Epilepsy & Behavior 64 (2016) 122–126
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The direct costs of epilepsy in Russia. A prospective cost-of-illness study from a single center in Moscow Alla Guekht a,b,c, Maria Mizinova a, Igor Kaimovsky a,b,c, Oksana Danilenko b, Elisa Bianchi d, Ettore Beghi d,⁎ a
Department of Neurology, Neurosurgery and Genetics, Russian National Research Medical University, Moscow, Leninsky Prospect 8, Block 8, Russian Federation Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Donskaya, 43, Russian Federation c Moscow City Hospital No. 12, Moscow, Bakinskaya, 26, Russian Federation d IRCCS-Institute for Pharmacological Research “Mario Negri”, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 14 July 2016 Revised 29 August 2016 Accepted 31 August 2016 Available online 11 October 2016 Keywords: Epilepsy Direct costs Diagnostic tests Drugs Russia
a b s t r a c t Objective: The objective of this study was to investigate prospectively the direct costs of epilepsy in Russia, taking a patient perspective and a bottom-up approach. Methods: The study was conducted in adolescents and adults with epilepsy seen in the ambulatory services of a city hospital in Moscow. Patients were assigned to different prognostic categories: newly diagnosed epilepsy; epilepsy in remission for 2+ years; epilepsy in remission for b 2 years or with occasional seizures; active, nondrug-resistant epilepsy; drug-resistant epilepsy; and drug-resistant epilepsy in surgical candidates. Patients were followed prospectively for 12 months. Demographic and clinical features at admission were collected and correlated with costs. Cost estimates were based on the Russian National Health Service perspective and its implementation in Moscow. Cost items included drugs and laboratory/instrumental tests. The costs per patient were calculated for the entire sample and for each prognostic category separately. Univariate and multivariate analyses were performed. Results: Included were 738 patients (393 men, 345 women aged 14–85 years). The median annual cost/patient was €955 (IQR 521–2134; range 51–10,904). The median cost of drugs was €643 (IQR 288–1866; range 0–9960), and the median cost of laboratory/instrumental testing was €202 (IQR 160–270; range 20–1217). Mean costs varied across prognostic categories ranging from €782 in newly diagnosed patients to €3777 in patients with drug-resistant epilepsy. Mean (SD) hospital costs ranged from €646.7 (109.0) in patients with occasional seizures to €950.0 (28.3) in surgical candidates. Independent predictors of total costs were younger age at diagnosis, disability status, generalized seizures, multiple seizure types, seizure severity, and etiology. Significance: The cost of epilepsy in Moscow varies significantly depending on disease characteristics and response to drug treatment. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Epilepsy is a chronic clinical condition that, in virtue of its high frequency and prolonged course, poses a considerable economic burden on society. The costs of epilepsy have been estimated in different countries with differing results. In a comprehensive review of the cost of brain disorders in Europe [1], the total annual cost per patient with epilepsy ranged from 695€ to 11,654€, and the corresponding direct costs ranged from 695€ to 4493€. This variability can be explained by the heterogeneity of the source populations, the study design, and the difficult separation of the intrinsic costs of epilepsy from the costs of the underlying causes and comorbidities [2]. Epilepsy is a treatable disorder with ⁎ Corresponding author at: Laboratory of Neurological Disorders, IRCCS-Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156 Milan, Italy. E-mail address: [email protected] (E. Beghi).
http://dx.doi.org/10.1016/j.yebeh.2016.08.031 1525-5050/© 2016 Elsevier Inc. All rights reserved.
differing severity and variable response to the available treatments [3]. Studies on the costs of epilepsy in patients with differing response to antiepileptic drugs have consistently shown that the annual expenditures per patient decrease when comparing the first to the subsequent years of follow-up [4–6] and increase exponentially when comparing patients with prolonged seizure remission to patients with occasional seizures, patients with frequent nondrug-resistant seizures, and patients with drug-resistant epilepsy [7–11]. As expected, the cost of drugs, among the highest source of expenditures, tends to increase when moving from the first generation to the second and third-generation compounds. In this complex scenario, a prospective cost-of-illness study was undertaken in Moscow (Russian Federation) taking a patient perspective and a bottom-up approach. The research aim was to assess the direct costs of epilepsy in patients included in different prognostic groups and to compare these costs to those calculated in patients from other countries.
A. Guekht et al. / Epilepsy & Behavior 64 (2016) 122–126
2. Material and methods The study was an observational prospective investigation conducted in the outpatient services of the Moscow City Hospital No. 12 in the period 2011–2013. At the time of the study, the hospital hosted an outpatient epilepsy service whose activities included the management of newly diagnosed and chronic epilepsy in patients living in the hospital's catchment area. There were three outpatient centers for epilepsy in Moscow, each covering 3–4 districts. Where possible, diagnostic testing and treatment changes were offered on an outpatient basis, limiting hospital admissions to patients requiring acute and/or intensive management. Consecutive individuals aged 15 years or older and seen for an outpatient consultation for epilepsy during the period from September 9, 2011 until June 1, 2013 were the target population. To be included in the study, a patient should have a confirmed diagnosis of epilepsy, i.e., two or more unprovoked seizures 24 h or more apart [12] and be willing to provide an informed consent. At entry, all eligible patients were assigned to one of the following prognostic categories: 1. Newly diagnosed epilepsy, i.e., an epilepsy firstly diagnosed in the participating institution; 2. Epilepsy in remission, i.e., with complete seizure control for 2 + years; 3. Epilepsy in remission for less than 2 years or with occasional seizures (not requiring treatment changes); 4. Active, nondrug-resistant epilepsy, i.e., with seizures that in the