Systematic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson's disease

Parkinsonism and Related Disorders 15 (2009) 728–741

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Parkinsonism and Related Disorders journal homepage: www.elsevier.com/locate/parkreldis

Review

Systematic review of apomorphine infusion, levodopa infusion and deep brain stimulation in advanced Parkinson’s diseaseq Carl E. Clarke a, e, *, Paul Worth b, Donald Grosset c, David Stewart d a

Department of Neurology, City Hospital, Dudley Road, Birmingham B18 7QH, UK Norfolk and Norwich University Hospital, Norwich, UK c Glasgow University, Glasgow, UK d Victoria Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UK e University of Birmingham, Birmingham, UK b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 June 2009 Received in revised form 14 September 2009 Accepted 17 September 2009

The effectiveness of oral levodopa in complex Parkinson’s disease (PD) is limited by its short half-life, and the resulting pulsatile dopaminergic stimulation leads to complex motor fluctuations and dyskinesia. Several treatments provide more continuous/less pulsatile dopaminergic stimulation by modifying the pharmacokinetics of levodopa or dopamine; however, patients with advanced disease can be refractory to these treatments. In such cases infusion therapies (apomorphine and intraduodenal levodopa) and neurosurgery (deep brain stimulation [DBS]) may be used. The purpose of this systematic review is to assess, as far as possible, the relative effectiveness of these therapies. There were no randomised controlled trials comparing the three treatment modalities or any directly comparable studies, therefore a descriptive analysis of the data was performed. Studies identified for levodopa infusion and DBS supported a significant benefit compared with best medical management in terms of improvements in the proportion of the waking day in a functional ‘‘on’’ state, activities of daily living and motor score. This finding was supported in observational studies for all three therapies. Adverse events were not adequately reported in the majority of included studies and it was therefore not possible to obtain a reliable tolerability profile of the different treatment options. The absence of direct comparative data means that, for the immediate future at least, treatment choices for advanced PD will be determined by clinical judgement and patient preference. There is an urgent need for well-designed clinical trials to generate reliable data to inform the clinical management of this difficult-to-treat subgroup of PD patients. Ó 2009 Elsevier Ltd. All rights reserved.

Keywords: Levodopa infusion Apomorphine infusion Deep brain stimulation

1. Introduction In most patients, Parkinson’s disease (PD) progresses over many years. It can be considered through four phases (diagnostic, maintenance, complex and palliative) although, in practice, there is much overlap [1]. This review focuses on the more advanced ‘complex’ phase when waning of the pharmacological response and motor complications (fluctuations and dyskinesia) become more prominent. ‘Wearing off’ at the end of a levodopa dose may be considered an early manifestation of transition from the maintenance to the complex stage, evolving into more troublesome motor problems including unpredictable fluctuations (‘‘on–off’’) and dyskinesia. The aetiology relates to progressive striatal denervation and the short half-life (60–90 min) of oral levodopa [2,3]. q The review of this paper was entirely handled by an Associate Editor, Professor Z.K. Wszolek. * Corresponding author. Tel.: þ44 (0) 121 507 4073; fax: þ44 (0) 121 507 5442. E-mail address: [email protected] (C.E. Clarke). 1353-8020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.parkreldis.2009.09.005

The complex stage is challenging to manage. Oral treatment strategies to provide smoother dopaminergic stimulation involve modifying the pharmacokinetics of levodopa (catechol-O-methyl transferase [COMT] inhibition) or dopamine (monoamine oxidaseB [MAOB] inhibition), the use of longer-acting dopamine agonists, or by modifying ‘downstream’ neurotransmitter systems (amantadine). Often, motor fluctuations become increasingly refractory to such treatments. At this stage infusion therapies (apomorphine and intraduodenal levodopa) and stereotactic surgery come into consideration. The rationale for using infusion therapies is to achieve more constant dopaminergic stimulation in the striatum, which more closely mimics the normal physiological state. This allows not only smoother motor control but is thought potentially to ameliorate ‘downstream’ changes in neural pathways responsible for the development of dyskinesia. Apomorphine is a potent dopamine agonist that is ineffective as oral therapy due to extensive hepatic first-pass metabolism.

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Apomorphine can be administered by intermittent subcutaneous injection as ‘rescue’ therapy for unpredictable ‘‘off’’ periods but is more commonly used as a subcutaneous infusion in the management of complex disease. Apomorphine is delivered by a portable syringe driver, usually for 12–16 h per day. The aim is to reduce oral medication as much as possible to avoid pulsatile therapy. In practice, most patients remain on a small dose of levodopa, particularly to cover night-time when the apomorphine infusion is not running. Levodopa in combination with a decarboxylase inhibitor is long established as the most effective drug for treating the motor syndrome of PD. Its effectiveness orally in complex disease is limited by its short half-life and consequent pulsatile action. The effectiveness of tablet or liquid forms of oral levodopa/carbidopa in complex disease may also be impaired because of erratic absorption due to delayed gastric emptying. Levodopa in combination with carbidopa in an intestinal gel formulation (Duodopa, co-careldopa) can be delivered by continuous infusion using a portable pump directly into the duodenum or upper jejunum by a permanent tube via a gastrostomy, with an outer transabdominal tube and an inner intestinal tube. This approach bypasses the stomach and avoids the problems associated with delayed gastric emptying delivering more stable plasma levels of levodopa. As with apomorphine, adjunctive oral therapy is kept to a minimum. Deep brain stimulation (DBS) aims to decrease overactivity in basal ganglia nuclei which occurs as a consequence of PD. Bilateral subthalamic nucleus (STN) stimulation is the currently favoured approach. Electrodes are introduced stereotactically into the subthalamic nuclei, which are then overstimulated. The mechanism of action of DBS is unclear; however, the results of DBS are reductions in ‘‘off’’ time, in dopaminergic medication and in dyskinesia [4]. It is worth noting that all three types of intervention are expensive and require considerable nursing support. For apomorphine and levodopa infusions, help is often required with setting up the delivery device (syringe driver or pump) in the morning, administering additional doses, or stopping the device at night. For DBS, aftercare following neurosurgery will require a hospital stay and the neurologist, nurse or technician will need to calibrate the programmable pulse generator to optimise stimulation over several meetings. As a result, all three interventions carry a significant cost burden which requires formal evaluation with health economics assessments running alongside clinical trials. Guidance published by the UK National Institute for Health and Clinical Excellence (NICE) in 2006 included a review of studies on PD therapy and stated that both apomorphine and surgery may be used in appropriate cases [5]. Levodopa infusion was not available for use in the UK at that time and was therefore not included in the guideline. The objective of this systematic review of the literature is to assess the clinical and cost-effectiveness of currently available treatment options for patients with advanced PD and motor fluctuations in whom available combinations of oral medicinal products have not given satisfactory results or are no longer effective. 2. Methods 2.1. Literature search A systematic search of the literature was performed in March 2009 using PubMed and the Cochrane Library Database. Searches were conducted using combined search terms that included ‘‘Parkinson’s disease’’ AND ‘‘treatment’’, ‘‘deep brain stimulation’’ OR ‘‘apomorphine’’ OR ‘‘levodopa’’ AND ‘‘jejun*’’ OR ‘‘duoden*’’. For DBS and apomorphine, search dates were limited to publications from February 2005 onwards to capture studies published since the development of the NICE 2006 guidelines in the UK. These guidelines included a review of apomorphine and STN studies published before January 2005 (no randomised controlled trials [RCTs] examining STN stimulation or globus pallidus interna [GPi] stimulation, or large GPi case series [N  40] were identified, but STN case series [N  40] were included) [5]. For this systematic review search restrictions were not necessary for levodopa infusion since it was launched after the publication of the NICE 2006 guidelines.

