Autologous Blood-Derived Products for Chronic Non-Healing Wounds

The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds under section 1862(a)(1)(A) of the Social Security Act (the Act).

CMS proposes that coverage of autologous PRP for the treatment of all other chronic non-healing wounds will be determined by local Medicare Administrative Contractors (MACs) under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision.  We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act (the Act).

TO:		Administrative File:  CAG-00190R4

FROM:	Tamara Syrek Jensen, JD
		Director, Coverage and Analysis Group

		Joseph Chin, MD, MS
		Deputy Director, Coverage and Analysis Group

		Melissa A. Evans, PhD, MSAE
		Director, Division of Policy and Evidence Review

		Lori Ashby, MA
		Deputy Director, Division of Policy and Evidence Review

		James Rollins, MD, PhD
		Lead Medical Officer

		David Dolan, MBA
		Lead Analyst

SUBJECT: 	Proposed National Coverage Determination for Autologous Blood-Derived Products for Chronic Non-Healing Wounds (CAG-00190R4)

DATE: 		December 21, 2020

I. Proposed Decision

The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds under section 1862(a)(1)(A) of the Social Security Act (the Act).

CMS proposes that coverage of autologous PRP for the treatment of all other chronic non-healing wounds will be determined by local Medicare Administrative Contractors (MACs) under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision.  We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act (the Act).

II. Background

Throughout this document we use numerous acronyms, some of which are not defined as they are presented in direct quotations.  Please find below a list of these acronyms and corresponding full terminology:

AAWC - Association for the Advancement of Wound Care
ABPI - Ankle Brachial Pressure Index
AE - Adverse Events
BMI - Body Mass Index
BWAT - Bates – Jensen Wound Assessment Tool
CED – Coverage with Evidence Development
CMS - Centers for Medicare & Medicaid Services
DFS - Diabetic Foot Syndrome
DFU-Diabetic Fool Ulcer
FDA - Food and Drug Administration
FGF - Fibroblast Growth Factor
HGF - Hepatocyte Growth Factor
ICTRP-International Clinical Trial Registry Platform
IGF - Insulin Growth Factor
NCA - National Coverage Analysis
NCD - National Coverage Determination
NICE - National Institute for Health Care Excellence
NSAID-Non-steroidal Anti-Inflammatory Drugs
PDGF - Platelet-Derived Growth Factor
PRGF - Platelet Rich Growth Factor
PRF - Platelet Rich Fibrin
PRP - Platelet Rich Plasma
PU-Pressure Ulcer
RCT - Randomized Controlled Trials
rhPDGF-BB - Recombinant Human Platelet-Derived Growth Factor-BB
SOE - Strength of Evidence
UCC - Usual and Customary Care
US - United States
VAS-Visual Analog Scale
VEGF - Vascular Endothelial Growth Factor
VLU - Venous Leg Ulcers
WHO-World Health Organization
WHS - Wound Healing Society
W-QOL - Quality of Life with Chronic Wounds

Note:  Throughout this document the terms “wounds” and “ulcers” are used interchangeably. 

Wound Etiology and the Wound Healing Process

Wound healing is a dynamic, interactive process that involves multiple cells and proteins. There are three progressive stages of normal wound healing and the typical wound healing duration is about four weeks.  While cutaneous wounds are a disruption of the normal anatomic structure and function of the skin, subcutaneous wounds involve tissue below the skin's surface.  Wounds are categorized as either acute or chronic.  In acute wounds, the normal wound healing stages are not yet completed but it is presumed they will be resulting in orderly and timely wound repair.  However, in a chronic wound, the wound has failed to progress through the normal wound healing stages and repair itself within a sufficient time period.

A wound is a disruption of normal anatomic structure and function and can range from a simple scratch to an interruption that goes through tissue and muscle down to bone.  Acute wounds are wounds of relatively new onset that heal in an orderly fashion, first by reestablishing epithelial integrity, then by laying down new collagen to strengthen the damaged tissue.  The result is re-establishment of anatomic and functional integrity.  Fortunately, most wounds are acute wounds that heal rapidly and uneventfully.

The process of wound healing involves an integrated series of cellular, physiologic, biochemical, and molecular events.  The stages of wound healing are defined as inflammatory, proliferative, and remodeling.  The inflammatory phase is characterized by platelet accumulation, coagulation, and leukocyte migration into the wound site.  During this phase, the platelets adhere to collagen to form a vascular plug and the leukocytes, along with macrophages, begin removing cellular debris and bacteria.  This inflammatory phase occurs during the first three to four days after a wound presents.  The cellular interactions in this phase help to provide a temporary stable wound environment.

The proliferative phase, also termed fibroblastic, is characterized by the regeneration of epidermis, angiogenesis, and the proliferation of fibroblast that forms collagen.  Angiogenesis, the formation of a new vascular supply, is important for allowing the nutrition required in the healing process to invade the wound area.  Collagen formation plays a prominent role in wound healing and there are over 20 different types of collagen in the human body.  Type III collagen, which is part of the granulation tissue, is produced by fibroblasts during the proliferative phase.  The re-epithelialization helps to restore the cutaneous barrier.  All of these physiologic events normally occur during the 10 to 14 day period after a wound presents.

The third and final phase of wound healing, the remodeling phase, takes place from a period of months up to two years (Bhanot & Alexi, 2002).  This phase is characterized by collagen synthesis and degradation.  The type III collagen is replaced by type I collagen that is instrumental in decreasing the wound size through contraction.  Contractile forces are produced by contractile proteins as well as the presence of type I collagen that ultimately results in scar formation.  At the end of remodeling, the resulting scar tissue is approximately only 80% the strength of normal skin (Bhanot & Alexi, 2002).

The stages of wound healing are sequential in the normal healing process of acute wounds.  Many chronic wounds fail to complete all the stages of normal wound healing (Loots et al., 1998).  When the healing process fails to progress properly and the wound persists for longer than one month, it may be described as a chronic wound. In chronic wounds, the healing process is disrupted by some underlying abnormality that prolongs the inflammatory phase, resulting in poor anatomic and functional outcome.  Common underlying abnormalities include diabetes, abnormal external pressures and arterial or venous circulatory insufficiency.

Since the etiology of wounds varies, the most effective therapy may vary as well.  For example, the etiology of a pressure ulcer relates to unrelieved pressure on the skin, whereas the origin of a diabetic ulcer has other etiologies.  Therefore, it is difficult to generalize the findings from studies on therapy from one type of ulcer to another type.  According to the "Guidance for Industry-Chronic Cutaneous Ulcer and Burn Wounds-Developing Products for Treatment," the Food and Drug Administration (FDA) states that "Wounds differ pathophysiologically, making it difficult-if not impossible-to generalize results obtained from a trial conducted in patients with one type of wound to those with another wound type.  Separate safety and efficacy data should be submitted for each wound type for which an indication is sought" (FDA, 2006).

Wound care must be directed at providing an environment in which the body can effectively carry out the healing process.  Conventional or standard therapy for chronic wounds involves local wound care as well as systemic measures.  Standard care considerations to promote wound healing include debridement or removal of necrotic tissue, wound cleansing and dressings that promote a moist wound environment.  Systemic treatments include the use of antibiotics to control infection and optimizing nutritional status.  Early concepts in wound management involved soaking the wound in antiseptics to kill bacteria and then covering the wound with a dry dressing.  As the biology of wound healing has become better understood, a variety of wound care strategies and products have been developed to help aid the healing process.  Various new dressings such as alginates, hydrogels, films, and foam products are now used.

There are other conventional therapeutic modalities that may be applied to certain subgroups of patients depending on their type of wound.  Specific conventional therapies for venous ulcers include the use of compression devices aimed at decreasing venous stasis.  Patients that have pressure ulcers require frequent repositioning to redistribute the pressure that is causing the ulcers.  Appropriate glucose control for diabetic foot ulcers and establishing adequate circulation for arterial ulcers have been used in addition to ulcer-specific therapies.

The multitude of wound care regimens demonstrates the complexity of wound care management and the lack of a unified, proven, universal treatment strategy.  Knowledge of the pathophysiology of healing combined with realistic patient outcomes will help guide the clinician in choosing the wound care treatment plan.  Authors reported that no single wound dressing is sufficient for all types of wounds and few are ideally suited for the treatment of a single wound through all phases of healing (Lait & Smith, 1998).

Some wound care specialists have proposed that chronic wounds do not heal due to a lack of vital growth factors that are believed to be deficient in chronic wounds (Belden, 1999).  Several authors have proposed that this deficiency is due to repeated trauma, ischemia, and infection that increases the level of pro-inflammatory cytokines, increases the level of matrix metalloproteinases, decreases the presence of tissue inhibitors of metalloproteins, and lowers the level of growth factors (Payne et al., 2001).

Role of Platelets and the Development of Platelet-rich Plasma

Originally, it was thought that platelets were important only for clot formation.  However, it is now clear that platelets contain a large number of growth factors.  The exact number and purpose of all of the growth factors is not known.  Four growth factors are most frequently cited (Atri et al., 1990).  The first is the vascular endothelial growth factor (VEGF) that causes new capillary formation from the existing microvasculature (Knighton et al., 1982; King et al., 1984).  Platelet-derived epidermal growth factor and platelet factor 4 (considered to be a chemoattractant for neutrophils) have also been identified.  The fourth type is platelet-derived growth factor (PDGF), which is a potent fibroblast mitogen and chemoattractant.  Other growth factors involved in the healing process include Fibroblast Growth Factor (FGF), Insulin Growth Factor (IGF), Transforming Growth Factor-β, and Hepatocyte Growth Factor (HGF) (Chicharro-Alcantara et al., 2018).

Due to the critical role that platelets and various growth factors play in tissue repair and regeneration, as well as its antibacterial properties in traumatic injuries, a number of platelet-derived products have been developed for medical use.  In 1985 researchers at the University of Minnesota developed a system to obtain multiple growth factors from platelets to treat patients at the facility.  A retrospective study based on the first patients treated with PDGF was published in 1986 (Knighton et al., 1986).  The first prospective trial was then conducted and the results were published (Knighton et al., 1990).  Dr. Knighton obtained a patent in 1992 on products released from platelets (i.e., platelet releasate) that are used for tissue repair.  Procuren Solution® produced by CuraTech (which later became Curative Health Services) was available throughout the United States through 150 wound care centers starting in 1986.  Marketing of Procuren Solution® ceased in 2001.  However, various PDGF products, which contain multiple proteins like Procuren but do not contain cells like those found in platelet-rich plasma (PRP), are in use for patient care.

In 1997, FDA approved the biologics license application of Ortho-McNeil Johnson Pharmaceuticals, Inc. to market Regranex® (becaplermin) Gel 0.01%.  The recombinant human platelet-derived growth factor-BB (rhPDGF-BB) was approved for the treatment of lower extremity diabetic neuropathic ulcers that extend into subcutaneous tissue or beyond and have an adequate blood supply.  It was not approved for superficial ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers.  Since this decision memorandum is primarily focused on autologous products, and because becaplermin is not an autologous product, it is not addressed in this memorandum.

In an attempt to improve the healing process, wound specialists have become more interested in PRP produced by an apheresis process first developed by Charles Worden in 1998.  In this process, blood is centrifuged to produce a concentrate high in both platelets and plasma proteins.  Individual growth factors are not identified or separated during this process.  Additives are used to change the consistency of the product.  Platelet Rich Plasma (PRP), a product derived from platelets and growth factor, has recently been used in the treatment of a number of medical conditions (Drago et al., 2013; Cieslik-Bielecka et al., 2009).

PRP can be created in an autologous or homologous forms.  Autologous PRP is the fraction of blood plasma from a patient's peripheral blood that contains higher than baseline concentrations of platelets including concentrated growth factors and cytokines.  Alternatively, homologous PRP is derived from blood from multiple donors.  The PRP preparation contains concentrated platelets, as few red blood cells as possible, and leukocytes at different levels for various indications.  Autologous PRP has been used for a variety of purposes such as an adhesive in plastic surgery and filler for acute wounds.  It is also now being used on chronic wounds.

In general, leukocyte-poor PRP preparations are more commonly used for intra-articular application, while leukocyte-rich PRP preparations are more commonly used in soft tissue pathology such as tendinopathy and wound care due to the leukocyte’s role in local cleaning and immune regulation of the wound healing process (Lin et al., 2018).  A patient may donate his or her blood and it is centrifuged at the point-of-care setting to produce an autologous product such as a gel, patch, or an infiltrate that has been used in the treatment of chronic, non-healing cutaneous wounds that persist for 30 days or longer and fail to properly complete the healing process.  As noted earlier, PRP is different from earlier products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts and is used by physicians in a clinical (point of care) or surgical setting.  In the preparation of PRP in wound care, a number of carriers may be employed to increase the efficacy of the product.  These include hydrogels, sponge-like dressings, powders/beads, nanoparticles and scaffolds (Babaei et al., 2017).  PDGF does not contain cells and was previously marketed as a product to be used by patients at home.  Both PDGF and PRP gels are derived from the patient's own blood.  PRP is frequently administered as a spray, or a gel.  Other systems and protocols have been used to administer PRP.  PRP for the treatment of chronic wounds is a challenge not only because of the variety of preparations, dosages, frequencies and preparations, but also because of the heterogeneity of studies documenting its effectiveness (Atri et al., 1990). 

In this decision memorandum as in previous ones, CMS is evaluating PRP as a service, and not a specific system for administrating PRP.  The scope of this national coverage analysis (NCA) is limited to PRP for chronic non-healing diabetic, venous, and pressure wounds.

III. History of Medicare Coverage

In 1992, CMS issued a national coverage determination non-covering platelet-derived wound healing formulas intended to treat patients with chronic, non-healing wounds.  CMS conducted reconsiderations in 2003, 2006, and 2008.  For those reconsiderations, national non-coverage was upheld, except that as part of the 2006 reconsideration, CMS noted coverage for routine costs when used in accordance with the clinical trial policy defined in section 310.1 of the National Coverage Determinations Manual.

As a result of the 2012 reconsideration, CMS issued a national coverage determination covering the use of autologous platelet-rich plasma (PRP) for the treatment of chronic wounds under Coverage with Evidence Development (CED) only for patients who have chronic non-healing diabetic, pressure, and/or venous wounds and when specific conditions were met.  The current policy is codified in 270.3 of the Medicare National Coverage Determinations manual.  Section 270.3 of the NCD Manual has been included at Appendix C.

A.  Current Request

On May 9, 2019, CMS received a complete, formal request from Nuo Therapeutics to reconsider the national coverage determination for Autologous Blood-Derived Products for Chronic Non-Healing Wounds.  The requester stated that autologous Platelet-Rich Plasma (PRP) is the prevalent blood-derived therapeutic product used for treating chronic non-healing wounds and asked that CMS re-evaluate the coverage of Aurix (the proprietary formulation of autologous PRP manufactured by Nuo Therapeutics, Inc.) for the treatment of chronic, non-healing diabetic foot ulcers.  CMS broadened the scope of this reconsideration to include autologous PRP for the treatment of chronic non-healing diabetic, venous, and pressure wounds.  The request letter can be found here: https://www.cms.gov/medicare-coverage-database/details/nca-tracking-sheet.aspx?NCAId=300.

B.  Benefit Category

Medicare is a defined benefit program.  For an item or service to be covered by the Medicare program, it must fall within one of the statutorily defined benefit categories outlined in the Social Security Act.

PRP qualifies as:

• Physicians’ services (§ 1861(s)(1))
• Incident to a physician’s professional service (§ 1861(s)(2)(A))

Note:  This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.

IV. Timeline of Recent Activities 

V.  Food and Drug Administration (FDA) Status

FDA has not licensed any Platelet Rich Plasma (PRP) products for any specific indications.  Depending on a variety of factors, including the intended use(s) of such products, they may be subject to regulation by FDA as biological products and drugs under the Public Health Service Act and Federal Food, Drug and Cosmetic Act. 

If a medical device is labeled or promoted for manufacturing PRP for the purpose of administering the device output to a patient, then the device would require FDA approval or clearance for that use prior to marketing in the U.S.  However, a physician may use a cleared or approved medical device for the treatment of a particular patient in a manner that differs from the cleared or approved indication (known as off-label use).

FDA has cleared medical devices that are indicated to prepare autologous PRP at the patient’s point of care, where the PRP is to be mixed with autograft and/or allograft bone prior to application to a bony defect for improving handling characteristics.  FDA has also cleared medical devices to prepare an autologous PRP gel at the patient’s point of care for management of certain types of wounds. For example, the Reapplix 3C patch (BK140211) is indicated for the “management of exuding cutaneous wounds, such as leg ulcers, pressure ulcers, and diabetic ulcers and mechanically or surgically-debrided wounds.” 

VI. General Methodological Principles

When making national coverage determinations, CMS generally evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service falling within a benefit category is reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.  The critical appraisal of the evidence enables us to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for beneficiaries.  An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary.

A detailed account of the methodological principles of study design that the Agency utilizes to assess the relevant literature on a therapeutic or diagnostic item or service for specific conditions can be found in Appendix A.