opinion of the treating physician are still amenable of treatment changes; 5. Drug-resistant epilepsy, i.e., with seizures that in the opinion of the treating physician cannot be improved by further treatment changes; and 6. Drug-resistant epilepsy in a surgical candidate. These categories have been previously used in Italian studies on the direct costs of epilepsy [10,11]. Each patient was interviewed at entry, and details were collected on patients' demographics (age and sex, education, occupation with monthly salary, marital and disability status) and the main clinical features of the disease (seizure types and annual frequency, disease duration, etiology, epilepsy syndrome, interictal EEG and imaging findings, past and current treatments). Comorbidities were recorded if deemed clinically relevant. Each patient was followed prospectively for 12 months. Cost estimates were based on the Russian National Health Service perspective and its implementation in the City of Moscow, which is based on mandatory health care insurance with reimbursement to the health care providers for services and treatments for the management of all diseases. The average monthly salary in Moscow was around 49,000 Rubles. The salary in Moscow was significantly higher than, in general, in Russia (estimated at about 29,000 Rubles) and was significantly higher than the income of people with epilepsy (16,000 to 32,000 Rubles, disability pensions included). All pensions, including disability, are provided according to the Federal Law. In 2013, the exchange rate was 42.3 Rubles/1 Euro and 31.54 Rubles/1 US$. Indirect costs were not taken into account. Descriptive statistics are reported as range, mean, standard deviation, and median with interquartile range (IQR) for quantitative variables or frequencies and percentages for qualitative variables. Univariate and multivariate generalized linear models (adjusting for all significant univariate predictors) were used to estimate the predictors of total epilepsy costs. Cost items included drugs, laboratory/instrumental tests, outpatient consultations, and hospitalizations. The costs per patient were calculated for the entire sample and for each prognostic category separately and were expressed as means with standard errors (SE) and medians (with IQR). Costs were also stratified according to each demographic and clinical variable. Statistical significance was set at the 5% level (p = 0.05). All analyses were performed with SAS (version 9.2; SAS Institute, Inc., Cary, NC, USA). The study has received IRB approval from the hosting institution. 3. Results The sample included 738 patients (393 men and 345 women) aged 14 to 85 years. The demographic characteristics of the sample are
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illustrated in Table 1. The mean age at diagnosis was 24.4 years. Seventy percent of cases were less than 30 years old. Almost 90% of cases had at least 12 years of education. Half of them were currently employed, one fifth were students, and one-sixth were unemployed. More than half were single. More than half of cases were moderately disabled, and 6% were severely disabled. Epilepsy was the reason for obtaining disability status in three-fourths of disabled individuals. Almost two-thirds of cases received a monthly salary ranging from 380 to 750 Euros. Disease duration was from two months to 65 months. A family history of epilepsy was recorded in about 6% of cases (Table 2). History of febrile seizures was experienced by less than 10% of patients. Almost 90% of patients had focal seizures with/without secondary generalization. Two or more seizure types were present in more than half of cases. Status epilepticus was reported in rare instances. The interictal EEG showed epileptiform abnormalities in more than half of cases. More than two-thirds of cases undergoing an MRI presented a structural lesion. Symptomatic epilepsy was the commonest syndrome, followed by cryptogenic and idiopathic epilepsy. About two-thirds of patients Table 1 Demographic characteristics of the sample. Variable Age at diagnosis (years) b10 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ NS Sex Male Female Education (years) None Elementary (3–4) Secondary (10–11) Professional (12–13) University (15–17) Occupation Unemployed Student Employed Working pensioner Pensioner NS Marital status Married Single Widowed NS Disability cause Epilepsy Other None NS Disability group Mild Moderate Severe None Unknown Disability pension Yes No Monthly salary (euros) b380 380–750 760–1090 1100–1400 1500+
N
%
113 242 158 84 61 41 19 11 2 7
15.5 33.1 21.6 11.5 8.3 5.6 2.6 1.5 0.3
393 345
53.2 46.7
5 12 66 469 186
0.7 1.6 8.9 63.5 25.2
130 148 392 5 62 1
17.6 20.1 53.2 0.7 8.4
312 414 11 1
42.3 56.2 1.5
341 102 294 1
46.3 13.8 39.9
11 389 43 294 1
1.5 52.8 5.8 39.9
50 688
6.8 93.2
96 274 75 2 –
21.5 61.3 16.8 0.4 –
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Table 2 Clinical characteristics of the sample. Variable Family history of seizures/epilepsy Yes No Unknown History of febrile seizures Yes No Unknown Seizure type Focal Generalized Unclassified Number of seizure types 1 2+ Seizure severity Flurries of seizures Status epilepticus None Unknown EEG report None Normal Slow Epileptiform NS Magnetic resonance imaging None Normal Abnormal NS Etiology Unknown/genetic Traumatic brain injury Tumor Degenerative disease Perinatal encephalopathy Cerebrovascular disease Infection Alcoholic encephalopathy NS Epilepsy syndrome Symptomatic Idiopathic Cryptogenic NS Number of drugs in the last year 0 1 2 3+ Hospitalizations Yes No Number of comorbidities 0 1 2 3+ Comorbidities Psychiatric Neurological Respiratory Cardiovascular Renal Urogenital Gastrointestinal Bone & joint Endocrine, metabolic Eye Skin Tumors Other
N
%
47 668 23
6.4 90.5 3.1
71 645 22
9.6 87.4 3.0
658 76 4
89.2 10.3 0.5
327 411
44.3 55.7
92 14 621 11
12.5 1.9 84.1 1.5
139 28 179 390 2
18.9 3.8 24.3 52.9
256 151 328 3
34.7 20.5 44.5
395 121 61 60 39 26 23 10 3
53.7 16.4 8.3 8.1 5.3 3.5 3.1 1.4
407 81 248 2
55.3 11.0 33.7
31 376 228 103
4.2 51.0 30.9 13.9
40 698
5.4 94.6
471 177 58 32
63.8 24.0 7.9 4.3
37 77 7 35 8 15 41 7 32 2 1 49 52
5.0 10.4 1.0 4.7 1.1 2.0 5.6 1.0 4.3 0.3 0.1 6.6 7.0
