The Economic Burden of Pediatric Postconcussive Syndrome.

OBJECTIVE: To estimate the direct costs of pediatric postconcussive syndrome (PCS). DESIGN: Retrospective cohort study. SETTING: Subspecialty sports medicine clinics of a large pediatric tertiary care network in the United States. PATIENTS: One hundred fifty-four patients aged 5 to 18 years with PCS, evaluated between 2010 and 2011. ASSESSMENT OF INDEPENDENT VARIABLES: Direct costs included visits to sports medicine clinic, visio-vestibular therapy, homebound education, subspecialist referral, and prescription-only medications (amantadine and amitriptyline), all measured beginning at 28 days after injury. MAIN OUTCOME MEASURES: Postconcussive syndrome was defined as persistence beyond 28 days from injury. RESULTS: The cost incurred by each PCS patient for sports medicine visits was $1575, for visio-vestibular therapy was $985, for homebound tutoring was $55, for prescription medications was $22, and for subspecialist referral was $120, totaling $3557 per patient, with a 95% confidence interval range of $2886 to $4257. CONCLUSIONS: Given the high economic costs of PCS determined in this study, therapies that mitigate this syndrome may have the potential to be cost-effective and even cost saving.

Pharmacological and electrical stimulation in chronic disorders of consciousness: new insights and future directions.

BACKGROUND: Chronic disorders of consciousness are costly and challenging conditions to treat. Although recent studies that have tested pharmacological and electrical stimulation for these conditions are promising, the optimal intervention, mechanisms of action and side effects of these experimental therapies are unclear. OBJECTIVE: To systematically review the clinical results of treatments for vegetative state (VS) and minimally conscious state (MCS) from the last 10 years. METHODS: MEDLINE, LILACS and SCOPUS were searched as data sources. Because the potential bias when search is limited to databases of peer-reviewed journals, reference lists were examined and experts in the field were contacted for other relevant or unpublished articles (i.e. negative studies). No negative unpublished studies were found. Studies were included related to therapeutic interventions in adult MCS or VS patients at least 3 and 12 months after non-traumatic and traumatic injuries, respectively. Eight studies met the inclusion criteria. The following interventions were reviewed: levodopa, amantadine, zolpidem, baclofen, dorsal column stimulation and deep brain stimulation. CONCLUSIONS: The adverse effects that were associated with these treatments were typically mild. Most of the studies demonstrated considerable improvements with the interventions, but their low strength of evidence limit the generalizability of the findings.

Amantadine, oseltamivir and zanamivir for the prophylaxis of influenza (including a review of existing guidance no. 67): a systematic review and economic evaluation.

OBJECTIVES: To evaluate the clinical effectiveness and incremental cost-effectiveness of amantadine, oseltamivir and zanamivir for seasonal and post-exposure prophylaxis of influenza. DATA SOURCES: A MEDLINE search strategy was used and searches were carried out in July 2007. REVIEW METHODS: An independent health economic model was developed based on a review of existing cost-effectiveness models and clinical advice.The model draws together a broad spectrum of evidence relating to the costs and consequences associated with influenza and its prevention. Where direct evidence concerning the effectiveness of prophylaxis within specific model subgroups was lacking, the model uses estimates from mixed subgroups or extrapolates from other mutually exclusive subgroups. RESULTS: Twenty-six published references relating to 22 randomised controlled trials (RCTs) were included in the clinical effectiveness review, along with one unpublished report. Eight, six and nine RCTs were included for amantadine, oseltamivir and zanamivir respectively. The study quality was variable and gaps in the evidence base limited the assessment of the clinical effectiveness of the interventions. For seasonal prophylaxis, there was limited evidence for the efficacy of amantadine in preventing symptomatic, laboratory-confirmed influenza (SLCI) in healthy adults [relative risk (RR) 0.40, 95% confidence interval (CI) 0.08-2.03]. Oseltamivir was effective in preventing SLCI, particularly when used in at-risk elderly subjects (RR 0.08, 95% CI 0.01-0.63). The preventative efficacy of zanamivir was most notable in at-risk adults and adolescents (RR 0.17, 95% CI 0.07-0.44), and healthy and at-risk elderly subjects (RR 0.20, 95% CI 0.02-1.72). For post-exposure prophylaxis, data on the use of amantadine were again limited: in adolescents an RR of 0.10 (95% CI 0.03-0.34) was reported for the prevention of SLCI. Oseltamivir was effective in households of mixed composition (RR 0.19, 95% CI 0.08-0.45). The efficacy of zanamivir in post-exposure prophylaxis within households was also reported (RR 0.21, 95% CI 0.13-0.33). Interventions appeared to be well tolerated. Limited evidence was available for the effectiveness of the interventions in preventing complications and hospitalisation and in minimising length of illness and time to return to normal activities. No clinical effectiveness data were identified for health-related quality of life or mortality outcomes. With the exception of at-risk children, the incremental cost-utility of seasonal influenza prophylaxis is expected to be in the range 38,000-428,000 pounds per QALY gained (depending on subgroup). The cost-effectiveness ratios for oseltamivir and zanamivir as post-exposure prophylaxis are expected to be below 30,000 pounds per QALY gained in healthy children, at-risk children, healthy elderly and at-risk elderly individuals. Despite favourable clinical efficacy estimates, the incorporation of recent evidence of viral resistance to amantadine led to it being dominated in every economic comparison. CONCLUSIONS: All three interventions showed some efficacy for seasonal and post-exposure prophylaxis. However, weaknesses and gaps in the clinical evidence base are directly relevant to the interpretation of the health economic model and rendered the use of advanced statistical analyses inappropriate. These data limitations should be borne in mind in interpreting the findings of the review.