Public comments sometimes cite published clinical evidence and give CMS useful information. Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. Public comments that contain personal health information will be redacted or not be made available to the public. CMS responds in detail to the public comments on a proposed national coverage determination when issuing the final national coverage determination.

VII. Evidence

A.  Introduction

This section provides a summary of the evidence that CMS considered for this NCD reconsideration.  There were a number of systematic reviews and meta-analyses found in the medical literature that investigated the use of PRP in patients with chronic wounds.  Most of the underlying studies consisted entirely of RCTs.  However, there was an RCT included in this current assessment that was not included in the systematic reviews or meta-analysis.  This review also assessed cohort studies, case control studies using comparisons, and uncontrolled observational data, such as case series.

B.  Discussion of Evidence

The ultimate goal for patients with chronic wounds is complete healing and improved quality of life.  These are the primary outcome measures.  A number of secondary outcome measures exist, and they may also be important to patient well-being.  Wounds may, depending on their anatomic location and severity, limit range of joint motion and ambulation.  Ideally, a wound would be completely cured and would not recur.  Avoidance of infection and elimination of pain are essential in the recovery process.  Chronic wounds that are malodorous may be embarrassing for a patient and thus can lead to social isolation.  Improvement in these outcomes should culminate in increased activity which will lead to resumption of normal activities and improved quality of life.

1.  Evidence Question(s)

Do Medicare beneficiaries that have chronic non-healing diabetic, pressure, and/or venous wounds who receive well-defined optimal usual care along with PRP therapy, experience clinically significant health outcomes compared to patients who receive well-defined optimal usual care for chronic non-healing diabetic, pressure, and/or venous wounds achieveat least one of the following:

1. complete wound healing;
2. ability to return to previous function and resumption of normal activities; or
3. reduction of wound size or healing trajectory, which results in the patient’s ability to return to previous function and resumption of normal activities?

2.  External Technology Assessments

In October, 2020, AHRQ published a technology assessment (TA) performed by the Mayo Evidence-based Practice Center (EPC) that evaluated the effectiveness of autologous platelet-rich plasma in individuals with lower extremity diabetic ulcers, lower extremity venous ulcers and pressure ulcers.  A number of data sources were used, including MEDLINE, Embase, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, PsycINFO, Scopus and various grey literature sources from database inception to June 11, 2020.  The EPC included randomized controlled trials (RCTs) and comparative observational studies that compared PRP to any other wound care without PRP in adult patients.  Pairs of independent reviewers selected and appraised studies.  Meta-analysis was conducted when appropriate and the strength of evidence (SOE) was determined based on a priori plan.

The literature search identified 4,147 citations.  An additional 172 references were identified through reference mining, grey literature search; and from Technical Experts. Based on inclusion and exclusion criteria, there were 27 studies and 1,796 patients included in the systematic review.  Of the 27 studies, 22 were randomized controlled trials (RCTs) and 5 were comparative observational studies.  Fifteen included patients with lower extremity diabetic ulcers, 11 included patients with lower extremity venous ulcers, and 2 included patients with pressure ulcers in any location.  Length of follow-up after treatment ranged from none to 11 months.

Diabetic ulcers
Fourteen RCTs and 1 comparative observational study with 1,096 patients evaluated autologous platelet-rich plasma (PRP) in lower extremity diabetic ulcers.  On average, diabetic patients in the analysis were 58.25 years old (range: 40.10 to 70.24); 37 percent were female; and 73 percent were Caucasian.  The average initial wound size varied greatly from 0.02 cm² to 28.40 cm², though most of the wound size ranged between 2 cm² and 4 cm².  Most of the studies included only lower grade wounds, but a few studies included severe wounds (Grade 4 and above).  For these diabetic patients the length of follow-up after intervention ranged from no follow-up to 11 months with a median of 6 weeks. 10 studies (66.67%) reported a minimum 1 month chronicity of the target ulcer before starting the PRP treatments.  Two studies indicated that, as the ulcers were presumed to be recurrent, they did not specify a minimum duration of ulcer formation.

Autologous PRP demonstrated a statistically significantly increase in complete wound closure or healing (RR: 1.20; 95% CI: 1.09 to 1.32; Moderate strength of evidence [SOE]), shortened time to complete wound closure (range: -40 to -4.90 days; Low SOE), and reduced wound area and depth (Low SOE), compared with management without PRP.  Evidence was insufficient to estimate an effect on important outcomes such as pain, hospitalization, amputations and wound recurrence.  There was no statistically significant difference in adverse events (AEs) and serious adverse events (SAEs) between PRP and management without PRP.

Venous ulcers
Eight RCTs and 3 observational studies with 615 patients evaluated PRP in lower extremity venous ulcers. Seven RCTs and 3 comparative observational studies compared PRP to management without PRP.  One RCT evaluated PRP in patients after skin grafting procedure.  Another RCT compared autologous platelet lysate to placebo buffer solution in 86 patients with venous leg ulcers.  On average, these patients were 61.13 years old (range: 32.50 to 76.80); and 49.10 percent were female.  The patients had their index venous ulcer for at least 6 weeks (range: 6 weeks to 8.50 years). The average initial wound size varied considerably from 2.90 cm² to 18.10 cm².  Only 1 study reported a two-week run-in time. All but two study reported less than 4 weeks’ length of follow-up.

Evidence was insufficient to estimate an effect of autologous platelet-rich plasma or autologous platelet lysate on the outcome of complete wound closure or time to complete wound closure in patients with lower extremity venous ulcers.  There was no statistically significant difference in AEs between PRP and management without PRP.

Pressure Ulcers
One RCT and one comparative observational study evaluated PRP in pressure ulcer.  The average age of these patients was 57.64 years old; 41 percent were female. Mean duration of pressure ulcers was 72.80 days.  Ulcers treated by PRP included Grade 2 (54.55%) and 4 (45.45%); while ulcers treated by management without PRP included Grade 2 (74.54%), 3 (7.27%) and 4 (18.18%).  The length of follow-up after intervention was none to at least 6 months.  No studies evaluated the outcome of complete wound closure, though the studies did document a degree in the reduction in the size of the wounds.  Evidence was insufficient to estimate an effect of autologous platelet-rich plasma on wound area in patients with pressure ulcers.

The available studies evaluating the use of PRP in diabetic, venous, and pressure ulcers suffered from important limitations, such as inadequate description of offloading and wound care procedures, wound characteristics, platelet-rich plasma formulation techniques, concentration and volume; inadequate length of follow-up; and lack of stratification by comorbidities and other patient characteristics including older adults.  Overall study limitations were moderate based on a mixture of RCTs of moderate and high risk of bias and an observational study.  Because of these problems, a sensitivity analysis was performed, but findings of the analysis were unchanged.

Conclusion
In conclusion the technology assessment found that compared with management without PRP, PRP therapy increased complete wound closure or healing in lower extremity diabetic ulcers (RR: 1.20; 95% CI: 1.09 to 1.32, moderate SOE), shortened the time to complete wound closure (range: -40 to -4.90 days) (low SOE), and reduced wound area and depth (low SOE).  No significant changes were found in terms of wound infection, amputation, wound recurrence, or hospitalization.  Evidence was insufficient to estimate an effect on important outcomes such as pain, hospitalization, amputations and wound recurrence.  There was no statistically significant difference in adverse events (AEs) and serious adverse events (SAEs) between PRP and management without PRP.  In patients with lower extremity venous ulcers, the SOE was insufficient to estimate an effect on critical outcomes, such as complete wound closure or time to complete wound closure.  And similarly, in patients with pressure ulcers, the evidence was insufficient to estimate an effect on any outcome in pressure ulcers.  There was no statistically significant difference in death, total adverse events or serious adverse events between PRP and management without PRP.

3.  Internal Technology Assessment

Literature Search Methods

We conducted a comprehensive systematic search in MEDLINE, EMBASE, and The Cochrane Library Clinical Trials Database starting from 2012 (the time of the posting of the last NCD on this topic) up until May 2020.  The search included human clinical studies written in English.  The following algorithm was used to search in MEDLINE via PubMed: (skin ulcer$ OR foot ulcer$ OR diabetic foot OR leg ulcer$ OR varicose ulcer$ OR venous ulcers OR pressure ulcer$ OR chronic ulcer OR chronic wound) AND (platelet-derived wound healing factor OR PDWHF OR platelet-rich OR (platelet adj rich) OR “platelet rich plasma” OR “platelet-rich plasma” OR PRP OR “platelet gel$” AND meta-analysis OR systematic reviews OR randomized clinical trials OR RCTs$ OR cohort studies OR case control studies OR observational studies).  We searched EMBASE data bases using a similar strategy, by using a combination of the terms: “platelet rich plasma”, “leg ulcer”, “foot ulcer.”  Case studies were excluded.  Of the 320 citations found, 24 studies met our criteria for inclusion and were part of this analysis. Because the literature uses the words “wounds” and “ulcers” interchangeably, we will consider the two terms synonymous.  The Summary of Evidence Table included in this assessment contains the studies that met our criteria and were included in this analysis (Appendix D).

Systematic Reviews

Alonso N, Lobato I, Hernández I, San Sebastian K, Rodríguez B, Grandes G, Andia I. Adjuvant Biological Therapies in Chronic Leg Ulcers. Int. J. Mol. Sci. 2017, 18, 2561; doi:10.3390/ijms18122561.

The objective of this systematic review was to assess two adjuvant biological treatments used for non-healing wounds: mesenchymal stromal cell products and platelet rich plasma.  The emphasis of this assessment is on the latter.  The authors identified 18 studies involving the use of platelets or PRP in chronic leg ulcers, including diabetic, pressure, venous, arterial, traumatic, and neurotrophic ulcers (all were published between 1986 and 2017; Ahmed et al. 2017; Anitua et al. 2008; Danielsen et al. 2008; Driver et al. 2006; Jeong et al. 2010; Kakagia et al. 2007; Karimi et al. 2016; Knighton et al. 1990; Krupski et al. 1991; Li et al. 2015; Moneib et al. 2017; Obolenskiy et al. 2017; Pravin et al. 2016; Saad Setta et al. 2011; Saldalamacchia et al. 2004; Senet et al. 2003; Stacey et al. 2000; Steed et al. 1992).  Although there are various procedures for deriving autologous PRP or platelet derived wound healing factors (PDWHF), different methods of application (topical or injected), different platelet and leukocyte concentrations, and combination products (i.e. [PRP plus collagen powder], [PRP plus oxidized cellulose-collagen]), most studies used in the systematic review used coagulated PRP (PR gel) (Ahmed et al. 2017; Anitua et al. 2008; Danielsen et al. 2008; Driver et al. 2006, Li et al. 2015; Moneib et al. 2017, Saad Setta et al. 2011; Saldalamacchia et al. 2004).  The total number of participants in the experimental and control groups across studies were 408 and 384, respectively, with a range of seven to 59 participants per study.  All but three of the studies were RCT (Moneib et al. 2017; Obolenskiy et al. 2017; Saldalamacchia et al. 2004); most of the studies were underpowered (Anitua et al. 2008; Danielsen et al. 2008; Kakagia et al. 2007; Knighton et al. 1990; Krupski et al. 1991; Saad Setta et al. 2011; Saldalamacchia et. al 2004; Senet, et al. 2003). The systematic review did not report the demographics for the patient populations in the underlying 18 studies.

One of the studies had three comparison groups (Kakagia et al. 2007).  The rest had two comparator arms.  The biological interventions were heterogeneous, assessing different platelet products, number of applications, and the interval between applications.

• Eight studies used topical PRP gel (Ahmed et al. 2017; Danielsen et al. 2008; Driver et al. 2006; Li et al. 2015; Obolenskiy et al. 2017, Saad Setta et al. 2017, Moneib et al. 2017;  Saldalamacchia et al; 2004) [although only seven were identified as such in the systematic review].
• One study (Pravin et al. 2016) compared PRP (generated through double spinning) with leukocyte-platelet rich fibrin (L-PRF) that underwent only the single spinning process.
• Three studies assessed topically applies PDWHF (i.e., platelet secretome) (Knighton et al. 1990; Krupski et al. 1991; Steed et al. 1992). One of these (Knighton et al. 1990), used PDWHF mixed with crystalline collagen. Allogenic platelets were used in two studies (Jeong et al. 2010; Steed et al. 1992).
• Two other studies used platelet lysate obtained by freeze/thawing or sonication (Senet et al. 2003; Stacey et al. 2000).

The authors did not specifically comment on the biological interventions compared in three of the studies.  However, they involved comparisons of oxidized regenerated cellulose/collagen biomaterial and/or autologous (Kakagia et al. 2007), sterile dressing impregnated with PRP (Karimi et al. 2016), and platelet-enriched plasma injected into the ulcer margins with the remaining plasma allowed to clot ex vivo and the fibrin matrix placed on the bed of the ulcer (Anitua et al. 2008).

The systematic review pointed out that the frequency of application varied between twice daily (Knighton et al. 1990), twice weekly (Ahmed et al. 2017; Saad Setta et al. 2011), or weekly (Pravin et al. 2016).

Results:  The most frequent endpoint measured was time to healing or reduction in the ulcer area.  Seven trials included primarily diabetic patients (Ahmed et al. 2017; Driver et al. 2006; Karimi et al. 2016; Krupski et al. 1991; Li et al. 2015; Saad Setta et al. 2011; Saldalamacchia et al. 2004), with the other studies reporting mixed ulcer etiology.  The systematic review noted that outcome results favored experimental treatments in eleven studies (Ahmed et al. 2017; Anitua et al. 2008; Driver et al. 2006; Jeong et al. 2010; Kakagia et al. 2007; Knighton et al. 1990; Krupski et al. 1991; Li et al. 2015; Saad Setta et al. 2011; Saldalamacchia et al. 2004; Steed et al. 1992).  The risk of selection bias was low in eight trials due to random sequence generation (Anitua et al. 2008; Danielsen et al. 2008; Driver et al. 2006; Jeong et al. 2010; Kakagia et al. 2007; Krupski et al. 1991; Li et al. 2015; Stacey et al. 2000) and six of these trials had low risk of selection bias sue to concealed allocation (Danielsen et al. 2008; Driver et al. 2006; Knighton, et al. 1990; Krupski et al. 1991; Li et al. 2015; Stacey et al. 2000).  Three studies were at high risk of selection bias (Moneib et al. 2017; Saad Setta et al. 2011; Saldalamacchia et al. 2004).  Lack of blinding of patient/personnel places most of the studies at a high risk of performance bias, except for one study (Krupski et al. 1991).  Three studies had a high risk of attrition bias (Anitua et al. 2008; Driver et al. 2006; Knighton et al. 1990), whereas seven studies had a high risk of reporting bias (Kakagia et al. 2007; Knighton et al. 1990; Moneib et al. 2017; Pravin et al. 2016; Saldalamacchia et al. 2004; Senet et al. 2003; Steed et al. 1992).

In summary the authors found that the heterogeneity of products and protocols hindered clinically meaningful quantitative synthesis in patients with chronic wounds (all types), though most patients in PRP studies were diabetic.  They concluded that there wasn’t sufficient evidence to inform routine care and further clinical research was necessary to realize the full potential of adjuvant regenerative medicine strategies in the management of chronic leg ulcers.

Martinez-Zapata MJ, Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L, Garcia J, Zaror C. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2016 May 25;(5):CD006899. doi: 10.1002/14651858.CD006899.pub3.

The objective of this systematic review was to determine whether autologous PRP promotes the healing of chronic wounds (chronic wounds were defined as pressure ulcers, venous leg ulcers, arterial ulcers, neurotrophic ulcers, and foot ulcers in people with diabetes).  This article is an update of a previous Cochrane Review performed on the same topic that was published in 2012 (Martinez-Zapata MJ,  Martí-Carvajal AJ, Solà I, Expósito JA, Bolíbar I, Rodríguez L, Garcia J 2012).  That study, which consisted of nine RCTs and a total of 325 participants (Anitua 2008; Driver 2006; Kakagia 2007; Knighton 1990; Krupski 1991; Planinsek 2007; Senet 2003; Stacey 2000; Weed 2004), failed to find any evidence to suggest that autologous PRP was of any value in the treatment of any type of chronic wounds.

A number of sources were used to find articles, including: Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library): Ovid MEDLINE; Ovid MEDLINE; Ovid EMBASE; and EBSCO CINAHL.  Also ongoing and unpublished clinical trials in the WHO International Clinical Trials Registry Platform (ICTRP) were searched.  Only randomized controlled trials (RCTs) that compared autologous PRP with placebo or alternative treatments for any type of chronic wound in adults were used in this study.  In this analysis, the primary outcomes included, the proportion of chronic wounds completely healed (defined as 100% epithelialization or skin closure without drainage), while secondary outcomes included the following:  Total area epithelialized at the end of the intervention (measured in cm2), percentage of wound area healed, time to complete wound healing, wound pain (measured by any validated scale), wound complications (infection, necrosis), quality of life (measured by any validated scale), and adverse events.  In performing this most recent analysis, one new RCT was found (Li 2012).

