Hand function and cost effectiveness after collagenase injection versus aponeurectomy for Dupuytren’s contracture: results of the CeCORD-J study

Background This study compared hand function and the cost effectiveness of treatment between collagenase Clostridium histolyticum (CCH) injection and limited fasciectomy for patients with Dupuytren’s contracture (DC). Methods The CeCORD-J study is a prospective, multicenter, non-randomized controlled, observational study of two parallel groups. Participants were DC patients with multiple affected ngers, including exion contracture of the proximal interphalangeal (PIP) joint. The primary outcome was the Hand10 score, as a patient-reported outcome measure. We set secondary outcomes of EQ-5D-5L score, degree of extension decit, and direct cost. Propensity score adjustment was used to balance differences in patient characteristics between groups. Results Participants comprised 52 in the Collagenase group and the Hand10 score was signicantly better in the Collagenase group at 1 and 2 weeks. EQ-5D-5L score was signicantly higher in the Collagenase group at 8 weeks. Mean direct cost was 248,000 yen higher in the Surgery group than in the Collagenase group. Extension decit angle of the PIP joint was signicantly larger in the Collagenase group at 26 weeks.


Introduction
Dupuytren's contracture (DC) is a broproliferative disease of the palmar hand. DC causes symptomatic and progressive exion contractures of the digits 1 . Flexion contracture often occurs in the metacarpophalangeal (MP) and/or proximal interphalangeal (PIP) joints of the ring and little ngers 2 .
Flexion contracture of the digits in uences daily activities and quality of life (QOL) by limiting hand function 3 . DC has been considered common in Caucasians of Scandinavian and Celtic ancestry, but reports on DC from Asian and African countries have increased recently 4,5 . Both genetic and environmental factors are considered to affect disease progression, and the prevalence of DC increases with age 6 .
Surgical procedures including fasciectomy, dermatofasciectomy, and needle fasciotomy have been standard treatment options for DC. Since Hurst et al. reported level 1 evidence for the utility of collagenase Clostridium histolyticum (CCH) injection compared with placebo in 2009, the United States Food and Drug Administration in 2010, the European Medicines Agency in 2011 and the Japanese Pharmaceuticals and Medical Devices Agency in 2015 have approved CCH injection for patients with DC 5,7 .
Hand function and degree of exion contracture after treatment are the most important issues for patients with DC. Some reports have described upper limb function using patient-reported outcome measures (PROMs) such as Disabilities of the Arm, Shoulder and Hand (DASH) and the Michigan Hand Outcomes Questionnaire (MHQ) before and after surgical treatment for DC 8,9,10 . However, few papers have reported results from PROMs before and after CCH injection for patients with DC. Furthermore, very few studies have prospectively compared results between surgery and CCH injection using PROMs.
Outcomes after treatment will differ depending on which joints are affected. Generally, exion contracture of MP joints shows better prognosis than that of PIP joints. Treatment is more di cult for PIP joints than for MP joints because of the higher frequencies of recurrence and complications. A study of patients with DC-affected PIP joints is thus necessary.
The cost effectiveness of DC treatments has been reported from European and North American countries.
Atroshi et al. reported costs for collagenase injections compared with fasciectomy in the treatment of DC as a retrospective cohort study in Sweden 11 . Although the follow-up period was as short as 6 weeks, treatment of DC with one collagenase injection cost 33% less than fasciectomy, while offering equivalent e cacy of contracture reduction. Baltzer and Binhammer in Canada estimated that injectable collagenase would be feasible for treating DC affecting a single nger if it cost signi cantly less than the current United States pricing 12 . On the other hand, the National Health Service (NHS) in the United Kingdom simulated the costs of treatment for patients with DC affecting more than three joints, revealing limited fasciectomy as more cost effective than percutaneous needle fasciotomy or CCH injection. CCH injection showed the worst cost effectiveness for patients with DC affecting multiple ngers 13 . However, the costs of CCH injections, surgical procedures, and hand therapy differ between countries. Most patients are interested in the prices of treatment and often ask hand surgeons about the costs. Hand surgeons thus need cost and utility data as well as results for hand function after treatment for DC to provide patients with su cient information on functional and economic aspects to make informed decisions before treatment.
The purpose of this study was to compare hand function and direct medical cost between CCH injection and limited fasciectomy for patients with DC-affected PIP joints. Our primary aim was to compare hand function between CCH injection and fasciectomy using the Hand10 PROM 14 . Secondary outcomes were set to compare QOL using the EQ-5D-5L 15 , patient satisfaction, degree of contracture, and direct cost. We hypothesized that no signi cant difference in hand function or QOL would be evident between groups, but that CCH injection would prove superior to fasciectomy in terms of cost effectiveness.