729

We conducted a separate literature search for fully published articles evaluating the cost-effectiveness of these treatment modalities in advanced Parkinson’s disease. Search terms included ‘‘cost analysis’’ OR ‘‘economics’’ OR ‘‘cost-benefit analysis’’ OR ‘‘healthcare costs’’ OR ‘‘hospital costs’’ OR ‘‘drug costs’’. These searches were supplemented by electronic searching of key general (the Lancet, British Medical Journal, Journal of the American Medical Association and New England Journal of Medicine) and neurological (Movement Disorders, Neurology, Parkinsonism and Related Disorders) journals, and by scanning reference lists published in review articles and other clinical reports. 2.2. Selection of studies We considered controlled trials, cohort studies, case-control studies and case series involving advanced Parkinson’s disease patients presenting with motor fluctuations and/or dyskinesia that could not be controlled with oral levodopa and dopamine agonist treatment. At least one arm of the study was required to assess the intervention as monotherapy, although we applied no restrictions on dosing, frequency or length of administration. Studies published in full and in English were included in this review. For apomorphine, studies were included if they used a continuous infusion, to reflect a comparable patient population to those likely to receive DBS or levodopa infusion. Studies relating only to intermittent subcutaneous apomorphine were excluded. For DBS, only non-RCT studies with 40 or more participants were included, and for levodopa and apomorphine infusions, studies of all sizes were included to be consistent with prior application of study inclusion criteria in the NICE guidelines [5]. For DBS studies this ensures more reliable data from larger studies is presented; however, excluding levodopa and apomorphine infusion studies with fewer than 40 participants would have excluded most of the relevant studies on these treatments. The identified studies were also reviewed to verify that they included assessment of outcomes related to motor complications, daily ‘‘off’’ time or Unified Parkinson’s Disease Rating Scale (UPDRS) III motor examination scores; those that did not were excluded. From the search results, the abstracts of potentially relevant studies were screened, with the full paper being obtained if the abstract did not provide sufficient information to determine eligibility for inclusion in the review. All identified cost-effectiveness analyses were included in this review. 2.3. Data extraction and analysis Although no formal assessment of the methodological quality of included studies was undertaken, we recorded information relating to trial design, including method of randomisation and concealment of treatment allocation where available. Studies were grouped according to the level of evidence provided; each study was rated using criteria adapted from the Oxford Centre for Evidence-Based Medicine (Table 1) [6]. Data extracted included UPDRS III (motor score), UPDRS II (activities of daily living [ADL]), and daily ‘‘on’’ and ‘‘off’’ time at the end of the study and change from baseline where available. Information on patient demographics, changes in levodopa requirements, dyskinesia ratings and quality of life were also extracted. Adverse events and cost-effectiveness data were tabulated separately. A meta-analysis of the identified randomised controlled trials (RCTs) was planned, but due to the level of data available this was not possible. Descriptive analysis of the extracted data was performed to review the different treatment modalities.

3. Results 3.1. Description of studies Twenty-seven studies of levodopa infusion, apomorphine infusion or STN stimulation were identified (Table 2) [7–41]. All of the studies found by the search strategy that met the inclusion criteria were included. Only two studies of GPi stimulation met the inclusion criteria; in one study patients treated with GPi stimulation were combined with those treated with STN stimulation for Table 1 Levels of evidence (adapted from the Oxford Centre for Evidence-Based Medicine) [6]. Level 1 Level 2 Level 3

Level 4 Level 5

Randomised controlled trial (RCT) Cohort study (consecutive patients) or low quality RCT Open-label, non-randomised study with historical or other control group or open-label study using convenience or unspecified sample; cohort studies with 5 or fewer patients Observational case series Expert opinion

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C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

analysis [12] and a second STN study included a GPi arm from which some data could be extracted [25]. Twelve studies examined levodopa infusion (three level 1 [7–9], four level 3 [20–23] and five level 4 [28–32] studies), three apomorphine infusion (two level 2 [13,14] and one level 3 [24] studies), and 15 STN stimulation (three level 1 [10–12], five level 2 [15–19] four level 3 [25–27] and three level 4 [33–35] studies). It should be noted that this includes STN studies published since January 2005; there were previously no randomised controlled trials (RCTs) and nine case series (N  40) examining STN stimulation [5]. No GPi RCTs or large case series (N  40) were identified in the NICE 2006 guidance [5]. None of the RCTs compared the three treatment modalities directly. Of the six (level 1) RCTs identified, three examined levodopa infusion (two levodopa/carbidopa intestinal gel versus best medical management and one levodopa/carbidopa duodenal solution versus placebo) [7–9] and three examined STN stimulation versus best medical therapy [10–12]; 481 patients were randomised in these six trials, but the majority were in one surgery trial (N ¼ 255) [12]. There were no RCTs with apomorphine infusion. 3.2. Methodological quality of included studies In view of the lack of rigorous scientific methodology in many of the studies, formal scoring of trial quality was not performed. Table 2 provides relevant descriptive details of the included studies. Of the six RCTs, the method of randomisation (e.g. blocking, random number generator, computer) and concealment of allocation (e.g. central randomisation service) were adequately described in three [9–11]. 3.3. Trials and participants (Tables 2 and 3) The number of patients randomised in the 27 included studies ranged from three to 255, with 1405 participants in total (mean study size 52 patients). In the six RCTs, 471 patients were randomised (mean size 79 patients; range 10–255). The mean length of follow-up in all studies was 55 weeks (range 6 days–4 years). However, the mean length of follow-up varied between the interventions (levodopa infusion 47 weeks; apomorphine infusion 70 weeks; STN stimulation 73 weeks). Mean follow-up in the three RCTs evaluating levodopa infusion was 2 weeks and in the three RCTs of STN stimulation it was 6 [10], 6 [12] and 18 [11] months. Patients entering the studies were young compared with the general population of patients with PD, with very few over the age of 70 years. Most had had the condition for over 10 years, except for one levodopa infusion study and one STN stimulation study with mean disease duration of 7 years. The majority had severe motor complications with an ‘at worst’ Hoehn and Yahr score of 3 or above. 3.4. Efficacy (Table 3) 3.4.1. ‘‘On’’ time increase or ‘‘off’’ time reduction In the three levodopa infusion RCTs, the percentage of the waking day in a functional ‘‘on’’ state was reported as 100%, 80% and 93% at the end of each study, respectively [7–9]. Only two of these studies assessed the time spent in an immobile ‘‘off’’ state at end of study; in one study this was 0% of the waking day [9] and in the other it was 23% of the waking day [7]. In the latter study, ‘‘on’’ time increased by 11% with levodopa infusion compared with control (conventional oral therapy, p ¼ 0.03) and ‘‘off’’ time was decreased by 32% compared with control (p ¼ 0.03) [7]. One-year data from a non-controlled study showed a reduction in ‘‘off’’ time from 39% of the waking day at baseline to 4% at the end of the study, although the actual change was not stated [21].

