Introduction

The presence of a chronic non-healing ulcer is a considerable health concern, with a global prevalence range of 1.9 to 13.1%.^1,2 The incidence of chronic ulcers is anticipated to rise as the population ages, as advancing age makes the healing process slower.³ One of the leading causes of non-healing ulcers is diabetes. In particular, one of the most severe long-term complications of diabetes mellitus is the development of foot ulcers as a consequence of the sustained effect of peripheral neuropathy and vascular insufficiency.⁴ Approximately 18.6 million people worldwide are affected by diabetic foot ulcers yearly, including 1.6 million people in the United States.⁵ A recent study, which investigated the changes in Medicare spending on chronic wounds between 2014 and 2019, revealed a noteworthy increase in the prevalence of DFU infections in both sexes. The rates of DFU infections among males increased from 3.2% to 4.7%, while those among females increased from 3.1% to 4.2%,⁶ significantly impacting the quality of life of 2.5% of the US population. The meta-analysis by Zhang et al (2017)⁵ on the global prevalence of diabetic foot ulcers shows that globally, 6.3% (95% CI: 5.4–7.3%) of people with diabetes suffer from foot ulcers. The prevalence was higher in males (4.5%, 95% CI: 3.7–5.2%) than in females (3.5%, 95% CI: 2.8–4.2%), and higher in patients with type 2 diabetes (6.4%, 95% CI: 4.6–8.1%) than in those with type 1 diabetes (5.5%, 95% CI: 3.2–7.7%). Belgium has the highest prevalence of 16.6% (95% CI: 10.7–22.4%), followed by Canada with 14.8% (95% CI: 9.4–20.1%), North America with 13.0% (95% CI: 10.0–15.9%), Africa with 7.2% (95% CI: 5.1–9.3%), Asia with 5.5% (95% CI: 4.6–6.4%), Europe with 5.1% (95% CI: 4.1–6.0%), Oceania with 3.0% (95% CI: 0.9–5.0%) and Australia with the lowest prevalence of 1.5% (95% CI: 0.7–2.4%).

Estimates suggest that Medicare spending for all wound types falls between $28.1 and $96.8 billion.⁷ Nussbaum’s study⁸ found that surgical wounds and diabetic foot ulcers are the most expensive, costing $11.7-$38.3 billion and $6.2-$18.7 billion, respectively. Diabetic foot ulcers, complicated by neuropathy, often lead to infections and prolonged healing, making them a significant risk factor for lower limb amputation.⁹

According to recent research, approximately 12% of individuals who are diagnosed with diabetic foot ulcers require amputation of the lower extremity.^10–12 Armstrong’s¹³ data indicates that diabetic foot ulcers significantly increase mortality in individuals with diabetes. They precede 80% of diabetes-related lower extremity amputations, with half becoming infected and 20% of moderate to severe infections leading to amputation. The 5-year mortality rate is about 30% for those with ulcers and over 70% for those with significant amputations. Mortality is higher among those with ulcers (231 deaths per 1,000 person-years) compared to those without (182 per 1,000 person-years). Each year, approximately 150,000 people in the United States undergo nontraumatic leg amputations, with most cases occurring among diabetic patients.¹⁴

In the US, diabetic foot ulcers (DFU) are responsible for 83% of all significant amputations and 96% of all minor amputations. DFUs significantly increase the cost of care, resulting in $1.38 billion per year compared to non-DFUs at $0.13 billion per year (p <0.001).¹⁵

Between 2000 and 2009, there was a decline of around 40% in the amputation rate among patients with diabetes. However, from 2009 to 2015, there was a subsequent increase of 50% in the amputation rate.¹⁴ According to a previous study,¹⁶ a lower limb is amputated due to diabetes every 30 seconds. Treating diabetic foot averages $8659 per patient annually.¹⁷ Furthermore, in the United States of America, the cost of medical treatment for diabetic foot diseases ranges from nine to thirteen billion dollars. This cost is an additional financial burden associated with diabetes, which already incurs significant expenses.¹⁸

