title: Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation.
abstract: BACKGROUND
  Dupuytren's disease is a slowly progressive condition of the hand, characterised by the formation of nodules in the palm that gradually develop into fibrotic cords. Contracture of the cords produces deformities of the fingers. Surgery is recommended for moderate and severe contractures, but complications and/or recurrences are frequent. Collagenase clostridium histolyticum (CCH) has been developed as a minimally invasive alternative to surgery for some patients.
  
  
  OBJECTIVE
  To assess the clinical effectiveness and cost-effectiveness of collagenase as an alternative to surgery for adults with Dupuytren's contracture with a palpable cord.
  
  
  METHODS
  We searched all major electronic databases from 1990 to February 2014.
  
  
  METHODS
  Randomised controlled trials (RCTs), non-randomised comparative studies and observational studies involving collagenase and/or surgical interventions were considered. Two reviewers independently extracted data and assessed risk of bias of included studies. A de novo Markov model was developed to assess cost-effectiveness of collagenase, percutaneous needle fasciotomy (PNF) and limited fasciectomy (LF). Results were reported as incremental cost per quality-adjusted life-year (QALY) gained. Deterministic and probabilistic sensitivity analyses were undertaken to investigate model and parameter uncertainty.
  
  
  RESULTS
  Five RCTs comparing collagenase with placebo (493 participants), three RCTs comparing surgical techniques (334 participants), two non-randomised studies comparing collagenase and surgery (105 participants), five non-randomised comparative studies assessing various surgical procedures (3571 participants) and 15 collagenase case series (3154 participants) were included. Meta-analyses of RCTs assessing CCH versus placebo were performed. Joints randomised to collagenase were more likely to achieve clinical success. Collagenase-treated participants experienced significant reduction in contracture and an increased range of motion compared with placebo-treated participants. Participants treated with collagenase also experienced significantly more adverse events, most of which were mild or moderate. Four serious adverse events were observed in the collagenase group: two tendon ruptures, one pulley rupture and one complex regional pain syndrome. Two tendon ruptures were also reported in two collagenase case series. Non-randomised studies comparing collagenase with surgery produced variable results and were at high risk of bias. Serious adverse events across surgery studies were low. Recurrence rates ranged from 0% (at 90 days) to 100% (at 8 years) for collagenase and from 0% (at 2.7 years for fasciectomy) to 85% (at 5 years for PNF) for surgery. The results of the de novo economic analysis show that PNF was the cheapest treatment option, whereas LF generated the greatest QALY gains. Collagenase was more costly and generated fewer QALYs compared with LF. LF was £1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was £10,871 per QALY gained. Two subgroup analyses were conducted for a population of patients with moderate and severe disease and up to two joints affected. In both subgroup analyses, collagenase remained dominated.
  
  
  CONCLUSIONS
  The main limitation of the review was the lack of head-to-head RCTs comparing collagenase with surgery and the limited evidence base for estimating the effects of specific surgical procedures (fasciectomy and PNF). Substantial differences across studies further limited the comparability of available evidence. The economic model was derived from a naive indirect comparison and was hindered by a lack of suitable data. In addition, there was considerable uncertainty about the appropriateness of many assumptions and parameters used in the model.
  
  
  CONCLUSIONS
  Collagenase was significantly better than placebo. There was no evidence that collagenase was clinically better or worse than surgical treatments. LF was the most cost-effective choice to treat moderate to severe contractures, whereas collagenase was not. However, the results of the cost-utility analysis are based on a naive indirect comparison of clinical effectiveness, and a RCT is required to confirm or refute these findings.
  
  
  BACKGROUND
  This study is registered as PROSPERO CRD42013006248.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Miriam
authors.initials: M
authors.lastname: Brazzelli
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Moira
authors.initials: M
authors.lastname: Cruickshank
authors.affiliation: Health Economics Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Tassie
authors.affiliation: Health Economics Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: McNamee
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Clare
authors.initials: C
authors.lastname: Robertson
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Elders
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Fraser
authors.affiliation: Health Economics Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Hernandez
authors.affiliation: NHS Grampian, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lawrie
authors.affiliation: Health Services Research Unit, University of Aberdeen, Aberdeen, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Ramsay
mesh_terms: D000328:Adult; D003362:Cost-Benefit Analysis; D004387:Dupuytren Contracture / Q000601:surgery* / Q000628:therapy*; D006801:Humans; D003012:Microbial Collagenase / Q000009:adverse effects / Q000191:economics / Q000627:therapeutic use*; D011183:Postoperative Complications; D019057:Quality-Adjusted Life Years
chemical_list: D003012:Microbial Collagenase