The researcher quantified the impact of statistical heterogeneity using the I² statistic (describes the percentage of total variation across studies that is due to heterogeneity rather than sampling error).  If the statistical heterogeneity was high (I² > 75%) or where there was clinical heterogeneity, the researchers investigated possible causes such as participants’ characteristics (e.g. wound etiology) and the method used to obtain the growth factors.  The researchers avoided pooling studies that had high statistical heterogeneity (I² > 75%).  For levels of I² less than 50%, researchers applied a fixed-effect model; for levels of I² over 50% but less than 75%, a random-effects model was used.  The authors also noted that because there were 10 studies or fewer included in the assessment, publication bias using a funnel diagram could not be assessed.

Results:  There were a total of ten RCTs included which consisted of 442 participants (mean age 61 years and 42% women).  In assessing the ten studies, four RCTs recruited people with a mix of chronic wounds; three RCTs recruited people with venous leg ulcers, and three RCTs considered foot ulcers in people with diabetes.  The median length of treatment was 12 weeks (range 8 to 40 weeks).

In terms of bias, only one study presented low risk of bias across all domains (Krupski 1991).  Three studies were at high risk of bias for at least one domain, with the remainder at overall unclear risk of bias.  The authors also noted substantial variations within trials regarding eligible participants, wound etiologies, and other design and conduct features.  Four trials treated people with mixed etiology chronic wounds (Knighton 1990; Krupski 1991; Anitua 2008; Weed 2004); three treated people with venous leg ulcers (Stacey 2000; Senet 2003; Planinsek Rucigaj 2007), and three treated people with diabetes and foot ulcers (Driver 2006; Kakagia 2007; Li 2012). Most of the RCTs (9/10) compared PRP plus standard care with standard care alone (with or without placebo).  The remaining trial evaluated PRP in the context of protease- modulating matrix (Kakagia 2007).  The systematic review noted that the process used to ’harvest’ autologous PRP varied between studies.  After assessing the data from eight RCTs, the authors analyzed the overall effect of PRP on complete wound healing and reported that there was uncertainty as to whether PRP affects the risk of complete healing (low quality evidence).  They stated that there were no data reported on quality of life.

The authors note that the evidence concerning the efficacy of autologous PRP in chronic wounds is low or very low quality; typically due to various risks of bias (such as poor reporting) and imprecision (due to small sample sizes and lack of statistical power).  The authors found that the use of PRP in combination with standard treatment was no better than standard treatment alone in patients with pressure ulcers, venous leg ulcers, arterial ulcers, and neurotrophic ulcers.  But for patients with diabetic foot ulcers, the authors were able to document that autologous PRP may increase the healing  compared with standard care (with or without placebo) (RR 1.22, 95% CI 1.01 to 1.49; I² = 0%, low quality evidence, 2 RCTs, 189 participants).  For this group, patients had a follow up of 12 to 24 weeks.  The study also revealed that it is unclear if autologous PRP affects the healing of venous leg ulcers (RR 1.02, 95% CI 0.81 to 1.27; I² = 0%), and if there is a difference in the risk of adverse events in people treated with PRP or standard care (RR 1.05, 95% CI 0.29 to 3.88; I² = 0%, low quality evidence from 3 trials, 102 participants).

The objective of this study  was to review the medical literature summarizing the evidenced-based body of knowledge regarding the treatment of diabetic chronic wounds by PRP.  Sources of literature included a PubMed as well as a Cochrane search (1978–2015).  Medical Subject Headings search terms included the following: (wound or chronic wound or wound healing or diabetic wound) and (platelet or PRP or PG).  The authors noted that the results included all studies assessing the clinical effect of PRP or PG in the healing of diabetic chronic wounds.  PRP could be autologous or homologous, and only diabetic patients were included in the study.  Results were limited to the English, French, Spanish and German literature, Case reports, in vitro studies, studies that did not use PRP or PG, and studies that did not assess a clinical endpoint of wound healing were excluded.  The outcome of interest was healing rate.

At the time of screening 7,555 articles were found, but after eliminating those that were not relevant, 56 potential articles were identified.  After eliminating those not appropriate from this number because they did not deal with pressure or venous ulcers, chronic wounds of other etiologies, etc. 12 studies were left (Setta et al. 2001; Kakagia et al. 2007; Driver et al 2006; Saldalmacchia et al. 2004; Steed et al. 1992; Steed et al. 1996; Jeong et al. 2009; Motolese et al. 2014; Shan et al. 2013; Tzeng et al. 2012; Kontopodis et al. 2015; Margolis et al. 2001).  In most of the studies, the number of participants ranged from 13 to 100 patients, though the retrospective study by Margolis included over 26,000 subjects.  All of the studies were prospective in nature except for the latter two.  Six of the prospective studies were randomized.  In these studies, PRP was applied either once or twice a week to the wound area.  A meta-analysis was not performed during this review due to the lack of standardization regarding the fabrication method of PRP, the method of PRP administration and the clinical assessment criteria.

Results:  The authors found that of the “six randomized studies included, five found significant benefits for the use of PRP on diabetic chronic foot ulcers, and the sixth randomized study, which did not publish a statistical analysis, did find favorable outcomes.  The two other controlled studies found significant benefits regarding the healing rate and the four uncontrolled studies included showed high rates of healing with the adjunction of PRP.  When looking at the method of use, PRP was applied on the wound as a gel twice a week (41.7% of studies) or once a week (33.3% of studies).”

The authors did not provide a detailed assessment of bias for each study, but did categorize the level of evidence according to the Oxford Centre for Evidence-Based Medicine 2 (with the lower levels corresponding to stronger evidence).  The authors assessed the six randomized trials as Level 1b, one prospective controlled study as Level iib, one retrospective controlled study as Level IV, four uncontrolled studies were also Level IV.

The authors concluded that “87.5% of controlled studies found a significant benefit for the adjunction of PRP to treat chronic diabetic wounds”.  The authors also noted that 83% of the randomized studies (five studies had Level 1B evidence), 100% of the prospective controlled studies (one study had Level IIB evidence), and 100% of the retrospective controlled studies (one study had Level IV evidence; 26,599 patients) found PRP to be of statistical benefit compared to standard care for velocity or rate of healing.  The authors further surmised that PRP may be beneficial in patients with chronic diabetic wounds. 

Xia, Zhao, Xie, et al. The Efficacy of Platelet-Rich Plasma Dressing for Chronic Non-healing Ulcers: A Meta-Analysis of 15 Randomized Controlled Trials. J Surg Res. 2020 Feb;246:284-291. doi: 10.1016/j.jss.2019.09.019. Epub 2019 Oct 14.

The purpose of this quantitative meta-analysis was to summarize the current evidence to evaluate whether using platelet-rich plasma in non-healing ulcers compared with traditional wound care led to better outcomes.  The meta-analysis follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.  The Investigators searched EMBASE, PubMed, EBSCO (Cumulative Index to Nursing and Allied Health Literature), and Cochrane databases to identify all available articles reporting the efficacy of platelet-rich plasma on refractory ulcers through November of 2018.  Keywords used in the literature search included: ulcer, chronic, non-healing, wound, cutaneous, open, diabetic ulcer, venous ulcer, pressure ulcer, autologous platelet-rich gel, APG, platelet rich plasma, platelet-rich gel, and platelet-rich plasma, integrated with the Boolean logical operators (AND or OR).  The search was limited to English and human studies. The inclusion criteria included: (1) study type (published randomized controlled trials); (2) population (adult patients with non-healing skin ulcers, such as venous ulcers, pressure ulcers, and diabetic foot ulcers); (3) interventions (platelet-rich plasma group underwent platelet-rich plasma gel sprayed on the wound bed, and the control patients underwent traditional wound care); and (4) types of outcome measures (e.g., number of wounds completely healed, complete healing rate, percentage of wound area healed, wound complications).  Exclusion criteria were: (1) no original data recorded or incomplete data; (2) duplicate publications; (3) postoperative wounds (e.g., cardiac surgery, knee arthroplasty, alveolar bone repair, dental implant surgery, mandibular reconstruction); (4) review articles, letters to the editor, editorials or conference abstracts, and preclinical studies (animal studies or in vitro studies); and (5) acute wounds.

Cochrane collaboration’s six item tool for assessing the risk of bias was used in determining quality of the articles.

Results:  The database search yielded 225 citations, of which 15 randomized controlled trials met all the inclusion criteria (Burgos-Alonso et al., 2018; Ahmed et al., 2017; Escamilla Cardenosa et al., 2017; Hersant et al., 2017; Oliveira et al., 2017; Volpe et al., 2017; Karimi et al., 2016; Raposio et al., 2016; Li et al., 2015; Saad Setta et al., 2011; Anitua et al., 2008; Driver et al., 2006; Weed et al., 2004; Senet et al., 2003; Stacey et al., 2000). Between 2000 and 2018, 630 adult patients were enrolled in 15 randomized controlled trials (RCTs); 252 were women. Mean age was 61.25 years and the mean follow-up was 5.10 months across all studies. Six of the 15 RCTs were limited to patients with diabetic ulcers and five RCTs were limited to patients with venous ulcers.  The other four studies, which included various refractory ulcers, were not limited to venous or diabetic ulcers solely.

Twelve studies documented the number of ulcers that healed completely after platelet-rich plasma application.  The number exposed to platelet-rich plasma per study ranged from seven to 59, for a total of 533 ulcers across studies.  The number of ulcers healed in the platelet-rich plasma group was higher than in the control group (risk ratio, 1.26; 95 percent CI, 1.11 to 1.42; p = 0.0003).  When limited to diabetic ulcers, the pooled results still favored more ulcers healed in the platelet-rich plasma group (risk ratio, 1.35; 95 percent CI, 1.14 to 1.59; p = 0.0004).  No significant differences were observed for venous ulcers or chronic skin ulcers.  In some studies patients were followed up to 12 weeks after healing. Six studies reported outcomes at four months or longer and one did not describe the length of follow-up (Hersant et al., 2017).  For the two (Ahmed et al. 2017, Karimi et al. 2016) followed up to 4 weeks post-healing, the number of ulcers healed in the platelet-rich plasma group was significantly greater than in the control group (risk ratio, 3.50; 95 percent CI, 1.80 to 6.81; p = 0.0002).  The complete healing rate of the platelet-rich plasma group was 52.83%, as compared to 15.09% (difference between the two groups was 37.74%).  The healing rate in the intervention group remained higher (66.67%) than in the control group even in the eight week (42.86%; risk ratio, 1.57; 95% CI, 1.06 to 2.33; p = 0.02; the difference between the two groups was 23.81%).  There were no significant difference in the number of ulcers healed in the twelfth week.

When assessing the percentage of wound area healed, a total of 209 chronic ulcers in four studies were included in the comparison between the experimental and control groups, and it was noted that the intervention group had a higher percentage of healed ulcers, and the difference was statistically significant (mean difference, 32.96%; 95 % CI, 5.55 to 60.38%; p = 0.02).  The pooled results for diabetic ulcers were inconclusive and highly heterogeneous.

The authors concluded that platelet-rich plasma was a valuable and safe treatment dressing for chronic non-healing ulcers, but further high-quality prospective studies are necessary to validate the results.

Randomized Clinical Trials

Ahmed M, Reffat S, Hassan A, et al. Platelet-Rich Plasma for the Treatment of Clean Diabetic Foot Ulcers. Ann Vasc Surg 2017; 38: 206–211.

The purpose of this study was to assess the value of autologous PRP gel in the treatment of clean diabetic ulcers by comparing it to an antiseptic ointment dressing that was being used in the surgical outpatient clinic.  Inclusion criteria included patients aged 18 or older, either gender, wounds that have failed to heal after 6 weeks or more of treatment, Grade I-II stage A or C according to University of Texas diabetic wound classification system.  Exclusion criteria included ulcers less than 2 cm² in size, symptoms or signs of infection, ankle-brachial pressure index <0.8, pregnancy or lactation, ejection fraction < 30, Hgb< 10 gm/dL., platelet count <150,000/dL., lymphedema, and patient refusal to donate blood for the procedure.  In this study, 56 patients were randomly assigned to either of two groups: the first group included 28 patients (the control group), which were treated according to the best practice guidelines.  This involved daily dressings, which included cleaning the wound with normal saline, and then povidone iodine 10% ointment was applied and covered by sterile dressing.  Patients were followed at the surgical outpatient twice weekly.  The second group included 28 patients, considered the study group and was treated by platelet gel, which was applied twice weekly.

Results:  There was no significant statistical difference regarding demographics between the two groups, as well as associated risk factors, laboratory parameters, and ankle-brachial pressure index.  Wound characteristics were matched in both groups.  The authors reported that “The most common site was the metatarsal area 50% and 57%, followed by the heel in 29% and 25% in the control and the PRP groups, respectively.  Wound size ranged from 2.2 to 10.2 cm² to 2.47 to 11.55 cm² in both groups, respectively...Complete wound healing was achieved after 2 weeks in 7% of the control group versus 29% of the PRP group.”  In the study, the researchers were able to document the mean rate of growth (0.5 vs. 0.7 cm²/week in the both groups, respectively).  By the end of 12 weeks, 68% of the control patients had healed ulcers in comparison to 86% of the PRP exposed patients.  The authors listed no limitation in the study, and concluded that autologous PRP gel does effectively accelerate wound healing in clean diabetic foot ulcers when compared with the conventional antiseptic ointment dressing.

Cardenosa M, Maldonado G, Fernandez A. Efficacy and Safety of the use of platelet-rich plasma to manage venous ulcers. J of Tissue Viability. 26 (2017)138e143.

The objective of this randomized controlled trial was to analyze the safety and efficacy of using platelet rich in growth factor (PRGF) as a local treatment in venous wounds.  A total of 58 subjects (with a total of 102 venous ulcers) were involved in the study.  Patients were allowed to participate if there was no improvement of the wound after six weeks of standard care.  Other inclusion criteria were: “ankle/arm index 0.8-1.2 who had not been operated for their venous insufficiency with normal blood count and platelet count above 150,000 platelets/mL.  Patients without long-standing treatment with non-steroidal anti-inflammatories, corticosteroids, anti-aggregates or anticoagulants.  Patients non-suffering from cancer-related, liver or kidney disease in addition to poorly controlled diabetics (HbA1C > 7.5%).”  Patients were randomly assigned to either the experimental group (PRP-a graft of autologous platelet gel), or to the control group (continuation of standard care).

There was a two-week run-in period prior to randomization when all patients underwent washing with chlorhexidine soap sponge, surgical debridement (if needed), dressing with saline soaked gauze covered by a dry gauze and compression dressing.  Those in the intervention group received PRGF weekly while the control group underwent dressing changes with gauze soaked in saline with a second cover of dry gauze and single layer pressure bandage at the same intervals as the intervention.  Pain, using VAS scale, was measured, but the main study variable was calculation of the healed area (change in size of ulcer area) using the Kundin method.

Results:  The 58 participants were homogenous in regard to age (mean 64 years both groups) and sex (men 34% controls, 27% exposed).  After 24 weeks of therapy, there was a statistically significant difference in healing—those in the PRGF group had 67% ± 41.54 healing rate, while those in the control group had a healing rate of 11.7% +/- 24.4 (p=0.001).  The study revealed a correlation in the intervention group between the percentage of healed area and ulcer area at the start of treatment compared to the control group (i.e. the lower the ulcer area at the start of therapy, the greater the reduction in the healed area at the end of treatment).  The study also revealed a statistically significant reduction in pain in the PRGF group compared to the control.  There were no adverse events in either treatment group.

The investigators identified the following study limitations: non-blinded measurements of ulcers, lack of histopathologic assessments or induced reparative PRP, a relatively small sample size to power identification of prognostic factors correlating with healed area and greater numbers to allow for stratification according to baseline area: < 5 cm2, > 5 cm2 and < 10 cm2 and > 10 cm2.

The authors concluded that plasma rich in platelets is an effective and safe method to speed up healing and reduce pain in patients with venous ulcers.

Game F, Jeffcoate W, Tarnow L, Jacobsen J, Whitham D, Harrison E, et al.  LeucoPatch system for the management of hard-to-heal diabetic foot ulcers in the UK, Denmark, and Sweden: an observer-masked, randomised controlled trial. Lancet Diabetes Endocrinol. 2018 Nov. 6 (11), 870-878  pii: S2213-8587(18)30240-7. doi: 10.1016/S2213-8587(18)30240-7.

