Diabetic Foot Ulcer Debridement with Collagenase

NewsBot · Oct 22, 2013

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Clinical and Economic Assessment of Diabetic Foot Ulcer Debridement with Collagenase: Results of a Randomized Controlled Study
Arthur Tallis, Travis A. Motley, Robert P. Wunderlich, Jaime E. Dickerson Jr, Curtis Waycaster, Herbert B. Slade, the Collagenase Diabetic Foot Ulcer Study Group
Clinical Therapeutics; Article in Press

Background
Despite significant advances, the treatment of diabetic foot ulcers (DFUs) remains a major therapeutic challenge for clinicians, surgeons, and other health care professionals. There is an urgent need for new strategies with clinically effective interventions to treat DFUs to reduce the burden of care in an efficient and cost-effective way.

Objective
This randomized trial evaluated and compared the clinical effectiveness, tolerability, and costs of clostridial collagenase ointment (CCO) debridement to that of debridement using saline moistened gauze (SMG) and selective sharp debridement for the treatment of DFUs.

Methods
Randomized, controlled, parallel group, multicenter, open-label, 12-week study of 48 patients with neuropathic DFUs randomized to 4 weeks of treatment with either CCO or SMG after baseline surgical debridement. The primary end point was the condition of the ulcer bed at the end of treatment as measured using a standardized wound assessment tool. Secondary end points were the percentage of reduction in wound area and therapeutic response rates. Adverse events were monitored for the tolerability analysis. In addition, a comparative cost-effectiveness analysis was performed from the perspective of the Centers for Medicare and Medicaid Services as a payer.

Results
Both the CCO and SMG groups had significantly improved wound assessment scores after 4 weeks of treatment (CCO, −2.5, P = 0.007; SMG, −3.4, P = 0.006). Only CCO treatment resulted in a statistically significant decrease from baseline in the mean wound area at the end of treatment (P = 0.0164) and at the end of follow-up (P = 0.012). In addition, the CCO group exhibited a significantly better response rate at the end of follow-up compared with the SMG group (0.92 vs 0.75, P < 0.05). Reported adverse events were similar between the 2 treatment groups. None of the reported adverse events were considered to be related to treatment. The economic analysis indicated that the direct mean costs per responder in the physician office setting of care were $832 versus $1042 for the CCO group versus the SMG group, whereas the direct mean costs per responder in the hospital outpatient department setting were $1607 versus $1980.

Conclusions
CCO treatment provides equivalent debridement of DFUs similar to SMG while fostering better progress toward healing as measured by decreasing wound area over time and improved response rates at the end of follow-up. In addition, CCO yields a more favorable cost-effectiveness ratio in both the physician office and hospital outpatient department settings of care. ClinicalTrials.gov identifier: NCT01056198.
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NewsBot · Mar 2, 2015

Cost-effectiveness of clostridial collagenase ointment on wound closure in patients with diabetic foot ulcers: economic analysis of results from a multicenter, randomized, open-label trial
Travis A Motley, Adrienne M Gilligan, Darrell L Lange, Curtis R Waycaster and Jaime E Dickerson
Journal of Foot and Ankle Research 2015, 8:7 doi:10.1186/s13047-015-0065-x

