The Direct Cost of Parkinson Disease at Juntendo Medical University Hospital, Japan

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1 ORIGINAL ARTICLE The Direct Cost of Parkinson Disease at Juntendo Medical University Hospital, Japan Asako Yoritaka 1,2, Jiro Fukae 3, Taku Hatano 2,EiseiOda 4 and Nobutaka Hattori 2 Abstract Objective Many studies on the cost of Parkinson disease (PD) have been published; however, there are limited studies pertaining to this issue in Asia. This study looks to assess the direct medical costs of patients with PD at a university hospital in Japan by calculating the average monthly direct medical costs of PD patients from July to December Methods We enrolled 724 consecutive patients (411 women and 313 men) with PD who were registered in Japan s Specified Disease Treatment Research Program and obtained data on the total direct medical costs of all patients. Results Values are reported as the mean (standard deviation). The major finding of the direct medical cost analysis was that the outpatient clinic cost per subject (n=715) was USD (376.31) per month. A multivariate analysis revealed that a younger age, the presence of wearing-off, hallucination, and longer disease duration increased the direct medical cost significantly. Disease severity had no influence on the direct medical costs. A longer disease duration was significantly correlated with higher hospitalization costs. Conclusion The direct medical cost of PD in Japan was found to be similar to that in Western countries. Costs due to productivity loss exceeded the direct costs, and they may be reduced through the better integration of PD patients in the work environment. Key words: Parkinson disease, economic burden, Medicare, direct cost, Japan (Intern Med 55: , 2016) () Introduction In recent years, the evaluation of health economics has become an integral part of the assessment of disease burden. The number of Parkinson disease (PD) patients in Japan in 1987, 1993, 1999 and 2005 were 76,000, 95,000, 126,000, and 145,000, respectively (1). In 2008, the average life span of Japanese women, at 86.1 years, was the longest in the world. Furthermore, in Japan, 22.1% of the population was over 65 years of age (2). Given the growing proportion of the elderly population in Japan, the number of individuals with PD is expected to increase by 150% by Such an increase is expected to place a significant burden on the healthcare system. In Japan, 100% of the population is covered by medical insurance, with patients required to pay 30% or 10% of their medical costs, according to their income or age; in the late-stage medical care system for the elderly, patients cover 10% of the medical cost. In addition, the Japanese Specified Disease Treatment Research Program (SDTRP) subsidizes medical care for patients with rare and intractable diseases. Under this program, the national and prefectural governments partially cover the patient s share of medical expenses. The SDTRP supports patients with PD who have advanced beyond stage 3 of the modified Hoehn and Yahr (H&Y) scale and who, at the acknowledgement of the SDTRP, require assistance. A thorough understanding of the costs of medical treatment and thoughtful consideration of treatment decisions can result in optimal healthcare utilization, without compromising a patient s health-related quality of life. The aim of this semi-prospective study was to evalu- Department of Neurology, Juntendo University Koshigaya Hospital, Japan, Department of Neurology, Juntendo University School of Medicine, Japan, Department of Neurology, Fukuoka University, Japan and Medical TOUKEI Corporation, Japan Received for publication November 8, 2014; Accepted for publication April 29, 2015 Correspondence to Dr. Asako Yoritaka, ayori@juntendo.ac.jp 113