In the non-controlled apomorphine infusion studies, Katzenschlager et al. reported a 20% improvement in ‘‘on’’ time from baseline, with functionality maintained for 79% of the waking day by the end of the study (p < 0.01 vs baseline) [13]. In the same study there was a 38% decrease in ‘‘off’’ time from baseline, with immobility reduced to 33% of the waking day (p < 0.05 vs baseline) [13], and in a second study there was a 51% reduction from baseline with 12% of the waking day spent in ‘‘off’’ time (p < 0.001 vs baseline) [24]. Garcia Ruiz et al. reported ‘‘off’’ time reduction from 55% of the waking day at baseline to 11% at the end of the study (p < 0.0001), although the actual change was not stated [14]. In the larger surgery RCT, there was a 66% increase in ‘‘on’’ time from baseline to the end of the study, with functionality maintained for 91% of the waking day, and a 41% reduction in ‘‘off’’ time, with immobility reduced to 28% of the waking day. The difference between the surgery and best medical therapy arms was significantly in favour of surgery (p < 0.001) but actual values were not reported [12]. Deuschl et al. reported a 138% increase in ‘‘on’’ time with full mobility for 49% of the waking day, and a 68% decrease in ‘‘off’’ time with full immobility for 13% of the waking day in the STN arm at the end of the study [10]. Again, the difference between the STN and best medical therapy arms was significantly in favour of immediate surgery (p < 0.001) but actual values were not reported [10]. In one non-controlled STN stimulation study a 271% increase in ‘‘on’’ time was reported, with functionality for 64% of the waking day at end of study, and a 56% reduction in ‘‘off’’ time to 23% of the waking day (p < 0.00001 for both vs baseline) [25]. The only non-controlled GPi stimulation study reported a 169% improvement in ‘‘on’’ time from baseline with good mobility for 69% of the waking day at end of study (p < 0.00001 vs baseline) and a 45% reduction in ‘‘off’’ time with bad mobility for 21% of the waking day at end of study (p < 0.002 vs baseline) [25]. 3.4.2. Clinician-rated disability scales One levodopa infusion RCT reported an improvement in UPDRS motor score from 25.5 at baseline to 14.5 at the end of the study (p ¼ 0.06 vs conventional therapy), although absolute change from baseline was not stated. UPDRS ADL score decreased from 16.0 at baseline to 14.0 at end of study [9]. Among the non-controlled studies, Antonini et al. reported no significant change in UPDRS motor score with levodopa infusion in either the ‘‘on’’ or ‘‘off’’ state, while UPDRS ADL score decreased significantly from 12.8 at baseline to 9.4 at end of study (p < 0.01) [22]. Similarly, although Stocchi et al. showed no significant improvement in the UPDRS motor score from baseline to end of study, measured in the ‘‘off’’ state, UPDRS ADL score decreased significantly from 45.0 to 20.3 (p < 0.001) [20]. In other uncontrolled studies, Meiler et al. reported end-of-study UPDRS motor scores in the range 37–60 compared with 49–72 at baseline, and UPDRS ADL scores in the range 7–17 compared with 13–18 at baseline [30]. Raudino et al. reported UPDRS motor scores in the range 19–52 and 34–51, respectively [32]. A recent uncontrolled study showed that 96% of patients undergoing treatment with levodopa infusion experienced an improvement in UPDRS motor score [31]. In the two non-controlled studies of apomorphine infusion reporting UPDRS motor scores, the ‘‘off’’-state score in one study was 28.6 (compared with 42.3 at baseline, p < 0.0001) [14] and in the other it was 32.9 (compared with 42.3 at baseline, p value not stated) [24]. None of the studies identified for apomorphine infusion reported the effect of treatment on UPDRS ADL score. All three surgery RCTs evaluated UPDRS change in each arm of the trial. All reported values are off medication. Schu¨pbach et al. reported a 69% improvement in UPDRS motor score (compared with a 29% worsening in those treated with best medical therapy, p  0.05) and a 28% improvement in UPDRS ADL score to 12.9 at the end of the study (compared with a 27% worsening in the best

Table 2 Characteristics of included studies. Study

Interventions

Design

Participants

Key outcome measures/endpoints

Levodopa/carbidopa solution for duodenal infusion Placebo Duodopa Sinemet CR

Randomised (method not stated) Double-blind, placebo-controlled Follow-up: 8 days

Eligibility: motor fluctuations and dyskinesia despite optimal oral therapy N ¼ 10

‘‘On–off’’ time (Parkinsonian Mobility Scale)

Randomised (method not stated) Follow-up: 6 weeks

Motor performance (25, 27 and 29 of UPDRS)

Duodopa Best medical management

Randomised (computer) Blinded assessment Allocation concealment (central randomisation service) Follow-up: 6 weeks

Eligibility: motor fluctuations despite individually optimised treatment N ¼ 16 Eligibility: motor fluctuations despite individually optimised treatment N ¼ 24

STN Best medical management

Randomisation (paired) Allocation concealment (central randomisation service) Follow-up: 6 months

PDQ-39; UPDRS III (off medication); UPDRS II; Schwab and England scale (on and off medication)

Schu¨pbach 2007 [11]

STN Optimised medical management

Weaver 2009 [12]

DBS (STN or GPi) Best medical management

Randomised (matched pair, computer) Allocation concealment (central randomisation service) Follow-up: 18 months Randomised (method not stated) Blinded assessment Follow-up: 6 months

Eligibility: clinical diagnosis of PD >5 years previously; <75 years of age; presence of limiting motor symptoms or dyskinesias despite optimised medical therapy N ¼ 156 Eligibility: <55 years of age; duration of PD 5– 10 years; H–Y  3; motor fluctuations with ‘‘off’’ periods during >25% of the day N ¼ 20 Eligibility: >21 years of age; H–Y  2; persistent disabling symptoms despite medication; 3 h per 24 h period in ‘‘off’’ state; stable medical therapy for 1 month N ¼ 255

Level 1 evidence Duodenal levodopa infusion Kurth 1993 [7]

Nyholm 2003 [8]

Nyholm 2005 [9]

Level 2 evidence Apomorphine continuous infusion Katzenschlager 2005 Apomorphine continuous [13] infusion

Garcia Ruiz 2008 [14]

Prospective, consecutive cohort analysis using blinded rating of video assessments Follow-up: 6 months

Apomorphine continuous infusion

Retrospective analysis of patient records Follow-up: 19.9 months (mean)

Deep brain stimulation Fraix 2006 [15]

STN

Perriol 2006 [16]

STN

Consecutive cohort with a double-blind, randomised motor evaluation at 3 months (method not given) Follow-up: 12 months Consecutive cohort Follow-up: 12 months

Tir 2007 [17]

STN

Derost 2007 [18]

STN

Analysis of consecutive patients undergoing STN between 1998 and 2003. Follow-up: 12 months Cohort study (with consecutive patients stratified according to age < or 65 years) Follow-up: 24 months

UPDRS II and IV; PDQ-39; neuropsychological tests (MDRS); psychiatric status (CORS)

‘‘On–off’’ time; UPDRS III; UPDRS II

Eligibility: diagnosis of PD, motor fluctuations and dyskinesias refractory to oral medication, scheduled to start CSAI N ¼ 12 Eligibility: severe on–off fluctuations despite optimum oral treatment N ¼ 82

Off hours/day, ‘‘on’’-time duration; UPDRS (items 32 and 33)

Eligibility: levodopa responsive PD complicated by motor fluctuations and dyskinesias N ¼ 95

UPDRS III; neuropsychological tests including MDRS; collection of resource use data including hospitalisations, outpatient visits, auxiliary care, medications etc Relationship between motor scores and cognitive/behavioural modifications; UPDRS III

UPDRS II (ADL), III and IV (dyskinesia); Schwab and England score Subscores of UPDRS III; neuropsychological tests (including MDRS)

(continued on next page)

731

Eligibility: severe, levodopa-induced motor complications despite optimised medical therapy N ¼ 58 Eligibility: >5 years since PD onset; levodopa response >30%. N ¼ 103 Eligibility: severe motor fluctuations and levodopa-induced dyskinesias despite optimised medical therapy N ¼ 87

UPDRS (total and III); daily ‘‘off’’ time; dyskinesia severity

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Deep brain stimulation Deuschl 2006 [10]

‘‘On–off’’ time (%); total UPDRS score; PDQ 39 summary index

732

Table 2 (continued) Study

Interventions

Design

Participants

Key outcome measures/endpoints

Ory-Magne 2007 [19]

