Health Care Spending in Patients With Stage 3 and Stage 4 Pressure Injuries and Patients With Diabetic Foot Ulcers Treated Early With Clostridial Collagenase Ointment: A Retrospective Data Review

Introduction. Clostridial collagenase ointment (CCO) is the only enzymatic agent indicated for debriding chronic dermal ulcers that is approved by the United States Food and Drug Administration. Objective. The objective of this study is to estimate health care spending among patients with Stage 3 and Stage 4 pressure injuries (PIs) and patients with diabetic foot ulcers (DFUs) who experienced early (ie, within 30 days of index diagnosis) versus late (31 to 90 days of index diagnosis) initiation of CCO. Methods. Patients with PIs and DFUs between January 2007 and March 2017 were identified. One-to-one matched cohorts were used to compare all-cause health care spending and disease-related health care spending between the early initiation and late initiation groups. Results. Compared to the early CCO initiation group, all-cause health care spending for the late CCO initiation group was higher in both patients with PIs and in patients with DFUs within the 12-month follow-up period. Compared to the early CCO initiation group, disease-related health care spending for the late CCO initiation group was higher in both patients with PIs and in patients with DFUs within the 12-month follow-up period. All computations were statistically significant. Conclusions. Early initiation of CCO provides both all-cause and disease-related health care savings to payers and persons managing patients with PIs or DFUs. Payers, providers, and facilities should consider mechanisms to encourage the early use of CCO to lower costs.

Chronic wounds are a tremendous burden for patients and health care systems,¹ with medical, social, psychological, and significant financial impact. A recent economic evaluation¹ suggested that nearly 15% of Medicare beneficiaries experience a wound or infection (excluding pneumonia) in a calendar year; yearly Medicare spending for the care of all wound types is in the billions of dollars.¹ As the population ages, these numbers are expected to worsen, given that nonhealing wounds are more likely to affect older adults.² Referencing only Medicare spending does not speak to the financial burden that is incurred by non-Medicare entities and caused by chronic wounds. As an increasing number of patients move from traditional Medicare to Medicare Advantage plans,³ the costs incurred by all non-Medicare payers deserve increased consideration. Furthermore, patients have a greater financial responsibility for their own care than they have had in many decades, thus increasing their burden.⁴ 

Additionally, chronic wounds are more likely to affect those who face financial difficulties; how effectively patients with chronic wounds progress is related to their economic status.⁵ Finally, the financial impact on the provider must be considered. In many cases, the costs attributed to the care of a provider’s patients are tracked, publicly reported, and affect that provider’s fee schedule. This is seen in aspects of the Quality Payment Program from the Centers for Medicare and Medicaid Service (CMS),⁶ in accountable care organizations, and in other payment models. For these reasons and more, both the financial and clinical consequences of these decisions should be taken into account when deciding which products to use and when to use them. 

A Stage 3 pressure injury (PI) is defined by the National Pressure Injury Advisory Panel⁷ (NPIAP) as an injury that causes “full-thickness loss of skin, in which adipose (fat) is visible in the ulcer and granulation tissue and epibole (rolled wound edges) are often present.” The NPIAP defines a Stage 4 PI as one in which there is “full-thickness skin and tissue loss with exposed or directly palpable fascia, muscle, tendon, ligament, cartilage or bone in the ulcer.”⁷ These Stage 3 and Stage 4 PIs are usually caused by prolonged pressure, shear, and/or friction.⁸ 

Treatment of PIs can include offloading, attention to nutrition, cleansing, attention to infection and biofilm, debridement, and use of both local and systemic agents that can influence the quality and composition of the ulcer bed.⁹ Multiple complications may arise from PIs, including soft tissue infection, osteomyelitis, sepsis, and death, resulting in high morbidity and mortality. 

Diabetic foot ulcers (DFUs) also have a high rate of morbidity and mortality; up to 15% of patients with diabetes will develop a DFU.¹⁰ Neuropathy, peripheral arterial disease, and systemic compromise as a result of hyperglycemia are among the factors that can contribute to the development and progression of DFUs. 

