Summary
Aims
To evaluate the efficacy, tolerability, and safety of long‐acting versus standard non‐ergot dopamine agonists (NEDAs) in Parkinson's disease (PD), we performed a meta‐analysis of randomized controlled trials (RCTs).
Materials and methods
The PubMed, EMBASE, Cochrane Library databases, and Web of Knowledge were searched up to November 20th 2013. The pooled weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated.
Results
Eight large‐scale RCTs, involving 2402 patients, were included in this meta‐analysis. Compared with the standard NEDAs, long‐acting NEDAs exhibited similar improvements in Unified Parkinson's Disease Rating Scale activities of daily living (ADL) score (WMD 0.09, 95% CI −0.33 to 0.50), motor score (WMD −0.35, 95% CI –1.60 to 0.90), and “off” time (WMD 0.18, 95% CI −0.14 to 0.50). No differences were found in overall withdrawals (RR 1.11, 95% CI 0.94 to 1.32), withdrawals due to adverse events (RR 1.19, 95% CI 0.91 to 1.56), or the ten commonly reported adverse events between the two formulations.
Conclusions
Our meta‐analysis showed long‐acting NEDAs were noninferior to standard NEDAs in efficacy, tolerability, and safety in the treatment of PD.
Keywords: Extended release pramipexole, Meta‐analysis, Parkinson's disease, Ropinirole prolonged release, Rotigotine transdermal patch
Introduction
Dopamine agonists (DAs) have been used as monotherapy in early Parkinson's disease (PD) or as an adjunctive therapy to levodopa in advanced PD for many years 1, 2. Although there is no strong evidence that a given active agonist is more potent than another, ergot DAs are no longer used as first‐line treatments of PD because of the risk of fibrotic adverse reactions 3, 4. While non‐ergot dopamine agonists (NEDAs) continue to be used as the first‐line agents 5, 6 and novel long‐acting formulations of NEDAs including extended release (ER) pramipexole, ropinirole prolonged release (PR), and rotigotine transdermal patch have been developed 7. Compared with the three‐times daily administration of standard NEDAs, once‐daily administration of long‐acting NEDAs provides a more stable plasma concentration over 24 h and is associated with a more continuous dopaminergic stimulation 8, 9, 10. Moreover, recent findings demonstrate that once‐daily administration of long‐acting NEDAs may improve patients' adherence to treatment 11, 12.
In the past decade, a number of randomized controlled trials (RCTs) have been carried out to evaluate the efficacy and safety of novel long‐acting NEDAs versus standard NEDAs 13, 14, 15, 16, 17, 18, 19, 20, but the results were inconsistent. Although most studies showed long‐acting NEDAs were noninferior to standard NEDAs 14, 15, 17, 18, 20, two studies evaluating rotigotine versus ropinirole immediate release (IR) and pramipexole ER versus pramipexole IR did not show the noninferiority 13, 16. Moreover, one study showed ropinirole PR was superior to ropinirole IR 19. To date, no long‐term RCT (>2 years) has been conducted, and no meta‐analysis has been performed to evaluate their efficacy and safety to our knowledge. Therefore, we pooled all the results of RCTs available and performed a comprehensive meta‐analysis to evaluate the efficacy, tolerability, and safety of long‐acting versus standard NEDAs in PD.
Materials and methods
Literature Search
We conducted systematic literature searches of PubMed, EMBASE, Cochrane Library databases, and Web of Knowledge up to November 20th 2013 without language limitations. A search strategy was performed using the following medical subject headings and keywords: “extended release pramipexole”, “ropinirole prolonged release”, and “rotigotine transdermal patch” in combination with “Parkinson's disease”, “Parkinson's” and “PD”. We also manually searched the references cited in clinical trial reports or reviews to identify additional relevant clinical trials. To maximize data requisition, we also contacted the authors whose articles contained insufficient information, where necessary.