STN

Analysis of consecutive patients undergoing STN between 1999 and 2003. Follow-up: 24 months

Eligibility: severe levodopa complications despite optimal oral therapy N ¼ 45

UPDRS II and III

Level 3 evidence Duodenal levodopa infusion Stocchi 2005 [20]

Duodopa

Open-label, prospective evaluation Follow-up: 6 months

UPDRS III (‘‘off’’ and ‘‘on’’); ‘‘on–off’’ time

Antonini 2007 [21]

Duodopa

Open-label, prospective study Follow-up: 12 months

Antonini 2008 [22]

Duodopa

Open-label, prospective evaluation Follow-up: 24 months

Eggert 2008 [23]

Duodopa

Open-label, multicentre study Maximum follow-up: 12 months

Eligibility: severe motor complications while receiving standard oral formulations of levodopa/carbidopa N¼6 Eligibility: H–Y 3; motor fluctuations and dyskinesia not controlled with levodopa and dopamine agonist oral treatment N¼9 Eligibility: H–Y 3; motor fluctuations and dyskinesia not controlled with levodopa and dopamine agonist oral treatment N ¼ 22 Eligibility: motor fluctuations despite individually optimised treatment N ¼ 13

Deep brain stimulation Rodriguez-Oroz 2005 [25] De Gaspari 2006 [24]

STN or GPi Apomorphine continuous infusion or STN

Prospective, non-randomised, matched group Follow-up: 12 months

Eligibility: age <70; presence of motor fluctuations and dyskinesia; H–Y 3; change in motor score>30% between ‘‘off’’ and ‘‘on’’ states N ¼ 25

UPDRS off and on medication; total ‘‘off’’ time in 12 h

Open-label Follow-up: 4 years Prospective, non-randomised, matched group Follow-up: 12 months

Eligibility: presence of >2 features of PD N ¼ 69 Eligibility: age <70; presence of motor fluctuations and dyskinesia; H–Y 3; change in motor score >30% between ‘‘off’’ and ‘‘on’’ states N ¼ 25 Eligibility: motor symptoms despite optimal oral therapy. Control group must have had PD for >5 years N ¼ 99 (control n ¼ 39) Eligibility: marked motor fluctuations and dyskinesia N ¼ 40

UPDRS II and III; dyskinesia score

Smeding 2006 [26]

STN

Non-randomised, case-control (historical control arm) Follow-up: 6 months

Cilia 2009 [27]

STN

Non-randomised, matched case-control Follow-up: 9–26 months

Case studies

Nilsson 2001 [29]

Levodopa (dissolved in 2% ascorbic acid solution) nasoduodenal continuous infusion, and oral carbidopa Duodopa

Case series

Meiler 2008 [30] Devos 2009 [31] Raudino 2009 [32]

Duodopa Duodopa Duodopa

Deep brain stimulation Weaver 2005 [33]

STN/GPi

Level 4 evidence Duodenal levodopa infusion Kurlan 1986 [28]

‘‘On–off’’ time

UPDRS off and on medication; total ‘‘off’’ time in 12 h

UPDRS III

UPDRS III

Improved mobility

Case series Retrospective case series Case series

Eligibility: parkinsonism with severe ‘‘on–off’’ fluctuations resistant to adjustments in the oral levodopa or addition of dopamine agonists N¼3 Eligibility: early onset of PD, long duration of levodopa therapy N ¼ 28 (N ¼ 9 reported in detail) N¼6 N ¼ 75 N¼6

Meta-analysis

Eligibility: not stated

UPDRS II and III;

Movement analyses (PLM test)

Not specified Motor fluctuations; quality of life Not specified

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Apomorphine continuous infusion De Gaspari 2006 [24] Apomorphine continuous infusion or STN

Daily ‘‘on‘‘ time with or without dyskinesia and daily ‘‘off’’ time: UPDRS III and IV; PDQ-39 domains (mobility, activities of daily living, stigma, bodily discomfort) UPDRS (total, I, II, II, IV); PDQ-39

STN

Uncontrolled case series Follow-up: 6, 12 and 24 months

UPDRS II and II

Meta-analysis

Eligibility: presence of >2 clinical features of PD; positive response to levodopa; presence of medication-resistant motor complications; age 80 N ¼ 89 Eligibility: not stated

Kleiner-Fisman 2006 [35]

STN

Level 5 evidence Duodenal levodopa infusion Wolters 2008 [36] Cost-effectiveness studies Deep brain stimulation Spottke 2002 [37]

Duodopa

Expert opinion

N ¼ 21

–

STN

Cohort Follow-up: 12 months

Eligibility: Advanced PD under stable drug therapy N ¼ 16

Sickness Impact Profile; direct healthcare costs; cost-effectiveness using UPDRS scores

McIntosh 2003 [38]

STN

Charles 2004 [39]

STN

Cohort Follow-up: 24 months

Meissner 2005 [40]

STN

Retrospective uncontrolled cohort analysis Follow-up: 24 months

Fraix 2005 [15]

STN

Prospective cohort analysis Follow-up: 12 months

Valldeoriola 2007 [41]

STN Best medical

Open, prospective, longitudinal study Follow-up: 12 months

Eligibility: Advanced, levodopa responsive PD with symptoms inadequately controlled by medications N ¼ 16 Eligibility: motor fluctuations and dyskinesia associated with dopaminergic therapy N ¼ 46 Eligibility: levodopa responsive PD complicated by motor fluctuations and dyskinesias N ¼ 95 Eligibility: advanced PD with severe disability related to motor fluctuations, tremor or dyskinesias not improved by medication N ¼ 29

UPDRS II and III; dyskinesia score

Costing of resources at each stage of surgery (preoperative assessment, surgery, postoperative management/follow-up) Medication costs pre- and post-operatively

Direct healthcare costs; UPDRS III; costeffectiveness UPDRS III; neuropsychological tests including MDRS; collection of resource use data including hospitalisations, outpatient visits, auxiliary care, medications etc UPDRS, AIMS, H–Y, Schwab & England; EQ-5D; direct medical costs; direct non-medical costs; ICER based on total UPDRS and QALY

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Lyons 2006 [34]

733

Study ID

Intervention

Study duration

734

Table 3 Effects on motor complications and quality of life. Age [SD] (range)

Duration of PD, years [SD] (range)

H–Y score (worst) [SD]

‘‘On–off’’ time at end of study

QoL at end of study

II (ADL), score (% change)

III (motor), score (% change)

% of waking day in functional ‘‘on’’ (% change)

% of waking day in ‘‘off’’ phase (% change)

PDQ39score (%change)

NA

93e

23e

NA

83e (difference 11%, p ¼ 0.03 between groups) 80 61 (difference 19%, p < 0.01 between groups) 100b

32e (difference 32%, p ¼ 0.03 between groups) NA

NA

0b

25b

81.3b (p < 0.01)

15b (p < 0.01)

35b (p < 0.01 between groups)

Level 1 evidence (prospective, unblinded, randomised, controlled, multicentre studies unless otherwise stated) Duodenal levodopa infusion 4.4 NA Kurth 1993 Levodopa/ 8 days 51.8 (40–71) 7.3 [3.9]d (double-blind, carbidopa placeboenteral controlled) [7] infusion Conventional oral therapy (N ¼ 10) Nyholm 2003 Duodopa 6 weeks NA NA NA NA [8] (cross-over Sinemet CR at 3 wks) (N ¼ 12) Nyholm 2005 [9]

Duodopa Conventionala (n ¼ 18, per protocol)

Deep brain stimulation Deuschl 2006 STN (n ¼ 78) Best medical [10] (n ¼ 78) Schu¨pbach 2007 [11]

Weaver 2009 [12]

