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Patients’ perspective on current treatment options for Parkinson’s Disease
Basal Ganglia 9 (2017) 7–11
Contents lists available at ScienceDirect
Basal Ganglia journal homepage: www.elsevier.com/locate/baga
Patients’ perspective on current treatment options for Parkinson’s Disease a,⁎
Wolfgang Jost , Jennifer Bausch a b
MARK
b
Zentrum für Bewegungsstörungen, Parkinson-Klinik Ortenau, Germany Medizinische Abteilung, Zambon GmbH, Berlin, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Parkinson’s disease Patient perception Self-report Treatment pattern Satisfaction Efficacy Tolerability Survey
To date, current data on the treatment situation of patients with Parkinson’s disease (PD) are limited. Therefore cross sectional surveys in 4485 patients and in addition, in office based neurologists, were performed. Patients were questioned about their disease history and current treatment, as well as their therapy satisfaction. The mean lag time between first diagnosis of PD and the first prescription of medication was in 68.9% of patients less than 3 months, in 15.6% between 3 and 6 months, in 7.1% 7 to 12 months, in 3.3% up to 2 years, and in 3.1% more than 2 years. Patient rated themselves in 9.7% to be in the initial course of PD, 44.3% in a progressed stage and 41.3% in an advanced stage. The success of therapy rated 4.9% as very good, 22.6% as good, 43.4% as satisfactory, 23.0% as unsatisfactory, and 2.1% as poor (4.1% no response). Treatment success was dependent on motoric symptoms in the view of 51.3% of patients, on non-motoric symptoms in 6.5%, in 23.4% with cognitive ability, in 57.0% with quality of life and in 21.5% with impairment caused by medication. With respect to current therapy 41.8% of patients were affected by frequency of drug intake, 3.2% by type of administration, 12.3% by number of drugs, 27.7% by unsatisfactory efficacy, and 41.3% by side effects (several answers possible). Overall, only 27.5% of patients rated their current PD medication as very good or a good, in contrast to the physicians (treatment success very good or good in 75.8%). Physicians named control of motoric symptoms (89.7%) and quality of life (86.7%) as key criteria for successful therapy. In summary, PD patients report deficits in drug treatment. There is a clear need for action with regard to the information transfer to patients (including the explanation of side effects or differentiation of symptoms of the PD) and possibly for a change of the medication schedules including other drugs or combination therapies.
1. Hintergrund Parkinson's disease (PD) is one of the most common neurological diseases with a prevalence of approximately 1680 cases per 100,000 individuals [1]. The disease is age dependent causing a further increase of new cases in the next decades [2]. PD is defined by the presence of akinesia and rigor or resting tremor, and also postural instability. A number of non-motoric autonomous and psychological symptoms are detectable in all stages of the disease [3]. Even today, the early and correct diagnosis of the disease is not always achieved [4]. Numerous drugs have been approved for the treatment of PD. The most important medication continues to be L-Dopa in combination with a decarboxylase inhibitor (benserazide or carbidopa) [5]. The second important approach is dopamine agonists, which are also the drugs of choice in younger patients in the early stage of disease. [6] Furthermore, the COMT inhibitors entacapone and tolcapone are used in the
⁎
presence of motor activity fluctuations, [7] the MAO-B inhibitors rasagiline and selegiline, the NMDA antagonists amantadine and bupidine, anticholinergics [8,9] and latterly safinamide [8,10,11]. Regarding different disease manifestations, differences in disease management [12], and the complex treatment options, which also include numerous combination options, it is difficult for patients with PD to compare drugs and to set pReferences Therefore, the present surveys were initiated with the aim of obtaining a representative picture of the current treatment situation and treatment success for patients with PD in daily practice. The entire picture of drug treatment, not individual preparations, was to be assessed by means of patient self-reports. The patients survey was supplemented by a survey of office-based neurologists treating patients with PD.
Corresponding author at: Parkinson-Klinik Ortenau, Zentrum für Bewegungsstörungen Kreuzbergstraße, 12-16 77709 Wolfach, Germany. E-mail address: [email protected] (W. Jost).
http://dx.doi.org/10.1016/j.baga.2017.05.001 Received 18 April 2017; Accepted 22 May 2017 Available online 15 June 2017 2210-5336/ © 2017 Elsevier GmbH. All rights reserved.