2 ate the direct costs related to the care of PD patients in Japan due to its classification as an intractable disease and its support by the SDTRP. Materials and Methods Clinical evaluation and costs We enrolled 725 consecutive patients with PD who received financial assistance under the SDTRP and who were either inpatients of Juntendo Medical University Hospital or who had visited the outpatient clinic of Juntendo University s Department of Neurology more than two times during the study period of June-December Informed consent was obtained from all patients when they applied for financial assistance. The medical and neurological examinations in our department were conducted by board-certified neurologists. The clinical diagnosis of PD was based on the criteria of the UK Parkinson s Disease Society Brain Bank (3). Patients diagnosed with dementia with Lewy bodies (DLB) (4) were excluded, as the prognosis and treatment of this condition differs slightly from PD. However, PD patients with dementia (5) or with mild cognitive impairments were included. The data on the costs of medical care were obtained from the health insurance charges during the June-December 2008 period. All charges that were levied by our hospital during the six-month period were calculated as the monthly direct medical cost. These charges were not equal to the total expenditure of the patients. This semi-prospective study was approved by the Juntendo Hospital Institutional Ethics Committee in February The daily levodopa equivalent dose (LED) was calculated on the basis of the following equivalences: 100 mg standard levodopa =10 mg bromocriptine =1 mg pergolide =5 mg ropinirole =1 mg pramipexole (6). The Japanese yen (JPY) was converted to US dollars (USD): USD 1= JPY 100 based on the exchange rate of June-December Statistical analysis The Statistical Analysis System (SAS, version 9.4 SAS Institute, Cary, USA) and the Statistical Package for the Social Sciences (SPSS, version 20, IBM, New York, USA) software programs were used in the statistical analysis. The cost data were presented as the mean and standard deviation (SD), and the median and range. The data were analyzed using univariate and multivariate linear models for the costs, which included age, disease duration, working status, wearing-off, hallucination, pain and on-phase stage (on the modified H&Y scale) as exploratory variables. The backward elimination method was used for variable selection in the models, with 65 years (the age of retirement for most office workers in Japan) selected as the dividing age. Results After excluding one patient for an erroneous input, a total of 724 patients with PD (411 women and 313 men) were enrolled in the study. Their mean (SD) age and disease duration were 68.2 (9.5) years and 12.5 (6.2) years, respectively. The mean H&Y stage of on-phase when they first visited our hospital was 2.2 (0.8), while the mean H&Y stage on their last outpatient clinic day was 3.06 (1.15). The duration between their first visit to out hospital and their final day of examination was 8.3 (5.6) years. Patients with a mild H&Y stage of on-phase were included because on the H&Y scale, the off-phase was defined as stages greater than 3, and some of them had improved by the examination day. The dose of levodopa on the last clinic day was (281.3) mg/day. A total of 19.2% of patients (n=139) had dementia. The outpatient clinic medical cost was USD (376.31) (n=715) per subject per month, while the annual cost was USD 5, The cost of anti-parkinsonian drugs and other drugs prescribed by our neurologist constituted 90.6% of the total outpatient clinic medical costs. The costdivided demographic and clinical features of the patients are shown in Table 1. No significant differences in the outpatient clinic medical costs were observed among the patients of various H&Y stages (p=0.410, univariate model). When the disease duration exceeded 10 years, the outpatient clinic medical cost was higher than that when the duration was less than 10 years (p=0.023, multivariate final model). Age, wearing-off, and the absence of hallucinations resulted in increased outpatient clinic costs (p=0.003, p<0.001, and p= 0.024, respectively in the final multivariate model). The mean (SD) cost for patients under 65 years of age was USD (411.95), while that for patients over 65 years of age was USD (351.65); there was a significant difference between the groups (p<0.001). The mean (SD) dose of levodopa in the patients under 65 years of age [627.0 (260.9) mg/day] was significantly higher (p<0.01) than that in the patients older than 65 years of age [561.6 (315.5) mg/day]. The LED of dopamine agonist per day was mg/day for patients under 65 years of age and mg/day for patients over 65 years of age (p<0.001). In patients under 65 years of age, the average dose of dopamine agonist was (142.2) mg for patients without hallucination and (125.7) mg for patients with hallucination (p<0.001). When patients had episodes of hallucination, their rate of working decreased (p<0.001, data not shown). The LED of dopamine agonists, excluding other anti-parkinsonian drugs, was (9.3) mg in working patients and (6.0) mg in nonworking patients (p<0.001). However, no significant variables were observed in patients under 65 years of age (Table 2). In patients older than 65 years of age, there were significant differences in the costs associated with disease duration and wearing-off; there were no differences associated with 114