Study Selection
Trials were included in our meta‐analysis if they met all the following criteria: (1) a randomized controlled trial, (2) study participants required to have a clinical diagnosis of PD, (3) intervention therapies consisting of long‐acting NEDAs versus standard NEDAs, and (4) assessment of the efficacy data in the form of Unified Parkinson's Disease Rating Scale (UPDRS) scores and/or “off” time, the tolerability data in the form of withdrawals, and/or the safety data in the form of adverse events. In trials for which there was more than one publication involving the same population, the longest study duration report was selected for analysis and shorter study duration reports were reviewed for missing data, where applicable.
Data Abstraction
Using a predesigned data extraction form, two investigators collected data independently with differences resolved by a third investigator. The following data were collected: first author's surname, year of publication, details of study design, methodological quality (assessed using Jadad criteria 21), patient characteristics (including gender, age, duration, and disease severity at baseline), sample size, treatment of early‐ or late‐stage, agent dose, duration of treatment, changes in UPDRS scores (including activities of daily living [ADL] score, motor score, and the ADL and motor subtotal score), “off” time, overall withdrawals, withdrawals due to adverse events, withdrawals due to lack of efficacy, and the incidences of adverse events.
Validity Assessment
Two investigators independently evaluated all trials. Any disagreement was resolved by discussion with a third investigator. The validated Jadad scale was used to assess the methodological quality of the included trials 21. This scale assesses inherent controllers of bias with the following quality assessment criteria: use of and methods for generating randomization, use of and methods for double‐blinding, and description of patient withdrawals/dropouts. One point was given for each satisfied criterion. The aggregate score was calculated for each included trial and ranged from 0 (weakest) to 5 (strongest); trials scoring <3 were deemed to have lower methodological quality.
Statistical Analysis
We combined the results of each trial by using standard meta‐analytic methods to estimate the overall efficacy, tolerability, and safety. We classified trials according to the randomized treatment comparison: long‐acting NEDAs versus standard NEDAs.
The mean changes in UPDRS scores and “off” time from baseline were treated as continuous variables and the weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated as the differences between long‐acting and standard NEDAs. Withdrawals and adverse events were treated as dichotomous variables and reported as relative risks (RRs) with 95% CIs. The overall effect was tested using z scores calculated by Fisher's z transformation, with significance set at P < 0.05. Statistical heterogeneity between trials was evaluated by the χ 2 and I 2 tests, with significance set at P < 0.10. If heterogeneity existed, the random‐effect model was used; otherwise, the fixed‐effect model was used. Because all the results were reanalyzed separately in the subgroups of early and advanced PD patients, heterogeneity was only reported in the subgroup analysis where it was statistically significant. Moreover, sensitivity analysis was also performed. All data analyses were carried out using the Review Manager Software version 5.1 (Cochrane Collaboration, Oxford, UK).
Results
Search Results and Study Characteristics
The literature searches identified 327 potential articles, of which 31 were randomized controlled clinical trials. Eight large‐scale RCTs 13, 14, 15, 16, 17, 18, 19, 20 involving 2402 patients were ultimately included in this meta‐analysis (Figure 1).
Figure 1.
Flow diagram of literature search and selection process. ER, Extended release; IR, immediate release; LD, levodopa; NEDAs, non‐ergot dopamine agonists; PR, prolonged release.
In the eight studies included, four studies were early PD 13, 14, 15, 16, and four studies were advanced PD 17, 18, 19, 20. In one study of early PD 13, concomitant levodopa was permitted, but in other studies of early PD, concomitant levodopa was not permitted 14, 15, 16. In all studies of advanced PD 17, 18, 19, 20, patients were treated with concomitant levodopa. Of these studies included, four studies 13, 14, 17, 18 compared pramipexole ER with pramipexole IR, two studies 15, 19 compared ropinirole PR with ropinirole IR, and two studies 16, 20 compared transdermal rotigotine with pramipexole IR and ropinirole IR, respectively. Moreover, different trial designs were found between studies: only one study 19 was designed to show the superiority of one agent over another, five studies 13, 14, 15, 16, 20 were designed to show the noninferiority between the two formulations, and two studies 17, 18 were not designed for formal noninferiority testing. Quality assessment showed all the studies had Jadad scores ranging between 4–5. The main characteristics of those studies were summarized in Table 1.
Table 1.