Basal Ganglia 9 (2017) 7–11
W. Jost, J. Bausch
2. Methods
A change to combination therapy occurred in 615 patients (13.7%) within one year, 942 (21.0%) after 1–3 years, 291 (6.5%) after 3 to 5 years, 5- 10 years at 114 (2.5%) and more than 10 years at 44 (1.0%) (not applicable in 8.9%) (Fig. 2). L-Dopa was prescribed as monotherapy in 402 patients (8.9%), 1430 (31.9%) with another drug, and 2217 (49.4%) with several other medications (no response 9.7%). The above-mentioned combination partners for L-Dopa are shown in Fig. 3. Dopamine agonists were mentioned in 1824 patients (40.7%), followed by amantadine in 1291 patients (28.8%), approximately equal to entacapone, rasagiline and selegiline (13 and 14% respectively). 2696 patients reported stable Ldopa therapy (60.1%, 15.7% not reported). Treatment success for PD was rated as very good by 218 patients (4.9%), as good by 1012 (22.6%), as satisfactory by 1947 (43.4%), as not satisfactory by 1031 (23.0%), and as poor by 93 (2.1%) (4.1% not stated) (Fig. 4). Success of therapy was associated by 2302 patients (51.3%) with drug effect on motoric symptoms, by 290 (6.5%) on nonmotoric symptoms, by 1050 (23.4%) on the perceptive capacity, by 2555 patients (57.0%) on quality of life and by 963 (21.5%) on medication impairment (Fig. 5). 2986 patients (66.6%) reported impairment of their mobility (no data at 4.8%). 1652 of the affected patients (36.8%) indicated that the treating physician had therefore considered a change of therapy. Regarding the current therapy, 1875 patients (41.8%) felt impaired by the frequency of use, 145 (3.2%) by type of application, 553 (12.3%) by multiple medication, 1243 (27.7 %) by insufficient efficacy and 1852 (41.3%) by side effects (Fig. 6).
The present work was designed as a pair of cross-sectional surveys. Ethics approval was not necessary for this study type. Only anonymous data were analysed and the data protection guidelines were closely followed. In collaboration with the Deutsche Parkinson Vereinigung e.V., the author developed a patient questionnaire with 22 questions. These questions mainly concerned the duration and course of the disease, medical care, drug therapy, efficacy and disadvantages of the treatment. It was submitted to office-based neurologists and other physicians in all regions of Germany. Patients were eligible for participation if they provided written confirmed consent. They received the questionnaires by the patient association by mail. The questionnaire was to be answered anonymously by the patients without the involvement of their doctors. Physicians had to be office-based and not linked to a hospital. They were contacted by the patient organisation and asked to fill out a medical questionnaire with 23 questions. They did not assess individual patients, but the overall situation of all Parkinson's patients in their practice. Patient and physician questionnaires are available in the online supplement. Study analyses were purely descriptive, and no inferential statistics were performed. 3. Results
3.2. Physician questionnaire 3.1. Patient questionnaire A total of 271 doctors participated in the physician survey. On average, they saw 143 ± 212 PD patients per quarter. A PD assistant was available in 14.8% and a PD nurse in 9.6% of the offices. 61.3% of physicians stated that they considered the available treatment options for the care of their patients in the early phase adequate, compared to 25.1% in the late phase of the disease. Therapy was started as monotherapy in 75.0% of the patients (L-dopa at 42.9%), and after 1 to 4 years by further medication completed. Dopamine agonists (94.8%), entacapone (77.1%), rasagiline (70.9%) and amantadine (51.3%) were mentioned as preferred combination partners. Physicians reported wearing off and/or fluctuations in 32.6% of the patients, and in slightly more than half of the affected patients they considered for this reason a change of therapy. Physicians described numerous symptoms of PD as “not satisfactorily treatable” (80.8%), in particular tremor (73.8%), freezing (61.3%), neuropsychiatric disorders (54.2%), gastrointestinal disorders (55.0%) and cardiovascular disorders (49.8%). Regarding the treatment success of PD therapy (from physician's view), in particular motoric symptoms (89.7%) and quality of life (86.7%) were noted as key factors. The treatment outcome was classified as predominantly very good (18.8%), predominantly good (56.8%) or predominantly satisfactory (21.8%). Patients with PD were mainly affected by adverse reactions (61.3%), the frequency of drug intake (57.6%), insufficient efficacy (38.8%) and multiple medications (38.0%). The type of application did not play a significant role (3.7%).
Of the 4485 participating patients, 966 patients (21.5%) had a disease duration of up to 5 years, 1339 (29.9%) 5–10 years, 1576 (35.1%) 10–20 years and 550 (12.3%) over 20 years (no data: 1.2%). The time between first-time occurrence of symptoms and the diagnosis was less than 3 months in 914 patients (20.4%), 3- 6 months in 986 (22.0%), 6- 12 months in 1004 (22.4%), 1 − 2 years in 796 (17.8%) and more than 2 years in 683 patients (15.2%, missing data: 2.3%). The diagnosis was made by a neurologist in 3908 patients (87.1%), by a general practitioner in 616 (13.7%), and by an internist in 168 (3.8%) (others specialists: 200 patients, 4.5%). The period between the diagnosis of the PD and the initial prescription of PD drugs was less than 3 months in 3088 (68.9%) of patients, 3–6 months in 701 (15.6%), 6–12 months in 317 (7, 1%), 1 − 2 years in 149 (3.3%) and more than 2 years in 138 patients (3.1%, no data: 2.1%). A total of 433 patients (9.7%) were in the initial stage of the disease, 1986 (44.3%) in the intermediate stage and 1850 (41.3%) in the advanced stage (no data: 4.8%). In 4323 patients (96.4%), the first PD drug had been prescribed by a neurologist, by a general practitioner in 140 patients (3.2%), and by an internist in 41 patients (0.9%) (other: 1.0%). At the time of survey participation, 4344 patients (96.9%) saw a neurologist, 380 (8.5%) a general practitioner, 70 (1.6%) an internist and 50 (1.1%) a general physician (other: 0.9%). 268 patients (6.0%) were cared for by a specially trained Parkinson nurse/assistant (no data: 2.8%). The quality and efficacy of the available PD drugs were assessed to be very good by 206 (4.6%) of the patients, as good by 1287 (28.7%), as satisfactory by 1450 (32.3%), as not satisfactory by 707 (15.8%) and as poor by 646 (14.4%) (no data in 4.2%) (Fig. 1). Initially, 2403 (53.6%) of the patients used only one PD drug (monotherapy) (missing data at 4.3%). This was L-Dopa in 1741 patients (38.8%) and another, unspecified drug in 2398 (53.5%, no data in 7.7%).
