Abstract
Parkinson’s disease (PD) is a long term disorder affects the central nervous system and we aim to determine the relative efficacy of the current available drugs used in PD. Firstly, we performed a systematic review in current literature and eligible studies were retrieved from online databases, relevant data were extracted. Efficacy of these medications was assessed by different Unified Parkinson’s Disease Rating Scales (UPDRS). Mean difference (MD) and odds ratio (OR) were produced by pairwise or network meta-analysis (NMA). Finally, we performed a cluster analysis for the included medications with respect to their surface under the cumulative ranking curve (SUCRA). Pairwise meta-analysis suggests that selegiline had a higher ranking in UPDRS II, UPDRS III and UPDRS total than bromocriptine and levodopa. Selegiline was more tolerable than bromocriptine (OR = 0.62, CI: 0.39 to 0.98) and pramipexole was less tolerable than levodopa (OR = 1.43, CI = 1.00 to 2.04). Results of NMA indicate that patients with levodopa, pramipexole, ropinirole and selegiline exhibited a significantly improved UPDRS III than those with lazabemide. To sum up, levodopa, selegiline, ropinirole and rotigotine were recommended for PD patients as they appeared relatively high efficacy and tolerability.
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Introduction
Parkinson’s disease (PD) is a chronic neurodegenerative disorder accompanied with several cardinal motor characteristic symptoms including resting tremor, postural instability, rigidity and bradykinesia. Previous studies have proved that PD was a result of the depletion of dopaminergic neurons in substantianigra1. In addition, age per se is a key factor that affects PD’s pathogenesis and progression by changing cellular processes and functions that related with neurodegeneration2.
PD is one of the most common neurodegenerative diseases ranking only second to Alzheimer’s disease3. According to a rough estimation performed by Twelves et al., incidence of PD around the world was around 16–19 per 100,000 people per year, with highest incidence in males aging between 70 and 79 years4. Since population worldwide is aging gradually, it is predicted by Dorsey et al. that the population of patients affected by PD will double in 20305. Apart from the high prevalence rate among elder males, PD is also characterized with a high mortality. In a 20 years follow-up of 136 patients diagnosed with new-onset PD, a high mortality of 74% was observed and dementia occurred in 83% of the remaining survivors6.
So far, all treatments for PD were aimed at alleviating its clinical symptoms and improving the life quality of patients and no curative therapy has been developed to reverse the underlying neurodegenerative process7. Levodopa, dopamine agonists (DA) and monoamine oxidase type B inhibitors (MAOBI) are mainstream drugs that are widely used as first-line treatments of PD. Among them, levodopa performed best in symptomatic control and it guaranteed at least 50% improvement in symptomatic for a period of 2 to 3 years8. However, levodopa would cause increased dyskinesia, motor fluctuations and other adverse effects in the long term9,10. To prolong the beneficial effect of motor symptomatic control, levodopa is often combined with DA or MAOBI as adjunctive therapy for all-stage PD patients. DA, such as bromocriptine, cabergoline, pergolide, pramipexole, ropinirole and rotigotine, is a class of drugs that act on D2 receptors and work well in controlling motor fluctuations7. Apart from acting as an adjunct therapy to levodopa, it’s also widely used as monotherapy for PD in early stages to delay the utilization of levodopa therapy11. Monoamine oxidase type B (MAOB) is the leading enzyme regulating concentrations of neurotransmitters such as acetylcholine and dopamine that are related with emotion, movement and cognition in human brain12. In clinical trials, its inhibitor has been used to down-regulate the degree of on-off motor fluctuations13. Rasagiline and selegiline are both selective and irreversible MAOBI and now used as anti-Parkinson drug or adjunct to levodopa, wherein former one is more potent in vivo13,14. Besides, lazabemide is also a drug of MAOBI. Similarly, their adverse motor effects such as dizziness, wearing-off, on-off phenomena and insomnia also raised concerns.
Tough numerous placebo-controlled trails have been implemented to assess efficacy of anti-Parkinson drugs, no comprehensive comparisons for efficacy and tolerability among all available treatments were conducted. As such, present study was designed to make comparisons of monotherapy’s efficacy and tolerability among ten drugs mentioned above by combining evidence from previous randomized controlled trials (RCTs).