Game and associates performed this multinational, multicenter, observer-masked, randomized, controlled trial with the objective of determining whether LeucoPatch used in conjunction with standard care in a multidisciplinary specialist diabetes foot clinic setting, was superior to standard care alone in healing of hard-to heal diabetic foot ulcers (not infected at the time of randomization).  This trial was undertaken in 32 diabetic foot clinics in the UK, Denmark, and Sweden. Following a 4-week run-in period, study participants were randomly allocated (1:1) to receive either the intervention plus standard care or standard care alone.  The intervention occurred across a 20-week period followed by a 6-week observation period.  To be eligible for the study, subjects had to be at least 18 years of age with a history of diabetes (as defined by WHO criteria), a baseline HbA1c of no more than 12% (108 mmol/mol), and have one or more foot ulcers (below the level of the malleoli), in which the cross-sectional area decreased by less than 50%, and the cross-sectional area of the index ulcer was 50–1000 mm², at the end of the 4-week run-in period.  At baseline, the index ulcer was clinically non-infected and either the ankle brachial pressure index of the affected limb was 0.50–1.40 or the dorsalis pedis pulse or tibialis posterior pulse was palpable.  Exclusion criteria included cross-sectional area of the index ulcer had increased by at least 25% or had decreased by less than 50% during the 4-week run-in period, or was either smaller than 50 mm² or larger than 1000 m² at the end of the 4-week run-in period, clinical signs of infection of the index ulcer, if a revascularization procedure in the affected limb was planned or had been undertaken within the 4 weeks before the baseline visit, the use of growth factors, stem cells, or an equivalent preparation within the 8 weeks before the baseline visit or the need for continued use of negative pressure wound therapy, as well as certain comorbid conditions.

In the study, “clinical investigators were instructed to manage all eligible ulcers according to the best available standard care (as per International Working Group of the Diabetic Foot guidelines), including offloading, either alone (during the run-in period and in the control group) or in addition to the intervention (during the 20-week active treatment phase in the intervention group).”  Demographic data and medical history were collected at baseline.  Wound characteristics, wound size, active medication including antibiotic prescriptions, type of off-loading used, adverse device effects, and serious adverse events, were recorded at every visit.  Participant visits were increased from every two weeks during the run-in period to weekly during the intervention period.  The primary outcome was the proportion of ulcers in the intention-to-treat population that healed within 20 weeks after randomization (healed was defined as complete epithelialization without drainage, maintained for four weeks).  Secondary ulcer-related outcomes included healing time, and incidence of secondary infection, while secondary patient-related outcomes were incidence of major or minor amputation affecting the target or contralateral limb, new anemia, quality of life (using Short Form-12 and EuroQol), and pain (as measured by a visual analogue scale).

Results:  In this study, 269 participants were randomly allocated to receive treatment or standard of care with one lost to follow-up, one consent withdrawal, and one randomization error (134 to receive standard care and 132 to receive LeucoPatch).  Baseline characteristics were balanced across the two groups with a mean age of 61.9 years (SD 11.6) and 217 (82%) were men.  Of the 266 participants, 222 (83%) had type 2 diabetes with a median diabetes duration of 16 years (IQR 10–23) and a median HbA1c of 8.2% (IQR 7.2–9.2; 66 mmol/mol, IQR 55–77).  Most index limbs were neuropathic, and most ulcers were greater than 100 mm² (74%), superficial (87%), and on the forefoot (78%).  The authors reported that “Within 20 weeks, 45 (34%) of 132 index ulcers in the LeucoPatch group had healed versus 29 (22%) of 134 in the standard care group, (unadjusted odds ratio (OR) of 1.58 (96% CI 1.04–2.40, p=0.0235) for healing in the intention-to-treat population)…In the per-protocol population, healing within 20 weeks was achieved in 44 (39%) participants in the intervention group versus 28 (26%) in the standard care group (OR 1.47 [96% CI 0.98–2.23], p=0.0488).”  The authors also noted that time to healing was shorter in the LeucoPatch group (p=0.0246) than in the standard care group. The study revealed that reductions in pain were similar between the groups, and there was no differences in minor or major amputations between groups.  There were no differences in adverse events between the groups.  The most common serious adverse event (SAE) was diabetic foot infection (24 events in the LeucoPatch group [24% of all SAEs] and 20 in the standard care group [27% of all SAEs].  There were no device-related adverse events. Information about quality of life was not reported.

A study limitation included that participants and providers were not blinded to treatment allocation; investigators were prevented from incorporating sham venipuncture due to ethical concerns.  The authors also reported that “an element of selection is evident in that the mean age was slightly less than anticipated (62 years as opposed to the expected 67 years), which might reflect the need for participants to attend each week for up to 5 months.  We recruited a high proportion of males (82% instead of the expected 67%), but this finding is now recognised as a typical feature of large trials in this field.  The overall incidence of healing was lower than anticipated, and lower than that observed in the pilot studies, but probably reflects the more rigid selection of a defined hard-to-heal population.”

The authors concluded that the trial demonstrated a clinically and statistically significant benefit associated with the weekly application of autologous immune cell, fibrin, and platelet patches (LeucoPatch) in a population of people with hard-to-heal diabetic foot ulcers compared to those who received the standard of care.

Gude W, Hagan D, Abood F, et al. Aurix Gel is an effective intervention for chronic diabetic foot ulcers: A pragmatic randomized controlled trial. Adv Skin Wound Care. 2019 Sep;32(9):416-426. doi: 10.1097/01.ASW.0000577140.19174.9e.

The purpose of this pragmatic randomized trial was to evaluate healing outcomes associated with Aurix hematogel when administered by providers within typical environments at participating sites of care.  This pragmatic trial differed from a conventional RCT in that:  investigators did not have (or had limited) research background, there was no designated study coordinator, the less stringent inclusion/exclusion criteria were designed to be inclusive of typical users, investigator training was limited (Good Clinical Practice guidelines, the protocol, the production and application of the autologous PRP) and recruitment/documentation of data were the responsibility of investigators/designees.  “This study was approved by CMS and conducted under the CED program to evaluate the “on-label” use of Aurix alongside usual and customary care (UCC) as compared with UCC only to treat chronic DFUs in an intended total study population of 760 patients in up to 100 sites across the US.”  In the study, the Aurix plus UCC and UCC only groups were created through randomization at a ratio of 1:1 at 28 investigative sites.  The authors noted that in standard clinical practice, differences in the patient demographics, provider skillsets, and approaches to UCC in various wound centers are variables that can influence treatment outcomes.  In order to evaluate the hematogel as used in clinical practice, investigator training was limited to instruction on the International Conference on Harmonisation Good Clinical Practice guideline, the CED protocol, and specific steps for the production and application of Aurix.

For those participating in the study, inclusion criteria required being age 18 years or older and having: Medicare as their primary insurance coverage, type 1 or type 2 diabetes, a Wagner grade 1 through 5 DFU located on the dorsal, plantar, medial, or lateral aspect of the foot or heel that was at least 1 month old, a debrided ulcer size between 0.5 and 50 cm², a demonstrated off-loading regimen, a demonstrated inadequate progress toward healing following active treatment with UCC at the investigative site for a minimum of 2 weeks immediately prior to screening, and  adequate venous access for periodic blood draws.  Exclusion criteria included patients on chemotherapeutic agents; patients with malignancy in the wound area; patients with or patients who had a serum albumin of less than 2.5 g/dL, platelet count of less than 100 x 10⁹/L, and/or hemoglobin of less than 10.5 g/dL.

In the study, the primary endpoint was complete wound healing after 12-weeks of treatment.  Additional analysis included the proportion of healed DFUs in the treatment period.  Also, immediately prior to randomization and again at the end of the 13-week study period, quality-of-life data was collected using the Quality of Life with Chronic Wounds short-form instrument (W-QOL).  The researchers also commented that correlation of changes in W-QOL scores and wound trajectory will be presented in a subsequent publication.  Data was gathered from centers using the Net Health Wound Expert (Pittsburgh, Pennsylvania) electronic medical record (EMR).

The authors reported that “At each patient visit, investigators recorded vital signs, conducted symptom-guided physical examinations as necessary, imaged the wound with digital photography, and assessed wound infection as well as the need for debridement and moisture management.  Wound measurements (length, width, depth) were performed at each visit.  To ensure a standardized approach for obtaining wound measurements, investigators were instructed to establish a “clock face” over the wound bed in which 12:00 was oriented toward the patient’s head.  The length and width of the wound were to be always considered from 12:00 to 6:00 and from 3:00 to 9:00, to reduce subjectivity…Following wound assessments, either Aurix and UCC or UCC only was administered.  The UCC-only group was treated with therapies that the provider and patient determined were in the best interest of healing.  All patients received standard of care that could include the use of semi-occlusive dressings or hydrocolloid dressings with or without an absorbent dressing.  For the UCC-only group, the use of chemically impregnated dressings was allowed.  Standard of care alone or in combination with advanced wound care such as hyperbaric oxygen, negative pressure, cellular and/or tissue-based products, and any other healing modality, with the exception of autologous blood products, was permissible in the UCC-only arm of this study….All patients randomized to the Aurix and UCC group received standard of care and Aurix hematogel…Patients were to receive two Aurix applications in each of the first 2 weeks of treatment followed by one application every week thereafter.”

Results:  The results of the study were based on 66 patients randomized to Aurix and UCC and 63 patients randomized to the UCC-only arm of the study (though enrollment of 760 patients was planned to provide statistical power for detailed subgroup analysis).  Demographic make-up between the two groups were comparable.  Twenty-eight facilities across the U.S. participated in this study.  To evaluate the effectiveness of Aurix as it is generally used in clinical practice, sites representing diverse urban and rural geographies were selected independent of the investigator and wound center staff’s previous clinical research experience.  The authors stated that “Average wound area prior to the first study treatment was 4.1 cm² for the Aurix and UCC group and 5.6 cm² for the UCC-only group.  The distribution of small (<1 cm²), intermediate (>1 to ≤7 cm²), and large (>7 cm²) ulcers was approximately the same for each treatment group…Small ulcers accounted for approximately 29%, intermediate-sized ulcers for approximately 53%, and large DFUs for approximately 18%of wounds in each treatment group.”  In the Aurix plus UCC group, 15 of 66 participants (22.7%) received concomitant advanced therapies (such as cellular or tissue based products, hyperbaric oxygen, negative pressure) compared with 34 of 63 participants (54.0%) in the UCC-only group.  However, of those healed in the Aurix plus UCC group (32 healed/66 total, 48.5%), 6 of the 32 healed (18.7%) had received additional advanced care.  In contrast, of those healed in the UCC group alone (19 healed/63 total, 30.2%), 11 of the 19 healed (57.9%) had received additional advanced care.  In terms of effectiveness 48.5% of participants treated with Aurix and UCC healed within the 13-week study period compared with 30.2% of participants treated with UCC only; the results did not clarify if the effectiveness differed at 12 weeks (primary endpoint) compared to the 13-week reported results.  The study also revealed that a higher percentage of healing was observed for Aurix across all wound severities (Wagner grade 1–4), and subgroup analysis revealed a significant healing advantage for Aurix when treating wounds accompanied by peripheral arterial disease and a demonstrated advantage for smokers.  Limitations noted by the researchers include the open-label design which prohibited blinding of the treating clinicians and participants, which could potentially introduce unintentional bias.  Also mentioned is the inability to determine durability past 2 weeks due to the copay issues.

The authors concluded that this pragmatic trial demonstrates that Aurix, alone or in combination with other advanced therapies, improves healing of chronic DFUs of all severities, even in the presence of serious comorbidities, in the Medicare population as compared with UCC as provided in an outpatient wound center.

Karimi R, Afshar M, Salimian M, et al. The Effect of Platelet Rich Plasma Dressing on Healing Diabetic Foot Ulcers. Nurs Midwifery Stud. 2016 September; 5(3):e30314.

The purpose of this randomized, controlled trial was to investigate the effect of PRP dressing on healing of DFUs.  The study consisted of 50 subjects.  Patients were randomly allocated to control (n = 25) and experimental (n = 25) groups.  Inclusion criteria included having a DFU in grades 1 or 2 (according to the Wagner classification system for DFU and based on physicians’ diagnosis), a hemoglobin level of 10 gr/dL and more, platelet count more than 100000mm³, receiving no immunosuppressive and contraceptive medications, having no known coagulopathy, immune deficiency, cancer, having no signs of ischemia around the ulcer, sepsis, osteomyelitis, deep vein thrombosis, limb paralysis, not receiving chemotherapy and lack of a history of spinal cord injury and stroke.  Patient’s decision to withdraw from the study and not completing the intervention were the only exclusion criteria.  The data collection instrument consisted of two checklists: one that looked at demographic information (e.g., patients’ age, gender, body mass index (BMI), type of diabetes, etc.) while the second checklist included questions about wound characteristics and its treatments (i.e. the wound grade, the number of wounds, duration of ulcer, and its location, wound area and depth, etc.).

Results:  Though 60 patients initially were randomized to either the control group or the intervention, the final analysis was based on 50 patients in the study due to lost to follow-up.

At baseline, the mean ulcer depth were 15.08 ± 10.43 and 19.08 ± 14.01mm in the control and intervention groups, respectively (P = 0.26), which decreased to 13.03 ± 14.1 and 4.560 ± 5.76 after three weeks (P = 0.04).  The mean ulcer surface area were 14.17 ± 8.52 and 12.791 ± 14.86mm² in control and intervention groups respectively (P = 0.69), which decreased to 11.88 ± 13.65 and 2.68 ± 5.94 after three weeks (P = 0.03).  After one month of treatments in the control and experimental groups, the frequency of complete wound healing were 36% and 40%, respectively (OR = 13.5, CI 95% = 1.56 - 117.14, and P = 0.005).  Limitations pointed out by the researchers include the lack of control over some confounding factors such as patients’ nutrition, activities and their level of adherence to their medical treatments as well as the small sample size.  The authors concluded that “This study revealed that PRP dressing could significantly decrease the depth and surface area of DFUs in a three-week period.”

Moneib H, Sahar S, Youssef S, Aly D, et al.  Autologous platelet-rich plasma versus conventional therapy for the treatment of chronic venous leg ulcers: A comparative study. J Cosmet Dermatol. 2018;17:495–501.

The purpose of this study was to compare the clinical efficacy of PRP in the management of chronic venous leg ulcers versus conventional treatment.  This randomized clinical trial [described erroneously as case-control study by the authors] followed 40 patients (39 males and 1 female, ages 20 to 59 years [mean 36.4 +/- SD 10.2 years]) with chronic venous leg ulcers for more than 6 months of duration.  Entry criteria included patients who had not received any previous treatment, wound size was less than 10 cm², and for their ulcer to be considered a venous ulcer, and all patients required to have an ankle/ brachial index of >0.80.  The study methods involved dividing study subjects  randomly in 2 groups: 20 patients with PRP weekly treatments for 6 sessions (Group A) and 20 patients (controls) treated conservatively by compression using graduated elastic stockings below the knee and dressing using saline and Vaseline gauze weekly for 6 weeks (Group B).”  Exclusion criteria included: saphenofemoral incompetency, uncontrolled diabetes mellitus (DM), active infection, ischemic heart disease, compromised immune function, coagulation disorders, those receiving or had received radiation or chemotherapy within 3 months of the study, history of cancer, and pregnant or lactating females.

Patients in Group A had platelet-rich plasma gel applied onto the ulcers after proper debridement of necrotic tissues, and irrigation with saline until clean.  A nonabsorbent dressing (Vaseline gauze) was then applied to the ulcer and remained in place for 3 days.  In addition to being advised to wear elastic stockings, patients were advised to elevate affected limb.  Similar to Group A, Group B (control) patients had a nonabsorbent dressing (Vaseline gauze) applied to the ulcer for 3 days and were advised to wear elastic stockings and to elevate affected limb.  However, patients in Group B did not receive PRP gel on the ulcer following initial debridement. Group A continued to receive PRP treatments weekly for 6 weeks and Group B continued to receive Vaseline gauze weekly for 6 weeks. In both groups, at baseline and every week, the ulcer area was calculated and photographs were taken using a digital camera.  Improvement in ulcer area was assessed by decrease in ulcer size.  Complete healing was defined as 100% epithelialization.  The treatment outcome was defined as a percentage improvement in area of the ulcer at 6 weeks.

Results:  The publication reported that “the intervention group (Group A) included 20 patients, 19 males (95%) and 1 (5%) female.  Their ages ranged from 20 to 59 years with a mean +/- SD of 36.4 +/- 10.2 years. Eighteen (90%) presented with primary ulcers, 2 (10%) presented with secondary ulcers, 11 (55%) had incompetent perforators above knee, 7 (35%) had below knee incompetent perforators, while 2 (10%) had no perforators...The control group (Group B) included 20 (100%) male patients.  Their ages ranged from 20 to 42 years with a mean +/- SD of 32.5 +/- 7.5 years.  Seventeen (85%) presented with primary ulcers, 3 (15%) presented with secondary ulcers, 10 (50%) had incompetent perforators above knee, 7 (35%) below knee incompetent perforators, while 3 (15%) had no perforators…No significant difference was detected in regards to personal, medical data, etiology of ulcers, and incompetent perforators between the studied groups (P -value >.05).”  The study revealed that compared to conventional therapy, a significantly higher improvement in the ulcer size was observed post-PRP therapy (P-value = .0001).  The mean change in the area of the ulcer post-PRP and conventional therapy was 4.92 +/- 11.94 cm and 0.13 +/- 0.27 cm, respectively, while the mean percentage improvement in the area of the ulcer post-PRP and conventional therapy was 67.6% +/- 36.6% and 13.67% +/- 28.06%, respectively.  The authors noted that subjective improvement in pain associated with the ulcer was noted by all patients in Group A and B.