4. Discussion The present results of detailed surveys of patients and neurologists provide a comprehensive picture of the treatment modalities and the treatment satisfaction of patients with PD who were treated predominantly by neurologists. Surveys are an important tool for assessing the experiences, attitudes, and attitudes of sufferers to their PD [12–16]. In a US study, patients were highly satisfied, especially when treated by neurologists who specialized in PD. [14] However, patients' self-reports are usually 8
Basal Ganglia 9 (2017) 7–11
W. Jost, J. Bausch
Fig. 1. Quality and efficacy of the available PD drugs.
Fig. 2. Time to switch from monotherapy to combination therapy.
Fig. 3. Medication in addition to L-Dopa on first combination.
Fig. 4. Treatment success of PD drug therapy.
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Basal Ganglia 9 (2017) 7–11
W. Jost, J. Bausch
Fig. 5. Patient criteria for the assessment of treatment success.
not verified by comparing the data with the files, and can be subject to various forms of bias (especially recall bias) [17]. As a comparative benchmark for our study, the Move for Change survey with more than 2200 patients in 35 European countries, lends itself. In that study, PD was diagnosed in 82.7% of patients within 2 years after the first symptoms. However, in the following two years, 43.8% of patients were not seen by a specialist for the disease [16]. In a further module of this study, only half of the patients (53%) regularly consulted a neurologist and only 12% were included in the medical decision on their therapy [16]. This data is in contrast with the situation in Germany, where PD patients have good access to specialists and are involved in therapy decisions. In the present survey, patients were not characterized in terms of age and gender for the purpose of fully anonymizing their data. Against this background, it is not possible to assess whether their onset of disease is classified as early or late. Current guidelines on PD generally state that the therapy should be timely, age-appropriate and efficient, differentiating between patients with early and those with a late onset of treatment [18]. While in patients with late onset, L-dopa therapy is most effective and well-tolerated, the situation is different in patients with early onset, unless they show significant comorbidities: in this case, the therapy initiation with a non-ergot dopamine agonist is preferred. [18] However, in previous surveys from 2005 and 2007 the respective PD guidelines were known by established neurologists in Germany only in about half of the interviewees, and the contents were not universally acknowledged as appropriate [19,20]. The great number (85.6%) of the patients in the present patient survey was already in an intermediate or advanced stage of PD and thus
had many years of experience with medication therapy. L-Dopa was prescribed for treatment, and only a few of the patients treated with LDopa (8.9%) received the drug as a monotherapy. The numerous possible treatment options with regard to the choice of the medication classes and combinations were used, which speaks for the doctors' efforts to address the individual patient needs. It is striking that symptom control on L-Dopa was achieved in only 60.1% of patients. In two-thirds of the cases, the effect of the therapy was wearing off over time, in the long term in almost all patients. [21] However, especially in younger patients on L-dopa wearing off can also occur at a relatively early stage [22,23], and be confused with a progression of the PD by patients as well as by physicians. With regard to the symptoms, the focus of the surveys was on motoric symptoms and non-motoric symptoms, and a further differentiation was not made, particularly in the late phase. Patients often report considerable fluctuating symptoms, such as neuro-psychiatric and autonomic disorders [3,24,25]. In the present surveys, 57.0% of the patients and even 86.7% of the physicians described the quality of life as an essential parameter for the success of therapy. The progressive decline in quality of life began years before disease diagnosis. [26] In studies on the quality of life, it was shown that the it generally decreases steadily, mainly due to the motoric impairment [27], but also because of the treatment-related side effects (especially under L-Dopa [28]). The main disadvantages of PD drug treatment from the patient perspective are in particular the frequency of drug intake and the need for combination therapy. It is known that the burden of the patients increases and the treatment adherence decreases, especially in elderly Fig. 6. Disadvantages of PD drug therapy.