STN (n ¼ 10) Medical treatment (n ¼ 10) DBS (n ¼ 121; STN n ¼ 60, GPi n ¼ 62) Best medical (n ¼ 134)

6 weeks (cross-over at 3 wks)

64b (50–75)

13b,c (5–21) 13b,c (6–18)

4b

6 months

60.5 [7.4] 60.7 [7.8]

13.0 13.8

51% at 4 53% at 4

18 months

48.4 [3.3] 48.5 [3.0]

7.2 [1.2] 6.4 [1.1]

4

6 months

62.4 [8.8]

10.8 [5.4]c

3.4

62.3 [9.0]

12.6 [5.6]c

68b (51–79)

Level 2 evidence (prospective, non-randomised, cohort studies unless otherwise stated) Apomorphine continuous infusion Katzenschlager Apomorphine 6 months 61.3 (51–80) 14.5 (6–23) 2005 [13] continuous infusion (N ¼ 12) Garcı´a Ruiz Apomorphine Mean 67 [11.1] 14.4 [5.7] 2008 [14] continuous follow-up (retrospective) infusion 19.9 months (N ¼ 82) Deep brain stimulation Fraix 2006 STN (N ¼ 95) [15] Perriol 2006 STN (N ¼ 58) [16]

NA

11 (baseline 17.5, change not given) 14 (baseline 16.0, change not given) (p < 0.01 between groups)

14.5 (baseline 25.5, change not given) 22.5 (baseline 36.5, change not given) (p ¼ 0.06 between groups)

13.7 (39) 22.9 (þ4) (p < 0.001 between groups) 12.9 (28) 21.7 (þ27) (p  0.05 between groups) 14.5 (24)

28.3 (41) 46.0 (1) (p < 0.001 between groups) (69) (þ29) (p  0.05 between groups) 30.7 (29)

63e (þ138) 21e (17) (p < 0.001 between groups) NA

17e (68) 46e (no change) (p < 0.001 between groups) NA

31.8 (23) 40.2 (þ0.5) (p ¼ 0.02 between groups) 28.9 (24) 41.9 (0)

91e (þ66)

28e (41)

37.3 (17)

3.3

19.7 (0) (p < 0.001 between groups)

41.6 (4) (p < 0.001 between groups)

66e (0) (p < 0.001 between groups)

58e (0) (p < 0.001 between groups)

44.8 (1) (p < 0.001 between groups)

4

NA

NA

79 (þ20) (p < 0.01)

33e (38) (p < 0.05)

NA

NA

NA

28.6 (baseline 42.3, change not given) (p < 0.0001) Off med

NA

11e (baseline 55.0, change not given) (p < 0.0001)

NA

13.8 (26.8, change not given) 19 (baseline 26.9, change not given)

19.4 (baseline 49.2, change not given) 27.0 (44)

88e (baseline 46, change not given) NA

NA

NA

NA

NA

4b

12 months

57 [8]

14 [5]

NA

12 months

59b (45–73)

14b (4–25)

4

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

UPDRS at end of study

Tir 2007 [17] Derost 2007 [18]

Ory-Magne 2007 [19]

STN (N ¼ 103) STN (N ¼ 87)

STN (N ¼ 45)

12 months 2 years

2 years (n ¼ 39)

58.7 [8.2] (40– 74) 57.4 [4.9] (n ¼ 53)

NA

11.5 [0.6]

2.5 [0.1]

68.8 [2.8] (n ¼ 34)

12.4 [0.7]

2.7 [0.2]

60 [9] (40–73)

13.5 [3.6] (6–23)

3.6 [0.8]

17.2 [4.5]

5

18 [5.5]

NA

Level 3 evidence (open-label, uncontrolled studies unless otherwise stated) Duodenal levodopa infusion Stocchi 2005 Levodopa 6 months 60 [20] methyl ester intestinal infusion (N ¼ 6) 66 [10] Duodopa 1 year Antonini 2007 [21] (N ¼ 9)

Antonini 2008 [22]

Eggert 2008 [23]

Duodopa (N ¼ 22)

Duodopa (N ¼ 13)

Apomorphine continuous infusion (vs STN) De Gaspari Apomorphine 2006 [24] (n ¼ 13) (matched group) STN (n ¼ 12)

Deep brain stimulation Rodriguez-Oroz STN 2005 [25] (n ¼ 49) GPi (n ¼ 20) Smeding 2006 [26] (case control) Cilia 2009 [27] (case-control)

STN (n ¼ 99) Historical control (n ¼ 39) STN (n ¼ 40) Matched control (n ¼ 21)

19 (34) (p < 0.0001) 15.6 (baseline 18.0, change not given) 16.7 (baseline 18.8, change not given) (p ¼ 0.001 between groups) 11.7 (14.2, change not given)

NA

NA

NA

NA

NA

Graphs only, no data given

22.1 (baseline 44.7, change not given)

NA

NA

NA

20.2 (baseline 45.0, change not given) Off state (p < 0.001) 9.7 (29.7; baseline 13.8) (p < 0.02)

77.0 (baseline 78.5, change not given) Off state

78 (change not given) (p < 0.001)

14 (78) (p < 0.001)

NA

(p ¼ NS)

NA

Graphs only, no data given

24.8 (baseline 24.6, change not given) (p ¼ NS)

NA

(9.5-fold reduction; mean reduction from 284 to 30 min) (p < 0.001) NA

NA

NA

11 (baseline 50, change not given) (p ¼ 0.0014)

NA

32.9 (baseline 32.1, change not given) – off APO treatment 15.7 (baseline 33.5, change not given) (p < 0.003)

NA

12 (51) (p < 0.001)

NA

28.6 (50) (p < 0.0001) 31.7 (39) (p < 0.0001) (34)

64 (271) (p < 0.00001) 69 (169) (p < 0.00001) NA

23 (56) (p < 0.00001) 21 (45) (p < 0.002) NA

NA

NA

NA

NA

2 years

NA

NA

NA

1 year

NA

NA

NA

6 months

– [Age at onset 51 (27–57)]

17b (10–24)

4–5

9.4 (baseline 12.8, change not given) (p < 0.01) 9.7 (baseline 13.8, change not given) (p < 0.02) NA

12 months

59 [13]

NA

3

NA

60.5 [6.5]

4 years

6 months

12 months

59.8 [9.8] (38– 75) 55.8 [9.4] (43– 70) 57.9 [8.1]

14.1 [5.9] (5.7–26.8) 14.4 [5.7] (7–26.4) 13.7 [6.1]

63.0 [9.1]

10.4 [4.6]

59.9 [6.7]

13.4 [4.4]

4.3 [0.8] (2–5) 4.0 [0.8 ] (3–5) 3.7 [0.9]

16.9 (43) (p < 0.0001) 19.2 (28) (p < 0.02) NA

29 (43) (p < 0.0001) (45)

(41)

49.2 (baseline 59.5, change not given) (p < 0.005)

4.2 (baseline 39, change not given)

7 (76) (p < 0.001)

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

13.6 [4.4]

NA

Data not available for control NA

NA

19.3 (54.1) 41.1 (þ7.3) (p < 0.01)

(continued on next page)

735

736

Table 3 (continued) Study ID

Intervention

Study duration

Age [SD] (range)

Level 4 evidence (prospective case series unless otherwise stated) Duodenal levodopa infusion Meiler 2008 [30] Duodopa 4–6 days 70.3 [4.7] (rapid switch (N ¼ 6) study) Devos 2009 Duodopa NA 72.7 (retrospective (N ¼ 75) case series) [31] Raudino 2009 Duodopa 10–35 months (56–77) [32] (N ¼ 6)

6 months (median)

GPi (n ¼ 136) Lyons 2006 [34]

Kleiner-Fisman 2006 [35] (review)

STN (N ¼ 89)

