- Email: [email protected]
PT009 Economics
Guided Poster Tours
140
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G309D-Pinkl knock-in mouse model of PARK6
G. Auburger*, S. Gispert, R. Nussbaum, A. Chen
*Frankfurt, Germany Objeetive: In order to study PARK6-induced abnormalities of mitochondrial phosphorylation in nigrostriatal depaminergic neurons, we generated a mouse model of PARK6. Method: The mouse strain 129sv/ev was selected for homologous recombination, and the vector pPNT-lox to clone the targeting construct. Results: Tile mouse Pinkl gene has been isolated from a BAC genomic library. After shotgun cloning into the pBluescript II KS+ vector, the G309D mutation has been inserted by in-vitro mutagenesis. The targeting construct has been made with a 4.2 kB NheI restriction fragment containing exons 2, 3, 4, 5 as left arm and a 3.2 kB NheI-BstZ171 restriction fragment as right arm. After linearization, electroporation into embryonic stem (ES) cells, and positive/negative selection tile homologous recombinant clones were confirnled by Southern blotting with internal and external probes. The mutation was demonstrated by Avail restriction digests of exon 4 PCR products. Microinjectien of mutant ES cells into B16 blastocysts has been carried out, and chimaeras have been obtained at this time. Conclusion: Introduction of tile G309D mutation into tile mouse mitochondrial protein kinase Pinkl has not produced any overt pathological phenetype in ES cells. Tile generation of a PARK6 knock-in mouse model seems possible.
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serine-threonine kinase activity of Pink1, the PARK6 disease protein
G. Auburger*, F. Ricciardi, S. Gispert
*Frankfurt, Germany Objective: Protein phosphorylation in tile mitochondria appears decisive for neuroprotection in the PARK6 variant ofautesomal recessive early onset Par!dnson syndrome. Pathogenic mutations of tile disease protein Pink1 thus have to be analysed for alterations o f ldnase activity and substrate binding. Method: We have constructed a GST-Pinkl fusion protein and purified its monomeric enzymatically active form from E. cell bacteria. In-vitro mutagenesis o f tile ldnase domain was performed, and tile phosphorylation activity of Pinkl was investigated for loss of function effects. Results: The autophespherylatien kinase activity of tile Pinkl mutants H271Q, G309D, L347P, E417G was determined in comparison to classical negative mutations of serine-threonine ldnase domains. Tile interaction with protein substrates in-vitro was analysed. Conclusion: Tile identification o f Pinkl phespherylatien substrates within mitechondria may help to define a pathogenetic pathway common to Par!dnson syndromes.
Monday, 6 June 2005, 12.3013.30, Hall 15.1
PT009 Economics Chair: Donald Grosset, Glasgow, United Kingdom Co-Chair: Ivar Sonbo Kristiansen, Oslo, Norway
•
Development and validation of a multi-outcome decision model for assessing effectiveness and cost-effectiveness of interventions in Parkinson's disease
R. Dodel*, B. Bornschein, G. Sroczyns!d, A. Spottke, U. Siebert
*Bomb, Germany Objeetive: To develop and validate a genetic decision-analytic modal for tile evaluation of long-terrn clinical and economic consequences of
interventions in patients with Parkinson's disease (PD) which can be applied to different research questions, interventions, and outcomes. Method: We developed a Markov model, in which a hypothetical cohort of patients moves through health states reflecting patient characteristics that are observed under treatment (Hoehn and "~ahr 'on' state [HYon]) and would be observed in the absence of treatment (Hoehn and Yahr 'off' state [HYott]). We used HYoff I-V s as Markov states, because those reflect underlying biologic progression of PD. Interventions: diagnostic or treatment strategies in PD patients such as Levodepa, depamine agonists, or other and-parldnsonian drugs as weft as surgical therapies such as deep brain stimulation. Data: Transition probabilities for HYoff states were derived from tile literature. Tile distribution of HYon was modeled conditional on HYoff using studies that report both characteristic. Complications were modeled conditional on HYon using data from a registry established by the 'Competence Network Parkinson Disease'. Utilities, and costs were modeled conditional on HYon and presence of complication. Mortality is a function of age- and gender-specific background mortality and PD-specific mortality Time horizon: lifetime with annual cycle length. Outcomes: rernaining (quMity-adjusted) life expectancy, direct costs, and incremental cost-effectiveness ratios. Further outcomes comprise clinical events or complications such as motor complications, dementia, depression, and hallucinations. In addition, complication-free survival, time in HYoff and HYon states, and UPDRS scores were modeled as additional outcomes. Perspective: societal and third party payer. Sensitivity analysis: 1-way and multiway. An interactive interface allows to model different settings or countries. XSalidation: InternM validation of HYoff input data showed a 97.4-99.9% accuracy. In external validation, mean HYon progression rate predicted by our model (0.42 HY stages/y) matched well with estimates reported in the literature (0.40 HY stages/y). Results: We developed a generic decision-analytic Markov model to simulate clinical and economic outcomes for different interventions in patients with Parldnson's disease. In this model, a hypothetical cohort of patients moves through health states reflecting patient characteristics that are observed under treatment (Hoehn and Yahr 'on' state [HY on]) and would be observed in tile absence of treatnlent (Hoehn and Yahr 'off' state [HY off]). For both characteristics, data are available from observational studies and randomized clinical trials. We used Hoehn and Yahr 'off' states as Markov states, because these states reflect the underlying