Results
Study characteristics
As presented in Figure S1, 110 publications involving 24,864 participants were finally included in the present study after screening 1,154 publications according to the inclusion criteria13,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118,119,120,121,122,123. Baseline characteristics were shown in Table 1. As we can see, all these studies were designed as RCTs and most of them were double-blind RCTs. Patients were diagnosed as either early or advanced PD and most of them were male above 60. Besides, we draw a network of included trials in Fig. 1, from which we observed that most RCTs had taken placebo as the control group. Among all interventions, Pramipexole, Ropinirole, Levodopa and Rasagiline were involved in most studies and had relative bigger sample sizes.
Each node represents a therapy of PD, the number beside the nodes represents the number of people involved and the number between two nodes represents the number of study involved in the head-to-head comparison.
Meta-analysis results for pair-wise comparisons
Meta-analysis results for pair-wise comparisons were shown in Table 2. We found that lazabemide exhibited a worse efficacy with respect to UPDRS II compared with placebo (MD = 0.82, CI: 0.29 to 1.34). Patients with levodopa, pramipexole, ropinirole, rotigotine and selegiline all functioned better with respect to UPDRS II and III than those with placebo. With respect to UPDRS total, lazabemide also functioned worse than placebo (MD = 1.88, CI: 0.57 to 3.19) while bromocriptine, levodopa, rasagiline and selegiline functioned better. Besides, selegiline had a higher score in UPDRS II, UPDRS III and UPDRS total than bromocriptine and levodopa. As for withdrawal, only rotigotine had a significant lower withdrawal rate than placebo. Besides, selegiline was more tolerable than bromocriptine (OR = 0.62, CI: 0.39 to 0.98) and pramipexole had a higher withdraw rate than levodopa (OR = 1.43, CI = 1.00 to 2.04).
Network meta-analysis results
As we can see in Table 3 and Figures S2–5, for UPDRS II, levodopa, pramipexole, ropinirole, rotigotine and selegiline exhibited increased efficacy compared to placebo and lazabemide All interventions except for cabergoline, lazabemide, pergolide and rasagiline exhibited an increased efficacy compared to the placebo with respect to UPDRS III. Patients with levodopa, pramipexole, ropinirole and selegiline exhibited a significantly improved UPDRS III than those with lazabemide. Our NMA suggests that only patients with selegiline exhibited significantly improved UPDRS total than those with placebo (MD = −6.04, CrI: −11.07 to −0.83). On the other hand, patients with levodopa or ropinirole exhibited a lower risk of withdrawals compared to those with placebo and bromocriptine (ORs < 1). Finally, selegiline appeared to have higher withdraw rate than levodopa, ropinirole and rotigotine with respect to the likelihood of withdrawals (OR = 2.43, CrI: 1.42 to 4.23; OR = 2.17, CrI: 1.27 to 3.84; OR = 1.93, CrI: 1.08 to 3.51).
Cumulative ranking probability as a ranking scheme
Table 4 and Figure S6 showed the cumulative ranking probability of all interventions based on each outcome. Three drugs including ropinirole, pramipexole, and selegiline ranked first in UPDRS II, III and total (with the value of 0.773, 0.777 and 0.918 respectively, and levodopa had the highest rank in withdraw rate. Besides, selegiline ranked the first in UPDRS total but the last in withdrawal. Levodopa and ropinirole had a high ranking when taking withdrawals into consideration. Besides, lazabemide was a mild intervention with both low efficacy rank and withdrawal rate. Cluster analysis presented results above in a more intuitional way (Fig. 2). Interventions with the same level of SUCRA values are displayed in the same color. Levodopa, ropinirole and rotigotine fall into the group with both the most favorable SUCRA values and tolerability as well.
The plot is based on cluster analysis of surface under the cumulative ranking curves (SUCRA) values. Each plot shows SUCRA values for two outcomes. Each color represents a group of treatments that belong to the same cluster. Treatments lying in the upper right corner are more effective and safe than the other treatments.