STN (N ¼ 959)

Level 5 evidence (expert opinion) Duodenal levodopa infusion Wolters 2008 Duodopa [36] (N ¼ 21)

57.8

H–Y score (worst) [SD]

12.6 [5.9]

3.8 [0.7]

17

UPDRS at end of study

‘‘On–off’’ time at end of study

QoL at end of study

II (ADL), score (% change)

III (motor), score (% change)

% of waking day in functional ‘‘on’’ (% change)

% of waking day in ‘‘off’’ phase (% change)

PDQ39score (%change)

37–60 (baseline 49–72, change not given) 26.8 (96% showed improvement)

NA

(29)

NA

NA

7–17 (baseline 13–18, change not given) NA

NA

NA

NA

(10–20)

4–5

NA

19–52 (baseline 34–51, change not given

NA

10–88 (baseline 22–81, change not given)

NA

NA

NA

14.8 (baseline 27.9, change not given) 17.2 (baseline 28, change not given) 13.7 (35.4)

22.8 (54.3)

NA

NA

NA

24.4 (41.3)

NA

NA

NA

55 NA

(40.1)

6 months (n ¼ 89) 12 months (n ¼ 83) 24 months (n ¼ 43) 14.8 months (6 mo–5 yrs)

59.7 [9.9]

12 [4.9]

59.2 [10.4]

12.7  5.1

14.6 (31.8)

25.2 (39.9)

57.2 [10.7]

12.5  5.4

14.5 (33.2)

25.6 (39.3)

58.6 [2.4] (53– 63)

14.1 [1.6] (8.4–16.4)

3.9

(49.9)

(52)

(68.2)

NA

(34.5)

Mean 5.3 months

65 (50–69)

17 (7–31)

NA

NA

NA

48 (baseline 39, change not given)f p ¼ ns

8 (baseline 31, change not given)f p ¼ significant although value not given

NA

p values are for baseline comparisons unless otherwise stated; for UPDRS, ‘‘on’’ or ‘‘off’’ state at baseline and time of assessment is stated where this information is available from the publication; DBS data comparisons are between off medication at baseline and off medication, on stimulation at follow-up, unless otherwise stated; proportion of daily time spent ‘‘on’’, ‘‘off’’, or ‘‘on’’ with dyskinesias was determined through the use of patient diaries unless otherwise stated; primary endpoint data for RCTs are highlighted in grey. Abbreviations: ADL, activities of daily living; CR, controlled release; GPi, globus pallidus interna; H–Y, Hoehn and Yahr; NA, not available; PD, Parkinson’s disease; PDQ, Parkinson’s Disease Questionnaire; QoL, quality of life; SD, standard deviation; STN, subthalamic nucleus stimulation; UPDRS, Unified Parkinson’s Disease Rating Scale. a Starting with oral and, in some cases, combined with subcutaneous pharmacotherapy. b Median value. c Duration of levodopa treatment rather than disease duration. d Duration of ‘‘on–off’’ fluctuations. e Calculated from the number of hours at that rating as a proportion of 12 h ‘awake’ time. f Estimated from bar chart, functional ‘‘on’’ defined as Treatment Response Scale 1 to þ1, ‘‘off’’ defined as 3 to 2.

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Deep brain stimulation Weaver 2005 STN [33] (n ¼ 565)

Duration of PD, years [SD] (range)

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

medical therapy arm, p  0.05) [11]. Deuschl et al. reported a 41% improvement in UPDRS motor score (48.0 at baseline to 28.3 at end of the study) vs a 1% improvement in the best medical therapy arm (p < 0.001); a 39% improvement in UPDRS ADL score (22.5 at baseline to 13.7 at end of the study) was seen vs a 4% worsening in the best medical therapy arm (p < 0.001) [10]. In the largest RCT, a 29% decrease in UPDRS motor score was reported, with a score of 30.7 at the end of study in the surgery arm (compared with a 4% improvement in the best medical therapy arm, p < 0.001); the UPDRS ADL score decreased by 24% to a score of 14.5 (compared with no change in the best medical therapy arm, p < 0.001) [12]. In the non-controlled STN stimulation studies, UPDRS motor scores improved by 34–54% from baseline to end-of-study [16– 18,25–27,34] and improvements in the UPDRS ADL score of 32–43% were observed in three of these studies [17,25,34]. Two further uncontrolled studies reported baseline and end-of-study UPDRS motor scores without stating the actual change; in one, the end-ofstudy score was 22.1 compared with 44.7 at baseline [19] and in the other the end-of-study score was 19.4 compared with 49.2 at baseline [15]. No p values were provided for these comparisons. A number of studies reported baseline and end-of-study UPDRS ADL scores: 15.6 at end of study compared with 18.0 at baseline [18], 11.7 compared with 14.2 [19], 13.8 compared with 26.8 [15], and 19.0 compared with 26.8 [16]. In the one non-controlled GPi stimulation study, UPDRS motor score improved by 39% and UPDRS ADL score by 28% (both p < 0.0001 vs baseline) [25]. 3.4.3. Patient-rated quality of life For levodopa infusion, one RCT reported a median end-of-study PDQ 39 Summary Index (SI) score of 25 (compared with 35 for conventional therapy, p < 0.01) [9] and one non-controlled study reported an improvement in the PDQ 39 SI score from 59.5 at baseline to 49.2 at end of study (p < 0.005) [22]. None of the identified studies for apomorphine infusion evaluated PDQ 39 SI. All three RCTs for DBS included assessment of PDQ 39 SI score. Schu¨pbach et al. reported a 24% improvement (p value not stated) [11], Deuschl et al. a 23% improvement (compared with a 0.5% worsening with best medical therapy, p ¼ 0.02) [10] and Weaver et al. reported a 17% improvement for surgery (STN or GPi) compared with a 1% improvement for best medical therapy (p < 0.001) [12].

3.5. Safety (Table 4) 3.5.1. Adverse events Details of adverse events were limited in the RCTs and the lower level studies. Only one RCT of levodopa infusion [9] and one of DBS [10] fully reported adverse events. From the data available it is not possible to obtain a reliable impression of the adverse event profile of any of the treatments. In two of the larger levodopa infusion studies (N ¼ 24 and 13) [9,23] adverse events occurred in around 70% of patients and included dyskinesia (17%) and somnolence (18%). Administration site problems with levodopa infusion occurred in 30 of 156 patients (19%) [22,23,30,31], but this may be an underestimate since these were not reported in all studies. Whether adverse events were serious was recorded in only one levodopa infusion study at a frequency of 8% [9]. Adverse events were reported in only two studies with apomorphine infusion [13,14]. One of these reported the overall frequency of adverse events at 84% [14]. These included somnolence (29%), hallucinations (18%), and nausea (6%) [14]. Administration-site reactions occurred in 87% [14] and 92% [13] of patients

