Comparative cost and clinical effectiveness of clostridial collagenase ointment for chronic dermal ulcers

Clostridial collagenase ointment (CCO) is currently the only enzymatic debriding ointment that has US FDA approval and has been used as a method of wound debridement for more than 50 years [12]. Bacterial collagenase isolated from Clostridium histolyticum is a selective enzymatic agent that causes hydrolytic cleavage of collagen molecules, which are a major component of nonviable tissue in the wound bed [13]. CCO effectively and selectively removes detritus without harming healthy tissue, thus contributing to the formulation of granulation tissue and subsequent epithelialization of dermal ulcers [14].

A large body of experimental data suggests that, in addition to its debriding activity, CCO may actively promote healing by potentiating cellular migratory, proliferative and angiogenic responses to injury [13]. Further, CCO may decrease the excessive and prolonged inflammation associated with nonhealing wounds by downregulating inflammatory cytokines [15]. In vitro and in vivo studies suggest that these effects are mediated by biologically active matrix fragments or peptides liberated via specific cleavages made by CCO during the debridement process [13,15]. Unlike endogenous human collagenases, CCO cleaves collagen at multiple sites, thus facilitating the production of multiple bioactive peptides [16]. Galperin et al. demonstrated that in differentiated THP-1 monocytes, clostridial collagenase-digested collagens suppressed lipopolysaccharide-induced release of TNF-α and lL-6 [15]. Furthermore, in 17 patients with DFUs treated with CCO versus hydrogel, the level of analytes associated with resolution of inflammation increased while those associated with inflammation (TNF-α and IL-6) decreased [15].

National wound registry data aggregated from electronic health records (EHRs) of hospital-based outpatient wound center patients revealed that between 13 and 20% of more than 28,000 DFUs, VLUs and PUs analyzed were treated with CCO [17–19]. The authors found that healthcare providers are using CCO in more severe, difficult-to-heal wounds; mean wound surface area was significantly larger in DFUs treated with CCO compared with wounds not treated with CCO (7.6 vs 5.4 cm², respectively; p < 0.0001), and the majority of PU wounds treated with CCO were stages III and IV (60.1 and 29.6%, respectively). In addition, relative to the overall population among all wound types, patients treated with CCO had substantially longer days in service and their wounds were more likely to receive debridement of all methods.

Only a small number of systematic reviews of the medical literature on the safety and effectiveness of CCO have been published in recent years. A systematic review by Ramundo and Gray published in 2009 analyzed 12 retrospective and prospective studies of CCO for treatment of PUs, leg ulcers or burn wounds: 5 randomized controlled trials (RCTs) compared CCO versus placebo  and 7 studies compared CCO with alternative active debridement methods (e.g., hydrogel, silver sulfadiazine and autolysis) [20]. The authors determined that CCO is a selective, effective method for debridement of PUs, leg ulcers and burn wounds that has been used safely in adult, geriatric and pediatric populations. A recently published (2017) systematic review and meta-analysis by Patry and Blanchette analyzed 22 RCTs evaluating enzymatic debridement with CCO in all types of wounds and ulcers across all care settings [21]. The authors qualitatively summarized outcomes of collagenase either for wound healing or wound debridement and supported its use for enzymatic debridement in PUs, DFUs and in conjunction with topical antibiotics for burns [21]. Meta-analysis (n = 10 studies) was performed for the risk of adverse events (primary outcomes were not meta-analyzed). An increased risk of adverse events was calculated in patients treated with collagenase compared with alternative therapies (relative risk: 1.79; 95% CI: 1.24–2.59; I² = 0%; p = 0.002). It should be noted that several studies were excluded from this analysis as two references were based on a single RCT, another RCT compared adverse events between different posology of collagenase and several studies did not report adverse events. Adverse events related to collagenase were seen in 11 of 17 RCTs (10 had values and relationships to adverse events made by authors). Subgroup analysis for significant adverse events related to collagenase or the alternative treatment (cellulitis was the only one suspected upon initial analysis) yielded no statistically significant relationships [21]. An examination of the individual studies included in this adverse event analysis reported infrequent pruritus, rash, edema, erythema (one case in one study), burning sensation at wound site (similar frequency between groups in several studies), burn bed infection (in a single study, seven cases with collagenase vs one case in control group), herpes infection (one case in one study), mild bleeding (one case in one study) and cellulitis (several cases in several studies). However, the risk ratio of developing cellulitis was not found to be statistically significantly different between treatment groups on subgroup analysis by Patry et al. [21–30], and a high risk of bias was noted by the Cochrane risk of bias tool among the majority of RCTs included. The systematic review and meta-analysis contained information from some, but not all, of the more recent studies in the literature as it was limited to RCTs, excluding cohort (prospective or retrospective) studies.