Response of hepatitis C genotype-4 naïve patients to 24 weeks of Peg-interferon-alpha2b/ribavirin or induction-dose interferon-alpha2b/ribavirin/amantadine: a non-randomized controlled study.

BACKGROUND AND AIM: Currently, pegylated interferon is the most effective therapy for hepatitis C but its cost is out of reach of most patients in the developing countries. The aim of this study was to assess the response rate of genotype-4 patients to 24 wks of peg-interferon-alpha2b (Peg-IFN-alpha2b) and ribavirin (RBV) or interferon-alpha2b (IFN-alpha2b) with RBV and amantadine (AMD) as an alternative option. METHODS: In a controlled study, 180 biopsy-proven naïve chronic hepatitis C patients were allocated into three groups based on their financial affordability to any of the study regimens. Group I (control) comprised 40 patients who received Peg-IFN-alpha2b in a flat dose of 100 mug/wk (the dose available in Egypt) plus RBV 1,000-1,200 mg per day based on body weight for 48 wks. Group II comprised 70 patients who received the same regimen for 24 wks. Group III comprised 70 patients who received induction-dose triple therapy (IDTT) in the form of IFN-alpha2b 3 MU once daily for the first 4 wks then reduced to TIW for 20 wks plus RBV 1,000-1,200 mg per day based on body weight and AMD 100 mg twice daily for 24 wks. Six patients from group I, eight patients from group II, and four from group III discontinued the study either due to financial limitations and/or intolerable adverse effects of the drugs. RESULTS: Intention-to-treat analysis revealed that sustained virological response (SVR) achieved in 22 (55.0%), 34 (48.6%), and 20 (28.6%) in groups I, II, and III, respectively. Adherence-to-treatment analysis (80/80/80) revealed that SVR achieved in 22 (64.7%), 34 (54.8%), and 20 (30.3%) in groups I, II, and III, respectively. In absence of eradication of hepatitis-C-virus-RNA at week 12, there was virtually no chance of achieving SVR. These data collectively may indicate that genotype 4 is "not difficult to treat" as previously reported. CONCLUSION: Response of genotype-4 patients to 24 wks of Peg-IFN-alpha2b/RBV did not significantly differ from 48 wks, but was significantly higher than IDTT. Although SVR achieved by IDTT is less than Peg-IFN-alpha, yet it might provide a second option when the latter is not affordable. Early virological response should be used as a predictor to SVR to avoid unnecessary expenses in nonresponders patients.

Economic evaluation of oseltamivir phosphate for postexposure prophylaxis of influenza in long-term care facilities.

