness ratio (ICER) of medication, laser trabeculoplasty, and trabeculectomy. Interventions were evaluated at a willingness-to-pay (WTP) threshold of 30,000,000 KRW ($29,152) per QALY gained. Deterministic and probabilistic sensitivity analyses were conducted to address the model uncertainty. RESULTS: The mean costs for medication, laser trabeculoplasty, and trabeculectomy were 29,661,740 KRW, 17,34,1342 KRW, and 22,275,438 KRW, respectively. The mean QALYs gained were 15.7, 15.3, and 14.8 for medication, laser trabeculoplasty, and trabeculectomy, respectively. Surgery was strongly dominated because it generated fewer expected QALYs but incurred greater expected cost than laser. The ICER was 30,885,179 KRW per QALY for medication versus laser trabeculoplasty. Laser was cost-effective, however, at a lower WTP threshold of 21,000,000 KRW per QALY gained or below. The results were most sensitive to the progression rates from mild to moderate glaucoma under laser treatment. CONCLUSION: Under the WTP threshold of 30,000,000 KRW per QALY, medication was cost-effective compared with laser trabeculoplasty and trabeculectomy for treating mild OAG in South Korean population. Laser, however, can be a cost-effective alternative in more resource-limited settings.

Protection of brain development by antenatal magnesium sulphate for infants born preterm.

Cerebral palsy (CP) remains the most significant neurological disorder associated with preterm birth. It disrupts quality of life and places huge cost burdens on society. Antenatal magnesium sulphate administration to females before 32 weeks' gestation has proven to be an effective intervention to reduce the rate of CP. In models of hypoxia, hypoxia-ischemia, inflammation, and excitotoxicity in various animal species, magnesium sulphate preconditioning decreased the resulting lesion sizes and inflammatory cytokine levels, prevented cell death, and improved long-term cognitive and motor behaviours. In humans, meta-analyses of five randomized controlled trials using magnesium sulphate as a neuroprotectant showed prevention of CP at 2 years. The benefit remained consistent regardless of gestational age, cause of preterm birth, and total dose received. Antenatal magnesium sulphate treatment is now recommended by the World Health Organization and by many obstetric societies. Its cost-effectiveness further justifies its widespread implementation. WHAT THIS PAPER ADDS: Neuroprotective effect of magnesium sulphate to reduce cerebral palsy in infants born preterm when administered to females at risk of imminent preterm birth. Neuroprotection regardless of gestational age, cause of preterm birth, and total dose. Antenatal magnesium sulphate treatment has good cost-effectiveness.

The High Cost of Stroke and Stroke Cytoprotection Research.

Acute ischemic stroke is inadequately treated in the USA and worldwide due to a lengthy history of neuroprotective drug failures in clinical trials. The majority of victims must endure life-long disabilities that not only affect their livelihood, but also have an enormous societal economic impact. The rapid development of a neuroprotective or cytoprotective compound would allow future stroke victims to receive a treatment to reduce disabilities and further promote recovery of function. This opinion article reviews in detail the enormous costs associated with developing a small molecule to treat stroke, as well as providing a timely overview of the cell-death time-course and relationship to the ischemic cascade. Distinct temporal patterns of cell-death of neurovascular unit components provide opportunities to intervene and optimize new cytoprotective strategies. However, adequate research funding is mandatory to allow stroke researchers to develop and test their novel therapeutic approach to treat stroke victims.

Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.

BACKGROUND: Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. OBJECTIVE: The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. METHODS: We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. RESULTS: A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. CONCLUSION: Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.

Experimental benznidazole treatment of Trypanosoma cruzi II strains isolated from children of the Jequitinhonha Valley, Minas Gerais, Brazil, with Chagas disease

Trypanosoma cruzi strains from distinct geographic areas show differences in drug resistance and association between parasites genetic and treatment response has been observed. Considering that benznidazole (BZ) can reduce the parasite burden and tissues damage, even in not cured animals and individuals, the goal is to assess the drug response to BZ of T. cruzi II strains isolated from children of the Jequitinhonha Valley, state of Minas Gerais, Brazil, before treatment. Mice infected and treated with BZ in both phases of infection were compared with the untreated and evaluated by fresh blood examination, haemoculture, polymerase chain reaction, conventional (ELISA) and non-conventional (FC-ALTA) serologies. In mice treated in the acute phase, a significant decrease in parasitaemia was observed for all strains. Positive parasitological and/or serological tests in animals treated during the acute and chronic (95.1-100%) phases showed that most of the strains were BZ resistant. However, beneficial effect was demonstrated because significant reduction (p < 0.05%) and/or suppression of parasitaemia was observed in mice infected with all strains (acute phase), associated to reduction/elimination of inflammation and fibrosis for two/eight strains. BZ offered some benefit, even in not cured animals, what suggest that BZ use may be recommended at least for recent chronic infection of the studied region.