biologic progression of PD. Technically, tile model is designed to compare two or more competing strategies in PD patients such as Levodepa, depamine agonists, or other anti-parldnsonian drugs as well as surgical therapies such as deep brain sthnulation. Transitions from one state to another are defined by transition probabilities derived from the published literature. Patients may (tie from other causes as a function of age and gender, remain in the same health state, progress or regress to another health state. Tile model discriminates states for HY off I-V and death. The distribution of HY on stages was modeled conditional on HY off stage using studies that report both characteristics for a patient cohort. Proportion of complications was modeled conditional on HY on stage using data from a registry established by the 'Competence Network Parkinson Disease'. UPDRS score, EQ-5D, and costs were modeled conditional on HY on stage and presence of complication based on the same registry. An annual cycle length was used and tile simulation can be carried out for any time horizon including a lifelong time horizon (i.e., until all patients in the model had died). PD-specific disease mortality can be switched on and offin tile analysis. A flexible interface connecting the structural part o f the model and the databases allows tile exchange of input pararueters, for example, for simultaneous anMyses in different hospitals, settings, comltries and health care systems. The model estimates remaining life expectancy, qualityadjusted life expectancy, and direct costs for each examined strategy. Further outcomes comprise clinical events or complications such as motor complications (motor fluctutations, dyskinesias), denlentia, depression, and hallucinations. In addition, time in HY off and HY on states and UPDRS scores were modeled as additional outcomes. Incremental cost-effectiveness is calculated in monetary units per (quality-adjusted) life year saved. Discount rate can be varied with a default of 3 % per annum. The model can take different perspectives depending on tile available resource utilization
Guided Pester Tours data. Numerous univariate and multivariate sensitivity analyses for modal parameters are built in. Conclusion: tn contrast to formerly published models, this generic and validated PD model has the ability to consider multiple interventions and outcomes and to switch between outcomes depending on which outcomes are reported in a clinical trial.
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cost-effectiveness of continuous duodenal delivery of levodopa (Duodopa@) in patients with severe Parkinson's disease I.S. Kristiansen*, C. Bingefors, D. Nyholm, D. Isacson
*Oslo, Norway Objective: To explore costs and health benefits of replacing conventional oral therapy with intraduodenal infusion of carbidepa/levodopa (Duodepa®) for severe Par!dnson's disease (PD). Method: In the DIREQT trial 24 patients aged 50-79 years with ttoehn&'Yahr stage 2.5 4.0 (at best) were randomised to receive either three weeks of conventional oral therapy followed by three weeks of Duodopa, or vice versa. Later, patients could choose to switch permanently to Duodepa. Health Related Quality of Life (HRQOL) was recorded with the 15D instrument at entry into the trial, (luring tile trial, and then at 8 follow-ups during the subsequent 6 months. Use of health care was registered before, (luring and after tile trial. Two-year costs and health consequences of Duodepa and conventional therapy were estimated in a decision analytic model. Costs were based on market prices and customary charges in Sweden. Results: The mean quality-of-life scores were 0.77 for Duodopa and 0.72 for conventional therapy with considerable variation in scores for individual patients over time. The expected two year cost was $93,600 for Duodopa and $28,700 for conventional oral therapy. Tile expected number of Quality Adjusted Life Years (QALYs) was 1.48 and 1.42 respectively, or $1.02 mill. per additional QALY (all values discounted at 3%). This amount would be $199,000 if patients used apomorphine as conventional therapy, $124,000 if EQ-5D were used to measure HRQOL, $99,000 if indirect costs were included. If Duodopa improves disease severity by one H&Y stage, the therapy will be cost-saving. Conclusion: The cost-effectiveneas of Duodepa depends in particular on the cost of alternative therapies (i.e. apomorphine and oral drugs) and the extent to which Duodopa postpones PD progression. Also, tile method for capturing quality-of-life has a considerable impact on tile cost-effectiveneas ratio. The study indicates that even costly therapies for late stages of PD may be cost-effective.
•
Economic evaluation of SPECT-DaTSCAN in the diagnosis of patients with clinically uncertain Parkinsonism in Italy M.R. Busca*, A. Antonini, S. Lopatriello, P. Berto
*Milan, Italy Objective: This study assessed the economic value of using SPECTDaTSCAN (123I-FP-CIT) in comparison with current clinical judgement, in the diagnosis of patients with clinically uncertain Parkinsenism in Italy. Method: A cost-effectiveness analysis was based on a Marker model, comparing a cohort of patients following a diagnostic pathway including or excluding DaTSCAN, using a time horizon of 5 years. The model was populated with direct medical costs (drugs, tests, exams, hospital admissions, management o f adverse events) assedated with diagnosis and treatment, diagnostic accuracy (sensitivity: 97%, specifidty: 100%), the underlying prevalence of diseases in tile tested population (estimated to be 49%), rates o f adverse events, therapy progression and death. Effectiveness was expressed as tile (gain in) nmnber of years of appropriate therapy per patient. Model input values were estimated using a double round Delphi panel performed with 12 Italian specialists. Diagnostic accuracy, adverse event rates and mortality rates were based on published studies.