OBJECTIVES: To compare the cost-effectiveness of oseltamivir postexposure prophylaxis during influenza A outbreaks with that of amantadine postexposure prophylaxis or no postexposure prophylaxis in long-term care facilities (LTCFs). DESIGN: Cost-effectiveness analysis based on decision analytic model from a government-payer perspective. SETTING: A Canadian LTCF, with high staff vaccination, at the beginning of influenza season. PARTICIPANTS: Elderly, influenza-vaccinated patients living in a Canadian LTCF. MEASUREMENTS: Incremental costs (or savings) per influenza-like illness case avoided compared with usual care. RESULTS: From a government-payer perspective, this analysis showed that oseltamivir was a dominant strategy because it was associated with the fewest influenza-like illness cases, with cost savings of $1,249 per 100 patients in 2001 Canadian dollars compared with amantadine and $3,357 per 100 patients compared with no prophylaxis. Costs for amantadine dose calculation and hospitalization for adverse events contributed to amantadine being a more-expensive prophylaxis strategy than oseltamivir. Both prophylaxis strategies were more cost-effective than no prophylaxis. CONCLUSION: Despite high influenza vaccination rates, influenza outbreaks continue to emerge in LTCFs, necessitating cost-effective measures to further limit the spread of influenza and related complications. Although amantadine has a lower acquisition cost than oseltamivir, it is associated with more adverse events, lower efficacy, and individualized dosing requirements, leading to higher overall costs and more influenza-like illness cases than oseltamivir. Therefore the use of oseltamivir postexposure prophylaxis is more cost-effective than the current standard of care with amantadine prophylaxis or no prophylaxis.

Deep brain stimulation of the subthalamic nucleus reduces antiparkinsonian medication costs.

This study reports a retrospective analysis of 16 patients to determine changes in medication costs associated with deep brain stimulation of the bilateral subthalamic nucleus (DBS B-STN). Antiparkinsonian medication (APMED) costs were evaluated pre- and post-operatively at 1 and 2 years, based on prescribed dosages. After treatment with DBS, patients experienced a 32% reduction in APMED costs after 1 year and a 39% reduction after 2 years. Hypothetical projections of total potential savings are presented, accounting for increasingly complex medication regimens and medication cost inflation. DBS patients may experience a significant long-term reduction in the cost of their pharmacologic treatment.

Management of influenza in adults older than 65 years of age: cost-effectiveness of rapid testing and antiviral therapy.

BACKGROUND: Although antiviral therapy is cost-effective in adults, its cost-effectiveness in older adults has not been studied. OBJECTIVE: To determine the cost-effectiveness of influenza testing and treatment strategies for older adults. DESIGN: Cost-utility decision model. DATA SOURCES: Clinical trials of antiviral drugs and epidemiologic data. TARGET POPULATION: Noninstitutionalized adults older than 65 years of age with influenza-like illness. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTIONS: Rapid diagnostic testing or empirical therapy with antiviral drugs. OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) saved. RESULTS OF BASE-CASE ANALYSIS: Compared with no intervention, empirically treating an unvaccinated 75-year-old patient with amantadine increased life expectancy by 0.0014 QALY at a cost of 1.57 dollars, a cost-effectiveness ratio of 1129 dollars per QALY saved. Compared with amantadine, rapid diagnostic testing followed by treatment with oseltamivir cost 5025 dollars per QALY saved and empirical treatment with oseltamivir cost 10,296 dollars per QALY saved. Testing and treatment strategies were less cost-effective if the patient was vaccinated, ranging from 2483 dollars per QALY saved with amantadine to 70,300 dollars per QALY saved with oseltamivir. RESULTS OF SENSITIVITY ANALYSIS: The decision was sensitive to the probability of influenza, the efficacy of oseltamivir in preventing hospitalizations, and hospitalization and case-fatality rates. The decision was not sensitive to the probability or severity of medication side effects, the quality of life for influenza illness or hospitalization, the efficacy of antiviral therapy in shortening influenza illness, or the rapid diagnostic test characteristics. CONCLUSIONS: For unvaccinated or high-risk vaccinated patients during the influenza season, empirical oseltamivir treatment is cost-effective. For other patients, rapid diagnostic testing followed by treatment with oseltamivir is cost-effective. Empirical amantadine treatment offers a low-cost alternative if patients cannot afford oseltamivir.