Materials And Methods
The CeCORD-J study is a prospective, multicenter, non-randomized controlled, observational study with two parallel groups. This study provides the utmost respect for the treatment choices of patients.

Study setting
After the ethics committee approval of Nagoya University Hospital (2017-0506-4), the CeCORD-J study was approved by the academic research project committee of the Japanese Society for Surgery of the Hand (JSSH) as an o cial project in 2017. We invited participation from all major referral centers of hand surgery in Japan with at least one hand surgery specialist. A nal total of 28 hand surgery centers accepted and joined this study. Patients were recruited from those centers. Investigators had to have specialist certi cation in hand surgery because CCH injection can only be performed by hand surgery specialists in Japan. All participating investigators had previously performed both CCH injection and fasciectomy before initiation of the study. Hand surgeons participating in this study held three meetings before starting this study to con rm the protocol.

Ethics and dissemination
Both treatment options are standard procedures for patients with DC in Japan. This study was not a randomized controlled study for intervention selection. We have the utmost respect for patient preferences in terms of treatment selection. This study was therefore not interventional but observational in nature. This policy offers substantial bene ts for patient recruitment. Our major concern was bias in the number of cases in each group. One solution to this issue is propensity score adjustment after study completion.
Information on the trial and patient approval Written information was used to explain the study to patients. Because this study was observational in nature, patients were able to select their preferred treatment after explanation of both treatments by hand surgery specialists. Hand surgery specialists obtained informed consent for participation from each patient after the decision-making process.

Participants
The inclusion criteria were: 1) patients with passive extension de cit in either only PIP joints or both PIP and MP joints; 2) exion contractures in at least two ngers of one hand; 3) age >20 years; and 4) the ability to answer questionnaires in Japanese.
Exclusion criteria were: 1) recurrent contracture in the nger to be treated; 2) contraindications for CCH injection; 3) pregnancy or planning to become pregnant; 4) need for continued anticoagulation; 5) participation in another clinical study; 6) judgement that study participation would be inappropriate by the enrolling investigator.

Baseline assessment
Baseline demographics of patients included age, sex, family history of DC, duration of symptoms, medical history, histories of smoking and drinking, involved ngers and joints, and PROMs for the hand (Hand10), EQ-5D-5L, and satisfaction (a 5-point scale).

Interventions
Patients requesting CCH injection were included in the Collagenase group. In this group, 0.58 mg of CCH was injected into the cord of the affected nger. One day after injection, the affected nger was manipulated under local anesthesia or wrist block. Patients could receive additional CCH injections up to 3 times in total if necessary, at intervals of >30 days.
Patients hoping to undergo fasciectomy were included in the Surgery group. In this group, aponeurectomy was performed under general anesthesia or axillary block.
Patients in both groups received hand therapy including splinting based on the judgement of the surgeon. An attending hand surgery specialist decided whether inpatient or outpatient treatment was warranted. Generally, patients in the Surgery group required inpatient treatment, and those in the Collagenase group could be treated using either outpatient or inpatient treatment.

Primary outcome
The primary outcome was the PROM score for the Hand10 before and 1, 2, 4, 8, and 26 weeks after intervention. The Hand10 is a valid instrument for patients with upper limb disorder, even in elderly individuals, as the questionnaire includes illustrations that provide favorable effects on reproducibility 14 . The Hand10 questionnaire consists of 10 self-reported questions designed to measure upper extremity disability and symptoms. Scores for the Hand10 range from 0 to 100, with lower numbers indicating lower levels of disability.