141
Results: The current diagnostic pathway prodeced on average 2.3 'adequately treated years' (ATYs) per patient at an estimated cost of £8893 to tile healthcare system ever 5 years. Tile DaTSCAN pathway generated on average 4.1 ATYs per patient at an estimated cost of ¢8410. Use of DaTSCAN rather than current diagnostic practice generated an additional 1.8 ATYs at a cost saving of ¢482 per patient over 5 years. Discounting at 5%, tile cost saving became ¢372 per patient over 5 years. If tile use of DaTSCAN decreased other diagnostic work-up costs by ¢450 (estimated by clinical expert), cost savings became ¢932 (undiscounted) per patient tested. The result is sensitive to the proportion of patients tested. Conclusion: The analysis suggests that using DaTSCAN in patients with clinically uncertain Parldnseniarn is an economically attractive intervention. Greater amounts of time on appropriate therapy are achieved at less cost to the healthcare system.
•
Methods of detecting sub-optimal medicine usage in Parkinson's disease D. Grosset*, K. Grosset, I. Bone, J. Reid
*Glasgow, United Kingdom Objective: To assess different methods of measuring therapy adherence in Parkinson's disease. Method: In a single centre observational study, 112 cases of idiopathic Par!dnson's were randomised to active monitoring (n= 69, simple tablet count and electronic monitoring condected), or to no monitoring (n 43, control group). All patients completed a self-report and visual analogue scale indicating therapy intake. Results: In the active monitoring group, 56 (81% of cases) used 80% of their medication, and 13 (19% of cases) used <80%, based on electronic monitoring. Median adherence for self-report was 100% (interqnartile range (IQ) 100 100) and for visual analogue was 100% (IQ 95 100), in both active and control groups. Patients ta!dng 80% of prescribed medication had median total adherence of 98% (IQ 93-101) by electronic monitoring, which was similar to that from other methods: self-report (100%, IQ 100-100); visual analogue scale (100%, IQ 95-100); simple tablet count 98% (IQ 89 100). Median total adherence in patients taldng <80% of medication was significantly lower by electronic monitoring (69%, IQ 44 74) than by other methods: self-report 100% (IQ 100 100); visual analogue scale 100% (IQ 95-100); and simple tablet count 90% (IQ 78-100) (all p < 0.0001). Sensitivities of self-report (10%), visual analogue scale (17%) and simple tablet count (50%) were all low for detecting suboptimal medicine intake. Conclusion: Self-report, visual analogue scale and simple tablet counts are insensitive in prediction of sub-optimal medicine usage in PD. How patients take their medicines itfftuences interpretation of the therapy response and consequent management decisions, with implications for clinical trial analysis and clinical practice.
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Direct and indirect costs in Parkinson's disease W. Jest*, N. Lenkel, I. Dengler, T. Menser
* VgTesbaden, Germany Objective: Processing and analysis of direct and indirect (economic) costs in the treatment of patients with Parldnson's disease (PD). Data regarding tile direct and indirect costs that incurred in tile treatment of parldnsoniarn have been incomplete so far. Particularly tile indirect costs are hardly being considered, although they do have a substantial bearing on tile national economy. To make up for this lack of primary data, a prospective study has been carried out during a period of three years that takes into account tile individual changes in treatment and costs. Method: This study prospectively ascertained all costs incurred over a period of three years in a sample of 117 patients with PD, that is, costs for medication, medical therapies, diagnostic procedures, hospitalizations, remedies and aids. Moreover, it included costs related to decreased earning capacity/disablement, housing modifications, home care, early retirement,
Guided Poster Tours
142
transportation costs etc. Tile fee schedules applicable within tile German Health Care system (GO]k, EBM) were used to evaluate tile individual items; drugs were rated according to their selling price in pharmacies; remedies and aids according to the reimbursements granted by costing units. Tile nursing rates legally provided for, flat mileage rates, and infermarion gathered from patients and manufacturers were - among others incorporated to assess tile indirect costs. We studied a total of 117 patients (78 of them male). Their mean age was 67.5 years, the majority of them graded in tile H&Y stages 2 and 3. Results: Tile average total costs per patient and month aruounted to 603.32 C. Breaking them down, pharmaceuticals run up to 480.23 C, remedies to 58.35 £, aids to 7.95 £, therapies to 11.56 £, extraordinary diagnostic workup (MRT, SPECT, PET) to 26.96 C and hospitalizations to 18.27 C. Tile total of average indirect costs per month and patient aruomlted to 404.22 C. These are made up by 162.18 C due to the inability to earn a living (including early retirernen 0, 145.96 £ for nursing/home care, 25.44 £ for transportation, 58.45 C for housing modifications and 12.19 C for ancillary expenses. Conclusion: Tile costs for pharmaceuticals are tile biggest item among
the direct costs (480.23 £ or equivalent to 80%), whereas inability to earn a living including early retirement constituted tile biggest factor among the indirect costs (41% or 162.18 Q. The nursing costs of 145.96 £ referring to outpatients alone, are explained by tile great number of subjects still in the early stage of disease.
