NIHR Signal Lack of evidence on whether collagenase or surgery is more clinically or cost effective in managing Dupuytren’s contracture

Published on 22 December 2015

This review aimed to compare injections of collagenase clostridium histolyticum with standard surgical treatments for Dupuytren’s contracture. Unfortunately existing trials are small and there are no head to head trials of surgery vs collagenase, so it is not possible to determine which therapy is more effective in the short or longer term - nor which is likely to be the more cost-effective. However, collagenase was clinically successful in 63% of cases, compared to just 6% for placebo. Draft guidance from NICE recommends against the use of collagenase clostridium histolyticum for Dupuytren’s, except in the context of research.

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Why was this study needed?

In Dupuytren's disease connective tissue in the palm of the hand thickens, forming fibrous cords which can cause one or more fingers to bend in towards the palm of the hand – this is called Dupuytren’s contracture. The condition isn't life-threatening, but it can get steadily worse over time and make normally daily activities difficult. Most people with mild Dupuytren’s disease don’t need or seek treatment.

Surgery is commonly used to treat moderate and severe contractures by removing the thickened tissue to release the tightness in the hand. Recurrence rates are high; it is not clear whether this is due to progression of the disease or to post surgical scarring. There were 18,222 hospital admissions for Dupuytren’s contracture in England between April 2012 and March 2013.

A recently developed alternative to surgery is an injection of the enzyme collagenase clostridium histolyticum. The collagenase initially weakens the cords over about 24 hours, after which the finger is straightened to help the cord to break. Mobilisation is encouraged and return to activity may be quicker than after open surgery. The aim of this review was to assess the effectiveness of collagenase for adults with Dupuytren's contracture compared with surgery.

What did this study do?

This was a systematic review that included a variety of study types. Five randomised controlled trials compared collagenase with placebo. The results of these were pooled in meta-analysis where possible. Two non-randomised trials compared collagenase with surgery, but no higher quality evidence was found. Six of these trials were from the USA and one was from Australia: all but one had fewer than 100 participants. Fifteen observational case series of people who had received collagenase were also included to investigate longer-term outcomes.

An economic model was developed using estimates of the costs of collagenase and the risks and benefits of each procedure. However, few studies have directly compared collagenase with surgery, and so there was considerable uncertainty about many of the assumptions used in the model.

The results need to be treated with caution. There were no randomised controlled trials comparing collagenase with surgery, and included trials were small and sponsored by companies involved in the development of collagenase.

What did it find?

  • Joints treated with collagenase were ten times more likely to achieve clinical success compared to those treated with placebo – 63% versus 6% (relative risk 10.21, 95% confidence interval 5.29 to 19.69). Clinical success was defined as a reduction in contracture to between 0° to 5° of normal, 30 days after the last injection. This was from a meta-analysis of three trials. The knuckle joints where the fingers meet the hand, improved more than the other small joints of the fingers.
  • Nearly all participants, 97%, treated with collagenase experienced an adverse event compared with around a quarter receiving placebo, most of which were mild or moderate (e.g. swelling, pain, injection site bleeding and itching). Four serious adverse events were observed in the collagenase group: three tendon ruptures and one case of severe, persistent pain.
  • Recurrence rates varied widely. For the knuckle joints they varied from 0% at one year to 27% at three years, whereas those for the first finger joints varied from 0% at one year to 56% at three years.
  • The two non-randomised controlled trials comparing collagenase with surgery gave mixed results and had a high risk of bias. This included making no attempt to take account of differences in patient characteristics between those given the alternative treatments.

What does current guidance say on this issue?

A NICE technology appraisal is currently being undertaken for collagenase clostridium histolyticum for Dupuytren's contracture. The expected publication date is unknown. The draft guidance recommends against the use of collagenase clostridium histolyticum for treating Dupuytren’s contracture, except in the context of research.

What are the implications?

The main limitation of this review was the lack of high quality trials directly comparing collagenase with surgery. Long-term data on rate of recurrence, complications and impact of repeated treatment after collagenase were also lacking.

While collagenase was significantly more effective than placebo, there was no evidence that collagenase was better or worse than surgical treatments. Two costing studies, conducted in the USA and Canada, suggest that the cost of collagenase needs to be significantly reduced if it is to offer a cost-effective alternative to surgery. The economic model produced by this study also indicated that surgery was more cost-effective than collagenase. It was estimated that one treatment with collagenase would have a total cost of around £1,739. However, due to various uncertainties these results should be treated with caution.