Background Approximately 10%–15% of people with diabetes develop at least one foot ulcer during their lifetime. Treatment of diabetic foot ulcers (DFUs) represents a significant economic burden. Enzymatic debridement with clostridial collagenase ointment (CCO) can be used to remove necrotic tissue from wounds. This study examined the impact of CCO as an effective adjunct therapy to serial sharp debridement (SSD) and assessed the cost-effectiveness of CCO compared with standard DFU treatments as an adjunct therapy to SSD over a span of 1 year.
Methods Adults 18 years or older with a diagnosis of type 1 or type 2 diabetes who had a neuropathic DFU were enrolled in a 12-week, randomized, open-label trial. Patients were randomly assigned to either treatment with CCO + SSD or to investigator-selected supportive care + SSD (Control). A 3-state Markov model with a 1-week cycle length was developed using wound-closure rates from the trial to estimate the number of healed-wound weeks and the expected DFU cost per patient. The 3 states included unhealed, healed, and death.
Results were extrapolated to 1 year to estimate the number of healed-wound weeks per treatment and the average cost to achieve epithelialization. The perspective of the analysis was that of the payer, specifically, the third party payer. Results The study sample included 55 patients (28 in CCO group; 27 Control). The majority were men (74.5%) with a mean age of 57.9 years. Projected healing rates were greater for the CCO + SSD group compared to Control (89% vs. 80%, respectively). The expected number of epithelialized weeks accumulated over 1 year was 25% greater in the CCO + SSD group than for Control (35 vs. 28 weeks, respectively). Over a 1-year time horizon, the expected cost per DFU was greater in the Control group than the CCO group ($2,376 vs. $2,099, respectively). The estimated cost per ulcer-free week was 40% higher for Control ($85/closed-wound week) than for CCO + SSD ($61/closed-wound week).
Conclusions CCO + SSD therapy is a cost-effective method of debridement in the management of patients with DFUs, providing better outcomes at a lower cost. Further high quality trials are needed to confirm this finding.
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NewsBot · Aug 15, 2015

Optimizing wound bed preparation with collagenase enzymatic debridement
Stanley K. McCallon, DPT, CWS, Dorothy Weir, RN, CWOCN, CWS, John C. Lantis II, MD, FACS
The Journal of the American College of Clinical Wound Specialists; Article in Press

Difficult-to-heal and chronic wounds affect tens of millions of people worldwide. In the U.S. alone, the direct cost for their treatment exceeds $25 billion.1 Yet despite advances in wound research and treatment that have markedly improved patient care, wound healing is often delayed for weeks or months. For venous and diabetic ulcers, complete wound closure is achieved in as few as 25%-50% of chronic or hard-to-heal wounds.2-10 Wound bed preparation and the consistent application of appropriate and effective debridement techniques are recommended for the optimized treatment of chronic wounds.11-16 The TIME paradigm (Tissue, Inflammation/Infection, Moisture Balance and Edge of Wound) provides a model to remove barriers to healing and optimize the healing process. While we often think of debridement as an episodic event that occurs in specific care giver / patient interface. There is the possibility of a maintenance debridement in which the chronic application of a medication can assist in both the macroscopic and microscopic debridement of a wound. We review the various debridement therapies available to clinicians in the United States, and explore the characteristics and capabilities of clostridial collagenase ointment, (CCO) a type of enzymatic debridement, that potentially allows for epithelialization while debriding. It appears that in the case of CCO it may exert this influences by removal of the necrotic plug while promoting granulation and sustaining epithelialization.17,18 It is also easily combined with other methods of debridement, is selective to necrotic tissue, and has been safely used in various populations.19-21 We review the body of evidence has indicated that this concept of maintenance debridement, especially when combined episodic debridement may add a cost an efficacious, safe and cost-effective choice for debridement of cutaneous ulcers and burn wounds and it will likely play an expanding role in all phases of wound bed preparation.19-28
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NewsBot · Sep 8, 2015

Optimizing Wound Bed Preparation With Collagenase Enzymatic Debridement
Stanley K. McCallon, DPT, CWS, Dorothy Weir, RN, CWOCN, CWS, John C. Lantis II, MD, FACS
The Journal of the American College of Clinical Wound Specialists ; April 2014Volume 6, Issues 1-2, Pages 14–23