737

on apomorphine infusion. Neither of the two apomorphine infusion studies reported whether adverse events were serious or not. The overall frequency of adverse events following STN stimulation was 50 and 53% in the two studies which reported this [10,25]. Details of dopaminergic and Parkinson’s disease-related adverse events were rarely reported; only the larger RCT reported nausea (4%) and hallucinations (4%) [10]. The total UPDRS score (part 4) improved by 6 points in one uncontrolled study (p value not stated) [19] and the Fahn–Obeso dyskinesia scale improved by 3.6 points from baseline with STN stimulation in the larger RCT (p value not stated) [10]. Surgical and device-related complications had occurred by 6 months follow-up in 22% of cases in the one STN stimulation RCT [10] and in 18.9% in the larger RCT [12]. Serious adverse events occurred in 13% of patients who underwent STN stimulation in the RCT [10], in 49% in the larger surgery RCT [12] and in 2% [15], 4% [19], and 24% [17] in the level 2 studies. Adverse events were reported in 35% of patients treated with GPi stimulation; surgery-related complications were recorded in 5% of patients [25]. 3.5.2. Patient withdrawal Withdrawal from treatment can only be reliably recorded from prospective studies, so this was not available in level 3 and 4 studies. The all-cause withdrawal rate in the levodopa infusion RCT was 25%, with 4% due to adverse events and presumably 21% due to lack of efficacy [9]. In the two level 2 studies with levodopa infusion, the withdrawal rate was 23%, mostly due to adverse events [22,23]. No data on withdrawal rates from apomorphine infusion were provided. Withdrawal rates from STN stimulation are not recorded in detail: 10% had the STN stimulator withdrawn for 6 months in one RCT [10], while 5% of the 87 patients were withdrawn in one level 2 surgery study [18]. No data on withdrawal rates from GPi stimulation were provided. 3.6. Cost-effectiveness (Table 5) No studies of the cost-effectiveness of levodopa or apomorphine infusions or GPi stimulation were found. Six studies examined the cost-effectiveness of STN stimulation, but five of these were cohort or retrospective studies with no best medical therapy control arms. The one study with a control arm was small (n ¼ 29), but did provide an incremental cost-utility analysis [41]. These studies showed considerable variation in the cost of STN stimulation surgery (V11,807–V41,276; £9371–£32,759; $17,363–$60,700)1 [15,38,40,41]. The one study with a best medical therapy control arm reported the cost-utility of STN stimulation at V34,389 per quality-adjusted life year (QALY; £27,293; $50,572)1 [41]. This was calculated over a follow-up period of only 12 months which may not have taken into account the long-term costs of STN stimulator system revisions. 4. Discussion To our knowledge, this is the first systematic review comparing the efficacy and tolerability of all three treatment options for these patients: DBS, apomorphine infusion and jejunal levodopa infusion. Consistent with the EMEA guideline on the clinical investigation of medicinal products in the treatment of PD [42], improvements in motor symptoms and activities of daily living were the principal endpoints assessed. Although no RCTs compared the three treatment modalities directly, RCTs identified for jejunal levodopa

1

Exchange rate as of 21/8/08: 1US$ ¼ V0.68, £1 ¼ V1.26.

Study

738

Table 4 Adverse events data. Total AEs, % (n)

Dyskinesia Dyskinesia scales, change from as AE, % (n) baseline (points) UPDRS IV Total Items 32 þ 33

Level 1 evidence Duodenal levodopa infusion Nyholm 2005 [9] Duodopa (n ¼ 24) Conventional (n ¼ 21)

71 (17) 17 (4) 76 (16) 33 (7)

NA NA

NA NA

NA NA

NA NA

NA NA

18 (3) 14 (4)

NA NA

NA NA

NA NA

8 (2) 5 (1)

25 (6)

NA NA

4 (1)

50 (39) (20) 64 (50) (41)

NA NA

NA NA

3.6 0

4 (3) NA

NA NA

NA NA

4 (3) NA

(4) (7)

22 (17) NA

13 (10) 10 (8) 4 (3) NA

NA NA

NA NA

(659) (236)

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

18.9 0

40 (49) NA 11 (15) NA

NA NA

NA NA

NA

NA

NA

NA

NA

NA

NA

NA

92 (11)

NA

NA

NA

NA

NA

NA

NA

6 (5)

NA

29 (24)

18 (15)

NA

87 (72)

NA

NA

NA

0

29 (29) NA

NA

NA

NA

NA

NA

NA

NA

2 (2)

5 (5)

2 (2)

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

24 (25)

24 (25) NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

3.8 (2)

NA

5 (4)

NA

NA

NA

NA

6.4 NA

NA

NA

NA

NA

NA

NA

11 (5)

4 (2)

NA

NA

4 (2)

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

NA NA

5 (1) NA

NA NA

5 (1) 69 (9)

NA NA

23 (5) NA

NA NA

14 (3) 23 (3)

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

3 (2) [type of DBS not stated]

NA NA

Level 2 evidence Apomorphine continuous infusion Katzenschlager 2005 NA NA [13] (n ¼ 12) Garcı´a Ruiz 2008 84 (69) NA [14] (n ¼ 82) Deep brain stimulation Fraix 2006 [15] (STN n ¼ 95) Tir 2007 [17] (STN n ¼ 103) Derost 2007 [18] (STN n ¼ 87) Ory-Magne 2007 [19] (STN n ¼ 45)

Level 3 evidence Duodenal levodopa infusion Antonini 2008 [22] (n ¼ 22) NA Eggert 2008 [23] (n ¼ 13) 69 (9) Deep brain stimulation Rodriguez-Oroz 2005 [25] (STN n ¼ 49; GPi n ¼ 20)

53 (26) 35 (7)

12 (6) 5 (1)

Level 4 evidence Duodenal levodopa infusion Kurlan 1986 [28] (n ¼ 3) Nilsson 2001 [29] (n ¼ 28) Meiler 2008 [30] (n ¼ 6) Devos 2009 [31] (n ¼ 91)

NA NA NA NA

NA NA NA NA

NA NA NA NA

NA NA NA NA

NA NA NA NA

NA NA NA NA

NA NA NA NA

NA NA NA NA

33 (1) NA NA NA

NA NA NA 2.2 (2)

NA 21 (6) 33 (2) 18 (18)

NA NA NA NA

33 (1) 21 (6) 17 (1) NA

NA 12 (3) NA 1.1 (1)

33 (1) NA NA 3 (3.2)

Level 5 evidence Duodenal levodopa infusion Wolters 2008 [36] (n ¼ 21)

NA

NA

NA

NA

NA

NA

NA

NA

NA

NA

62 (13)

NA

NA

NA

NA

Abbreviations: AE, adverse event; NA, not available; UPDRS, Unified Parkinson’s Disease Rating Scale.

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Deep brain stimulation Deuschl 2006 [10] STN (n ¼ 78) Medical (n ¼ 78) Weaver 2009 [12] DBS (n ¼ 121) Medical (n ¼ 134)

Nausea, Vomiting, Somnolence, Hallucinations, Psychosis, Administration-site Serious Withdrawal rate, % (n) % (n) % (n) % (n) % (n) % (n) reactions OR AEs, % surgery-related (n) Other scales All-cause Due to lack Due to complications, % (n) of efficacy AEs

Table 5 Analyses of cost-effectiveness. Study ID

Age (range or SD)

No. years since diagnosis years (range)

Hoehn and Yahr score (worst)

STN (n ¼ 9)

1 year

56.1  8.5

10.8  3.9

4.4  0.7

STN

5 years

STN (n ¼ 16)

2 years

57  10

Meissner 2005 [40] [retrospective, uncontrolled cohort]

STN (n ¼ 46)

2 years

58.6  1.0

16.0  0.7

V11,807

Fraix 2005 [15] [prospective cohort]

STN (n ¼ 95)

1 year

57  8

14  5

V27,625

Valldeoriola 2007 [41] [prospective comparison]

STN (n ¼ 14) Best medical management (n ¼ 15)

1 year

59.9  6.8 63.8  6.4

16.9  1.2 13.6  1.2

Costs per patient Device and procedure

Medication

UPDRS Direct medical (except medication)

Direct nonmedical

V18,456 V0

Change from baseline to study end (points)

ICER (Cost per unit of improvement)

V20,410

–V21.13 (total score)

V920

–V4 (UPDRS III)

V979

–V21.5 þV10.2 (total score)

V239.8

QALY

ICER (Cost per QALY)

0.76 0.54

V34,389

V41,276 (£32,526)a

V26,525 (£20,904)a

3.7 3.8 (median)

QALYs

Total

V2626 ($4128)a pre- and V4332 ($6811)a post-operation V11,230, 1 yr before; V4449, 2 yrs after surgery

V3799 V13,208

V1280 V4017

V4079 V2787

V15,991, before; V7223, 2 yrs after surgery V36,904– V10,087 before and V1673 after surgery V27,614 V20,013

C.E. Clarke et al. / Parkinsonism and Related Disorders 15 (2009) 728–741

Study duration

Spottke 2002 [37] [cohort] McIntosh 2003 [38] Charles 2004 [39] [cohort]

Intervention

Abbreviations: ICER: incremental cost-effectiveness ratio; QALY: quality-adjusted life year; STN: subthalamic nucleus stimulation; UPDRS, Unified Parkinson’s Disease Rating Scale. Exchange rate as of 21/8/08: 1US$ ¼ V0.68, £1 ¼ V1.26. a Denomination used in publication.