Treatment of DFUs can include offloading, addressing the underlying condition, glycemic control, attention to nutrition, cleansing, attention to infection and biofilm, debridement, and use of both local and systemic agents that can affect the quality and composition of the ulcer bed. Despite traditional good ulcer care, up to 49% of DFUs may fail to heal,¹¹ and they often lead to hospitalization, amputation, and death. The 5-year mortality rate for DFUs is higher than several types of cancer, including prostate, breast, colon, and Hodgkin’s disease.¹² Thus, the morbidity and mortality associated with PIs and DFUs support the need for advanced, evidence-based treatment. 

One mainstay of treatment for most PIs and DFUs is debridement, typically a combination of sharp and enzymatic.¹³ A randomized, controlled, multicentered trial¹³ demonstrated a much greater decrease from baseline in wound area among DFUs that received both sharp debridement and enzymatic debridement versus those that received sharp debridement without enzymatic debridement. Only 1 enzymatic debriding agent is approved by the United States Food and Drug Administration (FDA) for debriding chronic dermal ulcers—clostridial collagenase ointment (CCO; Collagenase SANTYL Ointment; Smith+Nephew). This ointment contains collagenase derived from the bacterium Clostridium histolyticum. This proteinase degrades collagen types I through V and is the only product in its class available in the US marketplace. Enzymatic debridement with clostridial collagenase promotes key aspects of wound healing, including granulation tissue formation and reepithelialization, more effectively than nonspecific proteases or inactive controls.¹⁴ Also, CCO may suppress inflammatory markers while promoting markers of inflammation resolution.¹⁵ The collagenase cleaves strands of denatured collagen, thereby facilitating removal of necrotic tissue from the wound bed. This is an essential element of maintaining a clean, healthy wound bed that is free of necrotic tissue. 

Multiple peer-reviewed studies support the benefits of using CCO in PIs, venous leg ulcers, DFUs, and burns. A retrospective review¹⁶ concluded that patients with Stage 2, Stage 3, and Stage 4 pressure ulcers treated with CCO had significantly fewer total clinic visits, fewer total selective sharp debridement sessions, and less need for negative pressure wound therapy (NPWT) compared with wounds treated with honey. A prospective, randomized, open-label study¹⁵ that compared DFUs treated with CCO versus those treated with hydrogel found that CCO use provided a significant and progressive reduction in mean percentage size change from baseline in weeks 1 through 4, while those treated with hydrogel experienced that same change only through the end of the first week. A retrospective review¹⁷ demonstrated a higher rate of venous leg ulcer closure among patients treated with CCO versus those treated with honey. A prospective study¹⁸ showed that patients whose burns were treated with CCO had an almost 50% shorter hospital stay than those treated with surgical excision. Multiple studies^16-18 have demonstrated a decrease in costs when CCO was used in place of alternative options.

Despite the abundance of literature demonstrating the clinical efficacy and cost savings associated with the use of CCO, some payers and facilities are hesitant to use it, resulting from concern with how it is used and when use is initiated. Some express a preference for an alternative product with a lower upfront cost. In some instances, there are limits with regard to dose, duration of use, or step edits that do not allow the initiation of CCO until other options have failed. These restrictions and limits may not be in the best interest of the patient when considering the peer-reviewed research that demonstrates the efficacy of CCO.^15-18 With an appreciation for the dire morbidity and mortality associated with Stage 3 and Stage 4 PIs and also with DFUs, the necessity for treatment must be balanced with the cost concerns for the most effective treatment as soon as possible. 

Although upfront costs associated with CCO alternatives may be lower, long-term costs deserve evaluation. This study was conducted to assess all-cause health care costs and disease-specific health care costs for patients with Stage 3 and Stage 4 PIs and those with DFUs who had early CCO initiation (ie, CCO provided within 30 days of index injury) compared with patients who had late CCO initiation (within 31–90 days of index injury) during a 12-month, follow-up period. With CCO clinical superiority already established, this study focused only on costs.