The authors commented on general challenges with PRP acceptance in clinical practice, such as lack of standardized protocols for its use and in differences in quality of autologous PRP based on the patients’ morbidity, but did not comment on the limitations of their study design.

They concluded that though Platelet-rich plasma is a safe nonsurgical procedure for treating chronic venous leg ulcers, additional studies with larger sample size and longer follow-up periods are required.

Obolenskiy V, Ermolova D, Laberko L. Clinical and economic effectiveness of the use of platelet-rich plasma in the treatment of chronic wounds. Wound Medicine 19 (2017) 27-32.

The objective of the randomized clinical trial was to determine the clinical and economic effectiveness of the use of platelet-enriched plasma in the treatment of chronic wounds of various etiologies.  The trial involved 100 patients with chronic wounds who were on inpatient treatment and outpatient monitoring.  To be included in the study, subjects had to have chronic wounds longer than 6 weeks duration, corresponding to the II-III phase of wound process.  Exclusion criteria included concomitant connective tissue disorders, cancers of other organs, and signs of wound malignancy.  In the study, 100 patients were divided in two groups: the experimental group that received the platelet-rich plasma along with standard of care, and the 50 patients in the control group that received standard care only. 

However, some patients also underwent surgical closure of the wound defect using the method of autodermoplasty (ADP).  In the test group, 8/50 patients were treated by ADP of wound defects with a free split flap on day 3 after dressing with clots, whereas 9 of the 50 patients in the control group were treated with ADP.

Results:  Of the 100 subjects, 53 were males and 47 were female.  The average age of participants was 58.9 (range 22 to 90).  The investigators reported that the groups were comparable by sex, age, the nature of the basic and accompanying pathologies, as well as the etiological factor that led to the formation of the chronic wound.  The most common cause of long-term non-healing wounds in patients of both groups was diabetes (27%) with neuropathy.  The most frequent duration of chronic wounds was 3-6 month (26% of cases), followed by 6-12 months of duration (24%). Some patients (8%) had wound duration as long as 3 years.  The average duration of wounds in the experimental group was 12.91 months, while in the control group the average duration of wounds was 8.21 months.  The average area of wound size in the experimental group was 19 cm2, while in the control group the average area of wound size was 21 cm2.  The investigators used wound planimetry to determine changes in the size of the wound defect during therapy.

Results showed a significant reduction in the duration of patient treatment achieved in the test group compared to the control group; the average epithelialization time for the experimental groups was 42 days, versus 124 days for the control.  The investigators also reported a reduction in healing time by an average of 95 days (p <0.001).  In 46 patients in the PRP group (92%), complete wound epithelization was achieved within 90 days.  The authors noted that the use of PRP also resulted in a reduction in the number of the number of dressings both at the inpatient stage of treatment as well as the outpatient setting.  The average length of hospitalization for PRP patients was 8.4 days, compared to 18.1 days for the control group.

In a retrospective analysis of the study results, the publication reported serious differences in both the test and control groups across patients treated with dressings only versus patients who also underwent surgical closure of the wound defect by ADP.  Therefore, patients that underwent ADP were identified through ad hoc methods for subgroup analyses.  For patients that did not undergo surgery by ADP, the wound healing rate in cm2 was: test 0.42 (n=42/50) vs control 0.27 (n=41/50).  For patients that underwent ADP, the wound healing rate in cm2 was: test 2.07 (n=8/50) vs control 0.49 (n=9/50).  Therefore, the greatest improvement in the rate of wound healing index was observed in patients who underwent surgical treatment in the form of ADP and who were exposed to PRP.

When evaluating the impact of other variables, the authors also stated that there was moderate positive correlation between the rate of wound healing and the initial surface area of the ulcer, whereas an arterial etiology of the disease had a significant negative effect on the rate of healing.  The authors did not comment on the limitations of their study but concluded that treatment methods involving PRP resulted in higher rates of healing as well as a reduction in cost.

Non-Randomized Clinical Trials

Etugov D, Mateeva V, Mateev G. Autologous platelet-rich plasma for Treatment of Venous Leg Ulcers: A Prospective Control Study. J Biol Regul Homeost Agents. 2018 May-Jun;32(3):593-597.

The aim of this prospective clinical study was to evaluate the efficacy of the intralesional injection of PRP in the management of venous leg ulcers (VLU).  The study included 46 VLU from 23 patients (9 males, 14 females aged 55 to 78).  For each patient, two VLU with similar location and clinical stage were selected for treatment.  The authors did not describe the method for selecting which ulcer received treatment and which served as control but stated that the control ulcers were comparable with similar characteristics.  One of the ulcers was treated with a single intralesional injection of PRP, the other with conventional therapy and served as a control.  Wound size was measured at baseline (visit 0), 15 days (visit 1), and 30 days after procedure (visit 2).  The authors did not describe their technique for measuring.

Results:  The study revealed that there was a significant reduction in size of the ulcers in both groups: those treated with PRP (mean surface area 1368.2 mm2 at visit 0 and 596.3 mm2 at visit 2), and in the control group (mean surface area 880.3 mm2 at visit 0 and 582.8 mm2 at visit 2).  The authors also noted that reduction in the size of the VLU was more pronounced in the group treated with PRP compared to the control group.  The analysis also revealed that a significant change in the size of the ulcer was observed between visit 0 and visit 2 in both groups (P< 0.0001).

The authors noted lack of randomization as a study limitation but concluded that “our results confirm the beneficial effect of PRP on improving the treatment outcome of VLUs, but further studies on large cohorts are needed to demonstrate its probable superiority to the conventional methods.”

Controlled Observational Studies

Miłek T, Baranowski K, Zydlewski P, Ciostek P, Mlosek K, Olszewski W. Role of plasma growth factor in the healing of chronic ulcers of the lower legs and foot due to ischaemia in diabetic patients. Postepy Dermatol Alergol. 2017 Dec; 34(6): 601–606.

The purpose of this controlled observational study was to determine the role of human growth factor in the healing of ulcers due to ischaemic diabetic foot syndrome (DFS) following previous angioplasty of the blood vessels of the lower leg and foot.  Study participants (N= 100) included “patients with ischaemic diabetic foot complicated by lower leg ulcers in which angioplasty of the stenotic arteries in the distal lower leg and foot was performed.”  Fifty patients in the study (intervention group) received platelet-rich plasma in the form of dressings, which were applied to ulcers, followed by hydrocolloid dressings.  The control group also consisted of 50 patients; they received hydrocolloid dressings, but were not treated with platelet-rich plasma.  For those in the intervention group, each dressing was replaced after 10 days, and this procedure was repeated after 20 and 30 days of treatment.  The study’s inclusion criteria included: ulcer < 5 cm, lower limb ischaemia clinically and radiologically proven by angio CT, condition after a successful revascularization and creatinine < 1.0 mg/dl. Exclusion criteria included:  < 18 years of age, ulceration > 5 cm, venous ulcer and ulcer without ischaemia.  The ulcers were assessed at four time points (baseline, 30-days, 3 months, 6 months), each time documenting their appearance and size, depth of the wound (which was assessed with an ultrasound probe with a frequency of 50 MHz), histological granulation formation, epithelialization of ulcers, and the formation of wound vessels.  The investigators divided ulcers in both groups into four categories based on the initial ulcer size, (calculated by tracing the ulcer on scaled marked carbon paper), and reported results of recanalization in both groups, as well as ulcer healing after recanalization in those in the platelet-rich plasma dressing group, and those in the non-platelet-rich plasma dressing group.

Results:  Recanalization- “Patency of the main artery was restored in 89% of the patients in the study group and 75% in the control group.  In 11% of cases in the study group and in 25% of cases in the control group, blood supply was delivered to an ulcer as a result of recanalisation of the collateral circulation.”

Ulcer healing- “After 3 months of combined treatment, all wounds in the study group healed, whereas in the control group, only wounds of the smallest size healed.  And at 6 months some of the wounds in the control group still persisted (non-healed).”  The investigators also provided the following descriptive assessment:  “When these growth factors were used we observed not only improvement in healing, but also changes of ulcer characteristics.  Wound discharge became lighter in colour, resembling plasma.  The bottom of the ulcer which was previously flat and covered with necrosis and fibrin had become rough and filled with granulation tissue.  Swelling and inflammation were significantly reduced.”

The authors did not comment on study limitations, but concluded that the combined treatment of ulcers due to ischaemic DFS with endovascular procedures to re-establish blood flow to vessels and dressings with autologous plasma-rich growth factors significantly shortens the healing time.

Uncontrolled Observational Studies

Babaei V, Afradi H, Gohardani H, Nasseri F, Azarafza M, Teimourian S. Management of chronic diabetic foot ulcers using platelet-rich plasma. Journal of Wound Care, VOL 26, NO 11, November 2017.

The objective of the uncontrolled observational study was to examine the application of PRP in the treatment of diabetic foot ulcers in patients.  This study was conducted in Zafar Clinic, Tehran, Iran between 2011 and 2014.  Study inclusion required subjects to have diabetes with a chronic foot ulcer, with an average wound duration of six months.  Exclusion criteria included platelet dysfunction syndrome, critical thrombocytopenia, unstable hemodynamics, pregnancy, and need for treatment with non-steroidal anti-inflammatory drugs (NSAIDS) from one week prior through one week after the study period.  Patients included in the study were categorized into three groups, according to the size of ulcer: Group 1: wound size diameter of 2–5.5 cm², Group 2: wound size diameter of 5.5–8.5 cm², and Group 3: wound size diameter of 8.5–12. 5cm².

Autologous PRP was applied to the surface of the wound and covered with a bandage.  The investigators photographed the wounds at weekly intervals to document changes to wound size.  The primary study outcome was time to wound healing.

Results:  In the study 186 patients were recruited, though a total of 150 patients completed the study (85 men and 65 women).  Women had a median age of 30 years and men, 35 years.  The investigators reported that no patient had more than one ulcer.  Before the study the average wound had a duration of 6 months.  The authors reported that after treatment with PRP, “in ulcers with a 2–5.5 cm² surface area (Group 1) complete closure happened after 7.2 weeks, 5.5–8.5 cm² ulcers (Group 2) completely closed after 7.5 weeks, and 8.5– 12.5 cm² ulcers (Group 3) healed completely after 8.8 weeks…complete closure time was significantly shorter for those patients with a wound surface area of 2–5.5cm² (Group 1) in comparison with those patients with a wound surface area of 8.5–12.5cm² (Group 3) (p< 0.05).  Average wound area closure rate per day, in the three groups, after treatment by PRP, was 0.055 cm² per day.”  The authors also noted that there was no reopening of the ulcers during the eight months of monitoring.

Study limitations noted by the authors included that the position of the ulcer may make accuracy in measuring wound healing challenging, participants were not blinded, and the study did not have an unexposed control group.

The authors concluded that the study provided more evidence of the effectiveness of autologous PRP for DFUs in patients.

Kossev P, Sokolov T. Clinical Results From The Treatment Of Chronic Skin Wounds With Platelet Rich Plasma. J of IMAG. 2015, VOL.21, issue 2/.

The purpose of this uncontrolled observational study was to demonstrate the effectiveness of platelet rich plasma (PRP) application on chronic skin wounds, and to evaluate the result of the treatment.  During a five year period (May 2009 to December 2014) 14 patients with chronic wounds were identified and followed.  The study population consisted of five males and nine females; the average age was 48.5 (ages ranged from 30 to 76), wounds included diabetic, traumatic, decubiti, infectious in nature, and atrophic wounds.  Wound size and depth were monitored, which ranged from 4-12 cm2 in size, and depth ranged from fat to bone.  Anatomic locations varied from ankle, Achilles, tendons, patella, medial and lateral malleolus, and calcaneous.  Treatment consisted of surgical treatment with debridement of the wound, followed by weekly applications of autologous PRP.  Outcomes were evaluated using Total anatomic score and Total score, tools that were developed by Cancela et.al.

Results:  Of the 14 patients included in the study, 4 patients had type 2 diabetes, 6 patients had decubitus, 8 patients had traumatic wounds, and 5 patients had infected wounds (some patients had multiple wounds of different etiologies).  The follow-up period was 4-6 months (average 4.5).  The authors note that on average between 12 and 20 applications of PRP were required, and the average period of healing was 5 months.  During their study, no side effects or complications were observed.  According to the authors, the baseline values at the beginning of the study period were as follows:  Total wound score – 12 p., Total anatomic score – 10 p, Total score – 17 p.  By the end of the treatment period the score was 0 p., which meant excellent results, (i.e. complete healing of the wounds).  The authors did not describe any limitations of their case series, but noted complete healing of all of the subjects regardless of the type of wound treated, and concluded that the application of PRP may become optimal therapy in the treatment of difficult to heal wounds involving joints, bones, tendons, and feet.

Kurapati K, Kumar P, Anbarasu K, Vaggu A, et al. Xeno-free autologous platelet rich plasma for chronic wound management –Case series. Wound Medicine 20(2018)54-57.

The purpose of this uncontrolled observational study was to evaluate the efficacy of single dose of non-activated PRP and self-polymerized platelet rich fibrin (PRF) in subjects with chronic wounds.  Study participants included 35 subjects (age range of 32–81 years) with chronic wounds of different etiologies who were being managed (November 2014–October 2016).  Wounds were assessed using Bates – Jensen Wound Assessment Tool (BWAT-a measurement tool using a 5-point Likert Scale).  For study inclusion, subjects were required to have a lower extremity wound of at least 3 months duration (BWAT score of 25 and higher).  Exclusion criteria included: blood disorder, systemic immune conditions, and existing systemic or localized infections.  Subjects were categorized based on wound size and depth: Group 1 had superficial, shallow and irregularly shaped wound and were treated with PRP along with conventional debridement, Group 2 had deep wounds and were treated with PRP and PRF, wherein PRF block was used to fill into deep wounds.  Every subject was given a single subcutaneous injection of either PRP alone or with PRP/PRF together and the wounds were closed with non-absorbent dressing.  All patients were monitored at 1, 3, and 6 months using digital photography, and measurement of BWAT score, functionality, and quality of life, as well as underwent surveillance for adverse events.

Results:  Of the 35 subjects included in the study, 52% had wounds secondary to diabetes and 23% of wound were venous in nature.  After the study was initiated, three subjects from PRP group and five from PRP+PRF group were excluded because they underwent other surgical procedure for wound closure.  Six subjects were excluded due to non-compliance.  At the end of study period, there were 10 subjects in PRP group and 11 subjects in PRP+PRF group.  There was no significant difference in age and sex distribution between the two groups.  Most of the subjects showed substantial improvement in terms of reduction in wound size and increase in tissue mass (significant reduction in BWAT score from baseline).  In PRP group, BWAT score of <13 (indicative of regeneration zone) was observed in 7 subjects (70%) and in PRP/PRF group, 4 subjects (36.36%) entered into regeneration zone.  Both PRP and PRP/PRF treatment was well tolerated by all patients without any serious adverse events.  The publication did not report results for quality of life and functionality assessments.

The authors did not discuss study limitations but offered the conclusion that a single dose of non-activated and/or physiologically activated PRP is an efficacious and cost effective treatment regime for management of chronic wounds.

Löndahl M, Tarnow L, Karlsmark T, et al.  Use of an autologous leucocyte and platelet-rich fibrin patch on hard-to-heal DFUs: a pilot study. JOURNAL OF WOUND CARE VOL 24, NO 4, APRIL 2015;172-178.

Löndahl and associates performed a multicentre uncontrolled observational study that was designed to evaluate the efficacy, safety, and feasibility of leucocyte platelet fibrin patch treatment in patients with hard-to-heal diabetic foot ulcers (DFUs).  (The Leucopatch is produced from the patient’s own blood.  Following centrifuge, the resulting three layers of fibrin, platelets and leucocyctes are compressed to form a final patch.).  To be included in the study, enrollees had to be 18 years or older with at least one full-thickness diabetic ulcer, classified as Wagner grade 1 or 2, at or below the ankle with a duration of more than 6 weeks, and a maximal area of 10 cm², palpable foot pulses, toe blood pressure above 30 mmHg or transcutaneous oxygen pressure above 30 mmHg. Exclusion criteria included inability to tolerate venesection, hemoglobin concentration below 6.5 mmol/l (10⁶g/l), HbA1c>12.0% (108 mmol/mol), platelet concentration below 100 x 10⁹/l, ongoing dialysis, presence of hemophilia, sickle cell anemia, leukemia or blood dyscrasias, child-bearing potential without appropriate contraception, lactation, participation in another study, expected poor adherence, or vascular reconstruction in the lower limbs within four weeks before the study.

The methods state that “All patients were treated at secondary or tertiary multidisciplinary diabetic foot clinics in Denmark or Sweden… If more than one DFU was present, the largest Wagner grade 1 or 2 ulcer was chosen for treatment and follow-up.  Treatment was preceded by a two-week run-in period, and only patients with less than 40% change in ulcer area during these two weeks were considered hard to heal and entered the trial.”

At each visit, the investigators debrided and cleaned the wounds and documented wound size with photographs.  The investigators used ulcer healing at 20 weeks as the primary end.  Secondary endpoints were comprised of “ulcer healing at 12 weeks, time to healing, change in ulcer area, safety, and feasibility.”