Difficult-to-heal and chronic wounds affect tens of millions of people worldwide. In the U.S. alone, the direct cost for their treatment exceeds $25 billion. Yet despite advances in wound research and treatment that have markedly improved patient care, wound healing is often delayed for weeks or months. For venous and diabetic ulcers, complete wound closure is achieved in as few as 25%–50% of chronic or hard-to-heal wounds. Wound bed preparation and the consistent application of appropriate and effective debridement techniques are recommended for the optimized treatment of chronic wounds. The TIME paradigm (Tissue, Inflammation/infection, Moisture balance and Edge of wound) provides a model to remove barriers to healing and optimize the healing process. While we often think of debridement as an episodic event that occurs in specific care giver/patient interface. There is the possibility of a maintenance debridement in which the chronic application of a medication can assist in both the macroscopic and microscopic debridement of a wound. We review the various debridement therapies available to clinicians in the United States, and explore the characteristics and capabilities of clostridial collagenase ointment (CCO), a type of enzymatic debridement, that potentially allows for epithelialization while debriding. It appears that in the case of CCO it may exert this influences by removal of the necrotic plug while promoting granulation and sustaining epithelialization. It is also easily combined with other methods of debridement, is selective to necrotic tissue, and has been safely used in various populations. We review the body of evidence has indicated that this concept of maintenance debridement, especially when combined episodic debridement may add a cost an efficacious, safe and cost-effective choice for debridement of cutaneous ulcers and burn wounds and it will likely play an expanding role in all phases of wound bed preparation.
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NewsBot · Mar 8, 2017

Enzymatic Debridement of Chronic Nonischemic Diabetic Foot Ulcers: Results of a Randomized, Controlled Trial.
Jimenez JC et al
Wounds. 2017 Feb 27. pii: WNDS20170227-2.

OBJECTIVE:
The aim of this randomized, controlled multicenter trial was to evaluate the clinical outcomes associated with the use of clostridial collagenase ointment (CCO) for up to 12 weeks in 215 patients with type 1 or type 2 diabetes mellitus and a neuropathic, nonischemic diabetic foot ulcer (DFU).
MATERIALS AND METHODS:
Patients were randomized into either a group receiving CCO applied once daily at a thickness of ~2 mm or a group receiving standard care (SC) consisting of a daily application of a hydrogel as needed to maintain a moist ulcer environment. All ulcers were covered with a nonadherent foam dressing that was changed once daily, and sharp debridement was allowed when the investigators deemed it medically warranted. Outcome measures included the percent change in ulcer area and the effect of baseline wound microbiota on subsequent healing. Patients with ulcers that showed no decrease in size after 4 weeks were crossed over to the other treatment group.
RESULTS:
The wound area decreased relative to baseline for both the CCO group (-60%, P < .0001; -65%, P < .0001) and the control group (-50%, P = .0001; -51%, P = .0001) after 6 and 12 weeks, respectively. While the intergroup differences at 6 and 12 weeks did not reach statistical significance (P = .3801; P = .3606), mean percent reductions for the CCO group were greater than the control at all 12 time points (averages: -55%; -41%, respectively). Overall closure rate was 21% and 41% (weeks 6 and 12, P = .3705; P = .2358) with no significant differences between groups. However, the 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 for those who switched to SC (8%). Baseline biopsy showed that despite the absence of clinical signs of infection, all ulcers were heavily colonized by 1 to 5 species of bacteria. No adverse events were assessed by the investigators as related to either treatment.
CONCLUSION:
These results confirm observations from previous studies demonstrating positive outcomes associated with enzymatic debridement with CCO following 6 weeks of treatment.
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NewsBot · Apr 26, 2017

Enzymatic debridement with collagenase in wounds and ulcers: a systematic review and meta-analysis
Jérôme Patry, Virginie Blanchette
International Wound Journal 25 April 2017

Enzymatic debridement with collagenase is a technique that is commonly used in clinical practice. This systematic review examines the effect of collagenase on all kinds of wounds, compared to an alternative therapy, on wound healing, wound bed characteristics, cost-effectiveness and the occurrence of adverse events. We conducted a systematic literature search on available literature in Cochrane databases, MEDLINE, EMBASE and CINAHL. Two investigators independently assessed the titles and abstracts of all randomised controlled trials obtained involving collagenase of all kinds of wounds based on inclusion criteria. Of the 1411 citations retrieved, 22 studies reported outcomes with the use of collagenase either for wound healing or wound debridement. Results support the use of collagenase for enzymatic debridement in pressure ulcers, diabetic foot ulcers and in conjunction with topical antibiotics for burns. However, studies presented a high risk of bias. Risk ratio of developing an adverse event related to collagenase versus the alternative treatment was statistically significant (for 10 studies, RR: 1·79, 95% CI 1·24–2·59, I2=0%, P = 0·002). There is very limited data on the effect of collagenase as an enzymatic debridement technique on wounds. More independant research and adequate reporting of adverse events are warranted
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NewsBot · Sep 2, 2017

Clostridial Collagenase for the Management of Diabetic Foot Ulcers: Results of Four Randomized Controlled Trials.
Lantis Ii JC et al
Wounds. 2017 Aug 25. pii: WNDS20170825-1.

