To review the effectiveness and cost-utility of entacapone as an adjunct to levodopa in the treatment of Parkinson's disease.

Numerous databases were searched using an extensive list of both disease specific and methodological terms (databases and search terms are detailed in the report). Other sources included contact with neurologists, Orion Pharma (the pharmaceutical company which manufactures entacapone) and examination of the bibliographies of relevant studies.

Study designs of evaluations included in the review

Randomised placebo controlled (phase III) trials evaluating entacapone as an adjunct to levodopa.

Specific interventions included in the review

Levodopa (up to 10 daily doses) and entacapone (200mg) Vs levodopa and placebo.

Participants included in the review

The stated inclusion criteria were patients with true idiopathic Parkinson's disease who have progressed to the fluctuation stage.

Outcomes assessed in the review

Duration of response ('on-off time'), Unified Parkinson's Disease Rating Scale (UPDRS), quality of life, and adverse events.

How were decisions on the relevance of primary studies made?

The authors do not state how the papers were selected for the review, or how many of the reviewers performed the selection.

Methodological quality was appraised according to the Critical Appraisal Skills Programme checklist (see Other Publications of Related Interest no.1). The first author evaluated methodological quality and the second checked that evaluation disagreements were resolved through discussion.

Data on efficacy, adverse events and methodology were extracted by the first author and checked by the second.

How were the studies combined?

The studies were combined in a narrative review.

How were differences between studies investigated?

Differences between the studies were not formally investigated. However, the two studies included were very similar to one another.

Two published phase III RCTs are described in detail (see Other Publications of Related Interest no.2 and no.3), and two recently completed phase III RCTs are summarised briefly.

The average increase in daily 'on' time in the two published trials was between 0.6 to 1.2 hours (relative to placebo). The change in daily 'on' time was significant for only one of the two published trials.

Both placebo and entacapone led to reductions in UPDRS scores, ranging from 1 to 1.1, and 0.6 to 4.4, respectively. Quality of Life gains were estimated at 0.24 (best case scenario) and 0 (worst case scenario), depending on which trial estimates were based. At six months treatment, patients gained up to 0.07 Quality Adjusted Life Years.

Adverse effects were more frequent in entacapone treated patients in both published phase III RCTs. In one study 20% of patients receiving entacapone experienced nausea and diarrhoea. Abdominal pain, and urine discolouration were also common, both affecting 10% of patients. Dyskinesia was also worsened. Adverse effects were severe enough to cause 11 patients (6%) to withdraw from one trial (six from the entacapone group and five from the placebo group) and 14 patients (7%) to leave the other trial (seven each from the entacapone group and placebo groups).

The cost of adding entacapone to levodopa (co-beneldopa) for a year is around £1,830 (for patients managed by neurology) and £1,700 (for patients managed by care of the elderly). Published efficacy data beyond six months are not yet available. As a best case scenario, based upon the assumption of maintained benefit with one year's treatment, the cost/QALY is between £12,100 and £30,500. The worst case scenario is based upon the assumption that treatment lasts for one year with uniformly declining benefit after six months to baseline levels. This produces a cost/QALY of between approximately £14,400 to £45,800. Figures vary according to the health related quality of life instrument (HRQLI) used. The cost/QALY could be considerably higher given the fact that there were no estimated quality of life gains for the Parkinson Study Group trial.

Entacapone has been shown to be effective in two relatively small published phase III randomised controlled trials. However, in one trial patients were less severely affected than those who would be treated in practice with the drug. There is no evidence on the ideal dose as phase III dose ranging studies have not been published and evidence for long-term effects is lacking.

This is, on the whole, a methodologically sound review. The review question was stated clearly and supported by study inclusion criteria. The literature search was comprehensive and efforts were made to find unpublished studies, though it is not clear whether language restrictions were applied. Validity assessment was performed using a validated checklist. Study details were generally reported well, though some details regarding participant characteristics for some studies were missing, e.g. age and sex. The authors' conclusions are consistent with the results presented.

Research: The authors state that further appraisal of this therapy will be warranted when additional data become available. In particular, when the three unpublished trials are published fully, when long-term safety trials of entacapone are completed, and on completion of a phase IV trial of entacapone. The authors note also the need for evidence regarding the ideal dose of entacapone, as phase III dose ranging studies have yet to be published, and that there are no published data concerning how entacapone performs beyond six months.

1. Critical Appraisal Skills Programme. Making sense of evidence about effective health care. Oxford: CASP; 1999. 2. Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated parkinson's disease patients. Ann Neurol 1997;42(5):747 55. 3. Rinne UK, Larsen JP, Siden A, Worm PJ. Entacapone enhances the response to levodopa in Parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998;51(5):1309 14.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.