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reasons of a cancellation of drug treatment at Parkinson's disease in Russia
E. Childna*
*Moscow, Russia Objective: To establish and analyse principal causes which result in a cancellation of drug treatment at Parkinson's Disease. Method: tn tile analysis have been included 241 patient with Par!dnson's Disease (male 127, female 114; mean age 66.1±7.5 years, durarion of disease 5.2-:3.2 years). The retrospective analysis have been carried out for treatment which patients received. Results: 160 patients accepted levodepa (mean dose 612.0-k327.Tmg daily); 105 patients accepted cholinolitics such as cyclodel (mean dose 5.0-:2.0mg daily); 83 patients accepted amantadine (mean dose 253.9±72.1mg daily); 41 patients accepted dopanfine agonist such as pramipexole (mean dose 2.4-t-1.0 mg daily); 35 patients accepted sdegiline (mean close 9.1±3.2 mg daily). Adverse events resulted in a cancellation of drug more often for cholinolitics (n 32), less often for levodepa (n 8), arnantadine (n = 5) and pramipexole (n = 4). Insufficient efficacy was the most often reason of a cancellation of treatment by cholinolitics (n 21), selegiline (n = 17), amantadine (n = 15) and the rare reason of a cancellation oftreatmentby levodopa (n 3), pranfipexole (n 2). High cost of drug was the most often reason o f a cancellation of pramipexole (n=27) and only in one case have led to a cancellation oflevodepa. For comparison, in our research mean daily dose of levodopa costs 0.9 USD, mean daily dose of pramipexole costs 3.96 USD, mean daily dose of selegiline costs 0.88 USD, mean daily close of arnantadine costs 0.05 USD and mean daily dose of cholinoliries costs 0.02 USD. Conclusion: More often patients cancelled cholinolirics (owing to adverse events and insufficient efficacy), most less often patients cancelled levodepa. Reduction of cost treatment by depamine agonist such as pramipexole could lead to increase in number of Parkinson's Disease patients which would continue to accept this drug in Russia.
Monday, 6 June 2005, 12.30 13.30, Hall 15.1
PTOIO Etiopathogenesis Chair: Joong-Seok Kim, Seoul, Republic of Korea
Co-Chair: Jacinto Duarte, Segovia, Spain
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natural history of treated Parkinson's disease: A prospective community based study with a mean 15 year follow-up
J. Duarte*, L.E. Claveria, S. Borja, A. Conde
*Segovia, Spain Segnvia is a small province, 100 km. North to Madrid, Spain, with a population of 150.000, with one only specialist referal centre, tile General Hospital in Segnvia capital. Segovia has a very stable elderly population with hardly any migratory movement which allows recollection of epidemiological and clinical data with a guaranteed long follow-up. A prospective study was deaigned to collect data in a clinical protocol in 274 consecutive clinically diagnosed parkinsonian patients, with 3~4 monthly follow-up by the same physician, summarizing data at 5, 10, 15 and 20 years of personal history (1984 2004). According to age of onset of Parkinson's disease, three groups of patients were sub divided and compared with each other, those with onset before tile age of 50 (8%), between 50-70 (61%) and those of late onset after 70 (31°/,,). Clinical symptoms and signs at onset and through out tile disease were recorded, mortality and Kl@lan-Meier curves, clinical scales and their evolution, type of trealment and desificarion, and correlation with clinical effect and secondary complications. The three groups of patients behave differently in their evolution despite similar therapeutic strategies and desificarion. Clinical evidence of neuroprotection? Aging as an agravating t:actor? They both seem to be relevant in our study.
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Recent changes in demographic factors of Parkinson's disease in Korea
J.-K. Kim*, Y Sohn, S.-Y. Kang, J.-S. Kim
*Seoul, Republic of Korea Objective: A recent survey showed that tile number of patients with Parkinson's disease (PD) visiting university hospitals in Korea had been increased 1.5 times from 1996 to 2000. Tiffs dramatic increase suggests that large number of Korean PD patients may get misdiagnosis, presumably clue to the iTtfluence of oriental medicine, in which PD is often regarded as a type of stroke. To investigate changes in demographic factors of PD with this increase, we reviewed the Yonsei Par!dnsoniarn Registry (YPR) in the past 12 years. Method: We reviewed demographic characteristics of de nero PD patients in YPR from 1992 to 2003. Patients with either insuffident infermarion or uncertain diagnosis were excluded. The patients were divided into two groups aeeording to their initial visiting time; group A (1992 1995) and group B (2000-2003). The demographic characteristics of both groups were compared. Results: Thirty three and thirty six patients who initially diagnosed as PD in our hospital were included in group A and B, respecrivel!c Group B patients were significantly older than group A patients (66±10 vs 59±10 years; p < 0.005). Accordingly symptom onset age of group B patients was also higher than that of group A (64±10 vs 57±11 years; p < 0.005). The duration between symptom onset and diagnosis was shorter in group B than group A (17 vs 22 months), and par!dnsonian disability was mild in group B compared with group A, although these differences did not attain statistical significance. Conclusion: These results suggest that recent increase in the numbers of PD patients visiting hospitals in Korea is mainly due to the increased number of older patients wile might have less education and then be easily
140
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G309D-Pinkl knock-in mouse model of PARK6
G. Auburger*, S. Gispert, R. Nussbaum, A. Chen
*Frankfurt, Germany Objeetive: In order to study PARK6-induced abnormalities of mitochondrial phosphorylation in nigrostriatal depaminergic neurons, we generated a mouse model of PARK6. Method: The mouse strain 129sv/ev was selected for homologous recombination, and the vector pPNT-lox to clone the targeting construct. Results: Tile mouse Pinkl gene has been isolated from a BAC genomic library. After shotgun cloning into the pBluescript II KS+ vector, the G309D mutation has been inserted by in-vitro mutagenesis. The targeting construct has been made with a 4.2 kB NheI restriction fragment containing exons 2, 3, 4, 5 as left arm and a 3.2 kB NheI-BstZ171 restriction fragment as right arm. After linearization, electroporation into embryonic stem (ES) cells, and positive/negative selection tile homologous recombinant clones were confirnled by Southern blotting with internal and external probes. The mutation was demonstrated by Avail restriction digests of exon 4 PCR products. Microinjectien of mutant ES cells into B16 blastocysts has been carried out, and chimaeras have been obtained at this time. Conclusion: Introduction of tile G309D mutation into tile mouse mitochondrial protein kinase Pinkl has not produced any overt pathological phenetype in ES cells. Tile generation of a PARK6 knock-in mouse model seems possible.