had no comorbidities, one-fifth had only one comorbidity, and about 10% had 2 or more comorbidities. Neurological comorbidities were the most frequent (10% of cases) followed by tumors, gastrointestinal, psychiatric, and cardiovascular diseases. EEG was the commonest instrumental test (total, 1627) followed by hematological and biochemical tests (1369 and 1561), ECG (1284), and neuroimaging (552). Plasma drug concentrations were obtained in 340 cases. Other specialists were consulted in 3968 instances. Only 40 patients were hospitalized during follow-up. During the study period, 31 patients (4.2%) were untreated, 376 (51.0%) received one drug, 228 (30.9%) two drugs, and 103 (13.9%) three or more drugs. The commonest active compounds were, in decreasing order, valproate (360 cases, 48.8%), carbamazepine (230, 31.2%), topiramate (155, 21.0%), lamotrigine (134, 18.2%), and levetiracetam (113, 15.3%). The six prognostic categories are illustrated in Table 3. Active nondrug-resistant epilepsy, epilepsy with occasional seizures, and epilepsy in remission were, in decreasing order, the commonest categories. Surgical candidates were only 3%. The median annual cost per patient was €955 (IQR 521–2134; range 51–10,904). The corresponding cost of drugs was €643 (IQR 288–1866; range 0–9960), and the cost of laboratory/instrumental tests/outpatient consultations was €202 (IQR 160–270; range 20–1217). Mean per patient costs varied considerably across prognostic categories ranging from €782 in newly diagnosed patients to €3777 in patients with drug-resistant epilepsy (Table 4). Drugs were the predominant source of costs. Seven of sixty-seven newly diagnosed patients (10.4%) were hospitalized during follow-up. The corresponding numbers were 12/191 (6.3%) in patients with occasional seizures, 10/267 (3.7%) in patients with active nondrug-resistant epilepsy, 3/49 (6.1%) in patients with drug-resistant epilepsy, and 8/23 (34.8%) in surgical candidates. No epilepsy-related hospital admissions were recorded in patients in remission. Considering only hospitalized patients, mean (SD) hospital costs per patient varied with prognostic category, ranging from €646.7 (109.0) in patients with occasional seizures to €950.0 (28.3) in surgical candidates. Along with prognostic category, significant predictors of total costs in univariate analysis included age at diagnosis, education, occupation, disability, seizure types, and etiology (Supplementary Tables 1 and 2). An inverse correlation was found between cost and age at diagnosis of epilepsy. Variables retaining significance in multivariate analysis models were prognostic category, age at diagnosis, disability, presence of generalized seizures, seizure severity, number of seizure types, and documented etiology (Table 5). Compared with patients with epilepsy in remission, patients with drug-resistant epilepsy carried more than twofold increased costs, while newly diagnosed patients showed a 15% reduction of costs. Costs decreased with age at diagnosis, with a 4% reduction for every 5-year increase. Patients with disability generated 44% increased costs. In contrast, patients with and without comorbidities incurred similar costs (data not shown). Compared with patients with focal seizures, patients with generalized seizures showed a cost increase amounting to about 30%, while having more than one seizure type corresponded to a 40% cost increase. Having experienced status epilepticus or flurries of seizures led, respectively, to 55% and 23% cost increase. The cost of alcohol-related epilepsy was about 50% lower and the cost of CNS infection was 70% higher than the cost of epilepsy of unknown or genetic etiology.
Table 3 Prognostic groups. Prognostic group
N
%
Newly diagnosed Remission Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate
68 140 191 267 49 23
9.2 19.0 25.9 36.2 6.6 3.1
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Table 4 Annual costs per patient by prognostic group. Prognostic group
Newly diagnosed Remission Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate
Mean (SE) cost Total
Laboratory & instrumental tests/outpatient consultations
Drugs
Hospitalizations
⁎⁎⁎
⁎⁎⁎
⁎⁎⁎
⁎⁎⁎
782.08 (0.09) 1215.41 (0.07) 1473.46 (0.06) 1544.93 (0.05) 3777.65 (0.11) 2851.67 (0.16)
237.38 (0.07) 233.01 (0.05) 222.41 (0.04) 224.62 (0.03) 274.46 (0.08) 350.61 (0.11)
447.05 (0.28) 982.40 (0.20) 1210.42 (0.17) 1294.69 (0.14) 3449.32 (0.33) 2170.63 (0.48)
97.65 (0.63) 0.00 (0.00) 40.63 (0.46) 25.62 (0.42) 53.88 (0.54) 330.43 (0.80)
SE = standard error of the mean. ⁎⁎⁎ p b 0.001.
4. Discussion Our results are in keeping with several other reports in confirming that the cost of epilepsy varies significantly depending on the timing of the disease (newly diagnosed vs. chronic) and the response to drug treatment. However, comparisons of economic reports from different countries are hampered by a number of factors, including the study design, the target population, and the country's cost of health care delivery. Tetto and coworkers [10] studied 525 children and adults with partial, generalized, or undetermined epilepsy from a network of epilepsy centers in Northern Italy. Patients were stratified in six prognostic groups, defined as in the present study, and followed prospectively for one year. Data were collected on hospital admissions, day-hospitals, ambulatory consultations, biochemical assays, EEG recordings, and neuroimaging tests. The total annual costs varied significantly across epilepsy groups, ranging from 412€ (epilepsy in remission) to 3945€ (surgical candidates). In another Italian study, 631 patients aged Table 5 Independent predictors of annual costs. Variable Prognostic group Remission (reference) Newly diagnosed Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate Age 5-year increase Disability No (reference) Yes Seizure type Focal (reference) Generalized Unclassified Number of seizure types 1 (reference) 2+ Seizure severity Flurries of seizures Status epilepticus None (reference) Unknown Etiology Unknown/Genetic (reference) Traumatic brain injury Tumor Degenerative disease Perinatal encephalopathy Cerebrovascular disease Infection Alcoholic encephalopathy
Relative change
95% CI
p value b0.0001
1 0.85 1.12 1.08 2.30 1.63
0.68–1.06 0.94–1.32 0.92–1.26 1.79–2.96 1.17–2.27
0.96
0.94–0.98
0.0008 b0.0001 1 1.44
1.27–1.63 0.0039
1 1.28 0.45
1.06–1.55 0.22–0.93 b0.0001
1 1.39
1.24–1.56 0.0071
1.23 1.55 1 0.77
1.04–1.46 1.04–2.30 0.50–1.19 0.0005
1 0.93 0.97 0.84 0.95 0.70 1.69 0.48
0.79–1.09 0.79–1.19 0.68–1.03 0.74–1.22 0.51–0.95 1.24–2.30 0.30–0.76
Legend: relative change = proportion reflecting the change of cost related to the reference category, a value b1 denotes a decreased cost, a value N1 denotes an increased cost; CI = confidence interval.