Results:  During the two-week run-in period, 16/60 recruited patients were excluded.  The remaining 44 patients are included in the intention-to-treat analysis.  However, five participants were subsequently excluded (due to death, osteomyelitis, non-compliance) leaving 39 for evaluation in the per-protocol analysis.  The average age of the 44 patients was 63 years, 77% were men, 20.5% had Type 1 diabetes and 79.5% had Type 2 diabetes.  At baseline, neuropathy was present in 42 of the 44 cases, and the median ulcer duration at time of inclusion was 35 (7–490) weeks with a median ulcer area of 1.1 (0.1–10.0) cm².  The study reported that “Complete epithelialization was achieved in 15 patients (34%) at 12 weeks and 23 patients (52%) at 20 weeks in the modified intention-to-treat population, and in 36% and 59%, respectively, in the per-protocol population…During the first two weeks of treatment, the ulcer area decreased 36% (14–56%), with the ulcer area reduction significantly higher in 12-weeks healers compared to non-healers, 53% (47–61%) versus 26% (13–48%); p<0.01.”  Patients with healed ulcers had larger ulcer area reduction during the first two treatment weeks compared to non-healers, although degree of change had been similar during the run-in period.  Serious adverse events (cumulative from run-in through follow-up) occurred in 12 patients and adverse events in 33 patients.  The investigators reported that none of the adverse events were judged related to the leucocyte patch treatment.  Study limitations noted by the authors included the potential for bias due to increased visits to the foot clinic and increased scrutiny of the outcomes.

The authors concluded that the leucocyte patch was well-tolerated, easy to use and has potential in the armamentarium of the DFU treatment, provided this outcome is confirmed in an appropriately powered randomized clinical trial.

Pinto N, Ubilla M, Zamora Y, et al. Leucocyte- and platelet-rich fibrin (L-PRF) as a regenerative medicine strategy for the treatment of refractory leg ulcers: a prospective cohort study. Platelets. 2018 Jul;29(5):468-475. doi: 10.1080/09537104.2017.1327654. Epub 2017 Jul 20.

The aim of this uncontrolled observational study was to determine “the benefits of L-PRF application on recalcitrant leg ulcers (DFU, VLU, PU) by measuring the changes in wound area longitudinally through planimetry, and by recording adverse events and changes in pain level over time.”  The researchers enrolled 44 consecutive patients with VLUs (n = 28, 32 wounds: 17 ≤ 10 cm² and 15 > 10 cm²), DPUs (n = 9, 10 wounds), PUs (n = 5), or complex wounds (n = 2), which failed to improve after optimal standard wound care (3 months; a wound was classified complex if more than one causal factor was involved without knowing which of them was the main contributing one).  Inclusion criteria stated that participants must be over 18 years of age, able to read, understand, and accept the background information and the study protocol, signature of informed consent, and a mental status adequate to comply with the treatment.  In the case of VLUs requiring surgery or vein sclerosing agents, chronic venous insufficiency treatment was completed prior to the L-PRF treatment.  Exclusion criteria included suboptimal standard wound care, peripheral artery disease (distal pulses absent or ankle-brachial index <0.8 and/or >1.2), active cancer, pyoderma gangrenosum, connective tissue disorders, cutaneous granulomatous diseases, mycobacterial or fungal infection, monoclonal gammopathy, leukemia, chronic steroidal, and/or immunosuppressive drugs.  The investigators took digital photos of the ulcers at baseline, and every 2nd–3rd follow-up visit that included a 3-6 cm scale calibration sticker external to the wound margin.  In the study, all patients received weekly a topical application of L-PRF membranes (L-PRF was prepared following the original L-PRF method using the Intra-Spin L-PRF centrifuge/system and the XPression box kit) until wound closure.  Following the wound dressing, compression therapy was applied for VLU, DFU, and complex wounds.  Patients were assessed every 3 months up to 1 year.

Results:  Of the 44 consecutive patients enrolled in the study, 18 were female and 26 were male (mean age at first L-PRF application 63.7 ± 14.3 years).  Mean age was similar for the VLU and DFU groups (65 and 68 years, respectively), while the patients in the PU and complex wound groups were younger (55 years).  The investigators reported that the majority of patients suffered from a systemic disease, especially diabetes or hypertension.  All wounds showed improvements after the L-PRF therapy.  All VLUs ≤ 10 cm², all DFUs, as well as the two complex wounds showed full closure within a 3-month period.  All wounds of patients with VLUs > 10 cm² who continued therapy (10 wounds) closed, whereas in the five patients who discontinued therapy wound size improved.  Two out of the five PUs were closed, with improvement in the remaining three patients who again interrupted therapy (surface evolution from 7.35 ± 4.31 cm² to 5.78 ± 3.81 cm²).

The authors did not comment on study limitations.  The authors noted that for DFUs, the L-PRF seems extremely efficient, with a 100% wound closure in sites where standard wound care had failed.  No adverse events were observed during the study.  The authors reported that at the beginning of the study, all patients with VLUs were suffering from severe pain requiring analgesic management.  After a few applications of L-PRF, the patients reported a significant decline in pain and in need of analgesic drugs.  After 3 months of treatment, none of the patients treated with L-PRF needed analgesic treatment any more.  The authors concluded that L-PRF represented a safe, convenient, easy-to use adjuvant therapy with significant potential for closing chronic wounds without adverse events.

Salazar-Álvarez A, Riera-del-Moral L, García-Arranz M, Álvarez-García J, et al. Use of Platelet-Rich Plasma in the Healing of Chronic Ulcers of the Lower Extremity. Actas Dermo-Sifiliograficas. 2014;105(6):597-604.

The aim of this uncontrolled observational study was to assess the safety and feasibility of using PRP in the treatment of chronic ulcers of the lower extremity, and to evaluate its potential benefits in directed healing.  Patients with non-ischemic ulcers of the lower extremity that had been present for at least 6 weeks were recruited from an outpatient clinic between December 2001 and January 2013 for study participation.  Other inclusion criteria required: age > 18 years, walking without assistance from others, ability to perform daily activities, and pedal/posterior tibial pulses present or ankle-brachial index > 0.8.  Exclusion criteria included: ulcers of ischemic etiology and ulcers present for more than 6 weeks but showing signs of healing (on photographic comparison with the previous week).

As part of the study, personal and demographic details, clinical data, etiology of the ulcer and time since onset, cardiovascular risk factors, and past medical and surgical history was collected.  PRP was injected subcutaneously into the peri-lesional tissue and applied topically in four sessions at 1-week intervals.  Outcome measure included assessment of quality of life (SF-12 questionnaire), pain (visual analog scale), and the circumference of the ulcer before and after treatment.

Results:  Eleven patients were included in the study.  The majority of patients were women (73%), and were hypertensive (82%).  The median duration of active ulceration was 17 months (range, 7-108 months).  The median age of the patients was 73 years (though in the abstract it says 79 years) and the median time since onset of the ulcer was 17 months (range, 6-108 months).  The most common etiology as venous insufficiency.  The investigators reported that “None of the patients with ulcers of venous etiology underwent surgery prior to, during, or after of the application of the PRP.  No adverse events of any type were detected related to the application of PRP.  In the 8 weeks after the final application of PRP, complete healing was observed in 5 ulcers and the mean ulcer surface area decreased by 59.8%.  The patient-perceived ulcer-related pain showed a statistically significant reduction (P < 0.05) between baseline (mean VAS score, 6.7) and end of treatment (mean VAS score,1.3).”  Also, there was a statistically significant improvement (P < 0.05) in the mental and physical quality of life components reported by the patients after the application of PRP.

The authors did not comment on the limitations of their study but concluded that the local application of PRP was a valuable and practical procedure that promotes the healing of chronic ulcers of the lower extremity; it can improve patient quality of life and is particularly effective in local pain relief.

Sarvajnamurthy S, Suryanarayan S, Budamakuntala L, Suresh D. Autologous Platelet Rich Plasma in Chronic Venous Ulcers: Study of 17 Cases. J Cutan Aesthet Surg. 2013 Apr-Jun; 6(2): 97–99. 10.4103/0974-2077.112671.

The objective of this uncontrolled observational study was to determine the efficacy of autologous platelet rich plasma in the management of chronic venous ulcer.  The study followed 12 patients with 17 ulcers from January 2011 to June 2012. Inclusion criteria included ulcers more than 6 weeks duration and patients who had received conventional therapies for at least 6 weeks.  Exclusion criteria included; bleeding disorders, uncontrolled sugar levels, ulcers with active infection, and aphenofemoral incompetency.  Participants received PRP once weekly for 6 weeks, and at weekly intervals ulcer area and volume was calculated and photographs were taken.  The study defined treatment outcome as a percentage change of the area and volume (calculated as initial measurement minus assessment day measurement divided by initial measurement).

Results:  The mean age of the participants was 33.5 years, 10 of the 12 patients (83.33%) were males.  Ulcer duration prior to enrollment ranged from 2 months to 1 year with a mean of 5.35 months.  The study showed mean duration of the healing of the ulcers to be 5.1 weeks; 100% improvement in the area was seen in 13 ulcers (76%) and 100% improvement in volume in 14 ulcers (82%).  The study reported that “baseline mean area of the ulcer was 10.08 cm² (SD 6.91) and baseline volume was 6.45 cm³ (SD 5.35).  The final area of the ulcer at the end of 6 weeks was 1.13 cm² (SD 2.56) and final volume of the ulcer was 0.76 cm³ (SD 1.91).  The mean percentage improvement in the area and volume of the ulcer was 94.7% (SD 11.12) and 95.6% (SD 10.19) respectively.  There were no side effects and there was a decrease in pain associated with the ulcers.”

The authors did not comment on the limitations of the studies but concluded that PRP is useful in enhancing the wound healing in chronic venous leg ulcers without any adverse events.  They also noted that since there is no standardization of the procedure, more randomized control studies are needed to make a standard protocol for the preparation of PRP.

Sokolov T, Manukova A, Karakoleva S, Valentinov B, Kosev P. Platelet-rich plasma (PRP) for the treatment of problematic skin wounds. J of IMAB. 2016, vol. 22, issue 4.
[The following study appears to be an extension of the case-series previously described by Kossev et al. 2015.]  

The objective of the uncontrolled observational study was to show the benefit of platelet-rich plasma (PRP) application in problematic skin wounds, and to evaluate the results from the treatment.  The investigators enrolled patients with “problematic skin wounds” defined as wounds that fail to heal after 6 weeks and were caused by high energy trauma.  They also comment that major types of problematic skin wounds are acute, hard-to-heal, and chronic wounds.  The study involved 31 patients with problematic skin wounds, which had been treated at the clinic for a period of five years (from May 2010 to September 2015).  Study participants were treated in a procedure developed by the researchers, which included platelet rich plasma obtained by PRGF Endoret system.  After blood collection and centrifuging, plasma is drawn off and activator is added.  Subsequently the “Fibrin clot is formed after approximately 40 minutes.  Activated plasma is used to infiltrate the wound edges and the fibrin clot is used to fill the wound itself.  A sterile dressing soaked with physiological saline is applied.”  The procedure was repeated on a weekly basis until the wound problem resolved in full.  No antibiotic treatment was administered to those participants.

Results:  There were 31 patients enrolled in the study; enrollees included 13 male patients and 18 female patients.  The study reported that average age was 46.5 (range 22-82).  Participants included 10 patients with Type 2 Diabetes, 2 patients with decubitus ulcers, 29 subjects with traumatic wounds, 12 subjects with infectious wounds, 15 patient with acute wounds, and 16 patients with chronic wounds.  The follow-up period was 4-6 months (average 4.5).  The results were evaluated using Total wound score, Total anatomic score and Total score, which was offered by Cancela et al. Baseline measurements included: Total wound score – 10 p., Total anatomic score – 8 p. and Total score – 15 p.  The investigators stated that “At the end of the treatment period, all items were respectively - 0 p., which meant excellent results, i.e., complete healing of the wounds in all of our patients,” regardless of the etiology of the wound or the accompanying diseases in the patient.

The authors did not comment on study limitations and conclude that the application of PRP has its place in the treatment of problematic skin wounds because it improves and accelerates wound healing.

Suthar M, Gupta S, Bukhari S, et al. Treatment of chronic non-healing ulcers using autologous platelet rich plasma: a case series. Journal of Biomedical Science (2017) 24:16. DOI 10.1186/s12929-017-0324-1

The objective of this uncontrolled observational study by Suthar and associates was to evaluate the safety and efficacy of autologous PRP in treating non-healing ulcer on lower extremity using a rapid, intraoperative point-of-care technology at the patients’ bed side.  The case series consisted of 24 patients between the ages of 18–85 years, who suffered with chronic or non-healing ulcers of various etiologies (e.g., pressure ulcers, venous ulcers, arterial ulcers or diabetic foot ulcers) who were treated with autologous PRP.  Eligibility criteria included having an ulcer of at least 4-weeks’ duration, index foot ulcer located on the plantar, medial, or lateral aspect of the foot (including all toe surfaces); and ulcer area (length x width) measurement between 0.5 and 10 cm².  The index ulcers had to be clinically non-infected (based on absence of clinical signs and symptoms of infection rather than culture results) and full-thickness without exposure of bone, muscle, ligaments, or tendons.

Subjects were treated with a single dose of subcutaneous PRP injections along with topical application of PRP gel. PRP was prepared using an advanced rapid point-of-care technology, the Res-Q™ 60 PRP system (Thermogenesis Corp., USA) at the patient’s bed side.  Following debridement to remove any necrotic and infected tissues, the ulcer area was cleaned with betadine solution.  PRP was injected subcutaneously inside and around the periphery of the ulcer.  PRP was then applied as a topical gel over the ulcer.  Endpoints included the percentage reduction in ulcer size over the 24 weeks follow-up period (based on visual inspection), safety and feasibility of autologous PRP injections, time to ulcer healing, improvement in pain or discomfort, and quality of life.

Results:  Of the 24 patients, 16 (66.6%) were male mean overall age was 62.5 ± 13.53 years; 16 (66.6%) were in 61– 80 years age group, 7 (29.17%) were in 41–60 years age group, and only 1 (4.17%) patient was <40 years.  All the patients showed signs of ulcer healing with reduction in ulcer size, and the mean time duration to ulcer healing was 8.2 weeks; all healed within a 14-week time period.  The authors reported that during the study there was a reduction in pain and serous discharge from ulcers noted within 1 week post-treatment.  The researchers noted that overall quality of life of the treated patients improved tremendously post- PRP therapy.  The authors concluded that PRP is a safe and effective treatment modality for chronic non-healing ulcers.

Volakakis E, Papadakis M, Manios A, et al. Platelet-rich Plasma Improves Healing of Pressure Ulcers as Objectively Assessed by Digital Planimetry. Wounds 2019;31(10):252–256. Epub 2019 July 31.

The purpose of this uncontrolled observational study was to objectively assess the impact of PRP therapy on pressure ulcers (PU) healing utilizing digital planimetry.  The study involved 43 patients with chronic pressure ulcers.  Eligibility criteria included patients with stage 3 and 4 PUs of a surface area > 1 cm² and > 3 months’ duration.  Exclusionary criteria included patients who were poor general condition (ie, a Karnofsky Performance Status Scale < 60%) and significant comorbidity, such as severe or uncontrolled cardiac or pulmonary disease, malignant or premalignant marrow disorder disease, kidney or liver failure, cerebral vascular disorders, coma, intracranial hypertension, or accompanying autoimmune diseases.  The investigators also excluded patients with PUs ≤ 1 cm², very deep ulcers with cavities not feasible for assessment by digital planimetry, or facial ulcers as well as women who were pregnant or lactating also were excluded from the study. 

For the purposes of the study, each PU was debrided surgically, and wound cultures were conducted to exclude local infection.  Patient were advised to continue conventional treatment for 4 weeks; repeat debridement was then performed as needed.  PRP, which was prepared by centrifuging 30 mL to 60 mL of the patient’s blood with an autologous platelet separator (Magellan MAG100 Autologous Platelet Separator System), was injected into the margins and PU bed once weekly for 4 weeks.  The publications states that “Following the PRP application, the wound was covered with a transparent, non-adherent dressing…During the period of PRP treatment, no local creams or dressings with potential healing action were allowed.” The investigators assessed the treatment’s effectiveness weekly using digital planimetry over the 8-week study duration.  To calculate the wound healing rate, the investigators analyzed several wound-related parameters, including surface area, maximal diameter, and circumference.  

Results:  At the beginning of the study, there were 43 patients with a total of 74 chronic stage 3 and 4 pressure ulcers, but due to dropout, the final sample consisted of 36 patients (22 men, 14 women) with a total of 64 chronic PUs and a median age of 62 years (range, 38–88).  The study showed that of “the 64 PUs, 44 were located in sacrogluteal region, 10 at the heel, 3 on the tibial region, 3 on the ankle, 2 on the thigh, 1 on the abdominal wall, and 1 at the stump of a high tibial amputation.  The median surface area was 20 cm² (range, 1 cm²–180 cm²), median diameter was 6.3 cm (range, 1.3 cm–18.6 cm), and median circumference was 16.8 cm (range, 4 cm–68 cm).”