Therefore, we performed a narrative review to discuss the results of more recent real-world studies that expand upon the RCT evidence base, to demonstrate the effectiveness and safety of CCO across wound types (VLU, PU, DFU, burns) and care settings (acute care, postacute care and long-term care) and illustrate the cost–effectiveness of CCO as a debridement option.

CCO has been studied for the treatment of PUs in several studies, both in the long-term care setting and in the outpatient setting, either as monotherapy versus AD with hydrogel or medicinal honey, or in combination with sharp debridement versus sharp debridement alone (Table 1) [12,34–37].

Milne et al. conducted a two-phase RCT on 27 patients with PUs residing in a long-term care facility, comparing CCO with AD plus hydrogel [34,35]. In the first phase of the study, which evaluated wound debridement for 6 weeks after randomization (based on Pressure Ulcer Scale for Healing Tool score and Wound Bed Score), CCO was superior to hydrogel in fully debriding nonviable tissue in 11 of 13 (85%) PUs versus 4 of 14 (29%) PUs in patients randomized to each treatment, respectively (p < 0.003). Of note, the mean wound size at baseline was significantly larger in the group treated with CCO (12.29 vs 7.90 cm², respectively) [35].

The second phase of the study recruited only patients with wounds that were completely debrided in each group 6 weeks after randomization; these patients were followed until wound closure or to day 84 [34]. Patients continued to receive either CCO or hydrogel on a daily basis, even though no visible devitalized tissue was present in the wounds. All patients (n = 3) in the hydrogel group reached complete epithelialization with a mean of 32.6 days, and 9 of 10 patients in the CCO group reached complete epithelialization with a mean of 45 days (p = 0.121; one patient in each group was eliminated within the first week). In aggregating Phase I and Phase II data, the closure rates at the end of the study were superior for collagenase (69%) versus hydrogel (21%; p = 0.0213). The authors concluded that these findings add to the evidence base that facilitating maintenance debridement, either by collagenase or hydrogel, can be used to complete wound closure when utilized in conjunction with a validated predictive wound healing tool that closely monitors therapy.

In a more recent publication, Waycaster et al. [36] report additional details and outcomes assessed in Phase I of the above study that further support the potential of CCO to improve clinical outcomes in patients with PUs in a long-term care setting. Patients treated in Phase I with CCO had a granulation rate approximately twice that of those receiving hydrogel (average 2% gain in granulation tissue per day vs 1% per day, respectively), and showed a significantly greater percentage of granulation tissue formation at week 6 (p = 0.003). Similarly, Wound Bed Score values improved more rapidly among patients treated with CCO, and improvements from baseline to week 6 were greater in patients who received CCO than in those treated with hydrogel (+4.6 vs +2.6 units, respectively). Patients treated with CCO also showed significant reductions in wound surface area from baseline (10.3 cm²) to week 6 (2.1 cm²; p = 0.009), which were not observed in hydrogel-treated patients.

The effectiveness of CCO has also been demonstrated in the hospital outpatient department setting, utilizing real-world data from the USWR [12,37]. Using an EHR purpose-built for wound care documentation, data transmitted to the USWR between 2007 and 2013 yielded 202 patients (337 stage IV PU wounds) treated with CCO plus selective sharp debridement (CCO group) and 232 patients (336 stage IV PU wounds) treated with selective sharp debridement alone (non-CCO group) [12]. The proportion of wounds closed at any time was two times greater in the CCO group compared with the non-CCO group (22.2% [75/337] vs 11.0% [37/336] at 1 year; p < 0.0001 and 26.7% [90/337] vs 13.7% [46/336] at 2 years; p < 0.0001, respectively). Kaplan–Meier analysis showed that time to wound closure at 1 year was significantly faster for PU treated with CCO versus PU not treated with CCO (Figure 1).

Another analysis utilizing the USWR compared the effectiveness of enzymatic debridement with CCO versus AD with medicinal honey in patients with PU [37]. Among 517 CCO-treated PUs (446 patients) and 517 matched corresponding honey-treated PUs (341 patients), CCO-treated PU were 38% more likely to achieve 100% granulation versus honey-treated PU at 1 year (p = 0.018) and 47% (p = 0.024) more likely to epithelialize at 1 year compared with honey-treated PU (Figure 2). CCO users also had significantly fewer total visits (9.1 vs 12.6; p < 0.001), fewer total selective sharp debridements (2.7 vs 4.4; p < 0.001) and fewer PUs requiring negative-pressure wound therapy (NPWT; 29 vs 38%; p = 0.002) compared with medicinal honey users.