18 years or older were recruited in 15 epilepsy centers distributed in the entire national territory and followed prospectively for one year [11]. Prognostic groups and cost items were the same. Again, the lowest costs were incurred by epilepsy in remission (561€) and the highest by surgical candidates (3619€). More recently, in France, de Zélicourt et al. [13] examined 405 adult patients with focal epilepsy classified as drug-resistant or drugresponsive. Data on the consumption of medical resources were collected retrospectively for 12 months preceding inclusion. The mean annual direct costs were 2.3 times higher in drug-resistant than in drugresponsive patients (€4485 vs. €1926), The costs of drugs, additional tests, and hospital admissions were, respectively, two, four, and thirteen times higher in the former compared with the latter category. Direct medical costs and indirect costs were calculated by Strzelczyk et al. [14] in 366 German adults with epilepsy during a 4-month period. In this sample, the total estimated annual direct costs cost per patient were €3128. Hospitalizations (€799), medications (€642), ancillary treatments (€369), and rehabilitation (€283) were the highest sources of expenditures. The higher costs of epilepsy in several other countries can be similarly explained. In the US, total direct healthcare costs per person ranged from $10,192 (€7840) to $47,862 (€36,816), and epilepsy-specific costs ranged from $1022 (€786) to $19,749 (€15,191), with markedly higher costs in those with uncontrolled or refractory epilepsy and in those with comorbidities [15]. In our study, only patients with epilepsy caused by CNS infection had significantly higher costs than patients with epilepsy of unknown etiology. Even in Europe, direct costs were slightly to significantly higher than ours. In Spain, the mean direct cost per patient was €1055 [16]. In Denmark, the annual cost of inpatient services, outpatient services, and drugs was €3465 (outpatient services, €270; drugs, €978) [17]. Annual direct costs in Sweden were €1047 (drugs €485) [18]. In Germany, the total annual direct costs amounted to €1698 per patient with anticonvulsants (59.9% of total direct costs) and hospitalization (30.0%) as the main cost factors [19]. In line with others [19], drugs represented the highest source of expenditures in the present study. In contrast, in China, the costs of epilepsy were lower than ours. Gao et al. [20] examined 141 epilepsy patients. The median direct costs were US$501.34 (€385.64). Cost of antiepileptic drugs (US$394.53; €303.48) followed by investigations (US$59.34; €45.64), and inpatient and outpatient care (US$9.62; €7.4) accounted for the majority of the direct medical costs. This study is at variance with several others [4,6,10,11,21] in showing that patients with newly diagnosed epilepsy are the lowest cost category. The difference can be explained by the different health resources used. As the cost of AEDs was the major determinant of total costs, newly diagnosed patients were the lowest cost category as they usually did not receive the newest, most expensive AEDs. In addition, the costs for medical services/procedures (excluding drugs), according to the mandatory international tariffs, are substantially lower in Russia than in Western Europe. The fairly low hospital costs are also worth noting as they not only reflect Russian tariffs but also the fairly low access of
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patients with epilepsy to hospital facilities regardless of the severity of the disease. We found an inverse correlation between costs and age at epilepsy diagnosis. This finding is in keeping with others [22]. We can explain the higher costs of epilepsies with childhood onset with the inclusion of cases with more severe disease varieties and persistence of uncontrolled seizures. As expected, costs predominated in patients with disability, different seizure types, and status epilepticus. These clinical conditions are mostly represented by epilepsies with uncontrolled seizures requiring treatment changes and more frequent use of newer antiepileptic drugs. Our costs of drug-resistant epilepsy are in keeping with other reports [10,11] but significantly lower than others [23-25]. Differences can be explained by the definition of drug-resistant epilepsy and the national item costs. This study has limitations. First, the breakdown of costs and the comparisons with reports from other European and non-European countries must be critically appraised in light of the peculiarities of the health system in Russia. Some of them have been addressed in the Materials and methods. Second, the study is not population-based. Thus, the overall cost of epilepsy might be lower in the community where epilepsies in remission are mostly represented. Third, the results may be biased by the marked predominance of symptomatic epilepsies with focal seizures. However, similar to this study, focal epilepsies were diagnosed in 81.6% of adolescents and adults enrolled in a Russian epidemiological survey [26]. Fourth, although we collected data on the etiology of epilepsy, the costs of epilepsy could not be disentangled from the costs of the underlying epileptogenic conditions and comorbidities. However, in contrast with a recent study in the US [27], in which the presence of comorbidities approximately tripled the health-care cost compared with the cost epilepsy alone, our costs were fairly similar in patients with and without comorbidities. The difference can be explained by the low proportion of cases with comorbidities in our sample, which were about 10-years younger than the US sample. Fifth, we included only patients with two or more unprovoked seizures because for the purposes of epidemiologic studies, solitary unprovoked seizures (including status epilepticus) and provoked seizures should be segregated from epilepsy [28]. Lastly, this is a study from a single center. Although we assume that the cost items are identical in other Russian centers, resource consumption may differ. In conclusion, in keeping with others, the cost of epilepsy in Russia varies significantly depending on the timing of the disease (newly diagnosed vs. chronic epilepsy) and the response to drug treatment. Costs are highest in disabled patients with symptomatic epilepsies and poor response of seizures to the available drugs.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosure of conflicts of interest Alla Guekht, Maria Mizinova, Igor Kaimovsky, Oksana Danilenko and E. Bianchi have nothing to disclose. E. Beghi serves on the editorial boards of Amyotrophic Lateral Sclerosis, Clinical Neurology & Neurosurgery, and Neuroepidemiology; has been an associate editor of Epilepsia and is an associate editor of Epilepsia Open; has received money for board membership from VIROPHARMA, SHIRE and EISAI; has received funding for travel and speaker honoraria from UCB-Pharma, Sanofi-Aventis and GSK; has received funding for educational presentations from GSK; and reports grants from the Italian Drug Agency and from the Italian Ministry of Health.