BACKGROUND:
Despite major treatment advances, diabetic foot ulcers (DFUs) remain a frequent and debilitating complication of diabetes mellitus and a major cause of significant morbidity and mortality.
OBJECTIVE:
This study evaluates and compares clinical effectiveness of clostridial collagenase ointment (CCO) with standard care (SC) in patients with DFUs, with the goal to define best clinical criteria under which to use CCO in the DFU population.
MATERIALS AND METHODS:
This is a pooled data analysis of 4 randomized controlled trials that compared clinical effectiveness of CCO to SC. A total of 174 adult patients with 1 target DFU each who underwent treatment with CCO (n = 88) or SC (n = 86) for 4 or 6 weeks were evaluated. Assessments included wound area reduction, wound bed status, and time to closure.
RESULTS:
Statistically significant mean percentage change in wound area from baseline was numerically greater for CCO than SC at the end of study (EOS) following 6 or 8 weeks of treatment; these values were -56% and -10%, respectively, in the subgroup of plantar surface ulcers (P = .05) and wounds assessed as "low necrosis" (≤ 25% necrotic) at baseline (-64% vs. -20%). When rapidly healing ulcers were excluded from the analysis, the difference in ulcer area reduction was even greater for CCO compared with SC at EOS (-53% vs. -7%; P = .05).
CONCLUSIONS:
Active CCO therapy was associated with a nonstatistically greater reduction in wound size than any of the passive or mechanical SC modalities at end of treatment. This was statistically significant when used in conjunction with sharp debridement and for slow healing ulcers, larger sized wounds, or plantar surface wounds.
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NewsBot · Apr 22, 2018

Clinical Outcomes for Diabetic Foot Ulcers Treated with Clostridial Collagenase Ointment or with a Product Containing Silver
Motley Travis A. , Caporusso Joseph M. , Lange Darrell L. , Eichelkraut Robert A. , Cargill David Innes , Dickerson Jaime E. Jr.
Advances in Wound Care Ahead of Print 16 Apr 2018

Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with clostridial collagenase ointment (CCO) or silver-containing products, both in combination with sharp debridement as needed.

Approach: One hundred two subjects with qualifying DFUs were randomized to daily treatment with either CCO or a silver-containing product for 6 weeks followed by a 4 -week follow-up period. The primary outcome was the mean percent reduction in DFU area. A secondary outcome was the incidence of ulcer infections between groups.

Results: At the end of treatment, the mean percent reduction in area from baseline of DFUs treated with CCO was 62% (p < 0.0001) and with silver was 40% (p < 0.0001). The difference between groups—22%—was not statistically significant (p = 0.071). Among ulcers closed by the end of treatment, the mean time to closure was 31.1 ± 9.0 days versus 37.1 ± 7.7 days, respectively (not statistically significant). There was a numerically greater incidence of target ulcer infections in the silver group (11, 21.6%) than in the CCO group (5, 9.8%; p = 0.208). No clinically relevant safety signals were identified in either group.

Innovation: CCO treatment can progress a wound toward closure. Ulcer infection prophylaxis may not be sacrificed when treating DFU with CCO in lieu of silver-containing products.

Conclusion: Both CCO and silver-containing products promote significant reduction in DFU area over 6 weeks of treatment with no clinically relevant safety concerns. Mean percent reduction in lesion area was numerically (22%) but not significantly greater with CCO compared to silver, as was time to ulcer closure, with an incidence of ulcer infection at least as low as for silver-containing products.
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NewsBot · Nov 1, 2018

Clinical Outcomes for Diabetic Foot Ulcers Treated with Clostridial Collagenase Ointment or with a Product Containing Silver.
Motley TA et al
Adv Wound Care (New Rochelle). 2018 Oct 1;7(10):339-348. doi: 10.1089/wound.2018.0784. Epub 2018 Oct 11.