Secondary outcomes
We set the following secondary outcomes: 1) EQ-5D-5L (QOL) score; 2) patient satisfaction; 3) degrees of extension de cit and exion of the treated joint, and 4) direct medical costs. We also investigated: 1) complications; and 2) recurrences as other outcomes. Recurrences were assessed 1 year after treatment, and all other secondary outcomes were evaluated up to 26 weeks after interventions.
Recurrence was considered to have occurred if the degree of extension de cit worsened by more than 30°a fter treatment. We classi ed complications as: grade I, minor complications without needing any unexpected surgery or anesthesia; or grade II, major complications needing unexpected surgery under anesthesia or inpatient treatment. Each outcome was compared with baseline data.

Discontinuation criteria
Discontinuation criteria were: 1) when the patient requested to withdraw from the study; 2) when the patient was found not to satisfy eligibility criteria after registration; 3) when continuation of the study was di cult because symptoms or complications worsened; or 4) when the hand surgery specialist decided on discontinuation for any other reason. When discontinuation occurred, data collection was stopped, but data collected up to the time of discontinuation were retained for use in the study.

Power analysis
Setting values of α=0.05 and β=0.8, sample size "n" was calculated as n=16s 2 /d 2 , where "s" is the standard deviation and "d" is the difference between two groups. According to previous papers, mean DASH score at 1 year postoperatively was 12.7 (standard deviation, 3.6) 8 , and mean DASH score at 1 year after CCH injection was 7 (standard deviation, 9) 16 . We did not use DASH score, but Hand10 was expected to show similar results. We therefore used "s" as 9, and "d" as 5.7 for sample size calculations. If both groups were to include the same number of patients, a sample size of 40 per group was required.

Statistical analysis
We compared baseline patient demographics between groups using the unpaired t-test or chi-square test.
Baseline patient demographics included age, sex, number of involved ngers and joints, degree of extension de cit, Hand10 score, EQ-5D-5L (QOL) score, and satisfaction.
As the primary outcome, Hand10 scores were compared between groups using the unpaired t-test.
EQ-5D-5L (QOL) score, satisfaction, and degree of extension de cit were compared between groups as secondary outcomes using the unpaired t-test. Satisfaction was compared between groups using the Mann-Whitney U test. We compared mean direct medical costs between groups.
Prevalence and severity of complications were summarized and compared between groups using the chisquare test.
Propensity score adjustment was used to balance differences in patient characteristics between Collagenase and Surgery groups. In a logistic regression model with treatment assignment variables (Collagenase group = 0, Surgery group = 1) as the dependent variables, the following independent variables were introduced to obtain the propensity score (= probability of undergoing surgery) for each patient: age, sex, total number of affected joints per patient, total number of affected ngers per patient, family history of DC, duration of symptoms, smoking, drinking, past or present history of diabetes mellitus, epilepsy, history of hand trauma, malignant tumor, baseline Hand10 score, baseline degree of extension defect of the primary PIP joint, degree of extension of the primary MP joint, and baseline EQ-5D-5L (QOL) score.
Outcomes were then compared between treatment groups after adjusting for propensity scores. Speci cally, a generalized linear model with treatment assignment variables (Collagenase group = 0; Surgery group = 1) and propensity scores as independent variables and outcomes as dependent variables was used to determine differences in outcomes and associated 95% con dence intervals and p-values in the collagenase-controlled Surgery group.

Data management
We used a central monitoring system in the data center. Each hand surgery center registered anonymized patient information to the data center. Hand surgery specialists noted patient data at each time point and those data were stored at each hand surgery center. Anonymized patient data were collected at the data center by mail after nishing the follow-up period. This study was monitored by an independent assessor during patient recruitment and after completion of the study.
This study followed and respected the Declaration of Helsinki and the principles of good clinical practice.

Participants
A total of 98 participants were initially enrolled in this study from April 2018 to July 2019. Of those, 20 were excluded, and data from 52 patients in the Collagenase group and 26 patients in the Surgery group (total cohort, 78 patients) were analyzed. The 20 patients were excluded due to contracture in only 1 nger (n=10), dropout (n=9), or voluntary withdrawal from the study before treatment (n=1) (Figure 1). Participant demographics are shown in Table 1. In the Collagenase group, 5 of 52 patients received a second injection at different sites.

Primary outcome
The time course for Hand10 score as primary outcome is shown in Figure 2. Hand10 scores were signi cantly higher in the Surgery group than in the Collagenase group at 1 and 2 weeks after treatment.