Therefore, it is clear that ulcers, besides causing a significant decline in patients’ quality of life, lead to high therapeutic costs.¹⁹

Chronic ulcers pose a significant financial burden for the patient and the healthcare system. With the population’s increasing age, rising cases of diabetes and obesity worldwide, and the persistent problem of infection, chronic wounds will continue to be a substantial clinical, social, and economic challenge.^7,20,21

The escalating prevalence of diabetes across several nations has resulted in a significant and growing public health challenge of foot ulcers.²²

Thus, the International Diabetes Foundation is currently undertaking measures to raise awareness regarding diabetic foot problems. This initiative responds to the condition’s significant medical, social, and economic implications.²³

The only solution is to evaluate strategies that improve wound prevention, management, and reduce amputations.

Regenerative medicine represents an innovative approach to promoting wound healing by utilizing autologous growth factors. Modern techniques now allow for the straightforward production of these growth factors by collecting a patient’s blood and processing it with specialized devices to create platelet-rich plasma (PRP),²⁴ which is characterized by its rich and complex secretion profile, including more than 300 proteins.²⁵ PRP is rich in thrombocytes, and its α-granules contain numerous growth factors like PDGF, TGF-β1, TGF-β2, platelet factor IV, interleukin-1, platelet-derived angiogenesis factor, VEGF, EGF, insulin-like growth factor, osteomacin, osteonectin, fibrinogen, vitronectin, fibronectin, and thrombospondin-1.²⁶

Autologous PRP gel is gaining widespread application across numerous surgical specialties, particularly for addressing various soft-tissue and hard-tissue defects, enhancing bone regeneration, and treating persistent, nonhealing wounds.^27.

It has been demonstrated that plasma growth factor (PGF), such as platelet-derived growth factor (PDGF), significantly shortens treatment duration and leads to healing in approximately 80% of wounds.^28–31 Many authors^28–31 found that platelet release has improved healing rates compared to standard remedies. On the other hand, other studies^28,29 found no significant difference in the healing outcome of leg ulcers between treatment groups with platelet release and control groups (placebo). An extensive review was performed by Picard et al 2015. They carried out a PubMed and Cochrane search (1978–2015), including all studies assessing the clinical effect of PRP on the healing of diabetic chronic wounds. The screening retrieved 7555 articles, and 12 studies were included. Of six randomized studies, five found significant benefits for using PRP on diabetic chronic foot ulcers. The authors concluded that 87.5% of controlled studies found a significant benefit for the adjunction of PRP to treat chronic diabetic wounds.

As PRP may be beneficial, they suggest using it on diabetic ulcers that remain unhealed after standard treatment. Platelet-derived growth factors can play a critical role in wound healing by driving key processes such as chemotaxis, cellular proliferation, and angiogenesis,³² supporting tissue repair³³ and promoting cell recruitment and differentiation.³⁴

Such emerging cellular therapies can serve as an adjunctive component within a standardized, high-quality treatment plan.³⁵

Recent meta-analyses and review articles further underscore the therapeutic potential of PRP in chronic wounds, demonstrating benefits such as complete wound closure, reduced wound surface area, minimized scarring, and a lower incidence of infections.^36–47 In particular, the review performed by OuYang⁴⁸ found that PRP significantly improved the healing rate (OR = 4.37, 95% CI 3.02–6.33, P < 0.001) and shortened the healing time (MD =−3.21, 95% CI−3.83 to−2.59, P < 0.001) of patients with DFU when compared to the conventional treatment.

These findings are consistent with the meta-analysis performed by Syafira⁴⁹ that revealed that PRP exhibited a healing rate that was twice as high as the control group (Relative Effects (REs) = 2.338; 95% Confidence Interval (CI) = 1.056 to 1.857, P = 0.019). Additionally, the healing time was shortened by two days (REs = −2.815; 95% CI = −3.252 to −0.576, P = 0.005), and there was a difference of 0.482 cm² in the reduction of ulcer area between the two groups (REs = 0.482; 95% CI = −2.428 to 4.002, P = 0.630).