Objective: To compare outcomes of diabetic foot ulcers (DFUs) treated with clostridial collagenase ointment (CCO) or silver-containing products, both in combination with sharp debridement as needed. Approach: One hundred two subjects with qualifying DFUs were randomized to daily treatment with either CCO or a silver-containing product for 6 weeks followed by a 4 -week follow-up period. The primary outcome was the mean percent reduction in DFU area. A secondary outcome was the incidence of ulcer infections between groups. Results: At the end of treatment, the mean percent reduction in area from baseline of DFUs treated with CCO was 62% (p < 0.0001) and with silver was 40% (p < 0.0001). The difference between groups-22%-was not statistically significant (p = 0.071). Among ulcers closed by the end of treatment, the mean time to closure was 31.1 ± 9.0 days versus 37.1 ± 7.7 days, respectively (not statistically significant). There was a numerically greater incidence of target ulcer infections in the silver group (11, 21.6%) than in the CCO group (5, 9.8%; p = 0.208). No clinically relevant safety signals were identified in either group. Innovation: CCO treatment can progress a wound toward closure. Ulcer infection prophylaxis may not be sacrificed when treating DFU with CCO in lieu of silver-containing products. Conclusion: Both CCO and silver-containing products promote significant reduction in DFU area over 6 weeks of treatment with no clinically relevant safety concerns. Mean percent reduction in lesion area was numerically (22%) but not significantly greater with CCO compared to silver, as was time to ulcer closure, with an incidence of ulcer infection at least as low as for silver-containing products
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NewsBot · Dec 11, 2018

Limitations to the use of bromelain-based enzymatic debridement (NexoBrid®) for treating diabetic foot burns: a case series of disappointing results
Juan Enrique Berner, Dejan Keckes, Matthew Pywell, ...
Scars, Burns & Healing December 5, 2018

Background:
Bromelain-based enzymatic debridement with Nexobrid® (Mediwound) is an alternative to traditional surgical tangential excision of deep dermal and full thickness burns. Early literature suggests that Nexobrid debridement could reduce the number of operations, infection rates, inpatient stay and the necessity for skin grafting to wounds by preserving viable tissue. To our knowledge there are no previous studies reporting the use of NexoBrid for treating burns in patients with established diabetic foot disease.

Case presentation:
We conducted a retrospective case series and identified four patients with diabetic foot burns that were treated with Nexobrid® debridement. All of these patients developed further eschar and deepening of their wounds a few days after NexoBrid was applied, requiring further surgery and skin grafting.

Conclusions:
We would recommend judicious use of this new product in patients with diabetic foot wounds.
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NewsBot · Dec 25, 2018

Limitations to the use of bromelain-based enzymatic debridement (NexoBrid®) for treating diabetic foot burns: a case series of disappointing results.
Berner JE et al
Scars Burn Heal. 2018 Dec 5;4

BACKGROUND:
Bromelain-based enzymatic debridement with Nexobrid® (Mediwound) is an alternative to traditional surgical tangential excision of deep dermal and full thickness burns. Early literature suggests that Nexobrid debridement could reduce the number of operations, infection rates, inpatient stay and the necessity for skin grafting to wounds by preserving viable tissue. To our knowledge there are no previous studies reporting the use of NexoBrid for treating burns in patients with established diabetic foot disease.

CASE PRESENTATION:
We conducted a retrospective case series and identified four patients with diabetic foot burns that were treated with Nexobrid® debridement. All of these patients developed further eschar and deepening of their wounds a few days after NexoBrid was applied, requiring further surgery and skin grafting.