Data source
The PearlDiver Patient Records Database (PearlDiver) was reviewed to identify payer claims for selected patients from January 2007 through March 2017. This database includes more than 20 million patients and contains information regarding patient demographics, hospitalizations, reimbursement, diagnoses, and procedures. The data can be evaluated using International Classification of Diseases, 9^th Revision Clinical Modification (ICD-9-CM) codes, International Classification of Diseases, 10^th Revision Clinical Modification (ICD-10-CM) codes, Current Procedural Terminology codes, and National Drug Codes. All data in this database are deidentified and anonymized and as such were deemed exempt from review by an institutional review board. The database and provided statistical software are contained on a password-protected server maintained by PearlDiver. The cost data were derived from paid claims, which allowed for exact dollars to be tracked. This differed from many other studies that estimated costs by extrapolation from clinical data or used economic models to estimate savings. 

Patient selection
Patients with Stage 3 and Stage 4 PIs were identified using ICD-9-CM diagnosis codes (707.23 and 707.24) and related ICD-10-CM codes from January 2007 through March 2016, allowing patients to have at least a 1-year follow-up period. Similarly, patients with DFUs were identified using ICD-9-CM diagnosis codes 707.14, 707.15 and related ICD-10-CM diagnosis codes and ICD-9-CM diagnosis code 250.XX and related ICD-10-CM diagnosis codes. The date with the first diagnosis claim of a PI/DFU was considered the index date for both groups. Patients identified as having Stage 3 and Stage 4 PIs and patients with DFUs were included in the cohort if they were continuously enrolled in the health plan for at least 12 months; this allowed for calculation of health care costs. Patients who were under 20 years of age at diagnosis or who had CCO prescribed before the index date or 90 days after the index date were excluded. Patients who received CCO within the first 30 days of index date were considered to have received early initiation; they were compared with patients who received CCO from 31 days to 90 days from the index date, deemed to have received late initiation. No other aspects of patient care were tracked or taken into account in this study.

Study variables
The primary outcome variable was total cost, calculated by combining all adjudicated claims in the 12 months after the index date. Wound-specific utilization from all claims in which a wound-related diagnosis code was used on the claim was calculated, as was cost by service location (ie, inpatient hospital, outpatient hospital, physician office, emergency room, pharmacy, and other). The number of visits to different service locations during the 12-month follow-up period was calculated. Independent variables assessed in the study were age at index diagnosis, sex, region, payer, year of index diagnosis, and Charlson Comorbidity Index (CCI) as a categorical and continuous variable. 

Statistical analyses
In order to remove selection bias and have a randomization-like effect on patient selection, patients with Stage 3 and Stage 4 PIs who were received early CCO initiation were matched with those who received late CCO initiation; a separate, exact matching occurred for the DFU groups. Patient demographic characteristics such as age at index diagnosis, gender, race (for Medicare patients only), geographical region, and CCI score were used to match the patients in both patient populations. Because exact matching for CCO early initiation and CCO late initiation was used in both patient populations, chi-squared tests were not run for categorical variables, nor was the t test used for continuous variables on demographic characteristics. Chi-squared tests were used to estimate statistical difference between CCO early initiation and CCO late initiation in terms of total health care costs. Separate multiple linear regression models were constructed for PI and DFU patient populations to estimate the effect of CCO early initiation versus late initiation along with other patient characteristics. For all statistical comparisons, all tests were 2-tailed; a P value less than .05 was considered statistically significant. 