Cost-effectiveness of newer treatment strategies for influenza.

PURPOSE: Recent advances in the diagnosis and treatment of influenza, such as rapid testing and neuraminidase inhibitor therapy, are available, but their place in clinical practice and their cost-effectiveness have not been determined. MATERIALS AND METHODS: To estimate the cost-effectiveness of these newer interventions, we used a decision model that compared several influenza management strategies: no testing or treatment, amantadine or rimantadine treatment without testing, testing then amantadine or rimantadine treatment, neuraminidase inhibitor treatment without testing, or testing then neuraminidase inhibitor treatment. Antiviral therapy began within 48 hours in febrile patients with characteristic symptoms of influenza. We assumed that antiviral treatment did not change rates of influenza complication or mortality, and chose parameter values in the baseline analysis to bias slightly against antiviral treatment and toward testing strategies. RESULTS: In the baseline analysis, testing strategies are more expensive and less effective than treatment strategies. Amantadine costs $9.06 per illness day avoided or $11.60 per quality-adjusted day gained. Compared with amantadine, zanamivir costs $198 per illness day avoided or $185 per quality-adjusted day gained, whereas oseltamivir costs $252 per illness day avoided or $235 per quality-adjusted day gained. In elderly patients who require reduced dosage, rimantadine costs $128 per quality-adjusted day gained compared with amantadine. In younger patients, amantadine is favored if the likelihood of influenza A is >67%; otherwise, neuraminidase inhibitors are favored. Testing strategies are more costly and less effective when the influenza probability is >30%. No testing or treatment is favored if the influenza probability is <32% and the influenza utility is >0.77. In elderly patients, amantadine is favored over rimantadine if the utility of medication side effects is >0.94. CONCLUSIONS: Antiviral treatment of influenza without rapid testing is reasonable economically in febrile patients with typical symptoms during influenza season. The choice of antiviral agent depends on age, the likelihood of influenza A, and the willingness to pay per quality-adjusted day gained.

Antiviral therapy for influenza virus infections.

Every year, influenza viruses cause global epidemics that result in significant morbidity and mortality. Influenza infections can be serious in children, especially infants and toddlers. Four antiviral agents, amantadine, rimantadine, oseltamivir, and zanamivir, are available for the treatment or prophylaxis of influenza. Experience with the use of these antiviral drugs for influenza in children is limited. Given the small degree of therapeutic gain that is reported from clinical trials, considerations about cost effectiveness are important in deciding whether to use these agents in the treatment of suspected or proven influenza infections in healthy children.

Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial.

Recent controlled trials on the efficacy of an amantadine/interferon combination in treatment-naive patients with chronic hepatitis C yielded contradictory results. We therefore conducted a large, double-blind, placebo-controlled, multicenter trial in naive patients with chronic hepatitis C: 246 patients were randomized to receive interferon alfa-2a (6 MIU sc thrice weekly for 20 weeks, then 3 MIU sc thrice weekly) and either amantadine sulphate (2 x 100 mg p.o. QD) or placebo. Treatment continued for a total of 52 weeks, if HCV-RNA in serum polymerase chain reaction (PCR) had fallen below detection limit (1,000 copies/mL) at treatment week 10, and stopped otherwise. All patients were followed for 24 weeks off therapy. After 10 weeks of treatment, 66/121 patients treated with amantadine (55%) and 78/125 treated with placebo (62%) had lost HCV-RNA (n.s.). After 24 weeks of follow-up, 25 patients in the amantadine (21%) and 17 (14%) in the placebo group remained HCV-RNA negative (n.s.). During therapy, virologic breakthroughs occurred less often in the amantadine than in the placebo group [14 (12%) vs. 27 (22%) patients; P =.04]. Multivariate logistic regression analysis revealed genotype, viremia level, age, and amantadine therapy [risk ratio 0.4 (95%CI 0.2-1.0), P =.05] as predictors of sustained virologic response. Adverse events and impact of therapy on quality of life were similar in amantadine and placebo treated patients. Compared with current standard treatment (interferon/ribavirin), the interferon/amantadine combination was not cost-effective. In conclusion, amantadine does not add to a clinically relevant extent to the treatment of naive patients with chronic hepatitis C.

Treatments for fatigue in multiple sclerosis: a rapid and systematic review.