CONCLUSIONS:
We would recommend judicious use of this new product in patients with diabetic foot wo
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NewsBot · Jun 16, 2019

Collagenase‐assisted wound bed preparation: An in vitro comparison between Vibrio alginolyticus and Clostridium histolyticum collagenases on substrate specificity
Roberta Di Pasquale Susanna Vaccaro Michele Caputo Christian Cuppari Salvatore Caruso Angela Catania Luciano Messina
Int W J: 31 May 2019

Bacterial collagenase from the aerobic non‐pathogenic Vibrio alginolyticus chemovar iophagus is an extracellular metalloproteinase. This collagenase preparation is obtained through a fermentation process and is purified chromatographically, resulting in a highly purified 82‐kDa single‐band protein that does not contain non‐specific proteases or other microbial impurities. V. alginolyticus collagenase was added to a hyaluronan (HA)‐based device to develop a novel debriding agent to improve the treatment of ulcers, necrotic burns, and decubitus in the initial phase of wound bed preparation. In this study, an in vitro biochemical characterisation of V. alginolyticus collagenase versus a commercial preparation from a Clostridium histolyticum strain on various dermal extracellular matrix (ECM) substrates was performed. V. alginolyticus collagenase demonstrated its ability to carry out the enzymatic cleavage of the substrate, allowing a selective removal of necrotic tissues while sparing healthy tissue, as reported in clinical studies and through routine clinical experience. in vitro tests under physiological conditions (pH, presence of Ca++, etc.) have demonstrated that V. alginolyticus collagenase exhibits very poor/limited non‐specific proteolytic activity, whereas the collagenase preparation from C. histolyticum is highly active both on collagen and on non‐collagenic substrates. This finding implies that while the V. alginolyticus enzyme is fully active on the collagen filaments that anchor the necrotic tissue to the wound bed, it does not degrade other minor, but structurally important, components of the dermal ECM. This feature could explain why collagenase preparation from V. alginolyticus has been reported to be much gentler on perilesional, healthy skin.
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NewsBot · Sep 19, 2022

The influence of adequate debridement and placental-derived allografts on diabetic foot ulcers
William H Tettelbach et al
J Wound Care. 2022 Sep 1;31(Sup9):S16-S26.

Objective: To determine the role of debridement when patients are using placental-derived allografts (PDAs), data from two prospective, multicentre, randomised controlled trials (RCTs) were evaluated for the quality or adequacy of debridement on diabetic foot ulcers (DFUs) treated with PDAs. Results were compared with real-world findings via a retrospective analysis of 2015-2019 Medicare claims for DFUs.

Method: Debridement adequacy in the prospective RCTs was adjudicated by three blinded wound care specialists. Treatments included two PDAs, dehydrated human amnion/chorion membrane (DHACM, n=54) or dehydrated human umbilical cord (DHUC, n=101), compared with standard of care (SOC, n=110). The key outcome was the influence of adequate debridement on rates of complete closure within 12 weeks. Additionally, a retrospective analysis of 2015-2019 Medicare claims for DFUs that received routine debridement at intervals ranging from every 1-7 days (18,900 total episodes), 8-14 days (35,728 total episodes), and every 15 days or greater (34,330 total episodes) was performed.

Results: Within the RCTs, adequate debridement occurred in 202/265 (76%) of patients, 90/110 (82%) SOC ulcers, 45/54 (83%) of DHACM-treated ulcers, and in 67/101 (66%) of DHUC-treated ulcers. Complete closure occurred in 150/202 (74%) of adequately debrided ulcers, and in only 13/63 (21%) of ulcers without adequate debridement, p<0.0001. Debridement was the most significant factor for closure even when controlling for other clinical characteristics. Within the Medicare claims data 21% (18,900/88,958) of episodes treated with SOC only had debridement intervals of ≤7 days. Short debridement intervals in combination with the use of DHACM demonstrated statistically significant better outcomes than SOC including: 65% fewer major amputations (p<0.0001), higher DFU resolution rates (p=0.0125), 42% fewer emergency room visits (p<0.0001) and reduced usage of other hospital resources (admissions and readmissions).

Conclusion: Prospectively collected data examining the quality of debridement and retrospectively analysed data examining the frequency of debridement supports routine adequate wound debridement, particularly at intervals of seven days, as an essential component of wound care. Optimal use of placental-derived allografts improves outcomes and lowers the use of healthcare resources.
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