CCO has also been assessed for PU management in the long-term acute care setting in conjunction with NPWT [38]. In a retrospective cohort study of patients (n = 114) in two long-term acute care hospitals, CCO in conjunction with NPWT demonstrated greater speed of wound healing and reduction of necrotic tissue compared with NPWT alone [38]. Of note, sharp debridement was performed in a subgroup of 41 patients. Analysis of this subgroup indicated that, compared with NPWT and sharp debridement alone, PUs treated with sharp debridement, NPWT and CCO demonstrated statistically significant increases in the rate of debridement (lower necrotic score on Bates−Jensen Wound Assessment Tool items 5 and 6) and the rate of healing (overall reduction in Bates−Jensen Wound Assessment Tool score), suggesting a possible synergistic effect between the use of sharp debridement and CCO for treating PU.

CCO has been examined for the treatment of DFUs in several studies in the outpatient setting, as monotherapy versus AD, monotherapy versus mechanical debridement (MD) plus selective sharp debridement or in combination with sharp debridement versus sharp debridement alone (Table 2) [15,39–41].

In a prospective, randomized, open-label trial by Motley et al. in patients with DFU, enzymatic debridement with CCO in conjunction with serial sharp debridement demonstrated benefit beyond serial sharp debridement with standard care alone [39]. Wound area was statistically significantly decreased from baseline at both end of treatment (6 weeks) and end of study (12 weeks) in the group receiving both CCO and sharp debridement (n = 28; -68 and -61%, respectively; p < 0.001 for both time periods), but not in those receiving only sharp debridement (n = 27; -36 and -46%, respectively). The intergroup difference did not reach statistical significance. On average, ulcers treated with serial sharp debridement plus adjunctive CCO decreased in size more rapidly than ulcers treated without adjunctive CCO debridement, with median time to closure for wounds that healed of 6 weeks for CCO and 8 weeks for control.

Similar CCO benefit was observed in another prospective, randomized, open-label trial comparing CCO monotherapy (n = 24) with a combined therapy of MD (saline-moistened gauze [SMG]) plus selective sharp debridement (n = 24). Only CCO treatment resulted in a statistically significant decrease from baseline in the mean wound area at the end of treatment (-44.9%; p = 0.0164) and at the end of follow-up (-53.8%; p = 0.012) [40]. Corresponding changes for the SMG group were +0.8 and +8.1%.

Jimenez et al. recently assessed outcomes associated with use of CCO in patients with diabetes and DFU in a prospective, randomized, open-label study of 215 patients [41]. All patients received sharp surgical debridement at baseline, then were randomized to receive CCO (n = 106) or standard care (hydrogel daily as needed to maintain wound moisture; n = 109). Sharp debridement was permitted for both treatment groups at the investigators’ discretion. Wound area decreased relative to baseline for both the CCO group (-60%; p < 0.0001 and -65%; p < 0.0001) and the control group (-50%; p = 0.0001 and -51%; p = 0.0001) after 6 and 12 weeks, respectively. While intergroup differences at 6 and 12 weeks did not reach statistical significance, mean percentage reductions in wound area were greater for the CCO group than the control group at all 12 time points (averages: -55 and -41%, respectively). Of note, DFUs that showed no improvement at 4 weeks (n = 24; 12/group) were crossed over to the other treatment group. A numerically greater proportion of subjects who switched to CCO achieved closure (33%) than did those who switched to standard care (8%).

Two retrospective cohort studies based on EHRs (2007–2013) of over 9000 patients with VLUs from the USWR demonstrated that VLUs treated with CCO were significantly more likely to improve (i.e., reduced wound surface area) relative to those treated with undifferentiated wound dressings alone (p < 0.05), and significantly more likely to achieve 100% granulation and to epithelialize by the end of therapy compared with wounds treated with medicinal honey (30 vs 19%, respectively, for granulation; p < 0.01 and 45 vs 31%, respectively, for epithelialization; p < 0.0001; Table 3 & Figure 3) [42,43].