The main characteristics of the included randomized controlled trails
| Study, year | Study design (Jadad score) | Stage of PD | Comparison | Participants | Primary outcome data reported |
|---|---|---|---|---|---|
| Rascol, 2010 13 | MC DB DD, Phase III, RCT (4) | Early | Pramipexole ER versus IR (104/52), Duration (w): 9 | Mean age (y): 64/64, Men (%): 55/60, Duration of PD (y): 3.4/3.2 | UPDRS ADL, motor and subtotal, withdrawals, adverse events |
| Poewe, 2011 14 | MC DB DD, Phase III, RCT (5) | Early | Pramipexole ER versus IR (223/213), Duration (w): 33 | Mean age (y): 61/62, Men (%): 57/57, Duration of PD (y): 1.0/1.1 | UPDRS ADL, motor and subtotal, withdrawals, adverse events |
| Stocchi, 2008 15, a | MC DB DD, Phase III, RCT (5) | Early | Ropinirole PR versus IR (70/80), Duration (w): 12 | Mean age (y): 60/60, Men (%): 62/52, Duration of PD (y): 2.7/2.7 | UPDRS ADL and motor |
| Giladi, 2007 16 | MC DB DD, Phase III, RCT (5) | Early | Rotigotine versus Ropinirole IR (225/228), Duration (w): 37 | Mean age (y): 61/62, Men (%): 55/60, Duration of PD (y): 1.4/1.3 | UPDRS ADL + motor subtotal, withdrawals, adverse events |
| Schapira, 2011 17 | MC DB DD, Phase III, RCT (5) | Advanced | Pramipexole ER versus IR (165/175), Duration (w): 18 | Mean age (y): 62/62, Men (%): 56/56, Duration of PD (y): 6.1/6.6 | UPDRS ADL, motor and subtotal, “off” time, withdrawals, adverse events |
| Mizuno, 2012 18 | MC DB DD, Phase II, RCT (4) | Advanced | Pramipexole ER versus IR (56/56), Duration (w): 12 | Mean age (y): 69/66, Men (%): 38/38, Duration of PD (y): 2.9/3.1 | UPDRS ADL + motor subtotal, “off” time, withdrawals, adverse events |
| Stocchi, 2011 19 | MC DB DD, Phase III, RCT (4) | Advanced | Ropinirole PR versus IR (177/173), Duration (w): 24 | Mean age (y): 65/66, Men (%): 60/54, Duration of PD (y): 7.9/7.5 | UPDRS ADL and motor, “off” time, withdrawals, adverse events |
| Poewe, 2007 20 | MC DB DD, Phase III, RCT (5) | Advanced | Rotigotine versus Pramipexole IR (204/201), Duration (w): 23 | Mean age (y): 64/63, Men (%): 66/56, Duration of PD (y): 8.9/8.4 | UPDRS ADL and motor, “off” time, withdrawals, adverse events |
ADL, Activities of daily living; DB, double‐blinded; DD, double‐dummy; ER, extended release; IR, immediate release; MC, multicenter; PD, Parkinson's disease; PR, prolonged release; RCT, randomized controlled trial; UPDRS, United Parkinson's Disease Rating Scale; vs, versus; W, week; Y, year.
This trial was a cross‐over study and only the changes of UPDRS ADL score and motor score in the titration phase were available.
Meta‐Analysis of Efficacy
All the eight trials evaluated the efficacy of long‐acting versus standard NEDAs using UPDRS scores (Table 2). In the six trials 13, 14, 15, 17, 19, 20 (n = 1786) that assessed UPDRS ADL score, no difference was found between long‐acting and standard NEDAs (WMD 0.09, 95% CI –0.33 to 0.50; P = 0.68; Figure 2). In the six trials 13, 14, 15, 17, 19, 20 (n = 1761) that assessed UPDRS motor score, no difference was found between the two formulations (WMD –0.35, 95% CI –1.60 to 0.90; P = 0.58; Figure 3). In the five trials 13, 14, 16, 17, 18 (n = 1460) that assessed the UPDRS ADL and motor subtotal score, no difference was also found (WMD 0.97, 95% CI –0.98 to 2.92; P = 0.33). All the four trials 17, 18, 19, 20 (n = 1188) of advanced PD reported the reduction in “off” time and no difference was found between long‐acting and standard NEDAs (WMD 0.18, 95% CI –0.14 to 0.50; P = 0.27; Figure 4).