Statistical analysis plan for the Erythropoietin in Traumatic Brain Injury trial: a randomised controlled trial of erythropoietin versus placebo in moderate and severe traumatic brain injury.

BACKGROUND: The Erythropoietin in Traumatic Brain Injury (EPO-TBI) trial aims to determine whether the administration of erythropoietin to patients with moderate or severe traumatic brain injury improves patient-centred outcomes. METHODS: EPO-TBI is a multicentre, blinded, randomised, parallel groups, placebo-controlled, phase III superiority trial of erythropoietin in ICU patients with traumatic brain injury conducted in Australia and New Zealand, Saudi Arabia and Europe; 606 critically ill patients aged 15 to 65 years with moderate or severe acute traumatic brain injury will be enrolled. Trial patients will receive either 40,000 IU erythropoietin or placebo by subcutaneous injection administered weekly for up to three doses during their ICU admission. The primary outcome measure is the proportion of unfavourable neurological outcomes, comprising death or severe disability, observed at 6 months following randomisation utilizing the Extended Glasgow Outcome Scale. Secondary outcomes, also assessed at 6 months following randomisation, include the probability of an equal or greater Extended Glasgow Outcome Scale level, mortality, the proportions of patients with proximal deep venous thrombosis or with composite thrombotic vascular events, as well as assessment of quality of life and cost-effectiveness. The planned sample size will allow 90% power to detect a reduction from 50% to 36% in unfavourable neurological outcomes at a two-sided alpha of 0.05. DISCUSSION: A detailed analysis plan has been developed for EPO-TBI that is consistent with international guidelines. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses. Application of this statistical analysis plan to the forthcoming EPO-TBI trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12609000827235 (22 September 2009). ClinicalTrials.gov: NCT00987454 (29 September 2009). European Drug Regulatory Authorities Clinical Trials: 2011-005235-22 (18 January 2012).

Isolation of the sapogenin from defatted seeds of Camellia oleifera and its neuroprotective effects on dopaminergic neurons.

Sasanqua saponin is a major active compound in the defatted seeds of Camellia oleifera but is always discarded without effective utilization. The sapogenin from hydrolysis of sasanqua saponin was purified, and its amination derivative was investigated on its neuroprotective effects, which were evaluated by animal models of Parkinson disease in mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results showed that the sapogenin and its derivative increased dopamine content in striatum and tyrosine hydroxylase (TH) positive cells in substantia nigra and relieved inflammation and behavioral disorder, but the effect on movement was reversed by dopamine receptor antagonist haloperidol and was not intervened by adenosine receptor antagonist CGS 15943. Molecular simulation showed the interaction between dopamine receptor and the sapogenin or its derivative. It is proven that the sapogenin can protect dopamine neurons through antineuroinflammation and activation of dopamine receptor rather than adenosine receptor, and its amination improves the effects. This research provides the prospective prodrugs for Parkinson disease and a new medicinal application of sasanqua saponin.

[Clinical efficacy and pharmacoeconomic characteristics of the neuroprotection with low doses of cortexin in the treatment of acute ischemic stroke].

OBJECTIVE: To assess the efficacy of the cytoprotective neuropeptide cortexin in the complex treatment in acute and early rehabilitation stages of ischemic stroke (II). MATERIAL AND METHODS: A multicenter prospective double-blind placebo-controlled trial has been carried out. Two hundreds and seventy-two patients with II have been enrolled in the trial. Cortexin was administered in low doses (10 mg three times a day intramuscular, using the following schemes: group 1: 2 courses of cortexin; group 2: 1 course of cortexin with the following course of placebo; group 3: two courses of placebo. The duration of treatment was 70 days. Patients were examined during 4 visits using clinical tests and instrumental methods. RESULTS: High efficacy and safety of cortexin in the complex treatment of patients with II has been shown. The best therapeutic effect was seen in group 1 (two 10-day courses of cortexin). The results were confirmed by the pharmacoeconomic analysis of treatment tactics based on the estimation of "net monetary benefit". CONCLUSION: Cortexin is recommended for treatment and rehabilitation of patients with II.