739

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infusion or DBS demonstrate a significant benefit for these therapies compared with best medical management in terms of improvements in the proportion of the waking day in a functional ‘‘on’’ state, ADL and motor scores [7–12]. Where assessed, improvements in such clinical assessments appeared to correlate with improvements in patient-rated quality of life compared with best medical management [9–12]. The DBS studies included a much larger number of patients than the jejunal levodopa infusion studies. No RCTs were identified for apomorphine infusion. Although only larger non-RCT DBS studies (40 participants) were assessed as a way of obtaining more reliable data and minimising risk of random errors, this was not possible for the apomorphine and levodopa infusion studies, most of which had fewer than 40 participants. In view of the limited information available from RCTs and the small numbers of patients commonly involved, we felt it was important to consider data from studies with less rigorous designs than RCTs. Indeed, the EMEA guideline on clinical trials in small populations states that ‘‘systematic review of all data (including data from other sources) will add weight to the evidence. Also combined analysis of individual case reports or observational studies should be considered’’ [43]. Where statistical analyses were performed, significant improvements in motor symptoms, ADL, proportion of waking day in a functional ‘‘on’’ state and proportion of waking day in the ‘‘off’’ state from baseline were observed for all three therapies in the majority of studies [13,14,17,18,20,23–25]. However, it should be noted that reliable interpretation of these data is significantly limited by methodological inconsistencies. For example, only three RCTs of individual treatments adequately described the method of randomisation and concealment of allocation; one for levodopa infusion and two for STN [9–11]. Furthermore, there was inconsistent reporting of endpoints, difficulties in determining whether assessments were made in the ‘‘on’’ or ‘‘off’’ state and many studies did not document absolute changes from baseline to end of study in the parameters assessed. As expected, many of the included studies were small and there was therefore a risk of random errors. Adverse events were not adequately reported in the majority of included studies and it was therefore not possible to obtain a reliable comparative tolerability profile of the different therapies. Although total adverse events reported appeared to be higher in studies of levodopa infusion and apomorphine infusion compared with DBS, insufficient reporting of the types of adverse events and whether or not they were classified as serious precludes further comment on the clinical significance of this observation. In the age of limited healthcare resources, cost-effectiveness as well as clinical effectiveness needs to be assessed. Therefore, we evaluated all cost analyses identified. Unfortunately, no studies of the cost-effectiveness of jejunal levodopa infusion, apomorphine infusion or GPi stimulation were found. Among the STN studies identified, there was considerable variation in associated costs, which related in part to the reimbursement systems within the different European countries where the studies were conducted. In addition, across all treatments there was limited data addressing costs for nursing, aftercare/follow-up management, replacement parts and complications associated with the therapies. As all three therapies require nursing and additional support, this needs to be fully costed and included as part of the healthcare assessment of these therapies. While acknowledging the limitations of this systematic review, imposed by the lack of high-quality evidence and inconsistent reporting of endpoints, our findings suggest that each treatment modality can provide additional benefit to those patients in whom best medical management is no longer effective. These data do not, however, enable us to conclude which treatment modality is the most efficacious, well-tolerated or cost-effective. As such, treatment choices must be determined by considering each individual’s history

of disease, age, co-morbidities and the risk of side effects. Although the patients suitable for apomorphine infusion, jejunal levodopa infusion and DBS may have similar characteristics, there are considerable differences in the contraindications for each modality; infusion techniques can be applicable for a relatively large population of PD patients with advanced motor fluctuations, while DBS is suitable for a subgroup of such patients who are relatively young and do not have dementia or psychiatric vulnerability (e.g. depression, anxiety). Furthermore, the differences in the ways in which these treatments are administered provide an opportunity for patient preference to form an important part of the decision-making process. Individualisation and tailoring of treatment is therefore important. In conclusion, clinical judgement remains the only tool to determine whether DBS, apomorphine infusion or levodopa infusion would be of greatest benefit to a particular patient with advanced PD and complex motor symptoms. Where possible, patient preference should form a significant part of the decisionmaking process. Ultimately, there is an urgent need for welldesigned clinical trials to generate reliable data that can help to inform the clinical management of this difficult-to-treat subgroup of PD patients. Although an RCT comparing the three treatment modalities is desirable in principle, contraindications to DBS would likely severely limit the number of patients who could be randomised between all three therapies, thus limiting the ‘generalisability’ of the results. Given the possibility that differences in efficacy between the three treatments could be quite small, there may be greater value in future RCTs comparing treatment-related adverse events and quality of life as the primary outcome measures, rather than changes in daily ‘‘on’’ and ‘‘off’’ time and UPDRS scores. Conflict of interests CC reports receiving consulting fees, honoraria, and educational grants from Britannia, Medtronic, and Solvay; DG reports receiving honoraria for lecture fees from Solvay; PW reports receiving honoraria from Britannia Pharmaceuticals and Solvay for consulting work; and DS reports receiving honoraria and consultancy fees from Solvay Pharmaceuticals. Acknowledgements The authors thank Helena Williams and Rosemary Washbrook, medical writers at Lucid, for their assistance in drafting the review. Editorial development was funded by Solvay Healthcare. References [1] Thomas S. Parkinson’s aware in primary care. Elder Care 1999;11:46. [2] Olanow CW, Obeso JA. Preventing levodopa-induced dyskinesias. Ann Neurol 2000;47:S167–76 [discussion S76–8]. [3] Chase TN, Oh JD. Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications. Ann Neurol 2000;47:S122–9 [discussion S9–30]. [4] Pahwa R, Factor SA, Lyons KE, Ondo WG, Gronseth G, Bronte-Stewart H, et al. Practice parameter: treatment of Parkinson disease with motor fluctuations and dyskinesia (an evidence-based review). Report of the quality standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:983–95. [5] National Institute for Health and Clinical Excellence. Parkinson’s disease: diagnosis and management in primary and secondary care, http://www.nice. org.uk/nicemedia/pdf/cg035niceguideline.pdf; June 2006 [accessed 07.08.08]. [6] Oxford Centre for Evidence-Based Medicine. Levels of evidence, http://www. cebm.net/levels_of_evidence.asp#levels [accessed 07.08.08]. [7] Kurth MC, Tetrud JW, Tanner CM, Irwin I, Stebbins GT, Goetz CG, et al. Doubleblind, placebo-controlled, crossover study of duodenal infusion of levodopa/ carbidopa in Parkinson’s disease patients with ‘on–off’ fluctuations. Neurology 1993;43:1698–703. [8] Nyholm D, Askmark H, Gomes-Trolin C, Knutson T, Lennernas H, Nystrom C, et al. Optimizing levodopa pharmacokinetics: intestinal infusion versus oral sustained-release tablets. Clin Neuropharmacol 2003;26:156–63. [9] Nyholm D, Nilsson Remahl AI, Dizdar N, Constantinescu R, Holmberg B, Jansson R, et al. Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005;64:216–23.

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