Secondary outcomes
The outcomes of EQ-5D-5L (QOL) score, direct cost, recurrence, complications, and satisfaction are summarized in Table 2. EQ-5D-5L (QOL) score was signi cantly higher in the Collagenase group than in the Surgery group at 2 weeks after treatment (Figure 3). The direct cost for the Collagenase group was 370,000 yen (about $3395 US dollars (USD) at an exchange rate of $1 = 109 yen) on average, compared to 580,000 yen (about $5321) for the Surgery group, representing a signi cant difference.
Recurrences were more frequent in the Collagenase group than in the Surgery group (18% vs 9.5%).
All complications in both groups were minor without additional surgery or anesthesia.
No signi cant difference in satisfaction was seen between groups. All patients in the Surgery group provided evaluations above neutral.
As other evaluation items, the time courses of extension de cit angle and exion angle of the PIP and MP joints are shown in Table 3. No signi cant difference in extension de cit angle of the PIP or MP joint was seen between groups ( Figure 4). Flexion angles of the PIP joint at week 4 and of the MP joint at weeks 4 and 26 were signi cantly smaller in the Surgery group than in the Collagenase group ( Figure 5).

Analysis with propensity score adjustment
Results from propensity score adjustment are presented in Table 4. Hand10 score was signi cantly higher in the Surgery group at 1 and 2 weeks, but not at other time points. No signi cant difference in EQ-5D-5L (QOL) score was seen after adjusting for propensity scores, except at 8 weeks. The direct cost was 248,000 yen (about $2275) higher in the Surgery group than in the Collagenase group on average. A signi cant difference in extension de cit angle of the PIP joint was apparent between groups at 26 weeks. Although exion angle after intervention was smaller in the Surgery group, no signi cant difference was evident between groups after propensity score adjustment.

Discussion
This multicenter, prospective observational study compared outcomes between CCH injection and aponeurectomy. This study was unique in that we included only patients with multiple affected ngers, including exion contracture of the PIP joint, which is di cult to treat. This study did not randomize patients, and treatment groups were divided according to the preferences of the patient. The Collagenase group was a double of the Surgery group, because many patients preferred treatment with CCH injection.
Change in Hand10 score, as the primary outcome, showed a signi cant difference between the acute phase of weeks 1 and 2 after treatment, indicating that patients injected with CCH were able to return to daily life earlier than patients who underwent surgery. The results of propensity score adjustment to balance differences in patient backgrounds between groups also revealed signi cant differences in Hand10 score at 1 and 2 weeks. Zhou et al. compared CCH injection with limited fasciectomy using propensity score matching and showed signi cant improvements in activities of daily living, work performance, and satisfaction in their collagenase group compared to surgery group using the Michigan Hand Outcomes Questionnaire 9 . In the present study, the Collagenase group showed better PROMs than the Surgery group in the short-term, similarly as reported by Zhou et al.
EQ-5D-5L (QOL) score was signi cantly higher in the Collagenase group than in the Surgery group after 2 weeks. However, after propensity score adjustment, a signi cant difference was only observed at 8 weeks. Given the difference of about 248,000 yen (about $2275) in direct costs even if the EQ-5D-5L (QOL) score is almost equivalent between groups, collagenase appears to offer better short-term costeffectiveness by 26 weeks, even for those patients with multiple affected joints, including PIP joints. The price of collagenase in Japan is 197,202 yen, and 24,900 yen is added as a procedure fee, for a total of 222,102 yen (about $2038). On the other hand, the cost of surgery is 224,800 yen for two or three affected ngers, plus 1,700 yen for regional anesthesia, for a total of 226,500 yen (about $2078). No signi cant difference in cost was seen between collagenase injection and surgery itself, but hospitalization and rehabilitation visits led to a difference in total direct costs. CCH injection is feasible for treating DC affecting a single nger, according to a Canadian cost-utility analysis 12 . Conversely, the NHS has estimated that CCH injection would yield the worst cost effectiveness for DC involving more than three joint contractures 13 . Although the follow-up period was short, at 26 weeks, the present study provided evidence for the cost effectiveness of CCH injection even for hands affected in multiple ngers, including PIP joints.
No signi cant difference in satisfaction was seen between groups using the 5-point scale, and all patients in the Surgery group provided evaluations above neutral. The satisfaction of patients in both groups was not poor, regardless of cost-effectiveness.
The number of complications tended to be higher in the Collagenase group. Skin laceration was the most frequent complication in the Collagenase group, and no serious complications showing a causal relationship to the treatment were encountered. Recurrence also tended to be more frequent in the Collagenase group. Recurrences were reported in 160 of 199 digits (80%) at an average of 7.2 years after collagenase injection despite a heterogeneous patient population 17 . Furthermore, Yoon et al. simulated recurrent DC in a 60-year-old patient and concluded that collagenase injections are not a cost-effective intervention and should not be preferred over percutaneous needle aponeurotomy or limited fasciectomy 18 . Leafblad et al. retrospectively reviewed 848 interventions for DC, and reported 2-year reintervention rates following needle aponeurotomy, collagenase, and fasciectomy of 24%, 41%, and 4%, respectively, and 5-year rates of 61%, 55%, and 4%, respectively 19 . Cumulative costs for possible reinterventions thus also need to be taken into consideration.
A signi cant difference in nger exion angle was seen between groups after treatment. Flexion angles of both the PIP and MP joints were reduced in the Surgery group. This phenomenon often occurs clinically, and although nger extension improves after surgery, bending the joint deeply when grasping becomes di cult. This effect is attributed to swelling of the ngers, surgical scarring, and tendon adhesion. Rehabilitation measures such as passive range-of-motion training were required after surgery. In the Collagenase group, the decrease in exion angle was slight and rehabilitation was often not required, which was considered to affect the cost. However, after adjusting for propensity scores, no signi cant difference in nger exion angle was evident between groups.
This study provided comprehensive evidence for a comparison of collagenase injection and surgery for DC with contractures of more than two ngers including a PIP joint. However, some limitations must be kept in mind when interpreting the ndings from this study. First, some degree of selection bias would be present, because this was a prospective observational study and patients were not randomly assigned. Surprisingly, the two groups showed no signi cant differences in background characteristics other than the number of patients. Furthermore, propensity score adjustments were performed to balance differences in patient background between groups without reducing the number of participants eligible for analysis. Second, recurrence was evaluated at 52 weeks, while all other outcomes had a follow-up period of 26 weeks. Although the nancial issue of multi-institutional, long-term follow-up study needs to be considered, comparison of longer-term results is certainly desirable. However, for the elderly individuals who represent the majority of patients with this disease, short-term results are also important.