Table 2.
Efficacy results of subgroup and sensitivity analyses
| Items | UPDRS ADL scorea | UPDRS motor scoreb | UPDRS ADL + motor scorea , b | “Off” time | ||||
|---|---|---|---|---|---|---|---|---|
| No. of trials | WMD (95% CI) | No. of trials | WMD (95% CI) | No. of trials | WMD (95% CI) | No. of trials | WMD (95% CI) | |
| Overall PD | 6 | 0.09 (−0.33, 0.50) | 6 | −0.35 (−1.60, 0.90) | 5 | 0.97 (−0.98, 2.92) | 4 | 0.18 (−0.14, 0.50) |
| Early PD | 3 | −0.01 (−0.38, 0.37) | 3 | −0.58 (−1.58, 0.43)c | 3 | 1.04 (−1.78, 3.86) | 0 | N/A |
| Advanced PD | 3 | 0.20 (−0.74, 1.14) | 3 | 0.09 (−2.33, 2.51) | 2 | 0.94 (−1.33, 3.20) | 4 | 0.18 (−0.14, 0.50) |
| Pramipexole ER versus IR | 3 | 0.27 (−0.33, 0.86) | 3 | 0.02 (−1.03, 1.06) | 4 | −0.07 (−1.16, 1.03) | 2 | 0.40 (−0.10, 0.90) |
| Excluding rotigotine | 5 | 0.04 (−0.44, 0.52) | 5 | −0.68 (−1.51, 0.16) | 4 | −0.07 (−1.16, 1.03) | 3 | 0.12 (−0.27, 0.51) |
| Excluding trial by Rascol et al.13 | 4 | 0.17 (−0.34, 0.68) | 4 | −0.16 (−1.55, 1.24) | 4 | 1.64 (−0.28, 3.56) | 4 | 0.18 (−0.14, 0.50) |
ADL, activities of daily living; CI, confidence interval; ER, extended‐release; IR, immediate‐release; N/A, not available; PD, Parkinson's disease; UPDRS, United Parkinson's Disease Rating Scale; WMD, weighted mean difference.
UPDRS ADL score was assessed during “on” time except for two studies 17, 18, in which the score was the average score for “off” and “on” time.
UPDRS motor score was assessed during “on” time.
The fixed‐effect model was used to combined the results.
Figure 2.
Effect of long‐acting versus standard NEDAs on UPDRS ADL score. NEDAs, Non‐ergot dopamine agonists; UPDRS, United Parkinson's Disease Rating Scale; ADL, activities of daily living.
Figure 3.
Effect of long‐acting versus standard NEDAs on UPDRS motor score. NEDAs, Non‐ergot dopamine agonists; UPDRS, United Parkinson's Disease Rating Scale.
Figure 4.
Effect of long‐acting versus standard NEDAs on “off” time. NEDAs, Non‐ergot dopamine agonists.
Meta‐Analysis of Withdrawals
In the present meta‐analysis, overall withdrawals, withdrawals due to adverse events, and withdrawals due to lack of efficacy were studied (Table 3). In the seven trials 13, 14, 16, 17, 18, 19, 20 (n = 2241) that reported the overall number of patient withdrawals from the trials, we found no difference between long‐acting and standard NEDAs (RR 1.11, 95% CI 0.94–1.32; P = 0.23). In the seven trials 13, 14, 16, 17, 18, 19, 20 that reported the number of patient withdrawals due to adverse events, the outcome occurred in 106/1143 (9.27%) patients treated with long‐acting NEDAs and 89/1098 (8.11%) patients treated with standard NEDAs. And no difference was found between the two formulations (RR 1.19, 95% CI 0.91–1.56; P = 0.19; Figure 5). In the six trials 13, 14, 16, 17, 19, 20 that reported the number of patient withdrawals due to lack of efficacy, no difference was also found between the two formulations (RR 1.56, 95% CI 0.83–2.92; P = 0.17).
Table 3.