Consistency
In node-splitting plot (Figure S7), all P-values are higher than 0.05, which indicated a relatively satisfactory consistency between direct and indirect evidence. In heat map (Fig. 3), consistency between direct evidence and NMA results in UPDRS II and withdrawal was well-pleasing. However, there appeared to be some significant inconsistency between direct and indirect evidence in UPDRS III and UPDRS total.
The size of the gray squares indicates the contribution of the direct evidence (shown in the column) to the network evidence (shown in the row). The colors are associated with the change in inconsistency between direct and indirect evidence (shown in the row). Blue colors indicate an increase of inconsistency and warm colors indicate a decrease.
Discussion
This study made a comprehensive comparison for the tolerability and efficacy among anti-Parkinson drugs by using a network meta-analysis. Interventions were grouped into placebo, DA (Pramipexole, Ropinirole and Rotigotine), MAOBI (- Rasagiline and Selegiline) and Levodopa. Efficacy outcomes included unified PD rating scale (UPDRS) II, UPDRS III and UPDRS total. Taking tolerability, efficacy and adverse effect into consideration, we also examined withdraw rate, treatments with high withdraw rate means lacking of efficacy, safety or easy to become tolerant. To our knowledge, this is the first study that well explored the efficacy and tolerability ranking of these three types of drugs for Parkinson with a great range of outcomes included.
Levodopa is an intervention that is widely used in clinical trials with good control of symptoms of PD. Noticeably, levodopa is one of the best tolerated treatments for PD, particularly in the elderly patients124. Our research indicated the same result that levodopa ranked high in UPDRS II and III, and maintained a very low withdraw rate, which possessed a very favorable balance between efficacy and tolerability and worthy of recommendation. However, it may still cause several long-term adverse events including motor complications and dyskinesia125.
The efficiency of DA in reducing motor fluctuations and dyskinesias has been reported by previous studies126,127. For instance, Rascol et al. found that patients with early PD can be well controlled with a low risk of dyskinesia by an initial therapy of ropinirole, an agent of DA, alone. Also, a levodopa-controlled trial conducted by FulvioBracco et al. suggested that patients with PD were in a lower risk of motor fluctuations when treated with cabergoline, another agent of DA, though the relative safety was at the expense of a mildly improved clinical symptom24. Thus, these drugs were usually added into levodopa to weaken its adverse effects in clinical trials.
Compared to levodopa, MAOBI was found to decrease the incidence of disability during the treatment and motor fluctuations without any notable mortality rate or adverse effects128. Whereas, this meta-analysis conducted by Ives N.J. et al. was short of direct comparisons between MAOBIs and other types of anti-Parkinson drugs and thus was not sufficient.
Though our results were consistent with most previous trials, there still exist several flaws. One of the limitations in this study is that we only research on the monotherapy for PD. However, in clinical trials, it’s common that these drugs were applied together to offset the corresponding adverse effects or the low efficacy rate raised by monotherapy. Besides, some other influence factors such as dosages, design and sample size may affect the accuracy and reliability of our results. For this, more clinical trials in comparisons of these interventions are in desperate need.
In our results, according to SUCRA, four drugs including levodopa, pramipexole, ropinirole and selegiline all had a well performance in UPDRS II and UPDRS III. And among them, selegiline had a highest UPDRS total and highest withdraw rate. Levodopa and ropinirole had a higher ranking when withdrawals were taken into consideration. Although lazabemide was a mild intervention with low efficacy rank and withdrawal rate, it has not been introduced in the market and not available for the patients. Besides, in cluster analysis, levodopa, ropinirole and rotigotine steadily ranked first in view of three endpoints including UPDRS II, UPDRS III and withdrawal. The network meta-analysis integrated evidence from 110 independent RCTs and thus provided an accurate results and smaller random errors.
In conclusion, levodopa, selegiline, ropinirole and rotigotine were recommended for PD patients for their relatively high efficacy and tolerability. If necessary, an appropriate composition of these drugs will perform well with a relative low risk of adverse effects and a high efficacy.
Methods and Materials
Search strategy
Publications in PubMed, Embase and Cochrane Library were retrieved without language restrictions. Keywords included Parkinson disease, bromocriptine, cabergoline, lazabemide, levodopa, pergolide, pramipexole, rasagiline, ropinirole, rotigotine, selegiline and RCTs. Publications were first screened by reviewing their titles and abstracts and further reviewed by scanning full texts. In addition, cited references attached to the included documents were also retrieved.