~ T h e
serine-threonine kinase activity of Pink1, the PARK6 disease protein
G. Auburger*, F. Ricciardi, S. Gispert
*Frankfurt, Germany Objective: Protein phosphorylation in tile mitochondria appears decisive for neuroprotection in the PARK6 variant ofautesomal recessive early onset Par!dnson syndrome. Pathogenic mutations of tile disease protein Pink1 thus have to be analysed for alterations o f ldnase activity and substrate binding. Method: We have constructed a GST-Pinkl fusion protein and purified its monomeric enzymatically active form from E. cell bacteria. In-vitro mutagenesis o f tile ldnase domain was performed, and tile phosphorylation activity of Pinkl was investigated for loss of function effects. Results: The autophespherylatien kinase activity of tile Pinkl mutants H271Q, G309D, L347P, E417G was determined in comparison to classical negative mutations of serine-threonine ldnase domains. Tile interaction with protein substrates in-vitro was analysed. Conclusion: Tile identification o f Pinkl phespherylatien substrates within mitechondria may help to define a pathogenetic pathway common to Par!dnson syndromes.
Monday, 6 June 2005, 12.3013.30, Hall 15.1
PT009 Economics Chair: Donald Grosset, Glasgow, United Kingdom Co-Chair: Ivar Sonbo Kristiansen, Oslo, Norway
•
Development and validation of a multi-outcome decision model for assessing effectiveness and cost-effectiveness of interventions in Parkinson's disease
R. Dodel*, B. Bornschein, G. Sroczyns!d, A. Spottke, U. Siebert
*Bomb, Germany Objeetive: To develop and validate a genetic decision-analytic modal for tile evaluation of long-terrn clinical and economic consequences of
interventions in patients with Parkinson's disease (PD) which can be applied to different research questions, interventions, and outcomes. Method: We developed a Markov model, in which a hypothetical cohort of patients moves through health states reflecting patient characteristics that are observed under treatment (Hoehn and "~ahr 'on' state [HYon]) and would be observed in the absence of treatment (Hoehn and Yahr 'off' state [HYott]). We used HYoff I-V s as Markov states, because those reflect underlying biologic progression of PD. Interventions: diagnostic or treatment strategies in PD patients such as Levodepa, depamine agonists, or other and-parldnsonian drugs as weft as surgical therapies such as deep brain stimulation. Data: Transition probabilities for HYoff states were derived from tile literature. Tile distribution of HYon was modeled conditional on HYoff using studies that report both characteristic. Complications were modeled conditional on HYon using data from a registry established by the 'Competence Network Parkinson Disease'. Utilities, and costs were modeled conditional on HYon and presence of complication. Mortality is a function of age- and gender-specific background mortality and PD-specific mortality Time horizon: lifetime with annual cycle length. Outcomes: rernaining (quMity-adjusted) life expectancy, direct costs, and incremental cost-effectiveness ratios. Further outcomes comprise clinical events or complications such as motor complications, dementia, depression, and hallucinations. In addition, complication-free survival, time in HYoff and HYon states, and UPDRS scores were modeled as additional outcomes. Perspective: societal and third party payer. Sensitivity analysis: 1-way and multiway. An interactive interface allows to model different settings or countries. XSalidation: InternM validation of HYoff input data showed a 97.4-99.9% accuracy. In external validation, mean HYon progression rate predicted by our model (0.42 HY stages/y) matched well with estimates reported in the literature (0.40 HY stages/y). Results: We developed a generic decision-analytic Markov model to simulate clinical and economic outcomes for different interventions in patients with Parldnson's disease. In this model, a hypothetical cohort of patients moves through health states reflecting patient characteristics that are observed under treatment (Hoehn and Yahr 'on' state [HY on]) and would be observed in tile absence of treatnlent (Hoehn and Yahr 'off' state [HY off]). For both characteristics, data are available from observational studies and randomized clinical trials. We used Hoehn and Yahr 'off' states as Markov states, because these states reflect the underlying biologic progression of PD. Technically, tile model is designed to compare two or more competing strategies in PD patients such as Levodepa, depamine agonists, or other anti-parldnsonian drugs as well as surgical therapies such as deep brain sthnulation. Transitions from one state to another are defined by transition probabilities derived from the published literature. Patients may (tie from other causes as a function of age and gender, remain in the same health state, progress or regress to another health state. Tile model discriminates states for HY off I-V and death. The distribution of HY on stages was modeled conditional on HY off stage using studies that report both characteristics for a patient cohort. Proportion of complications was modeled conditional