The study found that the median surface area (63% vs. 41%), median maximal diameter (33% vs. 20%), and median circumference (38% vs. 21%) were significantly (P < .001) smaller after PRP treatment compared with after conventional treatment.

In the study, the authors acknowledge a number of limitations, including the heterogeneity of the location of the pressure ulcers, as well as the application of conventional local therapies for 4 weeks in the study participants, which could have altered PRP action by stimulating or inhibiting its activity and potentially confounding the results.  Despite these handicaps, the authors concluded "PRP treatment accelerates healing of PUs as objectively measured by digital planimetry, and when compared with conventional treatment, a significantly higher reduction in surface area, diameter, and circumference of PUs was observed following application of PRP.”

Waniczek D, Mikusek W, Kaminskf T. The “Biological Chamber” Method—Use of autologous platelet-rich plasma (PRP) in the treatment for poorly healing lower leg ulcers of venous origin. Pol Przegl Chir. 2015 Jun;87(6):283-9. doi: 10.1515/pjs-2015-0055.

The aim of this uncontrolled observational study was to describe an original method of autologous platelet-rich plasma application through the formation of a sort of “biological chamber” containing a concentrate of growth factors.  The study involved patients who had been previously treated for at least six months due to poorly healing lower leg ulcers caused by chronic venous insufficiency.  (The authors reported that all patients had previously undergone saphenectomy and were treated for more than one year in the outpatient setting without improvement).  Participants, on average, had an ulcer area of 10.7 cm².  Ulcer areas were measured using the researcher’s own method of digital documentation (their own photography techniques and processing using “Pole” software).  Patients with evidence of infection, or ankle brachial pressure index (ABPI) < 0.8 were excluded from the study.  As part of the study, all patients were admitted to a hospital, and mechanical debridement of wound was performed.  Wounds were then covered with stoma paste, creating a chamber into which autologous platelet-rich plasma was introduced to the bottom of the ulcer in the form of an injection.  Autologous PRP gel foam was also applied to the wound, then foil as well as cotton and elastic bandages were applied.  PRP gel foam as well as dressing were reapplied every 3-5 days.  

Results:  Study participants included ten patients (seven women and three men; mean age 68.3).  After four weeks of treatment, the area of ulcers decreased by approximately 56%, and after 8 weeks of treatment by approximately 93%.  All of the treated patients achieved marked regression of the lesions, followed by complete healing of the wound within ten weeks.

The authors did not comment on limitations of their study but concluded that the use of growth factors and cytokines contained in platelets as well as leukocytes obtained from the patient’s own blood are an effective and relatively inexpensive method of allowing acceleration of chronic wound healing.

4.  Medicare Evidence Development & Coverage Advisory Committee (MEDCAC)

A MEDCAC meeting was not convened on this topic.

5.  Evidence-Based Guidelines

A summary clinical algorithm for a guideline by the Association for the Advancement of Wound Care published in 2013 was found during a search of the National Guideline Clearinghouse database (Kimmel et al. 2013).  The algorithm, titled “Summary algorithm for venous ulcer care with annotations of available evidence” briefly notes the use of biologic dressings for wounds at least 30 days old, as well as the use of PDGF.  However, an evidence strength rating of “C” was assigned to each.  This rating means that at least one of the following is lacking: results from a controlled trial, results of at least two case series or descriptive studies or a cohort study in humans, or expert opinion.  The use of platelet-rich plasma was not considered in the discussion.

In 2006, the Wound Healing Society (WHS) published evidence-based guidelines to demonstrate the best care for chronic wounds.  The guidelines were presented by type of chronic wound (diabetic ulcers, venous ulcers, pressure ulcers, and arterial insufficiency ulcers).  Only the venous ulcer guideline addressed a PRP-type of treatment and noted that this treatment has “yet to be shown to demonstrate sufficient statistically significant results or effectiveness to recommend” its use.

In 2015 the WHS provided an update of the 2006 document but provided no new information on the use of PRP in patients with venous ulcers.

In 2016 the Wound Healing Society (WHS) published an update of their 2006 guidelines on the use of PRP in the treatment of DFUs. The document states in

In 2015 the WHS published an update of their 2006 guidelines on the use of PRP in the treatment of pressure ulcers. The document states in

As of the date of the document they note that no growth hormone of platelet rich product has received approval for pressure ulcers treatment and evidence regarding the efficacy is conflicting.

The Association for the Advancement of Wound Care (AAWC) Guideline Task Force provided no information about the use of PRP in patients with diabetic, venous, as well as pressure wounds.

The Wounds International 2013 guideline recommends adjunctive PRP therapy “when diabetic wounds did not respond to standard care,” (Chadwick et al. 2014).

NICE (National Institute for Health Care Excellence) 2015 (updated in 2019) guideline does not recommend PRP for any condition.

6.  Professional Society Position Statements

An internet search failed to locate any professional society position statements exclusively addressing autologous PRP in the treatment of chronic wounds.  It is possible that CMS may receive professional society position statements following the posting of the proposed decision.

7. Expert Opinion

We may receive expert opinions on the proposed decision during the comment period.

8. Public Comment

Public comments sometimes cite the published clinical evidence and give CMS useful information.  Public comments that give information on unpublished evidence such as the results of individual practitioners or patients are less rigorous and therefore less useful for making a coverage determination. 

CMS uses the initial public comments to inform its proposed decision.  CMS responds in detail to the public comments on a proposed decision when issuing the final decision memorandum.  The tracking sheet for this NCD noted that CMS was seeking public comments on the evidence speaking to the health outcomes attributable to the use of PRP products in the treatment of chronic non-healing pressure ulcers, venous ulcers and diabetic foot ulcers.  All comments that were submitted without personal health information may be viewed in their entirety by using the following link https://www.cms.gov/medicare-coverage-database/details/nca-view-public-comments.aspx?NCAId=300&ExpandComments=n&NCDId=217.

Initial Comment Period: 04/03/2020 – 05/03/2020

During the initial 30-day public comment period, CMS received a total of 20 comments.  Fifteen of the commenters were in favor of Medicare coverage of PRP.  Of those in favor of coverage, eight specifically recommended the use of PRP in patients with diabetic wounds.  Also of those who favored PRP, seven referenced studies conducted under Coverage with Evidence Development (CED) as part of their reasoning for supporting Medicare coverage (those studies, as well as many others, have been included in this analysis).  There was one commenter not in favor of coverage because he believed that the evidence for PRP was not strong, two commenters expressed no clear position, and two commenters felt that CMS should maintain coverage under CED so that ongoing studies may continue.

CMS received a number of comments from physicians and surgeons, some who provided first-hand experience about patients who they had treated with PRP, and shared information about favorable outcomes as a result of PRP.  CMS received comments from other individuals within healthcare organizations, such as nurses, pharmacist, professors, hospital administrators, and from representatives from healthcare systems and healthcare coalitions.    CMS also received comments from representatives of manufacturing companies and other businesses and consulting firms.  These commenters include lawyers, sales representatives, consultants and executives.  During this comment period CMS did not receive any comments from patients who had been treated with PRP. 

VIII. CMS Analysis

Introduction:

National coverage determinations are determinations by the Secretary with respect to whether or not a particular item or service is covered nationally under title XVIII of the Social Security Act. (§1869(f)(1)(B),§1862(l).  Among other things, in order to be covered by Medicare, an item or service must fall within one or more benefit categories contained within Part A or Part B, and must not be otherwise excluded from coverage.  Moreover, with limited exceptions, items or services must be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.§1862(a)(1)(A).

When making national coverage determinations, we evaluate the evidence related to our analytic questions based on the quality, strength and totality of evidence presented in the reviewed literature.  As part of this evaluation, it is important to consider whether the evidence is relevant to the Medicare beneficiary population.  In determining the generalizability of the results of the body of evidence to the Medicare population, we consider, at minimum, the age, race and gender of the study participants.

Evidence Review Summary:

For this NCD reconsideration, CMS focused on the following questions:

Do Medicare beneficiaries that have chronic non-healing diabetic, pressure, and/or venous wounds who receive well-defined optimal usual care along with PRP therapy, experience clinically significant health outcomes compared to patients who receive well-defined optimal usual care for chronic non-healing diabetic, pressure, and/or venous wounds achieve at least one of the following:

1. complete wound healing;
2. ability to return to previous function and resumption of normal activities; or
3. reduction of wound size or healing trajectory, which results in the patient’s ability to return to previous function and resumption of normal activities?

A review of the medical literature since the 2012 NCD reconsideration on the use of autologous PRP in patients with chronic wounds has revealed a limited number of appropriate studies (22) for inclusion in this NCD analysis.  Some studies evaluated mixed populations (e.g., patients with pressure, venous, and diabetic chronic wounds), while other studies evaluated single populations (e.g., venous, or diabetic chronic wounds alone).  There was one study that evaluated pressure ulcers alone.  Study designs varied and included systematic reviews or Meta-Analylses (4), Randomized Clinical Trials (7), Non-Randomized Clinical Trials (1) Controlled Observation studies (1) and Uncontrolled Observational studies (11).  In addition to variations in study design, the published literature reflected a wide range in: the number of participants, the research design, outcomes (and the measurement of those outcomes), the PRP preparation (the process used to ’harvest’ autologous PRP), delivery (application of PRP), as well as frequency (how often PRP was applied to chronic wounds).  The two most common outcomes reported were wound healing and reduction in wound size.  None of the studies included in this assessment addressed whether PRP use, reduction in size, or healing trajectory had an impact on a patient’s ability to return to previous function and resumption of normal activities.  CMS uses an evidence-based approach when considering national coverage determinations (NCD).  As part of this assessment of evidence, CMS considers the question to be addressed, the strategy investigators use to address the question (such as study design), the quality of the methods, the strength of findings, the legitimacy of interpretation of the results, and whether gaps remain in the evidentiary base (among other considerations).

When considering an appropriate design to answer the research questions above, a randomized clinical trial can offer strong evidence given the experimental design that helps reduce bias.  Well conducted systematic reviews and meta-analyses that limit inclusion to quality studies and thoroughly consider those underlying studies can also yield strong evidence due to methodologic synthesis across many investigations.  Analytic observational studies (those with a control group) help in understanding the risk/benefit profile of interventions in the context of actual clinical use, typically without the select inclusion/exclusion criteria and rigorous protocol driven methods common to clinical trials.  While longitudinal uncontrolled observational studies typically report descriptive findings on a smaller numbers of patients (so offer less robust data), such data can help identify safety events or be hypothesis generating (exploring relationships and patterns), rather than hypothesis testing (putting an a priori hypothesis to an empirical test).

In addition to the strength of the study design, there are other issues that complicate assessing ulcer healing.  Such factors include:

• the number of ulcers per patient (and whether a study uses patients or ulcers as the denominator),
• location of the ulcers (similar across comparator groups?)
• duration of wound prior to study recruitment
• the length of any run-in period to assess for spontaneous healing and choosing a threshold for such non-healing that qualifies for study eligibility
• the large range in wound size
• measurement of wound – by hand or calibrated photograph, blinded?
• infection and whether antibiotics were issued (potentially impacting healing)
• whether advanced wound care methods are also used the proportion loss to follow-up by study arm distribution of potential confounders across the exposed and control (such as smoking).

These are just a few of the challenges posed in the literature.  Ulcer location appeared to be relatively balanced across the PRP and control groups based on the information included in the publications.  For publications that reported duration of ulcer (chronicity) prior to study inclusion, inclusion criteria ranged from a minimum of > 1 to > 6 months, although the mean might be notably higher.  Because the trials included controls with similarly selected patients, this allows for an unbiased assessment of healing, regardless of ulcer duration.  Still, trials selecting a longer duration for non-healing ulcers (such as Moneib) may be selecting for greater disease severity and might offer data supporting more salient patient outcomes of concern to Medicare providers and beneficiaries.  

Most trials attempted to limit enrollment to patients after infections were cleared; debridement and associated antibiotic use were part of the procedures prior to the follow-up for evaluation of ulcer healing.  Length of follow-up varied notably across trials spanning 3 weeks to 24/26 weeks. While trials of short duration may be valid in assessing healing over a short period, CMS has greater interest in assessing long-term healing as well as ulcer recurrence as outcomes of higher consequence for Medicare beneficiaries.  The trial by Game followed patients for 26 weeks and reported that there was no ulcer recurrence of healed wounds.  Also in the trial by Pinto, patients were followed for up to 1 year and noted no ulcer recurrence of healed wounds.

Given the myriad logistical challenges, the different approaches, and extent to which the trials addressed the challenges, it is notable that all the above trials consistently reported favorable outcomes for increased healing with PRP.

To answer the above questions, we considered the evidence according to the specific type of ulcer etiology, starting first with diabetic ulcers, venous ulcers, then pressure ulcers. 

Quality and strength of evidence

All of the studies included in this assessment (whether for diabetic, venous, or pressure wounds) evaluated whether or not the use of PRP resulted in complete wound healing, or reduction in size of wounds.  None of these studies addressed whether or not PRP affected a patient’s ability to return to previous function and resumption of normal activities, or resulted in reduction of wound size or healing trajectory as an intermediary towards a formal endpoint of a patient’s ability to return to previous function and resumption of normal activities.

Diabetic Wounds

In the evaluation of diabetic ulcers, there were studies in the form of systematic reviews, meta-analysis, RCTs, and controlled and uncontrolled observational studies.  Three of these systematic reviews and meta-analysis looked at a mixed population (patients suffering with diabetic, venous as well as pressure ulcers), while one systematic review looked exclusively at patients with diabetic ulcers (Picard et al).

Of the total number of systematic reviews and meta-analysis, three out of 4 revealed that diabetic patients who were treated with PRP had higher healing rates compared to the control group, which was treated with usual and customary care (UCC).  Only the Alonso study failed to show that patients treated with PRP had a higher healing rate than those treated with UCC.  And as mentioned earlier, all four systematic reviews and meta-analysis failed to demonstrate that PRP was more effective than UCC when looking at other types of chronic wound (e.g., venous, or pressure).  When looking at the studies that made up the systematic reviews or meta-analysis we note that:

• 15 of 18 studies in the Alonso systematic review were RCTs (this is the systematic review that showed PRP did not work in any type of chronic wound)
• All 10 of the studies in the Martinez-Zapata systematic review were RCTs
• Of the 12 studies included in the Picard systematic review, 6 were randomized prospective studies, 1 was prospective controlled study, 3 were prospective uncontrolled studies, 1 was retrospective controlled, and 1 was retrospective uncontrolled study
• All 15 of the studies in the Xia systematic review were RCTs.

Besides those RCTs that were in the systematic reviews or meta-analysis, there were other RCTs that evaluated PRP in diabetic patients (Ahmed et al.; Cardenosa et al.; Game et al.; Gude et al.; Karimi et al.; Moneib et al.; Obolinskiy et al.).  Studies ranged in size from 50 to 269.  All of these RCTs demonstrated that diabetic ulcer patients who received PRP had a higher healing rate, as well as a greater reduction in ulcer size than patients who received UCC.  Of the trials, the Game study followed by the Gude study appeared to have the strongest methods for assessing ulcer healing (see the table); both specifically addressed diabetic foot ulcers.

There was one controlled observational study (Milek et al.) which also demonstrated that patients who received PRP had a higher healing rate, as well as a greater reduction in ulcer size than patients who received UCC.  There were also two uncontrolled observational studies (Babaei et al.; Löndahl).  One study demonstrated that patients who received PRP had a higher healing rate compared to patients that received UCC (Löndahl), and the Babaei study showed complete wound healing, and no recurrence of ulcers during the next eight months that the patients were followed.  In summary, based on the review of the evidence, specifically the increased healing rate compared to UCC, PRP appears to benefit patients with diabetic ulcers.

Venous Wounds

With the exception of systematic reviews or meta-analysis, there were two RCTs that evaluated the use of PRP in venous patients (Cardenosa et al., Moneib et al).  The Cardenosa trial revealed that patients treated with PRP had a higher healing rate than patients treated with UCC.  The Moneib study revealed that patients who received PRP were more likely to have reduction in size of the wound than patients who received UCC, but there was no increase in healing in the PRP group.  Both studies had a moderate number of participants (58 and 40 respectively).  There was one non-randomized clinical trial (Etugov et al.), and it had 23 participants.  Patients only received a single application of PRP. The study was able to show a significant reduction in size of ulcers in patients that received that single preparation of PRP compared to those that received UCC, but there was no documentation of healing.  There were two uncontrolled observational studies (Sarvajnamurthy et al.; Waniczek et al.) that looked specifically at venous wounds, but they both had a low number of participants (12 and 10 respectively).  All of the remaining uncontrolled observational studies evaluated a mixed population which included patients with venous wounds, but the studies themselves had a moderate to very low number of participants (ranging from 14 to 44).  Also, as mentioned for pressure ulcers, all of the systematic reviews and meta-analysis, with the exception of that by Picard, contain mixed population (which included patients with venous wounds), but these studies fail to specifically identify the number of patients with venous ulcers.