Inclusion criteria
Studies were included when they met the following criteria:
-
1
Experiments were designed as RCTs comparing the efficacy of treatments for PD.
-
2
Patients or participants were adults diagnosed with PD.
-
3
Outcomes in studies included at least one of the following endpoints: Unified Parkinson’s Disease Rating Scale (UPDRS) II, UPDRS III, UPDRS total and withdrawals.
-
4
Interventions included at least one of the following drugs: bromocriptine, cabergoline, lazabemide, levodopa, pergolide, pramipexole, rasagiline, ropinirole, rotigotine and selegiline.
Data extraction
After reading through the full text, the following information was extracted from each independent study: author, publication year, sample size, gender ratio, design, blind, follow-up, age, condition of PD, intervention and dosage. As for outcomes, several unified PD rating scales (UPDRS) including UPDRS II, UPDRS III and UPDRS total were extracted if available, which has been considered as the primary efficacy outcomes in this analysis; meanwhile the rate of withdraw during the treatment was adopted as an endpoint integrating tolerability, efficacy and adverse effect as a whole.
Statistical analysis
STATA version 12.0 (Stata Corp, College Station, TX, USA) software was applied in traditional meta-analysis. Firstly, the heterogeneity was examined by using Cochran’s Q-statistic or I2 test. When significant heterogeneity did not exist (P > 0.05 or I2<50%), a fixed-effects model (Mantel-Haenszel method) was performed. Otherwise, we tried to find out the source of heterogeneity and eliminate the potential source of heterogeneity. Alternatively, a random-effects model (Der Simonian-Laird method) would be applied. For count data such as withdrawal, odd ratios (OR) and corresponding 95% confidence interval (CI) were calculated. For measurement data including UPDRS II, UPDRS III, UPDRS total, withdrawals, the mean difference (MD) and the corresponding 95% CI were calculated.
WinBUGS (MRC Bio-statistics Unit, Cambridge, UK) software was applied in network meta-analysis (NMA). To combine both direct and indirect evidence, a Markov chain Monte Carlo method and Bayesian networks were built. Similar with cases in traditional meta-analysis, OR and MD were separately used in count data and measurement data. Meanwhile, the corresponding 95% credential interval (CrI) was also calculated. To illustrate the results from NMA more directly, the surface under the cumulative ranking curve (SUCRA) was drawn and presented the ranking according to different endpoints. SUCRA enable us to identify the best treatment overall. The value of SUCRA would be 1 (i.e. 100%) for the best and 0 for the worst. In addition, a cluster analysis was conducted to combine the ranking under two independent endpoints and divide the interventions into several levels in view of their performan
Consistency between direct and indirect evidence was assessed by P-value and P > 0.05 exhibited a significant consistency. A heat map was plotted to present the consistency between direct evidence and NMA results, in which red indicates significant inconsistency while blue indicates significant consistency.
Additional Information
How to cite this article: Zhuo, C. et al. Comparison for Efficacy and Tolerability among Ten Drugs for Treatment of Parkinson’s Disease: A Network Meta-Analysis. Sci. Rep. 7, 45865; doi: 10.1038/srep45865 (2017).
Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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C. Zhuo: study concept and design, acquisition of data, statistical analysis and interpretation, drafting of manuscript. X. Zhu: acquisition of data, critical revision of manuscript for intellectual content. R. Jiang: Study design, manuscript revision. F. Ji: analysis and interpretation of data, critical review of manuscript. Z. Su: study concept and design, data analysis and interpretation, manuscript review, project supervision, critical revision of manuscript for intellectual content. R. Xue: analysis and interpretation of data, manuscript revision. Y. Zhou: acquisition of data, interpretation of data, manuscript revision.
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Zhuo, C., Zhu, X., Jiang, R. et al. Comparison for Efficacy and Tolerability among Ten Drugs for Treatment of Parkinson’s Disease: A Network Meta-Analysis. Sci Rep 7, 45865 (2017). https://doi.org/10.1038/srep45865
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DOI: https://doi.org/10.1038/srep45865
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