Also Deng⁵⁰ finds that autologous PRP has a significant positive effect on the healing rate (RR = 1.42, 95% CI 1.30–1.56, P < 0.001), reduces the healing time (MD = − 3.13,95% CI − 5.86 to − 0.39, P < 0.001), accelerates the reduction of ulcer area (MD = 1.02, 95% CI 0.51–1.53, P < 0.001), decreases the rate of amputation (RR = 0.35, 95% CI 0.15–0.83, P < 0.001), and does not increase the incidence of adverse events (RR = 0.96, 95% CI 0.57–1.61, P > 0.05) when compared to conventional therapy.

According to these data, PRP used to treat Diabetic Foot Ulcers (DFUs) has shown promising clinical results; however, the costs associated with this treatment may be higher than standard therapy. Therefore, its cost-effectiveness must be evaluated before implementing this approach in health systems. Only a few studies have directly dealt with the relationship between the costs and the results of PRP versus standard care, and, in addition, economic evaluations in parallel with clinical studies have yet to be reported. Two studies before 2014 found PRP treatment to be cost-effective or even dominant compared with usual care.^30,51,52 Recently, Linertová et al found that, in a 5-year time horizon, PRP treatment for DFU could be considered a cost-effective or even a cost-saving alternative in Spanish healthcare settings, depending on the method of obtaining the PRP (commercial kit versus manual method) and, to a large extent, on the price of the kit used. Consequently, these authors called for future studies on the effectiveness and costs of specific devices or methods to be used as inputs for more specific cost-effectiveness models.⁵³

This study aims to fill this gap by conducting a cost-effectiveness analysis of a specific PRP preparation procedure for treating DFUs versus standard care, with a 1-year time horizon. The methodology adopted follows a previous study carried out in the French context.⁵⁴ This analysis provides specific evidence and insights for clinical and managerial decision-making in a US setting.

Materials and Methods

Treatment

The present study focuses on analyzing autologous PRP gel in promoting the healing of chronic deep diabetic foot ulcers, classified as 3 A stage according to UT classification, comparing it with the standard of care. (Soc). Soc includes debridement, infection control, management of comorbidities, and off-loading.

According to clinicians’ opinions and previous studies, a series of assumptions are made for the model.⁵⁵ During PRP treatment, a gel is created from the patient’s blood. In the French study of reference, this practice is done by extracting platelet-rich, leukocyte-poor plasma with the help of a commercial kit called Regenkit (RegenLab, Switzerland). The kit includes three tubes (2 BCT and 1 ATS) used to produce the PRP gel. Then, PRP is used for wound medication. The treatment lasts six weeks or less if the wound has closed. Patients in the PRP gel group may receive more than one application, as decided by the investigator. The primary efficacy endpoint for wound closure is measured at six weeks, and efficacy is also evaluated during follow-up visits at nine and twelve weeks.

For the PRP arm, the patients only need to change the protective compress once a week at home. However, the dressing must be changed once daily at home for the control group.

In Table 1, we summarize the main parameters used.

Table 1 Data Collected

Model Description

A Markov model was utilized to conduct a cost-effectiveness analysis on a theoretical cohort of patients with chronic diabetic foot ulcers (DFU) lasting more than three weeks and facing a high risk of orthopedic complications. These patients had ulcers classified as grade 3A according to the UT classification, indicating deep ulcers reaching the bone, including tunneling and perforating wounds.

The decision-analytic model enabled us to establish a framework and integrate evidence from the “Le Creusot” study⁵⁵ and existing literature to generalize the findings. The flexibility of the Markov model made it particularly useful for modeling chronic conditions that progress over months or years. It can account for ongoing risks and recurrent events over time.⁵⁶

The first step involved defining DFUs (Diabetic Foot Ulcers) based on specific states that encompass all relevant health outcomes, with transitions between these states governed by transition probabilities. In this study, the Markov model included six potential health states: two temporary states, three standard states, and one absorbing state. These states were: (1) initial complete DFU treatment; (2) persistent DFU; (3) fully healed DFU; (4) amputation; (5) post-amputation; and (6) death from any cause and surgery. In the initial stages of the application model, patients with DFUs would receive the initial treatment based on one of the following strategies: PRP combined with the best SoC or SoC alone. Hypothetical patients started in state one and moved through predefined health states. Each clinical state was linked to a cost and effectiveness estimate. Hypothetical patients accrued costs and QALYs (quality-adjusted life years) corresponding to the time spent in each clinical state during the simulated three-month period. The cycle length was one week, and the time horizon was one year.