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The direct costs of epilepsy in Russia. A prospective cost-of-illness study from a single center in Moscow Alla Guekht a,b,c, Maria Mizinova a, Igor Kaimovsky a,b,c, Oksana Danilenko b, Elisa Bianchi d, Ettore Beghi d,⁎ a
Department of Neurology, Neurosurgery and Genetics, Russian National Research Medical University, Moscow, Leninsky Prospect 8, Block 8, Russian Federation Moscow Research and Clinical Center for Neuropsychiatry, Moscow, Donskaya, 43, Russian Federation c Moscow City Hospital No. 12, Moscow, Bakinskaya, 26, Russian Federation d IRCCS-Institute for Pharmacological Research “Mario Negri”, Milan, Italy b
a r t i c l e
i n f o
Article history: Received 14 July 2016 Revised 29 August 2016 Accepted 31 August 2016 Available online 11 October 2016 Keywords: Epilepsy Direct costs Diagnostic tests Drugs Russia
a b s t r a c t Objective: The objective of this study was to investigate prospectively the direct costs of epilepsy in Russia, taking a patient perspective and a bottom-up approach. Methods: The study was conducted in adolescents and adults with epilepsy seen in the ambulatory services of a city hospital in Moscow. Patients were assigned to different prognostic categories: newly diagnosed epilepsy; epilepsy in remission for 2+ years; epilepsy in remission for b 2 years or with occasional seizures; active, nondrug-resistant epilepsy; drug-resistant epilepsy; and drug-resistant epilepsy in surgical candidates. Patients were followed prospectively for 12 months. Demographic and clinical features at admission were collected and correlated with costs. Cost estimates were based on the Russian National Health Service perspective and its implementation in Moscow. Cost items included drugs and laboratory/instrumental tests. The costs per patient were calculated for the entire sample and for each prognostic category separately. Univariate and multivariate analyses were performed. Results: Included were 738 patients (393 men, 345 women aged 14–85 years). The median annual cost/patient was €955 (IQR 521–2134; range 51–10,904). The median cost of drugs was €643 (IQR 288–1866; range 0–9960), and the median cost of laboratory/instrumental testing was €202 (IQR 160–270; range 20–1217). Mean costs varied across prognostic categories ranging from €782 in newly diagnosed patients to €3777 in patients with drug-resistant epilepsy. Mean (SD) hospital costs ranged from €646.7 (109.0) in patients with occasional seizures to €950.0 (28.3) in surgical candidates. Independent predictors of total costs were younger age at diagnosis, disability status, generalized seizures, multiple seizure types, seizure severity, and etiology. Significance: The cost of epilepsy in Moscow varies significantly depending on disease characteristics and response to drug treatment. © 2016 Elsevier Inc. All rights reserved.
1. Introduction Epilepsy is a chronic clinical condition that, in virtue of its high frequency and prolonged course, poses a considerable economic burden on society. The costs of epilepsy have been estimated in different countries with differing results. In a comprehensive review of the cost of brain disorders in Europe [1], the total annual cost per patient with epilepsy ranged from 695€ to 11,654€, and the corresponding direct costs ranged from 695€ to 4493€. This variability can be explained by the heterogeneity of the source populations, the study design, and the difficult separation of the intrinsic costs of epilepsy from the costs of the underlying causes and comorbidities [2]. Epilepsy is a treatable disorder with ⁎ Corresponding author at: Laboratory of Neurological Disorders, IRCCS-Mario Negri Institute for Pharmacological Research, Via Giuseppe La Masa 19, 20156 Milan, Italy. E-mail address: [email protected] (E. Beghi).
http://dx.doi.org/10.1016/j.yebeh.2016.08.031 1525-5050/© 2016 Elsevier Inc. All rights reserved.
differing severity and variable response to the available treatments [3]. Studies on the costs of epilepsy in patients with differing response to antiepileptic drugs have consistently shown that the annual expenditures per patient decrease when comparing the first to the subsequent years of follow-up [4–6] and increase exponentially when comparing patients with prolonged seizure remission to patients with occasional seizures, patients with frequent nondrug-resistant seizures, and patients with drug-resistant epilepsy [7–11]. As expected, the cost of drugs, among the highest source of expenditures, tends to increase when moving from the first generation to the second and third-generation compounds. In this complex scenario, a prospective cost-of-illness study was undertaken in Moscow (Russian Federation) taking a patient perspective and a bottom-up approach. The research aim was to assess the direct costs of epilepsy in patients included in different prognostic groups and to compare these costs to those calculated in patients from other countries.