Of the 1674 patients with Stage 3 and Stage 4 PIs who had CCO initiated within 90 days of their index diagnosis, 1028 experienced early CCO initiation and 646 experienced late CCO initiation. Subsequently, 290 from the early CCO initiation group and 290 from the late CCO initiation group were matched for analysis. Demographics for the matched groups consisted of age (44% were 65 to 79 years old, and 41% were 80 years or older); region (79% were from the southern region of the US); gender (58% were female); and payer status (97% of patients with PIs and early CCO initiation and 68% of late CCO initiation patients had Medicare Advantage). The average CCI score was 5.92 ± 3.22 in both early and late initiation PI groups (Table 1). 

In the DFU group, 2956 patients received CCO within 90 days of their index diagnosis; 1796 experienced early CCO initiation, and 1160 experienced late CCO initiation. Also, 703 patients from the early CCO initiation group and 703 patients from the late CCO initiation group were matched for analysis. The majority of patients with DFUs were between 65 and 79 years of age (56%), male (63%), white (80%), from the southern region of the US (80%), and had Medicare Advantage coverage (93%). The mean CCI score in the DFU group was 5.21 ± 3.03 (Table 1). 

All-cause health care costs for matched Stage 3 and Stage 4 patients with PIs were 34% lower in the early CCO initiation patients compared with late CCO initiation patients ($51 106 per patient vs. $76 963 per patient) (Table 2). The lower all-cause health care costs among the early CCO initiation patients were a result of lower inpatient hospital costs ($31 219 vs. $46 118), lower outpatient hospital costs ($6943 vs. $9142), lower emergency department (ED) costs ($1255 vs. $1687), lower pharmacy costs ($6022 vs. $6311), and lower other costs ($14 971 vs. $23 321). These lower costs were consistent with lower average numbers of inpatient hospitals stays, outpatient hospital visits, emergency department encounters, pharmacy events, and other visits seen among the early CCO initiation patients (Table 3). Similarly, disease-specific health care costs associated with patients with Stage 3 and Stage 4 PIs were 48% lower for the early CCO initiation group compared with the late CCO initiation group ($12 938 per patient vs. $24 677 per patient). Similar to all-cause costs, lower disease-specific costs resulted from lower inpatient hospital costs, lower ED costs, lower pharmacy costs, and lower miscellaneous costs. Interestingly, patients with PIs with early CCO initiation had a lower average number of CCO-related pharmacy visits and lower CCO-related costs ($408 vs. $620) than the group that experienced late initiation of CCO.

All-cause health care costs attributed to matched patients with DFUs in the early CCO initiation group were 22% lower compared with the late CCO initiation group. In patients with DFUs receiving early CCO initiation, inpatient hospital costs ($31 486 vs. $37 840), outpatient hospital costs ($11 712 vs. $12 473), pharmacy costs ($5645 vs. $6176), and miscellaneous costs ($11 045 vs. $15 918) were all lower compared with the late CCO initiation patients. Again, these lower costs were consistent with a lower number of average inpatient hospitalizations, outpatient hospital visits, physician office visits, pharmacy events, and fewer other visits. Disease-specific health care costs for patients with DFUs were 9% lower in the CCO early initiation group compared with the late CCO initiation group. Costs from physicians’ offices, emergency rooms, and pharmacies were all lower in the early CCO initiation group. Patients with DFUs with early CCO initiation received an average of 1.63 CCO prescriptions, compared with 1.86 CCO prescriptions for late CCO initiation patients, and CCO costs were $129 lower per patient in the early CCO initiation group.

A multivariate linear regression model estimated that all-cause health care costs for patients with Stage 3 and Stage 4 PIs were significantly lower with early CCO initiation ($24 270 less per patient), as were disease specific costs ($9241 less per patient). The model also estimated $41 861 less per patient was spent among patients under the age of 65 years old compared with their older counterparts and that an additional $3169 was spent for each CCI score increase. A separate multivariate linear regression model for patients with DFUs estimated that CCO early initiation patients had significantly lower all-cause health care costs ($22 350 less per patient) and significantly lower disease-specific costs ($5305 less per patient) than CCO late initiation patients (Table 4, Table 5). 