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Basal Ganglia 9 (2017) 7–11
W. Jost, J. Bausch
Appendix A. Supplementary data
patients, with an increasing number of medications to be taken [29]. In a recent meta-analysis, PD patients reported non-compliance with medication intake in a range of 10–67% [30]. The main factors for noncompliance are mood swings, cognitive impairments, poor symptom control, and reduced quality of life. Certain side effects are frequently referred to as disadvantages of therapy, especially nausea, dyskinesia, drowsiness, impulsive behavior, psychoses and peripheral edema [31]. A patient-tailored therapy can improve tolerability [32]. Due to the numerous drugs and combinations, it was not possible for the patients in the present study to name the significant side effects. Overall, only about a quarter of patients rated their current therapy as very good or good, and most just as satisfactory or even as unsatisfactory. This resulted in a clear discrepancy between the physicians, who felt that their patients were significantly more satisfied. This was in contrast to the high prevalance of PD symptoms that, according to the physicians, cannot be treated well. According to the current survey, there is a lack of suitable drugs for the advanced and late phase of PD. Despite the existing selection of drug approaches, the disease cannot be cured or stopped. Accordingly, the development of new, more effective and compatible drugs or further therapeutic approaches should be promoted. The study was limited to a cross-sectional design (with questions on past treatments with the potential to induce recall bias) and information on potentially confounding factors were not collected (e.g. socioeconomic status, cognition, mood). When interpreting the study results, the particularities of the German health care system and bias due to selection effects must be considered. According to the German Statistical Office, there were 6400 active neurologists in 2016 in Germany. Patients with Parkinson’s disease are usually seen under ambulatory care conditions, irrespective of disease severity. Some practices treated many patients, which could lead to distortion of the results. The data of the patients who were willing to participate cannot be extrapolated directly to other patients that probably have fewer insights in their disease. A major limitation was that no information on invasive treatment (intestinal L-dopa, apomorphine pump or deep brain stimulation), was collected, as these approaches are rarely used by office-based physicians. Further, non-motor symptoms were not asked for individually and patients often do not relate their non motor problems to PD. In summary, patients experienced subjective limitations with respect to drug management, and a considerable portion expressed their dissatisfaction with the effects or tolerability. Patients and treating physicians alike stated that quality of life is an essential parameter for the success of the therapy. Satisfaction of patients might be improved by intensified information (among others, the explanation of side effects or differentiation of the medication effect of PD symptoms). Further, some patients might benefit from a switch of medication schemes to other preparations, or from the switch of monotherapies to drug combinations.
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.baga.2017.05.001. References [1] D. Riedel, et al., Estimating the prevalence of Parkinson's disease (PD) and proportions of patients with associated dementia and depression among the older adults based on secondary claims data, Int. J. Geriatr. Psychiatry (2016) (online first). [2] E.R. Dorsey, R. Constantinescu, J.P. Thompson, et al., Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030, Neurology 68 (2007) 384–386. [3] W.H. Jost, Urological problems in Parkinson's disease: clinical aspects, J Neural Transm (Vienna) 120 (2013) 587–591. [4] G. Rizzo, M. Copetti, S. Arcuti, et al., Accuracy of clinical diagnosis of Parkinson disease: a systematic review and meta-analysis, Neurology 86 (2016) 566–576. [5] J. Jimenez-Shahed, A review of current and novel levodopa formulations for the treatment of Parkinson's disease, Ther. Deliv. 7 (2016) 179–191. [6] R. Ceravolo, C. Rossi, E. Del Prete, et al., A review of adverse events linked to dopamine agonists in the treatment of Parkinson's disease, Expert Opin. Drug Saf. 15 (2016) 181–198. [7] S.Z. Marsala, M. Gioulis, R. Ceravolo, et al., A systematic review of catechol-0methyltransferase inhibitors: efficacy and safety in clinical practice, Clin. Neuropharmacol. 35 (2012) 185–190. [8] O. Rascol, S. Perez-Lloret, J.J. Ferreira, New treatments for levodopa-induced motor complications, Mov. Disord. 30 (2015) 1451–1460. [9] M.A. Faulkner, Safety overview of FDA-approved medications for the treatment of the motor symptoms of Parkinson's disease, Expert Opin. Drug Saf. 13 (2014) 1055–1069. [10] S. Perez-Lloret, O. Rascol, The safety and efficacy of safinamide mesylate for the treatment of Parkinson's disease, Expert Rev. Neurother. (2016) 1–14. [11] M. Fabbri, M.M. Rosa, D. Abreu, et al., Clinical pharmacology review of safinamide for the treatment of Parkinson's disease, Neurodegener. Dis. Manag. 5 (2015) 481–496. [12] L.A. Uebelacker, G. Epstein-Lubow, T. Lewis, et al., A survey of Parkinson's disease patients: most bothersome symptoms and coping preferences, J. Parkinsons Dis. 4 (2014) 717–723. [13] S. Buetow, L.S. Giddings, L. Williams, et al., Perceived unmet needs for health care among Parkinson's Society of New Zealand members with Parkinson's disease, Parkinsonism Relat. Disord. 14 (2008) 495–500. [14] T.S. Dorsey, et al., A U. S. survey of patients with Parkinson's disease: satisfaction with medical care and support groups, Mov. Disord. 