Citation

Brazzelli M, Cruickshank M, Tassie E, et al. Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation. Health Technol Assess. 2015 Oct;19(90):1-202.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 13/05/01).

Bibliography

Baltzer H, Binhammer PA. Cost-effectiveness in the management of Dupuytren’s contracture. A Canadian cost–utility analysis of current and future management strategies. Bone Joint J. 2013;95–B(8):1094–100.

Chen NC, Shauver MJ, Chung KC. Cost-effectiveness of open partial fasciectomy, needle aponeurotomy, and collagenase injection for dupuytren contracture. J Hand Surg Am. 2011;36(11):1826–34.

Horsley, W. Collagenase (Xiapex®) for Dupuytren’s Contracture. Newcastle: North East Treatment Advisory Group; 2011.

NHS Choices. Dupuytren's contracture. London: NHS Choices; 2015.

NICE. Dupuytren's contracture - collagenase clostridium histolyticum [ID621]. In Progress. London: National Institute for Health and Care Excellence; 2015.

NICE. Needle fasciotomy for Dupuytren's contracture. IPG43. London: National Institute for Health and Care Excellence; 2004.

NICE. NICE proposes research recommendation for Dupuytren’s disease finger contracture treatment [Press Release]. 26 February 2015. London: National Institute for Health and Care Excellence; 2015.

NICE. Radiation therapy for early Dupuytren's disease. IPG368. London: National Institute for Health and Care Excellence; 2010.

Why was this study needed?

In Dupuytren's disease connective tissue in the palm of the hand thickens, forming fibrous cords which can cause one or more fingers to bend in towards the palm of the hand – this is called Dupuytren’s contracture. The condition isn't life-threatening, but it can get steadily worse over time and make normally daily activities difficult. Most people with mild Dupuytren’s disease don’t need or seek treatment.

Surgery is commonly used to treat moderate and severe contractures by removing the thickened tissue to release the tightness in the hand. Recurrence rates are high; it is not clear whether this is due to progression of the disease or to post surgical scarring. There were 18,222 hospital admissions for Dupuytren’s contracture in England between April 2012 and March 2013.

A recently developed alternative to surgery is an injection of the enzyme collagenase clostridium histolyticum. The collagenase initially weakens the cords over about 24 hours, after which the finger is straightened to help the cord to break. Mobilisation is encouraged and return to activity may be quicker than after open surgery. The aim of this review was to assess the effectiveness of collagenase for adults with Dupuytren's contracture compared with surgery.

What did this study do?

This was a systematic review that included a variety of study types. Five randomised controlled trials compared collagenase with placebo. The results of these were pooled in meta-analysis where possible. Two non-randomised trials compared collagenase with surgery, but no higher quality evidence was found. Six of these trials were from the USA and one was from Australia: all but one had fewer than 100 participants. Fifteen observational case series of people who had received collagenase were also included to investigate longer-term outcomes.

An economic model was developed using estimates of the costs of collagenase and the risks and benefits of each procedure. However, few studies have directly compared collagenase with surgery, and so there was considerable uncertainty about many of the assumptions used in the model.

The results need to be treated with caution. There were no randomised controlled trials comparing collagenase with surgery, and included trials were small and sponsored by companies involved in the development of collagenase.

What did it find?

  • Joints treated with collagenase were ten times more likely to achieve clinical success compared to those treated with placebo – 63% versus 6% (relative risk 10.21, 95% confidence interval 5.29 to 19.69). Clinical success was defined as a reduction in contracture to between 0° to 5° of normal, 30 days after the last injection. This was from a meta-analysis of three trials. The knuckle joints where the fingers meet the hand, improved more than the other small joints of the fingers.
  • Nearly all participants, 97%, treated with collagenase experienced an adverse event compared with around a quarter receiving placebo, most of which were mild or moderate (e.g. swelling, pain, injection site bleeding and itching). Four serious adverse events were observed in the collagenase group: three tendon ruptures and one case of severe, persistent pain.
  • Recurrence rates varied widely. For the knuckle joints they varied from 0% at one year to 27% at three years, whereas those for the first finger joints varied from 0% at one year to 56% at three years.
  • The two non-randomised controlled trials comparing collagenase with surgery gave mixed results and had a high risk of bias. This included making no attempt to take account of differences in patient characteristics between those given the alternative treatments.

What does current guidance say on this issue?