3 Table 1. Monthly Cost of Out Clinic Parkinson s Disease per Subjects (US Dollars). Factor Category n mean SD for category total age < 65 years Reference - - Reference - Reference years (-176.5, -60.2) <0.001 *** (-132.3, 1.2) (-148.6, -31.5) ** Reference - [0.410] Reference - [0.367] (-217.4, 245.3) (-304.3, 232.1) (-325.3, 103.4) (-257.4, 92.7) cost Univariate model Multivariate initial model (-311.8, 41.4) (-310.3, 39.9) (-277.6, 78.4) (-265.8, 92.4) (-280.3, 101.9) (-245.2, 140.5) Unknown (-334.9, 107.5) (-340.0, 95.7) Multivariate final model disease duration < ten years Reference - - Reference - - Reference - - ten years (32.5, 145.2) ** 73.4 (13.8, 133.0) * 67.5 (9.5, 125.6) * working Reference - - Reference (25.4, 142.5) ** 41.0 (-26.0, 108.0) Unknown (164.7, 221.4) (-181.2, 199.4) wearing off Reference - - Reference - - Reference (92.7, 206.0) <0.001 *** (66.5, 185.4) <0.001 *** (63.9, 181.6) <0.001 *** hallucination Reference - - Reference - - Reference (-114.9, -2.2) * (-121.7, -3.9) * (-121.6, 8.5) * pain Reference - - Reference (-44.1, 74.1) (-38.3, 78.5)

4 Table 2. Monthly Cost of Out Clinic per Parkinson s Disease Subjects under 65 Years Old (US Dollars). Multivariate final model cost Univariate model Multivariate initial model Factor Category n mean SD Total Reference - [0.899] Reference - [0.813] (-266.0, 389.3) (-350.0, 345.4) (-321.2, 169.2) (-34.0, 139.8) (-348.1, 146.3) (-405.0, 102.9) (-342.3, 178.3) (-408.0, 133.0) (-433.1, 255.4) (-480.5, 237.6) Unknown (-475.6, 212.9) (-536.9, 160.0) disease duration < ten years Reference - - Reference - - ten years (-4.1, 212.8) (-10.8, 233.8) working Reference - - Reference (-64.1, 166.3) (-64.3, 174.0) Unknown (-205.1, 438.1) (-193.0, 458.9) wearing off Reference - - Reference (-34.7, 206.5) (-87.2, 179.6) hallucination Reference - - Reference (-133.7, 101.6) (-144.3, 109.7) pain Reference - - Reference (-87.5, 137.3) (-82.7, 151.2) the H&Y stage, hallucination, or pain in the univariate model (Table 3). In the multivariate final model, the presence of wearing-off, and absence of hallucination increased the direct medical cost (p<0.001, p=0.033 respectively). Fifty-one patients were hospitalized from June to December 2008, including 26 women. Their mean (SD) age and disease duration were 68.6 (10.3) years and 15.2 (8.4) years, respectively. The H&Y stage of on-phase on their first visit to the clinic was 2.4 (0.8); and the H&Y stage on their last visit to the outpatient clinic was 3.7 (0.9). The mean duration from the first visit to the final visit was 8.3 (5.6) years. The various reasons for hospitalization were as follows: drug adjustment for PD (n=26), pneumonia (n=10), operation for deep-brain stimulation (n=5), neuroleptic malignant syndrome (n=3), usual procedure (n=3), and stomach cancer (n=4). The mean cost per subject per month for one period of hospitalization was USD 10, (11,222.15) (n=51) (Table 4). Approximately 17.8% of the hospitalization costs could be attributed to drug costs. Imaging tests and various materials (other than drugs) accounted for 14.5% of the hospitalization costs, while the remainder of the cost was attributed to other factors, including rehabilitation and patient management. The mean (SD) hospitalization cost for patients who received deep-brain stimulation was USD 35, (19,452.90). A longer disease duration correlated with higher hospitalization costs (p<0.023). Discussion In this study, the factors that correlated with higher direct medical costs in PD were young age, wearing-off, disease duration, working, and the absence of hallucination. Drug costs constituted one of the primary components in outpatient clinic PD treatment, and in our study it accounted for more than 90% of the direct costs. Younger patients were treated with dopamine, and many were treated with dopamine agonists. The charge for levodopa is lower than that for dopamine agonists. In Japan, the price of 100 mg levodopa is USD 0.42, whereas the mean price of 100 mg LED of dopamine agonist (pramipexole, ropinirole, pergolide, cabergoline, or