25 (2010) 2128–2135. [15] B.R. Bloem, F. Stocchi, Move for change part I: a European survey evaluating the impact of the EPDA Charter for People with Parkinson's disease, Eur. J. Neurol. 19 (2012) 402–410. [16] B.R. Bloem, F. Stocchi, Move for change part III: a european survey evaluating the impact of the EPDA charter for people with parkinson's disease, Eur. J. Neurol. 22 (2015) e138–e139 (133–141). [17] M. Delgado-Rodriguez, J. Llorca Bias, J. Epidemiol. Community Health 58 (2004) 635–641. [18] W. Eggert, Parkinson-Syndrome ?Diagnostik Und Therapie (S2-Leitlinie), Reichmann Deutsche Gesellschaft für Neurologie (DGN), 2012 (Stand September AWMF-Registernummer: 030/010.). [19] K. Eggert, A. Larisch, R. Dodel, et al., Awareness and knowledge of the clinical practice guideline on Parkinson's disease among German neurologists, Eur. Neurol. 61 (2009) 216–222. [20] A. Larisch, W.H. Oertel, K. Eggert, Attitudes and barriers to clinical practice guidelines in general and to the guideline on Parkinson's disease. A National Survey of German neurologists in private practice, J. Neurol. 256 (2009) 1681–1688. [21] P. Jenner, Wearing off dyskinesia, and the use of continuous drug delivery in Parkinson's disease, Neurol. Clin. 31 (2013) S17–35. [22] S. Fahn, Parkinson disease, the effect of levodopa, and the ELLDOPA trial Earlier vs Later L-DOPA, Arch. Neurol. 56 (1999) 529–535. [23] F. Stocchi, O. Rascol, K. Kieburtz, et al., Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study, Ann. Neurol. 68 (2010) 18–27. [24] A. Schrag, R. Dodel, A. Spottke, et al., Rate of clinical progression in Parkinson's disease. A prospective study, Mov. Disord. 22 (2007) 938–945. [25] I. Csoti, W.H. Jost, H. Reichmann, Parkinson's disease between internal medicine and neurology, J. Neural. Transm. (Vienna) 123 (2016) 3–17. [26] N. Palacios, X. Gao, M. Schwarzschild, et al., Declining quality of life in Parkinson disease before and after diagnosis, J. Parkinsons Dis. 2 (2012) 153–160. [27] D. Muslimovic, B. Post, J.D. Speelman, et al., Determinants of disability and quality of life in mild to moderate Parkinson disease, Neurology 70 (2008) 2241–2247. [28] K.D. Sethi, The Impact of Levodopa on Quality of Life in Patients with Parkinson Disease. Neurologist 16 (2010), pp. 76–83. [29] W.F. Gellad, J.L. Grenard, Z.A. Marcum, A systematic review of barriers to medication adherence in the elderly: looking beyond cost and regimen complexity, Am. J. Geriatr. Pharmacother. 9 (2011) 11–23. [30] N. Malek, D.G, Grosset Medication adherence in patients with Parkinson's disease. CNS Drugs 29 (2015), pp. 47–53. [31] K.L. Chou, Adverse events from the treatment of Parkinson's disease, Neurol. Clin. 26 S65-83, vi (2008). [32] N.L. Diaz, C.H. Waters, Current strategies in the treatment of Parkinson's disease and a personalized approach to management, Expert Rev. Neurother. 9 (2009) 1781–1789.
Funding The present study was funded by Zambon GmbH, Berlin. Conflicts of interest WHJ is a consultant for Abbvie, Allergan, IPSEN, Merz, UCB, and Zambon. JB is a full-time employee of Zambon GmbH, Berlin. Acknowledgments AMS Advanced Medical Services GmbH, Berlin, carried out data collection, data management and analysis on behalf of Zambon GmbH. In the preparation of the first version of the manuscript, 3P Consulting, Seefeld, Germany, supported the authors. 11
Contents lists available at ScienceDirect
Basal Ganglia journal homepage: www.elsevier.com/locate/baga
Patients’ perspective on current treatment options for Parkinson’s Disease a,⁎
Wolfgang Jost , Jennifer Bausch a b
MARK
b
Zentrum für Bewegungsstörungen, Parkinson-Klinik Ortenau, Germany Medizinische Abteilung, Zambon GmbH, Berlin, Germany
A R T I C L E I N F O
A B S T R A C T
Keywords: Parkinson’s disease Patient perception Self-report Treatment pattern Satisfaction Efficacy Tolerability Survey
To date, current data on the treatment situation of patients with Parkinson’s disease (PD) are limited. Therefore cross sectional surveys in 4485 patients and in addition, in office based neurologists, were performed. Patients were questioned about their disease history and current treatment, as well as their therapy satisfaction. The mean lag time between first diagnosis of PD and the first prescription of medication was in 68.9% of patients less than 3 months, in 15.6% between 3 and 6 months, in 7.1% 7 to 12 months, in 3.3% up to 2 years, and in 3.1% more than 2 years. Patient rated themselves in 9.7% to be in the initial course of PD, 44.3% in a progressed stage and 41.3% in an advanced stage. The success of therapy rated 4.9% as very good, 22.6% as good, 43.4% as satisfactory, 23.0% as unsatisfactory, and 2.1% as poor (4.1% no response). Treatment success was dependent on motoric symptoms in the view of 51.3% of patients, on non-motoric symptoms in 6.5%, in 23.4% with cognitive ability, in 57.0% with quality of life and in 21.5% with impairment caused by medication. With respect to current therapy 41.8% of patients were affected by frequency of drug intake, 3.2% by type of administration, 12.3% by number of drugs, 27.7% by unsatisfactory efficacy, and 41.3% by side effects (several answers possible). Overall, only 27.5% of patients rated their current PD medication as very good or a good, in contrast to the physicians (treatment success very good or good in 75.8%). Physicians named control of motoric symptoms (89.7%) and quality of life (86.7%) as key criteria for successful therapy. In summary, PD patients report deficits in drug treatment. There is a clear need for action with regard to the information transfer to patients (including the explanation of side effects or differentiation of symptoms of the PD) and possibly for a change of the medication schedules including other drugs or combination therapies.