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2. Material and methods The study was an observational prospective investigation conducted in the outpatient services of the Moscow City Hospital No. 12 in the period 2011–2013. At the time of the study, the hospital hosted an outpatient epilepsy service whose activities included the management of newly diagnosed and chronic epilepsy in patients living in the hospital's catchment area. There were three outpatient centers for epilepsy in Moscow, each covering 3–4 districts. Where possible, diagnostic testing and treatment changes were offered on an outpatient basis, limiting hospital admissions to patients requiring acute and/or intensive management. Consecutive individuals aged 15 years or older and seen for an outpatient consultation for epilepsy during the period from September 9, 2011 until June 1, 2013 were the target population. To be included in the study, a patient should have a confirmed diagnosis of epilepsy, i.e., two or more unprovoked seizures 24 h or more apart [12] and be willing to provide an informed consent. At entry, all eligible patients were assigned to one of the following prognostic categories: 1. Newly diagnosed epilepsy, i.e., an epilepsy firstly diagnosed in the participating institution; 2. Epilepsy in remission, i.e., with complete seizure control for 2 + years; 3. Epilepsy in remission for less than 2 years or with occasional seizures (not requiring treatment changes); 4. Active, nondrug-resistant epilepsy, i.e., with seizures that in the opinion of the treating physician are still amenable of treatment changes; 5. Drug-resistant epilepsy, i.e., with seizures that in the opinion of the treating physician cannot be improved by further treatment changes; and 6. Drug-resistant epilepsy in a surgical candidate. These categories have been previously used in Italian studies on the direct costs of epilepsy [10,11]. Each patient was interviewed at entry, and details were collected on patients' demographics (age and sex, education, occupation with monthly salary, marital and disability status) and the main clinical features of the disease (seizure types and annual frequency, disease duration, etiology, epilepsy syndrome, interictal EEG and imaging findings, past and current treatments). Comorbidities were recorded if deemed clinically relevant. Each patient was followed prospectively for 12 months. Cost estimates were based on the Russian National Health Service perspective and its implementation in the City of Moscow, which is based on mandatory health care insurance with reimbursement to the health care providers for services and treatments for the management of all diseases. The average monthly salary in Moscow was around 49,000 Rubles. The salary in Moscow was significantly higher than, in general, in Russia (estimated at about 29,000 Rubles) and was significantly higher than the income of people with epilepsy (16,000 to 32,000 Rubles, disability pensions included). All pensions, including disability, are provided according to the Federal Law. In 2013, the exchange rate was 42.3 Rubles/1 Euro and 31.54 Rubles/1 US$. Indirect costs were not taken into account. Descriptive statistics are reported as range, mean, standard deviation, and median with interquartile range (IQR) for quantitative variables or frequencies and percentages for qualitative variables. Univariate and multivariate generalized linear models (adjusting for all significant univariate predictors) were used to estimate the predictors of total epilepsy costs. Cost items included drugs, laboratory/instrumental tests, outpatient consultations, and hospitalizations. The costs per patient were calculated for the entire sample and for each prognostic category separately and were expressed as means with standard errors (SE) and medians (with IQR). Costs were also stratified according to each demographic and clinical variable. Statistical significance was set at the 5% level (p = 0.05). All analyses were performed with SAS (version 9.2; SAS Institute, Inc., Cary, NC, USA). The study has received IRB approval from the hosting institution. 3. Results The sample included 738 patients (393 men and 345 women) aged 14 to 85 years. The demographic characteristics of the sample are
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illustrated in Table 1. The mean age at diagnosis was 24.4 years. Seventy percent of cases were less than 30 years old. Almost 90% of cases had at least 12 years of education. Half of them were currently employed, one fifth were students, and one-sixth were unemployed. More than half were single. More than half of cases were moderately disabled, and 6% were severely disabled. Epilepsy was the reason for obtaining disability status in three-fourths of disabled individuals. Almost two-thirds of cases received a monthly salary ranging from 380 to 750 Euros. Disease duration was from two months to 65 months. A family history of epilepsy was recorded in about 6% of cases (Table 2). History of febrile seizures was experienced by less than 10% of patients. Almost 90% of patients had focal seizures with/without secondary generalization. Two or more seizure types were present in more than half of cases. Status epilepticus was reported in rare instances. The interictal EEG showed epileptiform abnormalities in more than half of cases. More than two-thirds of cases undergoing an MRI presented a structural lesion. Symptomatic epilepsy was the commonest syndrome, followed by cryptogenic and idiopathic epilepsy. About two-thirds of patients Table 1 Demographic characteristics of the sample. Variable Age at diagnosis (years) b10 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80+ NS Sex Male Female Education (years) None Elementary (3–4) Secondary (10–11) Professional (12–13) University (15–17) Occupation Unemployed Student Employed Working pensioner Pensioner NS Marital status Married Single Widowed NS Disability cause Epilepsy Other None NS Disability group Mild Moderate Severe None Unknown Disability pension Yes No Monthly salary (euros) b380 380–750 760–1090 1100–1400 1500+
N
%
113 242 158 84 61 41 19 11 2 7
15.5 33.1 21.6 11.5 8.3 5.6 2.6 1.5 0.3
393 345
53.2 46.7
5 12 66 469 186
0.7 1.6 8.9 63.5 25.2
130 148 392 5 62 1
17.6 20.1 53.2 0.7 8.4
312 414 11 1
42.3 56.2 1.5
341 102 294 1
46.3 13.8 39.9
11 389 43 294 1
1.5 52.8 5.8 39.9
50 688
6.8 93.2
96 274 75 2 –
21.5 61.3 16.8 0.4 –
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Table 2 Clinical characteristics of the sample. Variable Family history of seizures/epilepsy Yes No Unknown History of febrile seizures Yes No Unknown Seizure type Focal Generalized Unclassified Number of seizure types 1 2+ Seizure severity Flurries of seizures Status epilepticus None Unknown EEG report None Normal Slow Epileptiform NS Magnetic resonance imaging None Normal Abnormal NS Etiology Unknown/genetic Traumatic brain injury Tumor Degenerative disease Perinatal encephalopathy Cerebrovascular disease Infection Alcoholic encephalopathy NS Epilepsy syndrome Symptomatic Idiopathic Cryptogenic NS Number of drugs in the last year 0 1 2 3+ Hospitalizations Yes No Number of comorbidities 0 1 2 3+ Comorbidities Psychiatric Neurological Respiratory Cardiovascular Renal Urogenital Gastrointestinal Bone & joint Endocrine, metabolic Eye Skin Tumors Other