on HY on stage using data from a registry established by the 'Competence Network Parkinson Disease'. UPDRS score, EQ-5D, and costs were modeled conditional on HY on stage and presence of complication based on the same registry. An annual cycle length was used and tile simulation can be carried out for any time horizon including a lifelong time horizon (i.e., until all patients in the model had died). PD-specific disease mortality can be switched on and offin tile analysis. A flexible interface connecting the structural part o f the model and the databases allows tile exchange of input pararueters, for example, for simultaneous anMyses in different hospitals, settings, comltries and health care systems. The model estimates remaining life expectancy, qualityadjusted life expectancy, and direct costs for each examined strategy. Further outcomes comprise clinical events or complications such as motor complications (motor fluctutations, dyskinesias), denlentia, depression, and hallucinations. In addition, time in HY off and HY on states and UPDRS scores were modeled as additional outcomes. Incremental cost-effectiveness is calculated in monetary units per (quality-adjusted) life year saved. Discount rate can be varied with a default of 3 % per annum. The model can take different perspectives depending on tile available resource utilization
Guided Pester Tours data. Numerous univariate and multivariate sensitivity analyses for modal parameters are built in. Conclusion: tn contrast to formerly published models, this generic and validated PD model has the ability to consider multiple interventions and outcomes and to switch between outcomes depending on which outcomes are reported in a clinical trial.
~ T h e
cost-effectiveness of continuous duodenal delivery of levodopa (Duodopa@) in patients with severe Parkinson's disease I.S. Kristiansen*, C. Bingefors, D. Nyholm, D. Isacson
*Oslo, Norway Objective: To explore costs and health benefits of replacing conventional oral therapy with intraduodenal infusion of carbidepa/levodopa (Duodepa®) for severe Par!dnson's disease (PD). Method: In the DIREQT trial 24 patients aged 50-79 years with ttoehn&'Yahr stage 2.5 4.0 (at best) were randomised to receive either three weeks of conventional oral therapy followed by three weeks of Duodopa, or vice versa. Later, patients could choose to switch permanently to Duodepa. Health Related Quality of Life (HRQOL) was recorded with the 15D instrument at entry into the trial, (luring tile trial, and then at 8 follow-ups during the subsequent 6 months. Use of health care was registered before, (luring and after tile trial. Two-year costs and health consequences of Duodepa and conventional therapy were estimated in a decision analytic model. Costs were based on market prices and customary charges in Sweden. Results: The mean quality-of-life scores were 0.77 for Duodopa and 0.72 for conventional therapy with considerable variation in scores for individual patients over time. The expected two year cost was $93,600 for Duodopa and $28,700 for conventional oral therapy. Tile expected number of Quality Adjusted Life Years (QALYs) was 1.48 and 1.42 respectively, or $1.02 mill. per additional QALY (all values discounted at 3%). This amount would be $199,000 if patients used apomorphine as conventional therapy, $124,000 if EQ-5D were used to measure HRQOL, $99,000 if indirect costs were included. If Duodopa improves disease severity by one H&Y stage, the therapy will be cost-saving. Conclusion: The cost-effectiveneas of Duodepa depends in particular on the cost of alternative therapies (i.e. apomorphine and oral drugs) and the extent to which Duodopa postpones PD progression. Also, tile method for capturing quality-of-life has a considerable impact on tile cost-effectiveneas ratio. The study indicates that even costly therapies for late stages of PD may be cost-effective.
•
Economic evaluation of SPECT-DaTSCAN in the diagnosis of patients with clinically uncertain Parkinsonism in Italy M.R. Busca*, A. Antonini, S. Lopatriello, P. Berto
*Milan, Italy Objective: This study assessed the economic value of using SPECTDaTSCAN (123I-FP-CIT) in comparison with current clinical judgement, in the diagnosis of patients with clinically uncertain Parkinsenism in Italy. Method: A cost-effectiveness analysis was based on a Marker model, comparing a cohort of patients following a diagnostic pathway including or excluding DaTSCAN, using a time horizon of 5 years. The model was populated with direct medical costs (drugs, tests, exams, hospital admissions, management o f adverse events) assedated with diagnosis and treatment, diagnostic accuracy (sensitivity: 97%, specifidty: 100%), the underlying prevalence of diseases in tile tested population (estimated to be 49%), rates o f adverse events, therapy progression and death. Effectiveness was expressed as tile (gain in) nmnber of years of appropriate therapy per patient. Model input values were estimated using a double round Delphi panel performed with 12 Italian specialists. Diagnostic accuracy, adverse event rates and mortality rates were based on published studies.