1. Hintergrund Parkinson's disease (PD) is one of the most common neurological diseases with a prevalence of approximately 1680 cases per 100,000 individuals [1]. The disease is age dependent causing a further increase of new cases in the next decades [2]. PD is defined by the presence of akinesia and rigor or resting tremor, and also postural instability. A number of non-motoric autonomous and psychological symptoms are detectable in all stages of the disease [3]. Even today, the early and correct diagnosis of the disease is not always achieved [4]. Numerous drugs have been approved for the treatment of PD. The most important medication continues to be L-Dopa in combination with a decarboxylase inhibitor (benserazide or carbidopa) [5]. The second important approach is dopamine agonists, which are also the drugs of choice in younger patients in the early stage of disease. [6] Furthermore, the COMT inhibitors entacapone and tolcapone are used in the
⁎
presence of motor activity fluctuations, [7] the MAO-B inhibitors rasagiline and selegiline, the NMDA antagonists amantadine and bupidine, anticholinergics [8,9] and latterly safinamide [8,10,11]. Regarding different disease manifestations, differences in disease management [12], and the complex treatment options, which also include numerous combination options, it is difficult for patients with PD to compare drugs and to set pReferences Therefore, the present surveys were initiated with the aim of obtaining a representative picture of the current treatment situation and treatment success for patients with PD in daily practice. The entire picture of drug treatment, not individual preparations, was to be assessed by means of patient self-reports. The patients survey was supplemented by a survey of office-based neurologists treating patients with PD.
Corresponding author at: Parkinson-Klinik Ortenau, Zentrum für Bewegungsstörungen Kreuzbergstraße, 12-16 77709 Wolfach, Germany. E-mail address: [email protected] (W. Jost).
http://dx.doi.org/10.1016/j.baga.2017.05.001 Received 18 April 2017; Accepted 22 May 2017 Available online 15 June 2017 2210-5336/ © 2017 Elsevier GmbH. All rights reserved.
Basal Ganglia 9 (2017) 7–11
W. Jost, J. Bausch
2. Methods
A change to combination therapy occurred in 615 patients (13.7%) within one year, 942 (21.0%) after 1–3 years, 291 (6.5%) after 3 to 5 years, 5- 10 years at 114 (2.5%) and more than 10 years at 44 (1.0%) (not applicable in 8.9%) (Fig. 2). L-Dopa was prescribed as monotherapy in 402 patients (8.9%), 1430 (31.9%) with another drug, and 2217 (49.4%) with several other medications (no response 9.7%). The above-mentioned combination partners for L-Dopa are shown in Fig. 3. Dopamine agonists were mentioned in 1824 patients (40.7%), followed by amantadine in 1291 patients (28.8%), approximately equal to entacapone, rasagiline and selegiline (13 and 14% respectively). 2696 patients reported stable Ldopa therapy (60.1%, 15.7% not reported). Treatment success for PD was rated as very good by 218 patients (4.9%), as good by 1012 (22.6%), as satisfactory by 1947 (43.4%), as not satisfactory by 1031 (23.0%), and as poor by 93 (2.1%) (4.1% not stated) (Fig. 4). Success of therapy was associated by 2302 patients (51.3%) with drug effect on motoric symptoms, by 290 (6.5%) on nonmotoric symptoms, by 1050 (23.4%) on the perceptive capacity, by 2555 patients (57.0%) on quality of life and by 963 (21.5%) on medication impairment (Fig. 5). 2986 patients (66.6%) reported impairment of their mobility (no data at 4.8%). 1652 of the affected patients (36.8%) indicated that the treating physician had therefore considered a change of therapy. Regarding the current therapy, 1875 patients (41.8%) felt impaired by the frequency of use, 145 (3.2%) by type of application, 553 (12.3%) by multiple medication, 1243 (27.7 %) by insufficient efficacy and 1852 (41.3%) by side effects (Fig. 6).