The effectiveness of CCO in burn treatment has been demonstrated in several studies compared with surgical excision, silver sulfadiazine or MD, in both the hospital and outpatient burn center (Table 4) [25,29,44–45]. Hansbrough et al. conducted a trial in 79 patients (age range: 5–60 years) with partial-thickness burn wounds in which paired wound sites of comparable size and severity in each patient were randomized to treatment with either CCO with polymyxin B sulfate/bacitracin powder or silver sulfadiazine. Comparison of paired treatment sites within each patient demonstrated that proportionally more CCO-treated sites were cleaned (p < 0.001) and healed (p < 0.001) before similar sites treated with silver sulfadiazine. Time to clean wound bed (mean: 9.3 vs 11.6 days) and time to epithelialization (mean: 19.0 vs 22.1 days) were both numerically faster in sites treated with CCO compared with those treated with silver sulfadiazine, but the difference did not reach statistical significance [25].

Another prospective, randomized trial comparing CCO/polymyxin with silver sulfadiazine performed in 100 children with partial-thickness burns found no differences in outcomes in skin graft rates, length of stay and hospital costs between treatment groups [29]. The similarities in overall costs between treatment groups support the finding that the more significant charges of hospital room, treatment room times and operative interventions far outweigh the minimal difference in topical agent expense, so that agent choice should not be determined by agent cost [29].

In a prospective study in 119 children with partial-thickness burns, the use of CCO shortened the hospital stay and reduced the overall need for surgery and blood transfusions [45]. In 78 patients, treatment was initiated with CCO, and in 41 patients (Group S), burn wounds (of similar surface area and wound depth to those treated with CCO) were surgically excised. In 49 of the 78 patients treated with CCO, total removal of eschar was accomplished with CCO alone (this responsive group was Group D). Among the remaining 29 who had initiated treatment with CCO (Group DS), CCO was terminated because of burn wound infection (n = 17) or a manifest need for wound grafting (n = 12). There was no significant difference between the time to achieve a clean wound bed among the three treatment groups (mean: 7.8, 8 and 7 days for Groups D, DS and S, respectively; p > 0.05). Blood transfusion was required in only 1/49 (2%) patients in Group D, compared with 18/29 (62%) patients in Group DS and 30/41 (73%) patients in Group S (p < 0.01 for Group D vs either of the other groups). Mean hospital stay was shortest for Group D (mean 12.5 days; p < 0.01) compared with Group DS (20.7 days) and Group S (20.2 days). The results of these studies suggest that CCO should be considered as the initial treatment of choice for removal of eschar in patients with a partial-thickness burn wound without infection.

As demonstrated in several studies discussed above [38,39], CCO is effective either alone or in conjunction with sharp debridement, providing synergistic effects when combined with the latter. An area of more limited study is the effectiveness of CCO in continuous debridement, which is a therapeutic intervention to address the problem of chronic wound beds with absent or slow healing despite appearing to be free from necrotic tissue [34,46]. The chronic wound contains a number of microbial, biochemical and cellular features and abnormalities that prevent or slow its progression to healing despite a seemingly adequate wound bed by appearance [46]. As noted earlier, CCO can potentiate cellular responses vital to wound epithelialization, such as proliferation and migration of keratinocytes and fibroblasts, while decreasing levels of analytes associated with inflammation [15]. As such, it may facilitate wound closure, as demonstrated in the trial by Milne et al. in which continuous debridement with CCO in institutionalized adults with PU resulted in superior wound closure rates from time of necrotic tissue removal to 84 days from enrollment [34].

Among models assessing PU patients, debridement with CCO is the economically dominant wound care strategy compared with other treatment strategies (Table 5). Carter et al. assessed the cost–effectiveness (from a US payer’s perspective; 2015 USD) of adding CCO to selective debridement compared with selective debridement alone (non-CCO) in the treatment of stage IV PU [50]. Outcome data were derived from retrospective deidentified EMRs of patients with stage IV PU from 2007 to 2013 using the USWR [12]. The analysis constructed a three-state Markov model over a 2-year time horizon [50]. Compared with the non-CCO group, CCO incurred lower costs (US$11,151 vs US$17,596) and greater clinical benefit (33.9 vs 16.8 ulcer-free weeks), resulting in an economically dominant treatment option (Figure 4). Over a 2-year period, an additional 17.2 ulcer-free weeks could be gained with a concurrent cost saving of US$6445 for each patient.

A similarly designed study by Mearns et al. assessed the cost–effectiveness of enzymatic debridement with CCO compared with autolytic treatment with medicinal honey for stage III or IV PU treatment [52]. A Markov model from a US payer perspective (2016 USD) was developed with a base-case of adult patients with PUs treated in a hospital outpatient department. The three health states in the model included inflammation/senescence, granulation/proliferation (patients achieving 100% granulation) and epithelialization, and were based on observed rates from an analysis of patients from the USWR [37]. CCO was the economically dominant strategy, resulting in 22.7 quality-adjusted life weeks at a cost of US$6161 over 1 year, compared with 21.9 quality-adjusted life weeks at a cost of US$7149 for medicinal honey.