The chronic ulcers that were treated in this study are associated with significant morbidity and mortality. Patients who experience chronic ulcers endure a tremendous clinical, social, psychological, and financial burdens. This financial burden is shared by insurance payers, facilities, and even the providers caring for the ulcers. Patients experience the financial burden in the form of copays, deductibles, insurance premium impacts, and noncovered services and products. Payers experience the financial burden when having to subsidize care for patients with chronic ulcers over many months and years. Facilities experience financial burden when having to care for a chronic ulcer that is present for an extended period of time. Finally, providers are impacted by this financial burden as the costs attributed to their patients are tracked and publicly reported. These costs then can factor into provider rankings, employment, credentialing, and ultimately reimbursement as is seen in the Quality Payment Program by CMS and Accountable Care Organizations. Given these facts, patients, payers, facilities, and providers may be motivated to decrease the costs associated with the care of chronic ulcers. This likely contributes to the situation sometimes seen in clinical practice, where a short-sighted decision is made to use a less expensive product in place of a product demonstrated to be more effective in peer-reviewed literature, as occurs too often with chronic ulcers that would benefit from enzymatic debridement. 

Despite the fact that CCO is the only FDA-approved enzymatic agent indicated for debriding chronic dermal ulcers, and published literature demonstrates its superiority over alternatives,^19,20 its use may be restricted or delayed in an effort to save money. This may occur when a payer or facility limits the quantity of CCO allowed or does not allow its use at all. This concept also plays out when facilities and/or payers institute step edits not allowing use of CCO until another product fails. With the high morbidity and mortality associated with these ulcer types, in many cases when a patient fails the first attempt at treatment, it is too late, and their healing potential has been set back significantly as a result of not receiving the better treatment early on.²¹ In treating chronic wounds, using what peer-reviewed literature demonstrates to be the best product available must be balanced with cost considerations. However, when considering costs, it is important to examine not just the short-term costs, but also to evaluate costs over an extended period of time.

Keeping the amount of necrotic tissue in a wound bed to a minimum is essential throughout all phases of wound healing and throughout the entire lifespan of an ulcer. Ulcers with necrotic tissue in their bed are more likely to stall in the inflammatory phase of healing and not progress to the proliferative and remodeling phases.²² Because ulcers typically first present to providers while stuck in the inflammatory phase,²² eliminating necrotic tissue is usually needed immediately upon presentation, and early initiation of CCO can help accomplish this. This is especially true of the Stage 3 and Stage 4 PIs and the DFUs described in this study. The potential complications of these ulcers are so profound that early use of advanced treatment options is necessary. A hallmark of treatment for most Stage 3 and Stage 4 PIs and DFUs is sharp and/or enzymatic debridement.^9,23 Motley et al¹³ demonstrated a much greater decrease from baseline in wound area among DFUs that received both sharp debridement plus enzymatic debridement versus those receiving sharp debridement without enzymatic debridement. In addition, the early use of the best treatment options is of profound importance in DFUs; if the wound percentage area reduction of a DFU is less than 50% after 4 weeks of conservative treatment, the ulcer only has a 10% chance of healing in 12 weeks.²¹ 

In this study, the decrease in both all-cause health care costs and disease-specific health care costs was significant when PIs were treated with early versus late CCO initiation. Delaying the use of CCO, often in an attempt to decrease costs, may be a short-sighted decision that is not only not cost effective, but may result in an increase in costs. Ironically, the study noted that when CCO was initiated late, perhaps in an attempt to decrease utilization of CCO, utilization increased with a higher number of CCO-related pharmacy visits and higher CCO-related pharmacy costs. 