141
Results: The current diagnostic pathway prodeced on average 2.3 'adequately treated years' (ATYs) per patient at an estimated cost of £8893 to tile healthcare system ever 5 years. Tile DaTSCAN pathway generated on average 4.1 ATYs per patient at an estimated cost of ¢8410. Use of DaTSCAN rather than current diagnostic practice generated an additional 1.8 ATYs at a cost saving of ¢482 per patient over 5 years. Discounting at 5%, tile cost saving became ¢372 per patient over 5 years. If tile use of DaTSCAN decreased other diagnostic work-up costs by ¢450 (estimated by clinical expert), cost savings became ¢932 (undiscounted) per patient tested. The result is sensitive to the proportion of patients tested. Conclusion: The analysis suggests that using DaTSCAN in patients with clinically uncertain Parldnseniarn is an economically attractive intervention. Greater amounts of time on appropriate therapy are achieved at less cost to the healthcare system.
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Methods of detecting sub-optimal medicine usage in Parkinson's disease D. Grosset*, K. Grosset, I. Bone, J. Reid
*Glasgow, United Kingdom Objective: To assess different methods of measuring therapy adherence in Parkinson's disease. Method: In a single centre observational study, 112 cases of idiopathic Par!dnson's were randomised to active monitoring (n= 69, simple tablet count and electronic monitoring condected), or to no monitoring (n 43, control group). All patients completed a self-report and visual analogue scale indicating therapy intake. Results: In the active monitoring group, 56 (81% of cases) used 80% of their medication, and 13 (19% of cases) used <80%, based on electronic monitoring. Median adherence for self-report was 100% (interqnartile range (IQ) 100 100) and for visual analogue was 100% (IQ 95 100), in both active and control groups. Patients ta!dng 80% of prescribed medication had median total adherence of 98% (IQ 93-101) by electronic monitoring, which was similar to that from other methods: self-report (100%, IQ 100-100); visual analogue scale (100%, IQ 95-100); simple tablet count 98% (IQ 89 100). Median total adherence in patients taldng <80% of medication was significantly lower by electronic monitoring (69%, IQ 44 74) than by other methods: self-report 100% (IQ 100 100); visual analogue scale 100% (IQ 95-100); and simple tablet count 90% (IQ 78-100) (all p < 0.0001). Sensitivities of self-report (10%), visual analogue scale (17%) and simple tablet count (50%) were all low for detecting suboptimal medicine intake. Conclusion: Self-report, visual analogue scale and simple tablet counts are insensitive in prediction of sub-optimal medicine usage in PD. How patients take their medicines itfftuences interpretation of the therapy response and consequent management decisions, with implications for clinical trial analysis and clinical practice.
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Direct and indirect costs in Parkinson's disease W. Jest*, N. Lenkel, I. Dengler, T. Menser
* VgTesbaden, Germany Objective: Processing and analysis of direct and indirect (economic) costs in the treatment of patients with Parldnson's disease (PD). Data regarding tile direct and indirect costs that incurred in tile treatment of parldnsoniarn have been incomplete so far. Particularly tile indirect costs are hardly being considered, although they do have a substantial bearing on tile national economy. To make up for this lack of primary data, a prospective study has been carried out during a period of three years that takes into account tile individual changes in treatment and costs. Method: This study prospectively ascertained all costs incurred over a period of three years in a sample of 117 patients with PD, that is, costs for medication, medical therapies, diagnostic procedures, hospitalizations, remedies and aids. Moreover, it included costs related to decreased earning capacity/disablement, housing modifications, home care, early retirement,
Guided Poster Tours
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transportation costs etc. Tile fee schedules applicable within tile German Health Care system (GO]k, EBM) were used to evaluate tile individual items; drugs were rated according to their selling price in pharmacies; remedies and aids according to the reimbursements granted by costing units. Tile nursing rates legally provided for, flat mileage rates, and infermarion gathered from patients and manufacturers were - among others incorporated to assess tile indirect costs. We studied a total of 117 patients (78 of them male). Their mean age was 67.5 years, the majority of them graded in tile H&Y stages 2 and 3. Results: Tile average total costs per patient and month aruounted to 603.32 C. Breaking them down, pharmaceuticals run up to 480.23 C, remedies to 58.35 £, aids to 7.95 £, therapies to 11.56 £, extraordinary diagnostic workup (MRT, SPECT, PET) to 26.96 C and hospitalizations to 18.27 C. Tile total of average indirect costs per month and patient aruomlted to 404.22 C. These are made up by 162.18 C due to the inability to earn a living (including early retirernen 0, 145.96 £ for nursing/home care, 25.44 £ for transportation, 58.45 C for housing modifications and 12.19 C for ancillary expenses. Conclusion: Tile costs for pharmaceuticals are tile biggest item among
the direct costs (480.23 £ or equivalent to 80%), whereas inability to earn a living including early retirement constituted tile biggest factor among the indirect costs (41% or 162.18 Q. The nursing costs of 145.96 £ referring to outpatients alone, are explained by tile great number of subjects still in the early stage of disease.