Tolerability results of subgroup and sensitivity analyses
| Items | Overall withdrawals | Withdrawals due to adverse event | Withdrawals due to lack of efficacy | |||
|---|---|---|---|---|---|---|
| No. of trials | RR (95% CI) | No. of trials | RR (95% CI) | No. of trials | RR (95% CI) | |
| Overall PD | 7 | 1.11 (0.94, 1.32) | 7 | 1.19 (0.91, 1.56) | 6 | 1.56 (0.83, 2.92) |
| Early PD | 3 | 1.23 (0.96, 1.56) | 3 | 1.25 (0.88, 1.76) | 3 | 1.67 (0.77, 3.61) |
| Advanced PD | 4 | 1.00 (0.78, 1.29) | 4 | 1.13 (0.74, 1.70) | 3 | 1.36 (0.46, 4.05) |
| Pramipexole ER versus IR | 4 | 1.33 (0.97, 1.83) | 4 | 1.12 (0.71, 1.78) | 3 | 1.79 (0.39, 8.24) |
| Excluding rotigotine | 5 | 1.13 (0.90, 1.43) | 5 | 1.22 (0.85, 1.77) | 4 | 1.43 (0.44, 4.69) |
| Excluding trial by Rascol et al.13 | 6 | 1.12 (0.94, 1.34) | 6 | 1.20 (0.92, 1.57) | 5 | 1.56 (0.83, 2.92) |
CI, Confidence interval; ER, extended‐release; IR, immediate‐release; PD, Parkinson's disease; RR, relative risk.
Figure 5.
Effect of long‐acting versus standard NEDAs on withdrawals due to adverse events. NEDAs, Non‐ergot dopamine agonists.
Meta‐Analysis of Adverse Events
Seven trials reported adverse events with an incidence of ≥5% in either study group. Adverse events reported in at least three trials were studied in the present study and the results of the meta‐analysis were summarized in Table 4. Moreover, the pooled incidence rates of adverse events in PD patients treated with long‐acting NEDAs and standard NEDAs are presented in Figure 6. The most commonly reported adverse events and serious adverse events are discussed below.
Table 4.
Safety results of subgroup analyses
| Adverse events | Early and advanced PD | Early PD | Advanced PD | |||
|---|---|---|---|---|---|---|
| No. of trials | RR (95% CI) | No. of trials | RR (95% CI) | No. of trials | RR (95% CI) | |
| Nausea | 7 | 0.95 (0.78, 1.16) | 3 | 0.88 (0.67, 1.16) | 4 | 1.02 (0.78, 1.35) |
| Somnolence | 7 | 0.99 (0.82, 1.19) | 3 | 1.05 (0.83, 1.32) | 4 | 0.92 (0.68, 1.24) |
| Dizziness | 6 | 0.90 (0.68, 1.20) | 2 | 0.95 (0.63, 1.43) | 4 | 0.94 (0.46, 1.91) |
| Headache | 5 | 1.00 (0.66, 1.51) | 2 | 1.08 (0.49, 2.36) | 3 | 0.97 (0.60, 1.58) |
| Constipation | 5 | 1.14 (0.81, 1.61) | 2 | 1.12 (0.73, 1.73) | 3 | 1.17 (0.66, 2.07) |
| Dyskinesia | 4 | 1.03 (0.77, 1.38) | 0 | N/A | 4 | 1.03 (0.77, 1.38) |
| Hallucination | 4 | 1.19 (0.76, 1.89) | 0 | N/A | 4 | 1.19 (0.76, 1.89) |
| Orthostatic hypotension | 4 | 0.66 (0.36, 1.23) | 0 | N/A | 4 | 0.66 (0.36, 1.23) |
| Vomiting | 3 | 0.52 (0.18, 1.51) | 1 | 1.16 (0.52, 2.57) | 2 | 0.28 (0.11, 0.76) |
| Back pain | 3 | 0.99 (0.55, 1.78) | 2 | 1.73 (0.60, 4.96) | 1 | 0.74 (0.36, 1.52) |
CI, Confidence interval; N/A, not available; PD, Parkinson's disease; RR, relative risk.
Figure 6.