A NICE technology appraisal is currently being undertaken for collagenase clostridium histolyticum for Dupuytren's contracture. The expected publication date is unknown. The draft guidance recommends against the use of collagenase clostridium histolyticum for treating Dupuytren’s contracture, except in the context of research.

What are the implications?

The main limitation of this review was the lack of high quality trials directly comparing collagenase with surgery. Long-term data on rate of recurrence, complications and impact of repeated treatment after collagenase were also lacking.

While collagenase was significantly more effective than placebo, there was no evidence that collagenase was better or worse than surgical treatments. Two costing studies, conducted in the USA and Canada, suggest that the cost of collagenase needs to be significantly reduced if it is to offer a cost-effective alternative to surgery. The economic model produced by this study also indicated that surgery was more cost-effective than collagenase. It was estimated that one treatment with collagenase would have a total cost of around £1,739. However, due to various uncertainties these results should be treated with caution.

Citation

Brazzelli M, Cruickshank M, Tassie E, et al. Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation. Health Technol Assess. 2015 Oct;19(90):1-202.

This project was funded by the National Institute for Health Research Health Technology Assessment programme (project number 13/05/01).

Bibliography

Baltzer H, Binhammer PA. Cost-effectiveness in the management of Dupuytren’s contracture. A Canadian cost–utility analysis of current and future management strategies. Bone Joint J. 2013;95–B(8):1094–100.

Chen NC, Shauver MJ, Chung KC. Cost-effectiveness of open partial fasciectomy, needle aponeurotomy, and collagenase injection for dupuytren contracture. J Hand Surg Am. 2011;36(11):1826–34.

Horsley, W. Collagenase (Xiapex®) for Dupuytren’s Contracture. Newcastle: North East Treatment Advisory Group; 2011.

NHS Choices. Dupuytren's contracture. London: NHS Choices; 2015.

NICE. Dupuytren's contracture - collagenase clostridium histolyticum [ID621]. In Progress. London: National Institute for Health and Care Excellence; 2015.

NICE. Needle fasciotomy for Dupuytren's contracture. IPG43. London: National Institute for Health and Care Excellence; 2004.

NICE. NICE proposes research recommendation for Dupuytren’s disease finger contracture treatment [Press Release]. 26 February 2015. London: National Institute for Health and Care Excellence; 2015.

NICE. Radiation therapy for early Dupuytren's disease. IPG368. London: National Institute for Health and Care Excellence; 2010.

Collagenase clostridium histolyticum for the treatment of Dupuytren's contracture: systematic review and economic evaluation

Published on 3 November 2015

Brazzelli, M.,Cruickshank, M.,Tassie, E.,McNamee, P.,Robertson, C.,Elders, A.,Fraser, C.,Hernandez, R.,Lawrie, D.,Ramsay, C.

Health Technol Assess Volume 19 , 2015

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. OBJECTIVES: 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. DATA SOURCES: We searched all major electronic databases from 1990 to February 2014. REVIEW 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 pound1199 more costly and generated an additional 0.11 QALYs in comparison with PNF. The incremental cost-effectiveness ratio was pound10,871 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. LIMITATIONS: 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. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013006248. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The British Society for Surgery of the Hand classifies Dupuytren’s disease as mild, moderate or severe:

Mild: No functional problems. No contracture or metacarpophalangeal (knuckle) joint contracture of less than 30°.

Moderate: Functional problems. Metacarpophalangeal joint contracture of 30° to 60°, or proximal interphalangeal joint (between the first and second bones of the finger) contracture of less than 30°.

Severe: Severe contracture of both metacarpophalangeal joint (greater than 60°) and proximal interphalangeal joint (greater than 30°).

Expert commentary

The key issues that this review does not address are the heterogeneity of disease, the technical challenges of a randomised controlled trial in Dupuytren’s disease and patient issues in its cost effectiveness analysis. Percutaneous needle fasciotomy is not widely used except for the simplest of cords and is not in general a suitable comparator for moderate and severe Dupuytren’s disease. Collagenase clostridium histolyticum is suitable for more complex cords and allows patients to return to taxpaying work, weeks sooner than surgery, a very relevant aspect of cost effectiveness which ought to be considered. In my view, and this is supported by many experienced hand surgeons with whom the topic has been discussed, a recommendation which does not take full account of the heterogeneity of disease and the “paint palette” requirement for clinical management, would do patients a disservice if it led to the withdrawal of one clinically useful treatment pending a head to head trial.

Professor David Warwick, Consultant Hand and Orthopaedic Surgeon, University Hospital Southampton