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reasons of a cancellation of drug treatment at Parkinson's disease in Russia
E. Childna*
*Moscow, Russia Objective: To establish and analyse principal causes which result in a cancellation of drug treatment at Parkinson's Disease. Method: tn tile analysis have been included 241 patient with Par!dnson's Disease (male 127, female 114; mean age 66.1±7.5 years, durarion of disease 5.2-:3.2 years). The retrospective analysis have been carried out for treatment which patients received. Results: 160 patients accepted levodepa (mean dose 612.0-k327.Tmg daily); 105 patients accepted cholinolitics such as cyclodel (mean dose 5.0-:2.0mg daily); 83 patients accepted amantadine (mean dose 253.9±72.1mg daily); 41 patients accepted dopanfine agonist such as pramipexole (mean dose 2.4-t-1.0 mg daily); 35 patients accepted sdegiline (mean close 9.1±3.2 mg daily). Adverse events resulted in a cancellation of drug more often for cholinolitics (n 32), less often for levodepa (n 8), arnantadine (n = 5) and pramipexole (n = 4). Insufficient efficacy was the most often reason of a cancellation of treatment by cholinolitics (n 21), selegiline (n = 17), amantadine (n = 15) and the rare reason of a cancellation oftreatmentby levodopa (n 3), pranfipexole (n 2). High cost of drug was the most often reason o f a cancellation of pramipexole (n=27) and only in one case have led to a cancellation oflevodepa. For comparison, in our research mean daily dose of levodopa costs 0.9 USD, mean daily dose of pramipexole costs 3.96 USD, mean daily dose of selegiline costs 0.88 USD, mean daily close of arnantadine costs 0.05 USD and mean daily dose of cholinoliries costs 0.02 USD. Conclusion: More often patients cancelled cholinolirics (owing to adverse events and insufficient efficacy), most less often patients cancelled levodepa. Reduction of cost treatment by depamine agonist such as pramipexole could lead to increase in number of Parkinson's Disease patients which would continue to accept this drug in Russia.
Monday, 6 June 2005, 12.30 13.30, Hall 15.1
PTOIO Etiopathogenesis Chair: Joong-Seok Kim, Seoul, Republic of Korea
Co-Chair: Jacinto Duarte, Segovia, Spain
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natural history of treated Parkinson's disease: A prospective community based study with a mean 15 year follow-up
J. Duarte*, L.E. Claveria, S. Borja, A. Conde
*Segovia, Spain Segnvia is a small province, 100 km. North to Madrid, Spain, with a population of 150.000, with one only specialist referal centre, tile General Hospital in Segnvia capital. Segovia has a very stable elderly population with hardly any migratory movement which allows recollection of epidemiological and clinical data with a guaranteed long follow-up. A prospective study was deaigned to collect data in a clinical protocol in 274 consecutive clinically diagnosed parkinsonian patients, with 3~4 monthly follow-up by the same physician, summarizing data at 5, 10, 15 and 20 years of personal history (1984 2004). According to age of onset of Parkinson's disease, three groups of patients were sub divided and compared with each other, those with onset before tile age of 50 (8%), between 50-70 (61%) and those of late onset after 70 (31°/,,). Clinical symptoms and signs at onset and through out tile disease were recorded, mortality and Kl@lan-Meier curves, clinical scales and their evolution, type of trealment and desificarion, and correlation with clinical effect and secondary complications. The three groups of patients behave differently in their evolution despite similar therapeutic strategies and desificarion. Clinical evidence of neuroprotection? Aging as an agravating t:actor? They both seem to be relevant in our study.
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Recent changes in demographic factors of Parkinson's disease in Korea
J.-K. Kim*, Y Sohn, S.-Y. Kang, J.-S. Kim
*Seoul, Republic of Korea Objective: A recent survey showed that tile number of patients with Parkinson's disease (PD) visiting university hospitals in Korea had been increased 1.5 times from 1996 to 2000. Tiffs dramatic increase suggests that large number of Korean PD patients may get misdiagnosis, presumably clue to the iTtfluence of oriental medicine, in which PD is often regarded as a type of stroke. To investigate changes in demographic factors of PD with this increase, we reviewed the Yonsei Par!dnsoniarn Registry (YPR) in the past 12 years. Method: We reviewed demographic characteristics of de nero PD patients in YPR from 1992 to 2003. Patients with either insuffident infermarion or uncertain diagnosis were excluded. The patients were divided into two groups aeeording to their initial visiting time; group A (1992 1995) and group B (2000-2003). The demographic characteristics of both groups were compared. Results: Thirty three and thirty six patients who initially diagnosed as PD in our hospital were included in group A and B, respecrivel!c Group B patients were significantly older than group A patients (66±10 vs 59±10 years; p < 0.005). Accordingly symptom onset age of group B patients was also higher than that of group A (64±10 vs 57±11 years; p < 0.005). The duration between symptom onset and diagnosis was shorter in group B than group A (17 vs 22 months), and par!dnsonian disability was mild in group B compared with group A, although these differences did not attain statistical significance. Conclusion: These results suggest that recent increase in the numbers of PD patients visiting hospitals in Korea is mainly due to the increased number of older patients wile might have less education and then be easily