Pressure injuries are associated with substantial morbidity and mortality. This morbidity can impact multiple body systems and help exacerbate a multitude of comorbidities that can involve the cardiovascular and pulmonary systems, renal function, and more.⁸ When a PI does not progress as it should, the risk of these complications that involve other systems is increased.⁸ 

The authors believe this accounts for the increase in all-cause health care costs seen when CCO was not initiated early. Peer-reviewed literature has established that PIs that do not receive CCO early in the healing process are likely to stay open longer, fail to progress, and require more caregiver time and more topical products and debridements; in addition, the longer they stay open, the more likely they are to result in comorbid complications. The results presented here confirm that late CCO initiation not only yields poorer clinical results, but it also increased all-cause health care costs.

These scenarios also were true for the DFU group. Similarly, the authors believe the increase in all-cause health care costs in the late CCO initiation DFU group was due to the increase in comorbid complications that come with DFUs staying open longer when they do not receive early CCO initiation; the increase in disease-specific health care costs in the late CCO initiation DFU group were related to the DFUs staying open longer and therefore necessitating more topical care, more professional intervention, and more procedures.  

Increased complications are often the main cause of increased costs in chronic wounds. It was not surprising to find that when CCO was withheld in the late CCO initiation group, there was an increase in costly hospitalizations, ED visits, and pharmacy events. 

Despite the fact that the clinical superiority of early versus late CCO initiation has been established and widely published, some care decisions appear to be based on what is perceived to be a savings in dollars, rather than what is clinically best for the patient. The current study has shown that withholding CCO, while possibly resulting in savings in the very short term, does not save money; in contrast, withholding CCO is costlier. These results should help guide prescribing habits, encourage early initiation of CCO, and decrease costs for all.

This retrospective study may not match the stature of a randomized controlled trial, but the matching applied to the 2 groups reduced selection bias and strengthened the study findings. However, the study may not have controlled for unknown and unmeasurable confounders inherent to the type of data collection employed. The authors believe that these variables were evenly distributed in both cohorts and likely had little to no effect on the results and interpretation of results.

PearlDiver did not have the technical capability to perform propensity score matching; as such, one-to-one exact matching was used from the early CCO initiation and late CCO initiation groups to try to reduce selection bias. The study used data from one of the largest payers in the country with a large enough sample size to allow for conclusions to be drawn. While the size of this single payer mitigates the concern, it is worth noting that all data coming from one payer can be viewed as a limitation. To the authors’ knowledge, this is the first attempt to estimate dollars spent on the care of chronic ulcers of different types from the perspective of the payer. 

This type of retrospective study is dependent on the accuracy of coding, billing, and data input from multiple providers and different sources. These types of errors are a potential source of inaccuracy in the data. The PearlDiver tool did not allow for checking data distribution characteristics and advanced generalized linear regression analysis, but the best available statistical methods with appropriate link function were used. Additionally, clinical information on wound size, wound depth, wound location, and other characteristics that can impact the progression of a wound are not available from claims data, and failure to include these items also may have had an impact on the results presented here. 

A retrospective review of clinical and financial data showed early treatment versus late treatment with CCO provided both overall and disease-related cost benefits in managing patients with Stage 3 and Stage 4 PIs and patients with DFUs and affirmed previously established clinical benefits of product use. Payers, providers, and facilities should encourage the early initiation of CCO in Stage 3 and Stage 4 PIs and DFUs to lower costs as well as to provide the clinical benefits of enzymatic debridement. Future research that helps underscore timely and appropriate use of CCO is warranted. 

Authors: Jeffrey Lehrman, DPM, FASPS, MAPWCA, CPC¹; Ankur Patel, MS²; and Gary Delhougne, MHA, JD²

Affiliations: ¹A Step Ahead Foot & Ankle Center, Fort Collins, CO; and ²Smith+Nephew, Hull, UK

Correspondence: Jeffrey Lehrman, DPM, FASPS, MAPWCA, CPC, A Step Ahead Foot & Ankle Center, Podiatry; JeffLehrman@LehrmanConsulting.com

Disclosure: Dr. Lehrman is a consultant and member of the Speaker’s Bureau for Smith+Nephew. Mr. Patel and Mr. Delhougne are employees of Smith+Nephew.