This review of chelator agents and zinc for initial treatment of Wilson disease concluded that there was a lack of high-quality evidence for the comparative efficacy of different drugs. Based on the low quality of the evidence this conclusion is reliable, but more information on the review methods is needed to confirm the reliability of the review.

To evaluate the clinical efficacy of D-penicillamine, trientine, tetrathiomolybdate and zinc as monotherapy for the initial treatment of Wilson disease.

MEDLINE, EMBASE and unspecified Cochrane databases were searched from inception to January 2008. Search terms were reported. The authors reviewed reference lists from included studies. Only studies written in English, French or German were included.

Studies that assessed D-penicillamine, trientine, tetrathiomolybdate or zinc monotherapy in patients with an established diagnosis of Wilson disease were eligible. Case reports or series and studies that did not evaluate anticopper therapy were excluded. Clinical outcomes had to be specified as asymptomatic, improved, unchanged, deteriorated or dead and determined after more than three months of follow-up. Outcomes had to be reported for all patients exposed to a single anticopper drug and relate to their initial presentation.

Most studies were retrospective or prospective cohort studies. They evaluated D-penicillamine (doses ranging from 0.6 to 1.8g/day) and elemental zinc (150 to 275mg/day) alone or together. The one randomised controlled trial (RCT) compared D-penicillamine (1 to 1.5g/day) with zinc (0.6 to 0.8g/day). There were some inconsistencies in reporting of doses. Most studies included presymptomatic patients or combinations of presymptomatic, hepatic and neuralgic patients. Mean patient ages at diagnosis were 14 years (range 1.5 to 52 years, D-penicillamine) and 12.5 (range three to 39, zinc). Outcomes were assessed after a mean of 64 months (D-penicillamine) or 81 months (zinc) with a range from three to 323 months.

The authors did not state how many reviewers performed study selection.

Study validity was assessed using Cochrane Collaboration criteria, which included: definition of participant characteristics; method for selecting patients; definitions of interventions, outcomes and outcome-assessment; correction for confounding factors and appropriate duration and percentage of follow-up.

The authors did not state how many reviewers performed validity assessment.

Data for the numbers and percentages of patients with a favourable outcome (presymptomatic/asymptomatic or improved) and those with an unfavourable outcome (unchanged, deteriorated or dead) were extracted by type of initial presentation (presymptomatic, hepatic, neurological and overall). Numbers and percentages of patients who experienced side effects and neurological deterioration were extracted. Data were extracted on a per protocol basis.

The authors did not state how many reviewers performed data extraction.

Results were presented in tables and as a narrative synthesis. Total numbers and percentages were reported in subgroups based on initial presentation, intervention and clinical outcome.

Thirteen studies were included: one RCT (n=67); seven prospective cohort studies (n=287 ); and five retrospective cohort studies (n=180). Not all patients were included in the systematic review, but overall 261 patients were treated with D-penicillamine and 249 with zinc. Most studies scored low for validity due to their observational design.

D-penicillamine treatment had a favourable effect in 100% (70 out of 70) presymptomatic, 73.7% (42 out of 57) hepatic and 80.6% (58 out of 72) of neurological patients. Zinc treatment had a favourable effect in 100% (66 out of 66) presymptomatic, 55.6% (five out of nine) of hepatic and 90% (nine out of 10) neurological patients.

Side effects were reported in 24.4% (50 out of 205) of patients who received D-penicillamine and 12.5% (28 out of 224) of patients who received zinc. Side effects were severe in 12.7% (26 out of 205) of D-penicillamine patients and resulted in withdrawal of treatment; the corresponding figure for zinc was 0.9% (two out of 224). Deterioration of neurological signs or symptoms after the start of treatment occurred in 5.7% (six out of 107) D-penicillamine and 0.8% (one out of 127) zinc patients.

There was a lack of high-quality evidence for estimating the relative treatment effects of drugs available for treatment of Wilson disease.

This review specified inclusion criteria for interventions and patients, but criteria for study design were broad. The search did not include unpublished literature and there were some language restrictions, so some studies may have been missed. It was not reported whether any methods were used to reduce errors and bias in study selection, validity assessment and data extraction. Studies were assessed for validity, but no results were reported. Results were presented narratively with outcomes presented as improved, deteriorated and so on, but no definitions of these terms were provided. Due to the low quality of the evidence, the author's conclusion is reliable but more information on the review methods is needed to confirm the reliability of the review.

Practice: The authors stated that zinc seemed the preferred initial treatment for presymptomatic patients.

Research: The authors stated that multicentre comparative randomised controlled trials with long-term follow-up were necessary.

Funded by a grant from the Sixth Framework Program of the European Commission.

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.