Using collagenase to treat Dupuytren’s disease: a hypothetical cost benefit analysis

Section: Hand Abstract Background: Dupuytren’s disease is a disorder of abnormal collagen production that may manifest in the palmar fascia. Treatment options vary according to clinical circumstances but surgical fasciectomy remains the gold standard. Collagenase, an enzyme produced by clostridium histolyticum (CCH), is a relatively new injection able to cleave collagen strands in vitro. While the drug is not yet available on the Pharmaceutical Benefits Scheme, its side effect profile and risk of recurrence are comparable to fasciectomy in appropriately selected patients. In this study, we aimed to demonstrate the safety and cost-effectiveness of collagenase for the treatment of Dupuytren’s disease.


Background
Dupuytren's disease is a disorder of abnormal collagen production that may manifest in the palmar fascia. 1 Contracture of the joints in the hand may ensue and this may adversely affect hand function. Extra-palmar manifestations may involve the knuckles (Garrod's pads), feet (Ledderhose disease) and penis (Peyronie's disease). 2 The Dupuytren's diathesis predicts a more aggressive disease course 3 and is defined by disease onset in youth, the involvement of multiple rays including the radial digits and extra-palmar disease. 4 The precise disease aetiology is unknown. A genetic predisposition is recognised and a northern European heritage portends a greater risk. 2 Known associations include male gender, advancing age, alcohol use, smoking, infection with HIV, diabetes mellitus, anti-epileptic medications and working with vibrating tools. 3,5 The pathogenesis of the disease also remains unknown. Several theories have been proposed including a perpetuating cycle of ischaemia, free radical production, tissue contracture and further ischaemia. 6 The observation that diseased cords have a much higher proportion of reparative type III collagen than normal fascial bands suggests a pathophysiology whose final pathway is tissue injury. Dupuytren's disease. The collagenase clostridium histolyticum (CCH) formulation consists of two distinct collagenases (types I and II) and both have been shown to cleave collagen strands in vitro. 8 The drug is injected directly into the target cord, which weakens over the ensuing 48 hours and is then ruptured, either spontaneously or by a controlled extension procedure.
The injection of collagenase into diseased cords in Dupuytren's disease has been shown to increase range of motion and reduce contractures (level 1 evidence). 9 Collagenase has the advantage of a side effect profile and risk of recurrence that is comparable to fasciectomy in appropriately selected patients and a much quicker return to work. 10 [11][12][13] Similarly well-designed studies have not yet been performed in Australia.

Aim
The aim of this study is twofold: to show that collagenase is a safe and cost-effective treatment in the Australian public healthcare system; and to demonstrate implementation of this finding in a small public health patient cohort.

Method
A retrospective review of our operating room data was undertaken to identify those patients who had undergone surgical fasciectomy at our institution between 2009 and 2014. Using the transitional II costing system, our finance department calculated all direct and indirect costs associated with admission to our hospital for surgical fasciectomy. The CORD I inclusion criteria were then applied to this population to identify patients who might have been suitable for collagenase injection. 9 These criteria include age 18 years or older and Dupuytren's contracture affecting one metacarpophalangeal (MCP) joint (contracture ≥20 to ≤100 0 ) or one proximal interphalangeal (PIP) joint (contracture ≥20 to ≤80 0 ). 10 Costs and benefits were compared between the surgical and hypothetical collagenase groups using the incremental costeffectiveness ratio (ICER).
The costs associated with supply of collagenase were provided by our local distributer. The additional associated costs were supplied by our hospital pharmacy department. Outpatient costs including initial assessment and post-procedural reviews were assumed to be the same in both groups, though it is likely that patients treated with collagenase would have had fewer outpatient appointments on the basis of collagenase treatment in the local private sector. 10 The incidence of complications and the risk of recurrence for each modality were determined from a review of the literature. [14][15][16] Complications were stratified according to severity using the Accordion classification ( Table 1). These strata were then weighted to give a post-operative morbidity index (PMI) where 0 represents perfect health and 1 represents death. This approach to grading postoperative complications has been validated for this purpose. 17 The risk of a given complication, represented by its incidence and expressed as a percentage, was then multiplied by its PMI to give a numerical value that is a function of both the severity and the incidence of the given complication. These values were then added together to give an aggregated complication risk as one measure of effect for a specific treatment modality.
The ICER was calculated using the following Patients who passed screening were offered an appointment. At the initial visit, patients were rescreened for inclusion, assessed with a QuickDash questionnaire and subjected to an examination.
The patient's treatment options were then

Results
Forty     see Table 5). Average pre-injection Tubiana stage  In this study, estimates of cost were conservative and, because of this, favoured surgical fasciectomy.
The number of outpatient visits was assumed to be the same for both groups, though it is likely that the surgical fasciectomy group would need more outpatient visits than the collagenase group.
Furthermore, the total time required per outpatient visit is likely less for collagenase patients as they rarely require dressings or removal of sutures.
The need for hand therapy may also be decreased.
These variables and others, including the effect of early return to work, were not measured in this study. A barrier to the implementation of outpatient injections of collagenase in a public hospital may be access to an appropriate facility and the availability of personnel trained in its use.
These barriers can be overcome and our study suggests that efforts to do this may be worthwhile, even if there is a material cost involved.

Conclusion
The data from our patient cohort who received collagenase injections corroborate findings from previous studies that injection of collagenase for Dupuytren's disease is effective in reducing joint contracture and improving range of motion. Our gains in range of motion are similar to those found in larger studies 9 and the injections have been shown to be well tolerated with low risk of adverse events. In light of the demonstrable clinical benefits to patients, and the apparent cost-effectiveness of this treatment, it is hoped that data from this study will encourage use of collagenase for Dupuytren's disease in the Australian public hospital system.