N
%
47 668 23
6.4 90.5 3.1
71 645 22
9.6 87.4 3.0
658 76 4
89.2 10.3 0.5
327 411
44.3 55.7
92 14 621 11
12.5 1.9 84.1 1.5
139 28 179 390 2
18.9 3.8 24.3 52.9
256 151 328 3
34.7 20.5 44.5
395 121 61 60 39 26 23 10 3
53.7 16.4 8.3 8.1 5.3 3.5 3.1 1.4
407 81 248 2
55.3 11.0 33.7
31 376 228 103
4.2 51.0 30.9 13.9
40 698
5.4 94.6
471 177 58 32
63.8 24.0 7.9 4.3
37 77 7 35 8 15 41 7 32 2 1 49 52
5.0 10.4 1.0 4.7 1.1 2.0 5.6 1.0 4.3 0.3 0.1 6.6 7.0
had no comorbidities, one-fifth had only one comorbidity, and about 10% had 2 or more comorbidities. Neurological comorbidities were the most frequent (10% of cases) followed by tumors, gastrointestinal, psychiatric, and cardiovascular diseases. EEG was the commonest instrumental test (total, 1627) followed by hematological and biochemical tests (1369 and 1561), ECG (1284), and neuroimaging (552). Plasma drug concentrations were obtained in 340 cases. Other specialists were consulted in 3968 instances. Only 40 patients were hospitalized during follow-up. During the study period, 31 patients (4.2%) were untreated, 376 (51.0%) received one drug, 228 (30.9%) two drugs, and 103 (13.9%) three or more drugs. The commonest active compounds were, in decreasing order, valproate (360 cases, 48.8%), carbamazepine (230, 31.2%), topiramate (155, 21.0%), lamotrigine (134, 18.2%), and levetiracetam (113, 15.3%). The six prognostic categories are illustrated in Table 3. Active nondrug-resistant epilepsy, epilepsy with occasional seizures, and epilepsy in remission were, in decreasing order, the commonest categories. Surgical candidates were only 3%. The median annual cost per patient was €955 (IQR 521–2134; range 51–10,904). The corresponding cost of drugs was €643 (IQR 288–1866; range 0–9960), and the cost of laboratory/instrumental tests/outpatient consultations was €202 (IQR 160–270; range 20–1217). Mean per patient costs varied considerably across prognostic categories ranging from €782 in newly diagnosed patients to €3777 in patients with drug-resistant epilepsy (Table 4). Drugs were the predominant source of costs. Seven of sixty-seven newly diagnosed patients (10.4%) were hospitalized during follow-up. The corresponding numbers were 12/191 (6.3%) in patients with occasional seizures, 10/267 (3.7%) in patients with active nondrug-resistant epilepsy, 3/49 (6.1%) in patients with drug-resistant epilepsy, and 8/23 (34.8%) in surgical candidates. No epilepsy-related hospital admissions were recorded in patients in remission. Considering only hospitalized patients, mean (SD) hospital costs per patient varied with prognostic category, ranging from €646.7 (109.0) in patients with occasional seizures to €950.0 (28.3) in surgical candidates. Along with prognostic category, significant predictors of total costs in univariate analysis included age at diagnosis, education, occupation, disability, seizure types, and etiology (Supplementary Tables 1 and 2). An inverse correlation was found between cost and age at diagnosis of epilepsy. Variables retaining significance in multivariate analysis models were prognostic category, age at diagnosis, disability, presence of generalized seizures, seizure severity, number of seizure types, and documented etiology (Table 5). Compared with patients with epilepsy in remission, patients with drug-resistant epilepsy carried more than twofold increased costs, while newly diagnosed patients showed a 15% reduction of costs. Costs decreased with age at diagnosis, with a 4% reduction for every 5-year increase. Patients with disability generated 44% increased costs. In contrast, patients with and without comorbidities incurred similar costs (data not shown). Compared with patients with focal seizures, patients with generalized seizures showed a cost increase amounting to about 30%, while having more than one seizure type corresponded to a 40% cost increase. Having experienced status epilepticus or flurries of seizures led, respectively, to 55% and 23% cost increase. The cost of alcohol-related epilepsy was about 50% lower and the cost of CNS infection was 70% higher than the cost of epilepsy of unknown or genetic etiology.
Table 3 Prognostic groups. Prognostic group
N
%
Newly diagnosed Remission Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate
68 140 191 267 49 23
9.2 19.0 25.9 36.2 6.6 3.1
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Table 4 Annual costs per patient by prognostic group. Prognostic group
Newly diagnosed Remission Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate
Mean (SE) cost Total
Laboratory & instrumental tests/outpatient consultations
Drugs
Hospitalizations
⁎⁎⁎
⁎⁎⁎
⁎⁎⁎
⁎⁎⁎
782.08 (0.09) 1215.41 (0.07) 1473.46 (0.06) 1544.93 (0.05) 3777.65 (0.11) 2851.67 (0.16)
237.38 (0.07) 233.01 (0.05) 222.41 (0.04) 224.62 (0.03) 274.46 (0.08) 350.61 (0.11)
447.05 (0.28) 982.40 (0.20) 1210.42 (0.17) 1294.69 (0.14) 3449.32 (0.33) 2170.63 (0.48)
97.65 (0.63) 0.00 (0.00) 40.63 (0.46) 25.62 (0.42) 53.88 (0.54) 330.43 (0.80)
SE = standard error of the mean. ⁎⁎⁎ p b 0.001.
4. Discussion Our results are in keeping with several other reports in confirming that the cost of epilepsy varies significantly depending on the timing of the disease (newly diagnosed vs. chronic) and the response to drug treatment. However, comparisons of economic reports from different countries are hampered by a number of factors, including the study design, the target population, and the country's cost of health care delivery. Tetto and coworkers [10] studied 525 children and adults with partial, generalized, or undetermined epilepsy from a network of epilepsy centers in Northern Italy. Patients were stratified in six prognostic groups, defined as in the present study, and followed prospectively for one year. Data were collected on hospital admissions, day-hospitals, ambulatory consultations, biochemical assays, EEG recordings, and neuroimaging tests. The total annual costs varied significantly across epilepsy groups, ranging from 412€ (epilepsy in remission) to 3945€ (surgical candidates). In another Italian study, 631 patients aged Table 5 Independent predictors of annual costs. Variable Prognostic group Remission (reference) Newly diagnosed Occasional seizures Active non drug-resistant Drug-resistant Surgical candidate Age 5-year increase Disability No (reference) Yes Seizure type Focal (reference) Generalized Unclassified Number of seizure types 1 (reference) 2+ Seizure severity Flurries of seizures Status epilepticus None (reference) Unknown Etiology Unknown/Genetic (reference) Traumatic brain injury Tumor Degenerative disease Perinatal encephalopathy Cerebrovascular disease Infection Alcoholic encephalopathy
Relative change
95% CI
p value b0.0001
1 0.85 1.12 1.08 2.30 1.63
0.68–1.06 0.94–1.32 0.92–1.26 1.79–2.96 1.17–2.27
0.96
0.94–0.98
0.0008 b0.0001 1 1.44
1.27–1.63 0.0039
1 1.28 0.45
1.06–1.55 0.22–0.93 b0.0001
1 1.39
1.24–1.56 0.0071
1.23 1.55 1 0.77
1.04–1.46 1.04–2.30 0.50–1.19 0.0005
1 0.93 0.97 0.84 0.95 0.70 1.69 0.48
0.79–1.09 0.79–1.19 0.68–1.03 0.74–1.22 0.51–0.95 1.24–2.30 0.30–0.76
Legend: relative change = proportion reflecting the change of cost related to the reference category, a value b1 denotes a decreased cost, a value N1 denotes an increased cost; CI = confidence interval.