The present work was designed as a pair of cross-sectional surveys. Ethics approval was not necessary for this study type. Only anonymous data were analysed and the data protection guidelines were closely followed. In collaboration with the Deutsche Parkinson Vereinigung e.V., the author developed a patient questionnaire with 22 questions. These questions mainly concerned the duration and course of the disease, medical care, drug therapy, efficacy and disadvantages of the treatment. It was submitted to office-based neurologists and other physicians in all regions of Germany. Patients were eligible for participation if they provided written confirmed consent. They received the questionnaires by the patient association by mail. The questionnaire was to be answered anonymously by the patients without the involvement of their doctors. Physicians had to be office-based and not linked to a hospital. They were contacted by the patient organisation and asked to fill out a medical questionnaire with 23 questions. They did not assess individual patients, but the overall situation of all Parkinson's patients in their practice. Patient and physician questionnaires are available in the online supplement. Study analyses were purely descriptive, and no inferential statistics were performed. 3. Results
3.2. Physician questionnaire 3.1. Patient questionnaire A total of 271 doctors participated in the physician survey. On average, they saw 143 ± 212 PD patients per quarter. A PD assistant was available in 14.8% and a PD nurse in 9.6% of the offices. 61.3% of physicians stated that they considered the available treatment options for the care of their patients in the early phase adequate, compared to 25.1% in the late phase of the disease. Therapy was started as monotherapy in 75.0% of the patients (L-dopa at 42.9%), and after 1 to 4 years by further medication completed. Dopamine agonists (94.8%), entacapone (77.1%), rasagiline (70.9%) and amantadine (51.3%) were mentioned as preferred combination partners. Physicians reported wearing off and/or fluctuations in 32.6% of the patients, and in slightly more than half of the affected patients they considered for this reason a change of therapy. Physicians described numerous symptoms of PD as “not satisfactorily treatable” (80.8%), in particular tremor (73.8%), freezing (61.3%), neuropsychiatric disorders (54.2%), gastrointestinal disorders (55.0%) and cardiovascular disorders (49.8%). Regarding the treatment success of PD therapy (from physician's view), in particular motoric symptoms (89.7%) and quality of life (86.7%) were noted as key factors. The treatment outcome was classified as predominantly very good (18.8%), predominantly good (56.8%) or predominantly satisfactory (21.8%). Patients with PD were mainly affected by adverse reactions (61.3%), the frequency of drug intake (57.6%), insufficient efficacy (38.8%) and multiple medications (38.0%). The type of application did not play a significant role (3.7%).
Of the 4485 participating patients, 966 patients (21.5%) had a disease duration of up to 5 years, 1339 (29.9%) 5–10 years, 1576 (35.1%) 10–20 years and 550 (12.3%) over 20 years (no data: 1.2%). The time between first-time occurrence of symptoms and the diagnosis was less than 3 months in 914 patients (20.4%), 3- 6 months in 986 (22.0%), 6- 12 months in 1004 (22.4%), 1 − 2 years in 796 (17.8%) and more than 2 years in 683 patients (15.2%, missing data: 2.3%). The diagnosis was made by a neurologist in 3908 patients (87.1%), by a general practitioner in 616 (13.7%), and by an internist in 168 (3.8%) (others specialists: 200 patients, 4.5%). The period between the diagnosis of the PD and the initial prescription of PD drugs was less than 3 months in 3088 (68.9%) of patients, 3–6 months in 701 (15.6%), 6–12 months in 317 (7, 1%), 1 − 2 years in 149 (3.3%) and more than 2 years in 138 patients (3.1%, no data: 2.1%). A total of 433 patients (9.7%) were in the initial stage of the disease, 1986 (44.3%) in the intermediate stage and 1850 (41.3%) in the advanced stage (no data: 4.8%). In 4323 patients (96.4%), the first PD drug had been prescribed by a neurologist, by a general practitioner in 140 patients (3.2%), and by an internist in 41 patients (0.9%) (other: 1.0%). At the time of survey participation, 4344 patients (96.9%) saw a neurologist, 380 (8.5%) a general practitioner, 70 (1.6%) an internist and 50 (1.1%) a general physician (other: 0.9%). 268 patients (6.0%) were cared for by a specially trained Parkinson nurse/assistant (no data: 2.8%). The quality and efficacy of the available PD drugs were assessed to be very good by 206 (4.6%) of the patients, as good by 1287 (28.7%), as satisfactory by 1450 (32.3%), as not satisfactory by 707 (15.8%) and as poor by 646 (14.4%) (no data in 4.2%) (Fig. 1). Initially, 2403 (53.6%) of the patients used only one PD drug (monotherapy) (missing data at 4.3%). This was L-Dopa in 1741 patients (38.8%) and another, unspecified drug in 2398 (53.5%, no data in 7.7%).
4. Discussion The present results of detailed surveys of patients and neurologists provide a comprehensive picture of the treatment modalities and the treatment satisfaction of patients with PD who were treated predominantly by neurologists. Surveys are an important tool for assessing the experiences, attitudes, and attitudes of sufferers to their PD [12–16]. In a US study, patients were highly satisfied, especially when treated by neurologists who specialized in PD. [14] However, patients' self-reports are usually 8
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Fig. 1. Quality and efficacy of the available PD drugs.
Fig. 2. Time to switch from monotherapy to combination therapy.
Fig. 3. Medication in addition to L-Dopa on first combination.
Fig. 4. Treatment success of PD drug therapy.