BACKGROUND: Multiple sclerosis (MS) is an important problem both for people with the disease and for society. There is no cure, and alleviation of symptoms forms the cornerstone of care. Excessive fatigue that severely limits activity is experienced by at least two-thirds of the estimated 60,000 people with MS in the UK. OBJECTIVES: (1) To identify current treatments for fatigue in MS and their evidence-base. (2) To systematically review the evidence for those treatments that have been investigated in more than one rigorous study, in order to determine their effectiveness and cost-effectiveness. METHODS: The review was carried out in two stages: a formal scoping review (to assess the range of interventions used by people with MS), and a systematic review for treatments that had been identified as promising and that had been investigated in clinical trials (as identified in the scoping review). A systematic review of research on costs and cost-effectiveness of those interventions identified as promising was also performed. Electronic databases, including MEDLINE and EMBASE, were searched for the period 1991-June 1999 (scoping review) and 1966-December 1999 (systematic review). Reference lists from publications were also searched, and experts were contacted for any additional information not already identified. RESULTS: Interventions identified for the treatment of fatigue in MS (1) Behavioural advice. This is the main element of initial clinical management and no rigorous research of its effectiveness was identified. (2) Drugs (amantadine, pemoline, potassium-channel blockers and antidepressants). (3) Training, rehabilitation and devices (cooling vests and electromagnetic fields). (4) Alternative therapies (bee venom, cannabis, acupuncture/acupressure and yoga). Only two drugs, amantadine and pemoline, met the criteria for full systematic review. RESULTS - EFFECTIVENESS OF AMANTADINE: One parallel and three crossover trials were found, involving a total of 236 people with MS. All studies were open to bias. All studies showed a pattern in favour of amantadine compared with placebo, but there is considerable uncertainty about the validity and clinical significance of this finding. This pattern of benefit was considerably undermined when different assumptions were used in the sensitivity analysis. RESULTS - EFFECTIVENESS OF PEMOLINE: One parallel and one crossover trial were found involving a total of 126 people with MS. Both studies were open to bias. There was no overall tendency in favour of pemoline over placebo and an excess of reports of adverse effects with pemoline. RESULTS - HEALTH ECONOMIC ANALYSIS: The drug costs of amantadine and pemoline are modest (pound 200 and pound 80 per annum, respectively). No economic evaluations were identified in the systematic review, and available data were insufficient to allow modelling of cost-effectiveness in this rapid review. CONCLUSIONS: There is insufficient evidence to allow people with MS, clinicians or policy makers to make informed decisions on the appropriate use of the many treatments on offer. Only amantadine appears to have some proven ability to alleviate the fatigue in MS, though only a proportion of users will obtain benefit and then only some of these patients will benefit sufficiently to take the drug in the long term. CONCLUSIONS - RECOMMENDATIONS FOR RESEARCH: The frequency, severity and impact of fatigue, the poverty of available research, and the absence of any ongoing research, suggest that new research is an urgent priority. People with MS, clinicians and policy makers should work together to ensure that the evidence required is collected as quickly as possible by encouraging involvement in rigorous research. Research should not be restricted to the two drugs reviewed in depth in this report. All interventions identified in the scoping review (see above) should be considered, as should basic scientific research into the underlying mechanism of fatigue in MS.

Cochrane reviews and systematic reviews of economic evaluations. Amantadine and rimantadine in the prevention and treatment of influenza.

Cochrane reviews provide standardised and regularly updated syntheses of evidence on the effects of healthcare interventions. We present the rationale for, and some of the results of, a Cochrane review of the effects of amantadine and rimantadine in the prevention and treatment of influenza. The estimates of effect will be incorporated into a decision-making model for tackling influenza in healthy adults (i.e. soldiers in the British Army). Our systematic review of the economics of influenza also provides the international context within which economic data can be interpreted and assessed as a preliminary to an economic evaluation comparing alternative prevention and treatment strategies. Systematic reviews provide powerful and relatively inexpensive evidence of effects and tolerability, which is more likely to convince decision-makers than evidence from single studies. Additionally, they can be used to focus clinical trial questions and provide strategic insight regarding the state-of-the-art knowledge of effects and economics of compounds in a specific field.