Bromocriptine versus levodopa in early Parkinson's disease.
BACKGROUND
Drugs that mimic dopamine as bromocriptine were introduced as monotherapy or in a combination with LD in the hope that this approach would prevent or delay the onset of motor complications in patients with Parkinson's disease (PD). However, hitherto, the role of bromocriptine (BR) in this issue has remained controversial. The present study is a systematic review of all randomized controlled trials of bromocriptine monotherapy compared with levodopa (LD) monotherapy in PD.


OBJECTIVE
To assess the efficacy and safety of bromocriptine (BR) monotherapy for delaying the onset of motor complications associated with levodopa (LD) therapy in patients with Parkinson's disease (PD).


METHODS
Sources including the Cochrane Library, the search strategy of the Movement Disorders Group (includes computerised searches of MEDLINE and EMBASE and hand searching of appropriate neurology journals), reference lists of the reviews found by the MEDLINE and EMBASE search-strategy, Sandoz -now Novartis- (manufacturer of BR), symposia reports, PD handbooks, contacts with colleagues who had co-ordinated trials on BR and reference lists of all included studies were used to identify randomized controlled trials (RCTs) of interest.


METHODS
Randomized trials were eligible for inclusion if they evaluated the efficacy of BR monotherapy for delaying the onset of motor complications compared to LD therapy in PD patients. Outcome measures that were evaluated included occurrence and severity of motor complications, changes in impairment and disability, and the occurrence of side effects.


METHODS
To determine the feasibility of a quantitative systematic review two independent reviewers evaluated the methodological quality of identified trials.


RESULTS
Over the period of 1974 to January 1999 we identified six studies randomizing more than 850 patients to a BR or a LD regimen. The majority of the studies lacked sample size calculations and randomization procedure remained unclear in three trials. Only two trials were performed according to a double-blind design. Important differences between studies concerning the duration of trials, the BR titration phase, the achieved mean dose of LD or BR, and the applied outcomes were found. Because of these differences, we could not pool the data from the different trials in an attempt to perform a meta-analysis. Therefore, the available data of the individual trials was re-analysed. Subsequently, the results were interpreted against the background of the sources of heterogeneity between the studies. The occurrence of dyskinesias in three short trials was too low to allow any conclusion. The results of the longer trials indicate a lower occurrence of dyskinesias in the BR tier. In five trials that evaluated dystonia, this motor complication occurred less frequent in the BR tier. However, for both dyskinesias and dystonia a statistically significant difference in favour of BR emerged only in the largest trial. There was a trend for wearing-off and on-off fluctuations to occur less frequently in the BR group. Although all trials evaluated patients at the impairment level, only the largest trial reported a significantly larger improvement for the LD tier during the first year of therapy. Concerning disability, which was evaluated by five trials no statistically significant differences were found. Overall, a statistically larger number of dropouts occurred in the BR group because of an inadequate therapeutic response or intolerable side effects.


CONCLUSIONS
This systematic review identified important sources of heterogeneity between trials. Inadequate powering of the studies and clinically relevant differences in trial duration, applied outcomes, and trial design may explain the different results and why many findings failed to reach a statistically significant level. Nevertheless, based on qualitative review of available data we conclude that in the treatment of early Parkinson's disease, bromocriptine may be beneficial in delaying motor complications and dyskinesias with comparable effects on impairment and disability in those patients that tolerate the drug.
Ramaker
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Department of Neurology, Leiden University Medical Center, P.O. Box 9600, Leiden, the Netherlands, 2300 RC. jvhilten@neurology.azl.nl
van Hilten
J J
JJ
D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001971:Bromocriptine / Q000627:therapeutic use*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic
D000978:Antiparkinson Agents; D001971:Bromocriptine; D007980:Levodopa