Bioactive stilbenes from Vitis vinifera grapevine shoots extracts.

BACKGROUND: Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-ß peptide aggregation of original stilbenes from Vitis vinifera shoots. RESULTS: A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-ε-viniferin (trans-ε-viniferin), ω-viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-ß fibril formation. Vitisinol C was found to exert a significant activity against amyloid-ß aggregation. CONCLUSION: Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C.

Magnesium sulphate for fetal neuroprotection: a cost-effectiveness analysis.

BACKGROUND: The aim of this study was to assess the cost-effectiveness of administering magnesium sulphate to patients in whom preterm birth at < 32+0 weeks gestation is either imminent or threatened for the purpose of fetal neuroprotection. METHODS: Multiple decision tree models and probabilistic sensitivity analyses were used to compare the administration of magnesium sulphate with the alternative of no treatment. Two separate cost perspectives were utilized in this series of analyses: a health system and a societal perspective. In addition, two separate measures of effectiveness were utilized: cases of cerebral palsy (CP) averted and quality-adjusted life years (QALYs). RESULTS: From a health system and a societal perspective, respectively, a savings of $2,242 and $112,602 is obtained for each QALY gained and a savings of $30,942 and $1,554,198 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is imminent. From a health system perspective and a societal perspective, respectively, a cost of $2,083 is incurred and a savings of $108,277 is obtained for each QALY gained and a cost of $28,755 is incurred and a savings of $1,494,500 is obtained for each case of CP averted when magnesium sulphate is administered to patients in whom preterm birth is threatened. CONCLUSIONS: Administration of magnesium sulphate to patients in whom preterm birth is imminent is a dominant (i.e. cost-effective) strategy, no matter what cost perspective or measure of effectiveness is used. Administration of magnesium sulphate to patients in whom preterm birth is threatened is a dominant strategy from a societal perspective and is very likely to be cost-effective from a health system perspective.

Cost-effectiveness analysis of the neuroprotective agent edaravone for noncardioembolic cerebral infarction.

BACKGROUND: The free radical scavenger edaravone has been reported useful for improvement in activities of daily living and for prevention of recurrent stroke in the edaravone versus sodium ozagrel in acute noncardioembolic ischemic stroke (EDO) trial. The aim of this report was to evaluate the cost-effectiveness of edaravone compared to the intravenous antiplatelet drug ozagrel sodium (ozagrel) for noncardioembolic stroke (non-CES) based on the EDO trial data. METHODS: A cost-effectiveness analysis was performed using the Markov model, which also incorporated the long-term course after the acute stage of non-CES. From the perspective of a health care payer, direct medical costs and nursing care costs were taken into account in the cost analysis. The quality-adjusted life year (QALY) served as an indicator of effectiveness. Simulation at 5 and 10 years after the onset of non-CES was carried out. The study involved 68-year-old patients with non-CES, selected against the EDO trial subject selection criteria. A 14-day treatment with edaravone 60 mg/day or ozagrel 160 mg/day was assumed as acute treatment for non-CES. RESULTS: The use of edaravone was associated with a reduction in total costs (0.51 million yen [$6,374] at 5 years and 0.64 million yen [$8,039]) at 10 years after the onset of non-CES) and improvement in QALYs (0.23 at 5 years and 0.38 at 10 years). Compared to ozagrel therapy, edaravone therapy was a cost-saving strategy for treating non-CES. CONCLUSIONS: Compared to ozagrel therapy, edaravone therapy for non-CES is not only useful from a clinical viewpoint, but also valuable from a socioeconomic perspective.

Improving Alzheimer's disease phase II clinical trials.

Over the past 30 years, many drugs have been studied as possible treatments for Alzheimer's disease, but only four have demonstrated sufficient efficacy to be approved as treatments, of which three are in the same class. This lack of success has raised questions both in the pharmaceutical industry and academia about the future of Alzheimer's disease therapy. The high cost and low success rate of drug development across many disease areas can be attributed, in large part, to late-stage clinical failures (Schachter and Ramoni, Nat Rev Drug Discov 2007;6:107-8). Thus, identifying in phase II, or preferably phase I, drugs that are likely to fail would have a dramatic impact on the costs associated with developing new drugs. With this in mind, the Alzheimer's Association convened a Research Roundtable on June 23 and 24, 2011, in Washington, DC, bringing together scientists from academia, industry, and government regulatory agencies to discuss strategies for improving the probability of phase II trial results predicting success when considering the go/no-go decision-making process leading to the initiation of phase III.