Patients received their initial complete treatment during the first phase, after which they transitioned to the second state with a 100% probability. In the second state, also known as persistent DFU, patients received weekly care. For PRP treatment, some patients might need a new complete treatment, which is more costly than the weekly care. We modeled the need for a second treatment as a transient event rather than a state. Therefore, we used transition rewards to associate a one-time cost with the patient requiring a second treatment. It is crucial to note that the need for a new treatment is not a state itself and does not impact state transitions. However, it may result in additional costs and/or disabilities, unlike traditional care involving daily dressing changes until the wound heals.

In state 2, the home nurse for the PRP arm opens the dressing and checks the cleanliness of the primary dressing. This is performed once a week, according to the “Le Creusot” study⁵⁵ protocol, unless complications arise. If the dressing is clean, the nurse replaces the secondary dressing. If not, a second complete treatment is scheduled. Meanwhile, in state 2, for the standard treatment arm, a home nurse performs a complex dressing change daily by cleaning and dressing the wound five days a week.

Progressing to state 3, patients will incur the costs and benefits of a fully healed ulcer. However, there is a risk of recurrence for diabetic patients, which may necessitate new medications and a transition from the state of complete wound healing to relapse. Finally, state 6 is an absorbing state that includes individuals who die from any cause (life table), including those who succumb to surgery. The results regarding the incremental cost-effectiveness ratio (ICER) are presented.

Cost Inputs

The costs related to healthcare states and transition costs in the Markov model have been expressed in dollars for 2022, as presented in Table 1. We have estimated the costs using a micro-costing approach that considers the resources used in the “Le Creusot” study.⁵⁵ These costs reflect the viewpoint of the US healthcare system.

We have made some estimations to determine the average cost of a simple dressing (PRP group) and a complex dressing (SoC group). Jelonet, Adaptic, Grassolind, and a serum secondary dressing were used for a simple dressing. Depending on the wound characteristics, different product families were used for a complex dressing. The utilization rate of hydrocellular dressing was 70%, superabsorbent hydrocellular dressing (Cutimed, Wilsabord, Sorbact) was 20%, and Urgostart was used in 10% of the cases. The main parameters used are summarized in Table 1.

In State 1, the PRP cost is due to the use of Regent BCT-1 (X2) and ATS (X1) kits, along with the cleaning procedure and medication and the time spent by the nurse. On the other hand, the comparator’s cost is due to the cost of complex dressing, cleaning procedures, and nurse time.

In State 2, the PRP cost is due to the medication’s repair and the nurse’s time. The comparator’s cost is due to the cost of complex dressing, cleaning procedures, and nurse time multiplied by five times per week. In Table 2 we reported the costs used in the model.

Table 2 Data Used in the Model: Costs

Utility Inputs

Quality of life assessments for six potential health states were based on general health status profiles, which, though less sensitive than illness-specific scales, allow for comparisons beyond specific diseases. Common generic preference-based measures include the EuroQol EQ-5D, SF-6D, and HUI.⁵⁹ These questionnaires generate a score (0 for dead, 1 for perfect health) based on public values, used to calculate QALYs (Quality-Adjusted Life Years). The advantage of these methods is their ability to compare outcomes across different health conditions and assess the economic impact of health interventions, aiding informed decision-making. This analysis utilized the EuroQol instrument and data from Redekop et al (2004), using the time trade-off method (Table 3) to estimate utility weights for health states related to diabetic foot ulcers (DFUs).