Waycaster et al. analyzed the cost–effectiveness of CCO versus AD with a hydrogel dressing using clinical and resource utilization data derived from a US-based, prospective, randomized, two-phase trial [9,54]. Patients were residents of a long-term care center and had stages III and IV PUs with ≥85% necrotic nonviable tissue. In the analysis of Phase I (42-day end point), the average cost per patient for 42 days of PU care in 2012 was US$1817 for CCO and US$1611 for hydrogel, but days spent with a granulated wound were 3.6 times higher with CCO (23.4 vs 6.5) than hydrogel [54]. The incremental cost–effectiveness ratio was US$12, yielding an estimated cost per granulation day more than 3.2 times higher for hydrogel (US$249) versus CCO (US$78). At the end of Phase II of this study, direct cost per patient for PU care was US$2003 for CCO and $5480 for hydrogel, and the number of closed wound days was 1.5 times higher with CCO than hydrogel (317 vs 218 days) [9]. The estimated cost–effectiveness ratio was $6/closed-wound day for CCO and US$25/closed-wound day for hydrogel, indicating a fourfold higher cost per PU-free day for hydrogel versus CCO. These findings demonstrate economic dominance of CCO debridement over AD with hydrogel, which occurs when CCO is both clinically superior and cost effective.

Two cost analyses of CCO debridement in patients with DFU also yielded estimates favoring CCO over alternative debridement methods [40,53]. In an analysis of results from a randomized, open-label trial of 55 patients with DFU using a three-state Markov model, Motley et al. calculated that the number of epithelialized weeks was 25% greater in patients treated with the CCO plus serial sharp debridement (35 weeks) versus other debridement methods (28 weeks) [39,53]. Using a 1-year time horizon from a third-party payer perspective, the expected cost per treated DFU was greater for standard DFU care plus serial sharp debridement compared with CCO plus serial sharp debridement: 2376 versus US$2099, respectively (Figure 5). Cost per ulcer-free week was 40% higher for standard DFU care plus serial sharp debridement versus CCO plus serial sharp debridement (85 vs US$61 per closed-wound week).

Tallis et al. [40] conducted an economic analysis alongside a multicenter, open-label, 12-week RCT of 48 patients with DFU treated with either CCO or SMG after baseline surgical debridement (with further surgical debridement as deemed necessary in either group). Resource use estimates included frequency of selective sharp debridement procedures between groups (mean of 1 and 7 for CCO and SMG groups during the trial, respectively) and physician office visits (6 and 12 during the trial, for CCO and SMG groups, respectively) associated with the evaluation and management of patients with DFU and CCO use. Response rates were categorized as follows: large response (ulcer area reduction from baseline ≥50%), moderate response (ulcer area reduction from baseline <50% but >10%) or stalled response (ulcer area reduction from baseline ≤10%, or increase in size). Direct mean cost per responder for CCO versus SMG was 832 versus US$1042 in the physician office setting and 1607 versus US$1980 in the hospital outpatient setting.

Recently, Dreyfus et al. analyzed the impact of CCO compared with medicinal honey on healthcare utilization among patients with PU in real-world inpatient and outpatient hospital settings [51]. Hospital discharge records (from 2000 to 2016) of patients receiving debridement with an International Classification of Diseases – ninth edition code for PU were extracted from the US Premier Healthcare Database, which contains data from more than 646 million patient encounters (∼1 in every 5 discharges in the nation). The frequency of inpatient and outpatient revisits up to 6 months after an index encounter for CCO-treated PU versus medicinal honey-treated PU was compared with multivariate analysis. Among inpatients, n = 44,725 (60% of discharges) were treated with CCO and n = 3542 (5%) with medicinal honey. Among outpatients, n = 1826 (7%) and n = 773 (3%), respectively, were treated with CCO and medicinal honey. In adjusted models, those treated with medicinal honey had greater odds for inpatient re-admissions (odds ratio [OR]: 1.16; 95% CI: 1.07–1.25) after inpatient index visits, and greater odds for outpatient re-encounters both after inpatient (OR: 1.37; 95% CI: 1.26–1.48) and outpatient (OR: 1.28; 95% CI: 1.05–1.57) index visits during 6 months of follow-up.