18 years or older were recruited in 15 epilepsy centers distributed in the entire national territory and followed prospectively for one year [11]. Prognostic groups and cost items were the same. Again, the lowest costs were incurred by epilepsy in remission (561€) and the highest by surgical candidates (3619€). More recently, in France, de Zélicourt et al. [13] examined 405 adult patients with focal epilepsy classified as drug-resistant or drugresponsive. Data on the consumption of medical resources were collected retrospectively for 12 months preceding inclusion. The mean annual direct costs were 2.3 times higher in drug-resistant than in drugresponsive patients (€4485 vs. €1926), The costs of drugs, additional tests, and hospital admissions were, respectively, two, four, and thirteen times higher in the former compared with the latter category. Direct medical costs and indirect costs were calculated by Strzelczyk et al. [14] in 366 German adults with epilepsy during a 4-month period. In this sample, the total estimated annual direct costs cost per patient were €3128. Hospitalizations (€799), medications (€642), ancillary treatments (€369), and rehabilitation (€283) were the highest sources of expenditures. The higher costs of epilepsy in several other countries can be similarly explained. In the US, total direct healthcare costs per person ranged from $10,192 (€7840) to $47,862 (€36,816), and epilepsy-specific costs ranged from $1022 (€786) to $19,749 (€15,191), with markedly higher costs in those with uncontrolled or refractory epilepsy and in those with comorbidities [15]. In our study, only patients with epilepsy caused by CNS infection had significantly higher costs than patients with epilepsy of unknown etiology. Even in Europe, direct costs were slightly to significantly higher than ours. In Spain, the mean direct cost per patient was €1055 [16]. In Denmark, the annual cost of inpatient services, outpatient services, and drugs was €3465 (outpatient services, €270; drugs, €978) [17]. Annual direct costs in Sweden were €1047 (drugs €485) [18]. In Germany, the total annual direct costs amounted to €1698 per patient with anticonvulsants (59.9% of total direct costs) and hospitalization (30.0%) as the main cost factors [19]. In line with others [19], drugs represented the highest source of expenditures in the present study. In contrast, in China, the costs of epilepsy were lower than ours. Gao et al. [20] examined 141 epilepsy patients. The median direct costs were US$501.34 (€385.64). Cost of antiepileptic drugs (US$394.53; €303.48) followed by investigations (US$59.34; €45.64), and inpatient and outpatient care (US$9.62; €7.4) accounted for the majority of the direct medical costs. This study is at variance with several others [4,6,10,11,21] in showing that patients with newly diagnosed epilepsy are the lowest cost category. The difference can be explained by the different health resources used. As the cost of AEDs was the major determinant of total costs, newly diagnosed patients were the lowest cost category as they usually did not receive the newest, most expensive AEDs. In addition, the costs for medical services/procedures (excluding drugs), according to the mandatory international tariffs, are substantially lower in Russia than in Western Europe. The fairly low hospital costs are also worth noting as they not only reflect Russian tariffs but also the fairly low access of
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patients with epilepsy to hospital facilities regardless of the severity of the disease. We found an inverse correlation between costs and age at epilepsy diagnosis. This finding is in keeping with others [22]. We can explain the higher costs of epilepsies with childhood onset with the inclusion of cases with more severe disease varieties and persistence of uncontrolled seizures. As expected, costs predominated in patients with disability, different seizure types, and status epilepticus. These clinical conditions are mostly represented by epilepsies with uncontrolled seizures requiring treatment changes and more frequent use of newer antiepileptic drugs. Our costs of drug-resistant epilepsy are in keeping with other reports [10,11] but significantly lower than others [23-25]. Differences can be explained by the definition of drug-resistant epilepsy and the national item costs. This study has limitations. First, the breakdown of costs and the comparisons with reports from other European and non-European countries must be critically appraised in light of the peculiarities of the health system in Russia. Some of them have been addressed in the Materials and methods. Second, the study is not population-based. Thus, the overall cost of epilepsy might be lower in the community where epilepsies in remission are mostly represented. Third, the results may be biased by the marked predominance of symptomatic epilepsies with focal seizures. However, similar to this study, focal epilepsies were diagnosed in 81.6% of adolescents and adults enrolled in a Russian epidemiological survey [26]. Fourth, although we collected data on the etiology of epilepsy, the costs of epilepsy could not be disentangled from the costs of the underlying epileptogenic conditions and comorbidities. However, in contrast with a recent study in the US [27], in which the presence of comorbidities approximately tripled the health-care cost compared with the cost epilepsy alone, our costs were fairly similar in patients with and without comorbidities. The difference can be explained by the low proportion of cases with comorbidities in our sample, which were about 10-years younger than the US sample. Fifth, we included only patients with two or more unprovoked seizures because for the purposes of epidemiologic studies, solitary unprovoked seizures (including status epilepticus) and provoked seizures should be segregated from epilepsy [28]. Lastly, this is a study from a single center. Although we assume that the cost items are identical in other Russian centers, resource consumption may differ. In conclusion, in keeping with others, the cost of epilepsy in Russia varies significantly depending on the timing of the disease (newly diagnosed vs. chronic epilepsy) and the response to drug treatment. Costs are highest in disabled patients with symptomatic epilepsies and poor response of seizures to the available drugs.
Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Disclosure of conflicts of interest Alla Guekht, Maria Mizinova, Igor Kaimovsky, Oksana Danilenko and E. Bianchi have nothing to disclose. E. Beghi serves on the editorial boards of Amyotrophic Lateral Sclerosis, Clinical Neurology & Neurosurgery, and Neuroepidemiology; has been an associate editor of Epilepsia and is an associate editor of Epilepsia Open; has received money for board membership from VIROPHARMA, SHIRE and EISAI; has received funding for travel and speaker honoraria from UCB-Pharma, Sanofi-Aventis and GSK; has received funding for educational presentations from GSK; and reports grants from the Italian Drug Agency and from the Italian Ministry of Health.
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