bromocriptine) is much higher, at USD In a German study, the onset of disease at under 65 years of age was correlated with a higher cost, and greater cognitive impairment appeared to reduce drug treatment cost (7). Our elderly patients could not be medicated with dopamine agonists, given the risk of hallucination (the rates of hallucination were 45.2% and 28.4% for patients over and under 65 years of age, respectively; p<0.001); thus, the drug costs for elderly patients were lower than those for younger patients. Most hallucinations observed in our study were ameliorated with a reduction of some of the medication. Patients who could be treated sufficiently through the administration of dopamine agonists, selegiline, amantadine, and entacapone, without any adverse effects, retained the ability to work. 116

5 Table 3. Monthly Cost of Out Clinic per Parkinson s Disease Subjects over 65 Years Old (US Dollars). Factor Category n mean SD Total Reference - [0.781] Reference - [0.412] (-345.4, 370.3) (-351.3, 345.1) (-289.1, 294.5) (-316.8, 251.9) cost Univariate model Multivariate initial model Multivariate final model (-341.0, 235.9) (-348.9, 178.5) (-285.1, 292.6) (-316.8, 251.0) (-270.5, 322.9) (-282.9, 301.0) Unknown (-341.3, 316.9) (-377.8, 264.7) disease duration < ten years Reference - - Reference - - ten years (16.4, 145.0) * 56.5 (-11.6, 124.7) working Reference - - Reference (-51.5, 111.9) (-44.8, 120.7) Unknown (-344.7, 149.4) (-341.9, 142.2) wearing off Reference - - Reference - - Reference (92.5, 218.0) <0.001 *** (93.5, 224.3) <0.001 *** (98.9, 224.5) <0.001 *** hallucination Reference - - Reference - - Reference (-115.4, 11.0) (-148.3, -17.7) * , -5.4) * pain Reference - - Reference (-61.7, 73.9) (-56.5, 77.5)

6 Table 4. Monthly Cost of Hospitalization of Parkinson s Disease Subjects per Patients (US Dollars). Multivariate final model cost Univariate model Multivariate initial model Factor Category n mean SD total 51 10, , age < 65 years 11 12, ,826.8 Reference - - Reference years 40 9, , ,140.4 (-10,843.6, 4,562.8) ,359.0 (-6,911.1, 13,629.2) , ,279.8 (-31,269.3, 14,709.7) ,967.2 (-25,338.8, 21,404.5) , , ,407.2 (-23,085.5, 1,027.1) ,459.0 (-18,834.4, 15,916.3) , ,892.3 Reference - [0.308] Reference - [0.160] , , ,060.5 (-15,519.2, ) * -10,239.0 (-18,217.6, -2,260.4) * , , ,075.9 (-12,415.1, 4,263.3) ,127.5 (-15,654.5, 3,399.5) disease duration < ten years 18 5, ,249.8 Reference - - Reference - - Reference - - ten years 33 13, , ,394.1 (1,065.4, 13,722.7) * 10,080.2 (2,851.3, 17,309.1) ** 7, (1,065.4, 13,722.7) * working , ,492.7 Reference - - Reference , , ,525.5 (-3,723.8, 10,774.9) ,438.8 (-5,466.5, 12,344.1) wearing off , ,015.7 Reference - - Reference , , ,705.9 (-4,251.8, 9,663.6) ,270.0 (-6,998.7, 8,852.7) hallucination , ,639.6 Reference - - Reference , , ,924.0 (-8,341.1, 4,493.1) (-7,012.1, 6,225.6) pain , ,382.6 Reference - - Reference , , ,856.2 (-2,819.5, 10,531.9) ,281.6 (-3,296.7, 9,859.9) The direct medical costs for patients who experienced wearing-off were higher than those for patients who did not. In contrast, a study on the cost of PD in Russian patients reported no significant difference in medical costs due to wearing-off; however, that study reported a significant difference in cost due to the severity of disease (8). Approximately 78.2% of our patients underwent treatment with dopamine agonists; this value was similar to that reported in the German study, wherein 67-72% of patients with PD received dopamine agonist medication (7, 9). However, for economic reasons, only 20.4% of the Russian patients with PD were administered dopamine agonists. A study in the United States in 2008 (10) reported the annual outpatient clinic cost for PD patients to be USD 4,451, whereas a study conducted in Germany in 2000 reported the annual drug costs and other direct costs to be EUR 4,411 (USD 6,174) and EUR 13,158 (USD 18,417), respectively (11). In a study from Sweden, the annual drug costs and outpatient care costs (not including drug costs) were SEK 15,880 (USD 2,223) and SEK 20,599 (USD 2,884), respectively (12). In 2008, the direct medical cost for PD in Singapore was SGD 5,105 (USD 4,558) (13). As such, we found that the direct medical costs associated with caring for PD patients in Japan was similar to the costs in the United States, Europe, and Singapore. Previous studies have reported increases in nonmedical costs with disease progression (7-11). The mean (SD) direct nonmedical cost expressed as expenditure per subject per month in 87 patients of our study was USD (8.50), USD (144.60), USD (127.03), USD (824.18), and USD (171.24) in patients in H&Y stage 1 (n=10), stage 2 (n=38), stage 3 (n=20), stage 4 (n= 12), and stage 5 (n=7), respectively (p<0.01). Older age and disease duration were associated with increased nonmedical costs (data not shown). The Japanese nursing-care insurance system supports 90% of a patient s nursing care costs; as a majority of the nonmedical costs of patients in H&Y stages 3, 4, and 5 comprised nursing-care costs, the actual nursing care expenses would have been several times higher than those reported here. Furthermore, caring for PD patients often leads to family members giving up work; the resulting decrease in income affects not only the patients (9) but also younger family members. Our hospital cannot be considered a local hospital. About half of our patients (n=362) lived outside Tokyo. Many patients whose condition had worsened were unable to continue with hospital visits; hence, the number of patients with severe PD was smaller than that of patients with mild symptoms. The data of many patients with advanced disease who were in nursing homes are missing from our study. These factors, along with the features of our hospital, could have introduced selection bias into the study. Another limitation of our study is that we did not include patients who were in early stages of the disease or who died early after disease onset. 118

7 Conclusion To the best of our knowledge, this is the first study to evaluate the costs of PD in Japan. The direct medical cost was found to be similar to that in the United States, Western Europe and Singapore. In conclusion, we found that costs due to productivity losses exceeded the direct costs, and that they may be reduced by the better integration of PD patients in the work environment. Author s disclosure of potential Conflicts of Interest (COI). Eisei Oda: Leadership Position, Medical TOUKEI Corporation. Financial Support This work was supported in part by Health and Labour Sciences Research Grants for research on intractable diseases, from the Ministry of Health, Labour, and Welfare of Japan Acknowledgement We would like to thank the staff of the medical affairs section of Juntendo Hospital for their data preparation. References 1. Health and Welfare Statistics Association. Patient Survey 2005 (All Japan), Vol. I. Tokyo, Statistics and Information Department, Minister s Secretariat. Ministry of Health, Labour, and Welfare, Tokyo, 2005 (in Japanese). 2. Statistics Beureau, Prefectural and Municipal Governments. Japan population census [Internet]. [cited 2010 Jun 6]. Available from: 3. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson s disease. Neurology 57: , 2001 (in Japanese). 4. McKeith IG, Dickson DW, Lowe J, et al; Consortium on DLB. Diagnosis and management of dementia with Lewy bodies: third report of DLB Consortium. Neurology 65: , Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated Parkinson s disease. Mov Disord 22: , Minguez-Castellanos A, Escamilla-Sevilla F, Katati MJ, et al. Different patterns of medication change after subthalamic or pallidal stimulation for Parkinson s disease; target related effect or selection bias? J Neurol Neurosurg Psychiatry 76: 34-39, Bach JP, Riedel O, Klosche J, Spottke A, Dodel R, Witchen HU. Impact of complications and comorbidities on treatment costs and health-related quality of life of patients with Parkinson s disease. J Neurological Sci 314: 41-47, Winter Y, von Campenhausen S, Popov G, et al. Costs of illness in a Russian cohort of patients with Parkinson s disease. Pharmacoeconomics 27: , Spottke AE, Reuter M, Machat O, et al. Cost of illness and its predictors for Parkinson s disease in Germany. Pharmacoeconomics 23: , Noyes K, Liu H, Li Y, Dick AW. Economic burden associated with Parkinson s disease on elderly medicare beneficiaries. Mov Disord 21: , Winter Y, Balzer-Geldsetzer M, Spottke A, et al. Longitudinal study of the socioeconomic burden of Parkinson s disease in Germany. Eur J Neurol 17: , Lökk J, Borg S, Svensson J, Persson U, Ljunggren G. Drug and treatment costs in Parkinson s disease patients in Sweden. Acta Neurol Scand 125: , Zhao YJ, Tan LC, Li SC, et al. Economic burden of Parkinson s disease in Singapore. Eur J Neurol 18: , The Japanese Society of Internal Medicine 119