The pooled incidences of adverse events.
In the seven trials 13, 14, 16, 17, 18, 19, 20 (n = 2241) reported the incidences of nausea and somnolence, no differences were found in nausea (RR 0.95, 95% CI 0.78–1.16; P = 0.62; Figure 7) or somnolence (RR 0.99, 95% CI 0.82–1.19; P = 0.92; Figure 8) between long‐acting and standard NEDAs. All the four studies of advanced PD 17, 18, 19, 20 reported the incidence of dyskinesia and no difference was found between the two formulations (RR 1.03, 95% CI 0.77–1.38; P = 0.85). Seven trials 13, 14, 16, 17, 18, 19, 20 reported the incidences of serious adverse events, and no difference was also found (RR 0.98, 95% CI 0.69–1.40; P = 0.92).
Figure 7.
Effect of long‐acting versus standard NEDAs on the incidence of nausea. NEDAs, Non‐ergot dopamine agonists.
Figure 8.
Effect of long‐acting versus standard NEDAs on the incidence of somnolence. NEDAs, Non‐ergot dopamine agonists.
Subgroup Analyses
All the results were reanalyzed separately in the subgroups of early PD patients and advanced PD patients. In early PD patents, the results of UPDRS scores, withdrawals, and adverse events were consistent with the results for all PD patients combined. In the analysis of UPDRS ADL and motor subtotal score, statistically significant heterogeneity was found between trials (P = 0.0007; I 2 = 86%). This heterogeneity was explained by the atypical study data in the study by Giladi et al. 16, which reported the absolute mean change in UPDRS ADL and motor subtotal score instead of the adjusted mean change. When this study was excluded, no heterogeneity was found (P = 0.21; I 2 = 35%), and the result (WMD −0.37, 95% CI –1.63 to 0.88; P = 0.56) was consistent with the previous one.
In advanced PD, the results of UPDRS scores, withdrawals, and adverse events were consistent with the results for all PD patients excepted for vomiting. Long‐acting NEDAs was associated a lower incidence of vomiting compared with standard NEDAs in advanced PD (RR 0.28, 95% CI 0.11–0.76; P = 0.01). Moreover, statistically significant heterogeneity between trials was found in the analyses of UPDRS ADL score (P = 0.02; I 2 = 73%) and motor score (P = 0.009; I 2 = 79%) due to the study by Stocchi et al. 19. When this study was excluded, no heterogeneity was found in UPDRS ADL score (P = 0.41; I 2 = 0%) or motor score (P = 0.62; I 2 = 0%). And patients treated with standard NEDAs exhibited a significant improvement in UPDRS ADL score (WMD 0.66, 95% CI 0.06 to 1.26; P = 0.03) and a borderline significant improvement in UPDRS motor score (WMD 1.36, 95% CI 0.04–2.68; P = 0.04), compared with patients treated with long‐acting NEDAs. However, the study by Stocchi et al. 19 was the only trial designed to show the superiority of one agent over another. Of the two trials remained, one 20 was designed to show the noninferiority and the other 17 was not designed for formal noninferiority testing. Therefore, the effect size of long‐acting versus standard NEDAs in UPDRS ADL score and motor score may be underestimated, when the study by Stocchi et al. 19 was excluded.
Sensitivity Analyses
There were four studies comparing pramipexole ER with pramipexole IR 13, 14, 17, 18. When we pooled all the results from the studies of pramipexole ER, the results of UPDRS scores and withdrawals were consistent with the results for all PD patients combined. In the study by Rascol et al. 13, patients were under the treatment of pramipexole IR for at least 3 months before the random allocation. When this study was excluded, the results of UPDRS scores and withdrawals were consistent with the results for all PD patients combined. In the trials by Giladi et al. 16 and by Poewe et al. 20, transdermal rotigotine (once‐daily) was compared with oral agents of ropinirole IR (three‐times daily) and pramipexole IR (three‐times daily), respectively. When the two studies were excluded, the results of UPDRS scores and withdrawals were consistent with previous results.