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Fig. 5. Patient criteria for the assessment of treatment success.
not verified by comparing the data with the files, and can be subject to various forms of bias (especially recall bias) [17]. As a comparative benchmark for our study, the Move for Change survey with more than 2200 patients in 35 European countries, lends itself. In that study, PD was diagnosed in 82.7% of patients within 2 years after the first symptoms. However, in the following two years, 43.8% of patients were not seen by a specialist for the disease [16]. In a further module of this study, only half of the patients (53%) regularly consulted a neurologist and only 12% were included in the medical decision on their therapy [16]. This data is in contrast with the situation in Germany, where PD patients have good access to specialists and are involved in therapy decisions. In the present survey, patients were not characterized in terms of age and gender for the purpose of fully anonymizing their data. Against this background, it is not possible to assess whether their onset of disease is classified as early or late. Current guidelines on PD generally state that the therapy should be timely, age-appropriate and efficient, differentiating between patients with early and those with a late onset of treatment [18]. While in patients with late onset, L-dopa therapy is most effective and well-tolerated, the situation is different in patients with early onset, unless they show significant comorbidities: in this case, the therapy initiation with a non-ergot dopamine agonist is preferred. [18] However, in previous surveys from 2005 and 2007 the respective PD guidelines were known by established neurologists in Germany only in about half of the interviewees, and the contents were not universally acknowledged as appropriate [19,20]. The great number (85.6%) of the patients in the present patient survey was already in an intermediate or advanced stage of PD and thus
had many years of experience with medication therapy. L-Dopa was prescribed for treatment, and only a few of the patients treated with LDopa (8.9%) received the drug as a monotherapy. The numerous possible treatment options with regard to the choice of the medication classes and combinations were used, which speaks for the doctors' efforts to address the individual patient needs. It is striking that symptom control on L-Dopa was achieved in only 60.1% of patients. In two-thirds of the cases, the effect of the therapy was wearing off over time, in the long term in almost all patients. [21] However, especially in younger patients on L-dopa wearing off can also occur at a relatively early stage [22,23], and be confused with a progression of the PD by patients as well as by physicians. With regard to the symptoms, the focus of the surveys was on motoric symptoms and non-motoric symptoms, and a further differentiation was not made, particularly in the late phase. Patients often report considerable fluctuating symptoms, such as neuro-psychiatric and autonomic disorders [3,24,25]. In the present surveys, 57.0% of the patients and even 86.7% of the physicians described the quality of life as an essential parameter for the success of therapy. The progressive decline in quality of life began years before disease diagnosis. [26] In studies on the quality of life, it was shown that the it generally decreases steadily, mainly due to the motoric impairment [27], but also because of the treatment-related side effects (especially under L-Dopa [28]). The main disadvantages of PD drug treatment from the patient perspective are in particular the frequency of drug intake and the need for combination therapy. It is known that the burden of the patients increases and the treatment adherence decreases, especially in elderly Fig. 6. Disadvantages of PD drug therapy.
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Appendix A. Supplementary data
patients, with an increasing number of medications to be taken [29]. In a recent meta-analysis, PD patients reported non-compliance with medication intake in a range of 10–67% [30]. The main factors for noncompliance are mood swings, cognitive impairments, poor symptom control, and reduced quality of life. Certain side effects are frequently referred to as disadvantages of therapy, especially nausea, dyskinesia, drowsiness, impulsive behavior, psychoses and peripheral edema [31]. A patient-tailored therapy can improve tolerability [32]. Due to the numerous drugs and combinations, it was not possible for the patients in the present study to name the significant side effects. Overall, only about a quarter of patients rated their current therapy as very good or good, and most just as satisfactory or even as unsatisfactory. This resulted in a clear discrepancy between the physicians, who felt that their patients were significantly more satisfied. This was in contrast to the high prevalance of PD symptoms that, according to the physicians, cannot be treated well. According to the current survey, there is a lack of suitable drugs for the advanced and late phase of PD. Despite the existing selection of drug approaches, the disease cannot be cured or stopped. Accordingly, the development of new, more effective and compatible drugs or further therapeutic approaches should be promoted. The study was limited to a cross-sectional design (with questions on past treatments with the potential to induce recall bias) and information on potentially confounding factors were not collected (e.g. socioeconomic status, cognition, mood). When interpreting the study results, the particularities of the German health care system and bias due to selection effects must be considered. According to the German Statistical Office, there were 6400 active neurologists in 2016 in Germany. Patients with Parkinson’s disease are usually seen under ambulatory care conditions, irrespective of disease severity. Some practices treated many patients, which could lead to distortion of the results. The data of the patients who were willing to participate cannot be extrapolated directly to other patients that probably have fewer insights in their disease. A major limitation was that no information on invasive treatment (intestinal L-dopa, apomorphine pump or deep brain stimulation), was collected, as these approaches are rarely used by office-based physicians. Further, non-motor symptoms were not asked for individually and patients often do not relate their non motor problems to PD. In summary, patients experienced subjective limitations with respect to drug management, and a considerable portion expressed their dissatisfaction with the effects or tolerability. Patients and treating physicians alike stated that quality of life is an essential parameter for the success of the therapy. Satisfaction of patients might be improved by intensified information (among others, the explanation of side effects or differentiation of the medication effect of PD symptoms). Further, some patients might benefit from a switch of medication schemes to other preparations, or from the switch of monotherapies to drug combinations.
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Funding The present study was funded by Zambon GmbH, Berlin. Conflicts of interest WHJ is a consultant for Abbvie, Allergan, IPSEN, Merz, UCB, and Zambon. JB is a full-time employee of Zambon GmbH, Berlin. Acknowledgments AMS Advanced Medical Services GmbH, Berlin, carried out data collection, data management and analysis on behalf of Zambon GmbH. In the preparation of the first version of the manuscript, 3P Consulting, Seefeld, Germany, supported the authors. 11