Table 3 Data Used in the Model: Effectiveness (at 3 Months) Source: Redekop et al, in 200460

The source used in this study has been previously used to provide quality-of-life estimates for a cost-effectiveness analysis of a negative pressure device for treating DFUs. Quality-Adjusted Life Years (QALYs) were calculated by multiplying the quality-of-life utility weight for a particular health state by the number of years spent there.

Probabilities

The probability of healing in this study was estimated based on the percentage of ulcers that were completely healed after 12 weeks of treatment. The “Le Creusot” study⁵⁵ found that 77.3% of patients who received PRP care had fully healed ulcers, while only 35.1% of patients who received usual care had healed ulcers. However, in our cost-effectiveness analysis, we took a conservative approach and used data from a meta-analysis of five clinical trials. This analysis found that the success rate for healing with PRP was 58.33%, compared to 50.31% for usual care.⁴⁰ The study conducted in “Le Creusot” study⁵⁵ found that out of the patients involved, 27 received one injection, 17 received two injections, and two individuals received an unknown number of applications. On average, patients received 1.46 PRP treatments. Based on the study, there is a 50% chance of receiving a second complete treatment during a cycle. This is a conservative estimate as the actual probability of receiving a second complete treatment, according to the study, is 0.2. To create a more generalized model, the risk of amputation and relapse were also included. Amputation is considered a temporary state that leads to a post-amputation state. The probability of amputation was taken from the Moulik study⁶¹ and adjusted according to the model cycles, which are one week long. The 'new occurrence' probability was taken from the Eurodiale study.⁶²

Sensitivity Analysis

Deterministic sensitivity analysis was conducted to evaluate the impact of parameter uncertainty on the model’s results (Table 4). A sensitivity analysis was performed on the most critical parameters of the model. This analysis helps to deal with different uncertainties, such as model uncertainty, parameter uncertainty, and heterogeneity. One-way DSA and tornado analysis were run for every parameter, with a minimum and maximum scenario reported.⁶²

Table 4 Data Used in the Model: Probability of Healing (at 3 Months)

Moreover, probabilistic sensitivity analysis was conducted through a Monte Carlo simulation, performing 10,000 cases. This analysis was carried out to assess the uncertainty around the ICER and the probability of the PRP therapy being cost-effective at various willingness-to-pay thresholds. A probability distribution was assigned to each model input parameter to describe the different values the parameter can have with different probabilities. The effectiveness and probabilities were modeled with Beta distributions, while costs were represented as Gamma distributions, as recommended in the literature.⁶³ For the parameters cited in literature where standard error was not estimated, a general standard error of 25% of the mean value was assumed.⁶²

To conduct all the analyses about the study, we utilized the advanced software tool TreeAge Pro 2021. This cutting-edge software enabled us to carry out complex and detailed analyses, providing accurate and reliable research results.

It was deemed unnecessary to seek ethical approval for the study, as secondary data was used.

Results

In the base case scenario (1 year), the average cost per QALY is around $133.21 for the comparator and $140 for PRP, respectively. PRP treatment has an ICER of $2,801, which is lower than the classical wtp threshold, indicating the dominance of the PRP therapy.

A one-way sensitivity analysis was performed for the main parameters to determine each parameter’s influence on the results (Table 5).

Table 5 One-Way Sensitivity Analysis

The analysis shows that the most sensitive parameters are the number of weekly dressings performed for the SoC, the PRP complete procedure, and the number of core PRP dressings.

According to the one-way analysis, we highlight that:

1. The number of SoC dressings ranges from a minimum of 3 to a maximum of 7. If the dressings performed are 3 instead of the base case 5, the ICER goes from 2,800 to almost 15,000 dollars/QALY. On the other hand, if the number of SoC dressings is 7, the PRP choice becomes cost-saving (ICER = - 10,011.82).
2. The total procedure costs for PRP range from a minimum of 733 to a maximum of 1,100. If the total procedure costs for PRP were equal to 1,100 instead of the base case, the ICER from 2,800 goes to 9,766 dollars/QALY. On the other hand, if the procedure cost is 733, the PRP choice becomes cost-saving (ICER = - 4,163).
3. The number of PRP medications ranges from a minimum of 1 to a maximum of 4. If the number of medications for PRP equals 4 instead of the base case, the ICER from 2,800 goes to 13,655 dollars/QALY. On the other hand, if the procedure cost is 1, the PRP choice becomes equal to the base case scenario (ICER = 2,800).
4. The SoC preparation time ranges from a minimum of 10 to a maximum of 20. If the preparation time is 10 instead of the base case 20, the ICER goes from 2,800 to almost 12,562 dollars/QALY.
5. The Regen KIT’s price ranges from a minimum of $750 to a maximum of $990. If the PRP kit was priced at $990 instead of the base case, the ICER from 2,800 goes to 7,360 dollars/QALY, remaining cost-effective. On the other hand, if the price was 750, the PRP choice becomes cost-saving (ICER = - 1,756).

 A Threshold analysis was carried out to define the price level at which PRP would be cost-saving. Regarding the first research question, it emerged that PRP became cost-saving in the first year after the fifth medication. About the second question, it was found that when the price of the regen kit is below $797, it becomes a cost-saving strategy.

A threshold analysis was also performed to determine the number of weekly medications needed for the Soc and the PRP. In detail, a two-way sensitivity analysis was performed. We find out that the number of PRP and Soc medications per week affects the final results. Starting from the two extremes, when PRP has its base case scenario of one per week complete medication and the Soc medication is three, the ICER goes up to around 15,000 $/QALY. Enhancing the number of PRP full medications increases the ICER. For example, if PRR would need four complete medications per week and Soc the base case (five), the ICER would be 13,655 $/QALY. Keeping the four full medications for the PRP strategy and lowering the medication to three per week would have an ICER of around 26,000 $/QALY. The definition of the PRP as the cost-effectiveness strategy is based on robust data but can be reduced by different elements, such as the number of medications for the two strategies.

Finally, a Monte Carlo simulation was employed to conduct a comprehensive probabilistic sensitivity analysis. This simulation methodically explored a vast array of possible scenarios, totaling 10,000. This approach allowed for a thorough exploration of the factors that could influence the outcome of the analysis, providing a more complete and nuanced understanding of the situation at hand. The model’s parameters and variables vary based on the assigned distribution. Table 6 shows the results of corresponding acceptability curve with WTP thresholds. For each WTP threshold, the percentage of cases favoring PRP or HA is displayed, where the percentage of convenient iterations is derived from the Monte Carlo simulation. For instance, at $12,000/QALY, PRP treatment has an 87% probability of being convenient, while at $18,000/QALY, the probability is almost 100%.

Table 6 CE Acceptability Curve Results

Conclusion

This study conducts a comparative analysis of the cost-effectiveness of platelet-rich plasma (PRP) therapy versus standard care for treating diabetic foot ulcers (DFU) in high orthopedic risk patients, specifically those with grade 3A ulcers, according to the University of Texas (UT) classification. The study employs a micro-costing method, which allows for a detailed assessment of each treatment’s direct and indirect costs. The data is based on a conservative meta-analysis, ensuring the comparison is grounded in reliable clinical evidence. Some conclusions that have been drawn lead to beneficial considerations regarding the following issues:

1. Economic Efficiency: Although PRP therapy has a higher initial cost, it requires fewer interventions and additional treatments than standard care.

2. Reduced Resource Utilization: given that PRP therapy may decrease the need for dressings, hospitalizations, and other medical procedures, leading to lower healthcare costs within the first year of treatment.

3. Clinical Benefits: PRP has the potential to promote faster and more sustained healing, which can reduce long-term complications and improve the patient’s quality of life.

Despite the higher upfront cost, the potential of PRP therapy to minimize additional interventions supports its economic viability, making it a promising alternative for managing advanced diabetic foot ulcers. This study and others that have compared PRP practices indicate that PRP procedures can be fundamental in treating specific health conditions. These conditions impact the aging process and improve the patient’s overall health, resulting in better performance.