Discussion
To our knowledge, this is the first meta‐analysis of RCTs to assess the efficacy, tolerability, and safety of long‐acting versus standard NEDAs in PD patients. In our meta‐analysis, long‐acting NEDAs showed noninferiority to standard NEDAs in efficacy, as evidenced by reductions in UPDRS ADL score, motor score, the ADL and motor subtotal score, and “off” time. In the subgroup analyses of early and advanced PD, consistent results were also found in the changes of UPDRS scores.
Our results showed no differences were found in the overall withdrawals or withdrawals due to lack of efficacy between the two formulations. No difference was also found in the incidence of withdrawals due to adverse events between long‐acting NEDAs (9.27%) and standard NEDAs (8.11%). The results are similar to that for monoamine oxidase type B inhibitors (10.3%) and lower than that for catechol‐o‐methyltransferase inhibitors (14.3%) 22, 23.
In our meta‐analysis, long‐acting NEDAs showed a similar adverse events profile to standard NEDAs in overall PD patients and in subgroups of early and advanced PD, excepted for vomiting. Long‐acting NEDAs was associated with a lower incidence of vomiting compared with standard NEDAs in advanced PD. The pooled incidences of adverse events showed somnolence, nausea, and dyskinesia were the three most common adverse events in the two formulations. And the incidence of somnolence (15.5%) in long‐acting NEDAs is similar to the incidence of somnolence (14.1%) in previous study for DAs 24. However, the incidences of nausea (14.5%) and dyskinesia (12.8%) in long‐acting NEDAs are lower than the incidences of nausea (21.1%) and dyskinesia (17.7%) in previous study for DAs 24.
There were four studies of advanced PD included in present study 17, 18, 19, 20. Although once‐daily administration of long‐acting NEDAs provides a more physiological and continuous dopaminergic stimulation 8, 9, 10, no differences were found in the reduction in “off” time or in the incidence of dyskinesia between long‐acting and standard NEDAs in advanced PD. In the studies of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated primates and common marmosets, continuous dopaminergic stimulation was associated with a greater improvement of “on” state and a lower incidence of dyskinesia compared with intermittent dopaminergic stimulation 25, 26, 27, 28. These discrepancies may be due to the fact that only one study 19 included was designed to show the superiority of one agent over another in the present study,whereas most studies 13, 14, 15, 16, 20 included were designed to show the noninferiority between the two formulations. No claims of superiority of one agent over another can be made based on the noninferiority study design of these studies. Moreover, the differences between animal models and PD patients should also be taken into consideration.
As with any meta‐analysis, there are some limitations that should be mentioned to appropriately interpret the results of our study. First, most of the P values reported in this meta‐analysis did not reach significance, and this may be associated with the noninferiority trial design. Of the studies included, only one study was designed to show the superiority of one agent over another 19, five studies 13, 14, 15, 16, 20 were designed to show the noninferiority between the two formulations, and two studies 17, 18 were not designed for formal noninferiority testing. No claims of superiority of one agent over another can be made based on the noninferiority study design of these studies. Further studies are also needed to confirm our findings. Second, the safety variables were considered only as secondary objectives, and most trials did not report adverse events with incidences of <5%. And a classic bias in analyses of adverse events in RCTs is the inclusion of studies with short observation periods. Therefore, the conclusions can only be drawn for the most common adverse events, and the pooled incidences of adverse events might have been underestimated. Finally, the assessment of the publication bias was not performed because only eight trials were included in the present study.
In conclusion, our meta‐analysis showed long‐acting NEDAs were noninferior to standard NEDAs in efficacy, tolerability, and safety. Previous studies showed once‐daily administration of long‐acting NEDAs provided a more stable plasma concentration and improved patients' adherence to treatment. These findings suggest long‐acting NEDAs may be superior over standard NEDAs in clinical practice. In the present meta‐analysis, most studies included were designed to show the noninferiority between the two formulations and no claims of superiority of one agent over another can be made based on the noninferiority study design. Therefore, further studies, especially with superiority trial design, are needed to confirm our findings.
Disclosure
We would like to declare that the work described is an original research that has not been published previously, and not under consideration for publication elsewhere in whole or in part. No conflict of financial interest exits in the submission of this manuscript.
Acknowledgments
None.
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