Conclusion
For DC with multiple affected ngers, including exion contracture of the PIP joint, this multicenter, prospective, observational study was conducted by dividing patients into an injectable collagenase group and a surgical group, giving priority to the wishes of the patient. Propensity scores were adjusted to balance differences in patient background between groups. As a primary outcome, the PROM of Hand10 score was signi cantly better in the Collagenase group at 1 and 2 weeks after treatment, but no differences were evident between groups at 26 weeks. EQ-5D-5L (QOL) score tended to be higher in the Collagenase group, and the direct cost was 248,000 yen (about $2275 US dollars at the exchange rate of $1 = 109 yen) higher in the Surgery group than in the Collagenase group. Short-term cost-effectiveness appeared better in the Collagenase group. The degree of extension de cit of the PIP joint after treatment was signi cantly larger in the Collagenase group, and minor complications and recurrences tended to be more frequent in the Collagenase group. The CeCORD-J study was able to compare comprehensive data on hand function and cost effectiveness between collagenase injection and surgery. The results of this study will help in treatment decisions.    Figure 1 Study owchart Twenty patients were excluded because of single affected nger (n=10), loss to follow-up (n=9), or withdrawal before treatment (n=1). n, number

Figure 2
Page 20/21 Time course for Hand10 scores Hand10 score was assessed as the primary outcome. Hand10 scores were signi cantly higher in the collagenase group compared to the surgery group at both 1 week and 2 weeks. w, week Figure 3 Time course for EQ-5D-5L (QOL) scores QOL scores were signi cantly higher in the Collagenase group than in the Surgery group from 2 weeks to 26 weeks. w, week Time course for degree of contracture No signi cant difference was identi ed between groups. w, week Time course for exion angle Mean exion angle of the PIP joint was signi cantly smaller in the Surgery group than in the Collagenase group at 4 weeks. Mean exion angle of the MP joint was signi cantly smaller in the Surgery group than in the Collagenase group at both 4 and 26 weeks. w, week