Based on the totality of the evidence generated through coverage with evidence development and peer-reviewed articles and varying patient characteristics, there is some indication that some patients may benefit from this treatment, so we are proposing to allow MACs to make the section 1862(a)(1)(A)  coverage determination for PRP for venous wounds.  The evidence supporting the use of PRP in venous wound is not as robust as when comparing the use of PRP in diabetic wounds.  First, there were a lower number of studies found, no systematic reviews evaluating PRP in venous wound patients, there are a low number of RCTs, as well as decreased number of participants.  All of the studies investigating venous wounds showed either an increase rate of healing wounds, or a reduction in the size of the wounds. Two of these studies were RCTs, but they had small sample sizes.    In summary, because of the limited positive findings of the two RCTs, we propose to allow MACs to make the section 1862(a)(1)(A)  coverage determination for PRP for venous wounds.  We believe the MACs are better positioned to make coverage determinations as the evidence base evolves and to take into consideration individual patient characteristics and local provider factors.

Pressure Wounds

There was only one article that specifically addressed the use of PRP in patients with pressure ulcers (Volakakis et al. 2019).  This uncontrolled observation study had 36 participants and stated that PRP was able to reduce the size of wounds (compared to prior treatment), though there was no actual wound healing.  Pressure ulcers were also addressed in some articles with multiple etiologies.  With the exception of systematic reviews or meta-analysis, the largest mixed etiology study was conducted by Obolinskiy, which had 100 participants.  The author did not specifically identify pressure wounds, nor quantify the number of patients with pressure wounds.  With the exception of the Picard study, all of the systematic reviews and meta-analysis contain ulcers of mixed etiology, (which included patients with pressure wounds), but these studies fail to specifically identify the number of patients with pressure ulcers.  The Volakaksi study did demonstrate that PRP was able to reduce the size of ulcers, though no complete wound healing was observed.  Also this study did not reveal any untoward effects related to PRP in this population. We must be mindful that because of the small number of studies and participants, we are not able to definitively say that PRP does not work in this patient group.  Because of the insufficient evidence available, we are proposing that MACs make the determination on whether or not to cover PRP for pressure wounds based on whether the service is reasonable and necessary for the individual beneficiary after considering the individual’s specific circumstances.

Health Disparities

Studies performed not only in the United States but the rest of the world should provide evidence about benefits or harms related to other population classifiers that have been associated historically with healthcare access or outcome disparities, such as gender, age, sexual orientation and religion, and encourages additional studies in which such associations might be studied.  While no studies reviewed specifically addressed health disparities, it is helpful when clinical studies include data on racial and ethnic factors where they are relevant to the conclusions that may be drawn about the impact of the investigational item or service.  That is especially important because one of the comments received during the comment was submitted by a representative of a coalition of minority health organizations, who went on to discuss how diabetes disproportionately affects racial and ethnic minority populations.  

Summary

There is sufficient evidence to demonstrate that patients with diabetic ulcers who are treated with autologous PRP have better outcomes (complete wound healing) when compared to patients who receive standard care.  The evidence also supports the use of PRP in venous wounds, however, the relative number of RCTs and decreased study population, it is not as robust when compared to the use of PRP in diabetic wounds.  All of the studies investigating venous wounds showed either an increased rate of healing wounds, or a reduction in the size of the wounds.  Two of these studies were RCTs, but they had small sample sizes.  Two studies are currently in progress (see clinicaltrials.gov): one is looking specifically at PRP and its effect on venous wounds, and another study is looking at PRP and its effect on mixed wounds, which includes venous wounds.  Because of the favorable findings of the two RCTs, as well as ongoing studies evaluating the use of PRP in venous wounds, we propose that Medicare Administrative Contractors (MACs) should make the coverage determination under section 1862(a)(1)(A).  We also believe that results of ongoing studies will be beneficial to the MACs in making coverage determinations.   

For patients with pressure wounds, studies have demonstrated that the use of PRP does result in reduction in wound size, though no actual wound healing.  There were no studies that addressed the ability to return to previous function and resumption of normal activities, nor reduction of wound size or healing trajectory as an intermediary towards the patient’s ability to return to previous function and resumption of normal activities.  We are proposing that MACs make the determination on whether or not to cover PRP for pressure wounds based on whether the treatment is reasonable and necessary.

IX.   Conclusion

The Centers for Medicare & Medicaid Services (CMS) proposes to cover autologous platelet-rich plasma (PRP) for the treatment of chronic non-healing diabetic wounds under section 1862(a)(1)(A) of the Social Security Act (the Act).

CMS proposes that coverage of autologous PRP for the treatment of all other chronic non-healing wounds will be determined by local Medicare Administrative Contractors (MACs) under section 1862(a)(1)(A) of the Act.

See Appendix B for the proposed manual language.

CMS is seeking comments on our proposed decision.  We will respond to public comments in a final decision memorandum, as required by §1862(l)(3) of the Social Security Act (the Act).

When making national coverage determinations, CMS evaluates relevant clinical evidence to determine whether or not the evidence is of sufficient quality to support a finding that an item or service is reasonable and necessary.  The overall objective for the critical appraisal of the evidence is to determine to what degree we are confident that: 1) the specific assessment questions can be answered conclusively; and 2) the intervention will improve health outcomes for patients.

We divide the assessment of clinical evidence into three stages: 1) the quality of the individual studies; 2) the generalizability of findings from individual studies to the Medicare population; and 3) overarching conclusions that can be drawn from the body of the evidence on the direction and magnitude of the intervention’s potential risks and benefits.

The methodological principles described below represent a broad discussion of the issues we consider when reviewing clinical evidence.  However, it should be noted that each coverage determination has its unique methodological aspects.

Assessing Individual Studies

Methodologists have developed criteria to determine weaknesses and strengths of clinical research. Strength of evidence generally refers to: 1) the scientific validity underlying study findings regarding causal relationships between health care interventions and health outcomes; and 2) the reduction of bias.  In general, some of the methodological attributes associated with stronger evidence include those listed below:

• Use of randomization (allocation of patients to either intervention or control group) in order to minimize bias.
• Use of contemporaneous control groups (rather than historical controls) in order to ensure comparability between the intervention and control groups.
• Prospective (rather than retrospective) studies to ensure a more thorough and systematical assessment of factors related to outcomes.
• Larger sample sizes in studies to demonstrate both statistically significant as well as clinically significant outcomes that can be extrapolated to the Medicare population.  Sample size should be large enough to make chance an unlikely explanation for what was found.
• Masking (blinding) to ensure patients and investigators do not know to that group patients were assigned (intervention or control). This is important especially in subjective outcomes, such as pain or quality of life, where enthusiasm and psychological factors may lead to an improved perceived outcome by either the patient or assessor.

Regardless of whether the design of a study is a randomized controlled trial, a non-randomized controlled trial, a cohort study or a case-control study, the primary criterion for methodological strength or quality is to the extent that differences between intervention and control groups can be attributed to the intervention studied.  This is known as internal validity.  Various types of bias can undermine internal validity.  These include:

• Different characteristics between patients participating and those theoretically eligible for study but not participating (selection bias).
• Co-interventions or provision of care apart from the intervention under evaluation (performance bias).
• Differential assessment of outcome (detection bias).
• Occurrence and reporting of patients who do not complete the study (attrition bias).

In principle, rankings of research design have been based on the ability of each study design category to minimize these biases.  A randomized controlled trial minimizes systematic bias (in theory) by selecting a sample of participants from a particular population and allocating them randomly to the intervention and control groups.  Thus, in general, randomized controlled studies have been typically assigned the greatest strength, followed by non-randomized clinical trials and controlled observational studies.  The design, conduct and analysis of trials are important factors as well.  For example, a well-designed and conducted observational study with a large sample size may provide stronger evidence than a poorly designed and conducted randomized controlled trial with a small sample size.  The following is a representative list of study designs (some of that have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias:

Randomized controlled trials
Non-randomized controlled trials
Prospective cohort studies
Retrospective case control studies
Cross-sectional studies
Surveillance studies (e. g. , using registries or surveys)
Consecutive case series
Single case reports

When there are merely associations but not causal relationships between a study’s variables and outcomes, it is important not to draw causal inferences.  Confounding refers to independent variables that systematically vary with the causal variable.  This distorts measurement of the outcome of interest because its effect size is mixed with the effects of other extraneous factors.  For observational, and in some cases randomized controlled trials, the method in that confounding factors are handled (either through stratification or appropriate statistical modeling) are of particular concern.  For example, in order to interpret and generalize conclusions to our population of Medicare patients, it may be necessary for studies to match or stratify their intervention and control groups by patient age or co-morbidities.

Methodological strength is, therefore, a multidimensional concept that relates to the design, implementation and analysis of a clinical study.  In addition, thorough documentation of the conduct of the research, particularly study selection criteria, rate of attrition and process for data collection, is essential for CMS to adequately assess and consider the evidence.

Generalizability of Clinical Evidence to the Medicare Population

The applicability of the results of a study to other populations, settings, treatment regimens and outcomes assessed is known as external validity.  Even well-designed and well-conducted trials may not supply the evidence needed if the results of a study are not applicable to the Medicare population.  Evidence that provides accurate information about a population or setting not well represented in the Medicare program would be considered but would suffer from limited generalizability.

The extent to that the results of a trial are applicable to other circumstances is often a matter of judgment that depends on specific study characteristics, primarily the patient population studied (age, sex, severity of disease and presence of co-morbidities) and the care setting (primary to tertiary level of care, as well as the experience and specialization of the care provider).  Additional relevant variables are treatment regimens (dosage, timing and route of administration), co-interventions or concomitant therapies, and type of outcome and length of follow-up.

The level of care and the experience of the providers in the study are other crucial elements in assessing a study’s external validity.  Trial participants in an academic medical center may receive more or different attention than is typically available in non-tertiary settings.  For example, an investigator’s lengthy and detailed explanations of the potential benefits of the intervention and/or the use of new equipment provided to the academic center by the study sponsor may raise doubts about the applicability of study findings to community practice.

Given the evidence available in the research literature, some degree of generalization about an intervention’s potential benefits and harms is invariably required in making coverage determinations for the Medicare population.  Conditions that assist us in making reasonable generalizations are biologic plausibility, similarities between the populations studied and Medicare patients (age, sex, ethnicity and clinical presentation) and similarities of the intervention studied to those that would be routinely available in community practice.

A study’s selected outcomes are an important consideration in generalizing available clinical evidence to Medicare coverage determinations.  One of the goals of our determination process is to assess health outcomes.  These outcomes include resultant risks and benefits such as increased or decreased morbidity and mortality.  In order to make this determination, it is often necessary to evaluate whether the strength of the evidence is adequate to draw conclusions about the direction and magnitude of each individual outcome relevant to the intervention under study.  In addition, it is important that an intervention’s benefits are clinically significant and durable, rather than marginal or short-lived.  Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.

If key health outcomes have not been studied or the direction of clinical effect is inconclusive, we may also evaluate the strength and adequacy of indirect evidence linking intermediate or surrogate outcomes to our outcomes of interest.

Assessing the Relative Magnitude of Risks and Benefits

Generally, an intervention is not reasonable and necessary if its risks outweigh its benefits.  Health outcomes are one of several considerations in determining whether an item or service is reasonable and necessary.  CMS places greater emphasis on health outcomes actually experienced by patients, such as quality of life, functional status, duration of disability, morbidity and mortality, and less emphasis on outcomes that patients do not directly experience, such as intermediate outcomes, surrogate outcomes, and laboratory or radiographic responses.  The direction, magnitude, and consistency of the risks and benefits across studies are also important considerations.  Based on the analysis of the strength of the evidence, CMS assesses the relative magnitude of an intervention or technology’s benefits and risk of harm to Medicare beneficiaries.

Draft

We are seeking public comments on the proposed language that we would include in the Medicare National Coverage Determinations Manual. This proposed language does not reflect public comments that will be received on the proposed decision memorandum, and which may be revised in response to those comments.

Table of Contents
(Rev.)

Wound healing is a dynamic, interactive process that involves multiple cells and proteins.  There are three progressive stages of normal wound healing, and the typical wound healing duration is about 4 weeks.  While cutaneous wounds are a disruption of the normal, anatomic structure and function of the skin, subcutaneous wounds involve tissue below the skin's surface.  Wounds are categorized as either acute, in where the normal wound healing stages are not yet completed but it is presumed they will be, resulting in orderly and timely wound repair, or chronic, in where a wound has failed to progress through the normal wound healing stages and repair itself within a sufficient time period.

Platelet-rich plasma (PRP) is produced in an autologous or homologous manner.  Autologous PRP is comprised of blood from the patient who will ultimately receive the PRP.  Alternatively, homologous PRP is derived from blood from multiple donors.

Blood is donated by the patient and centrifuged to produce an autologous gel for treatment of chronic, non-healing cutaneous wounds that persist for 30 days or longer and fail to properly complete the healing process.  Autologous blood derived products for chronic, non-healing wounds includes both: (1) platelet derived growth factor (PDGF) products (such as Procuren), and (2) PRP (such as AutoloGel).

The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts.

The PRP is used by physicians in clinical settings in treating chronic, non-healing wounds, open, cutaneous wounds, soft tissue and bone.  Alternatively, PDGF does not contain cells and was previously marketed as a product to be used by patients at home.

C. Nationally Non-Covered Indications

• Autologous PDGF for the treatment of chronic, non-healing cutaneous wounds.
• Autologous PRP for the treatment of chronic, non-healing, cutaneous wounds.
• Becaplermin, a non-autologous growth factor for chronic, non-healing subcutaneous wounds.
• Autologous PRP for the treatment of acute surgical wounds when the autologous PRP is applied directly to the closed incision, or for dehiscent wounds.

APPENDIX C – NCD 270.3 (2012)

Platelet-rich plasma (PRP) is produced in an autologous or homologous manner. Autologous PRP is comprised of blood from the patient who will ultimately receive the PRP. Alternatively, homologous PRP is derived from blood from multiple donors.

Blood is donated by the patient and centrifuged to produce an autologous gel for treatment of chronic, non-healing cutaneous wounds that persists for 30 days or longer and fail to properly complete the healing process. Autologous blood derived products for chronic, non-healing wounds includes both: (1) platelet derived growth factor (PDGF) products (such as Procuren), and (2) PRP (such as AutoloGel).

The PRP is different from previous products in that it contains whole cells including white cells, red cells, plasma, platelets, fibrinogen, stem cells, macrophages, and fibroblasts.

The PRP is used by physicians in clinical settings in treating chronic, non-healing wounds, open, cutaneous wounds, soft tissue, and bone. Alternatively, PDGF does not contain cells and was previously marketed as a product to be used by patients at home.

B. Nationally Covered Indications

Effective August 2, 2012, upon reconsideration, The Centers for Medicare and Medicaid Services (CMS) has determined that platelet-rich plasma (PRP) – an autologous blood- derived product, will be covered only for the treatment of chronic non-healing diabetic, venous and/or pressure wounds and only when the following conditions are met:

The patient is enrolled in a clinical trial that addresses the following questions using validated and reliable methods of evaluation. Clinical study applications for coverage pursuant to this National coverage Determination (NCD) must be received by August 2, 2014.

The clinical research study must meet the requirements specified below to assess the effect of PRP for the treatment of chronic non-healing diabetic, venous and/or pressure wounds. The clinical study must address:

The required clinical trial of PRP must adhere to the following standards of scientific integrity and relevance to the Medicare population:

1. The principal purpose of the CLINICAL STUDY is to test whether PRP improves the participants’ health outcomes.
2. The CLINICAL STUDY is well supported by available scientific and medical information or it is intended to clarify or establish the health outcomes of interventions already in common clinical use.
3. The CLINICAL STUDY does not unjustifiably duplicate existing studies.
4. The CLINICAL STUDY design is appropriate to answer the research question being asked in the study.
5. The CLINICAL STUDY is sponsored by an organization or individual capable of executing the proposed study successfully.
6. The CLINICAL STUDY is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46.
7. All aspects of the CLINICAL STUDY are conducted according to appropriate standards of scientific integrity set by the International Committee of Medical Journal Editors (http://www.icmje.org).
8. The CLINICAL STUDY has a written protocol that clearly addresses, or incorporates by reference, the standards listed here as Medicare requirements for coverage with evidence development (CED).
9. The CLINICAL STUDY is not designed to exclusively test toxicity or disease pathophysiology in healthy individuals. Trials of all medical technologies measuring therapeutic outcomes as one of the objectives meet this standard only if the disease or condition being studied is life threatening as defined in 21 CFR §312.81(a) and the patient has no other viable treatment options.
10. The CLINICAL STUDY is registered on the ClinicalTrials.gov website by the principal sponsor/investigator prior to the enrollment of the first study subject.
11. The CLINICAL STUDY protocol specifies the method and timing of public release of all pre-specified outcomes to be measured including release of outcomes if outcomes are negative or study is terminated early. The results must be made public within 24 months of the end of data collection. If a report is planned to be published in a peer reviewed journal, then that initial release may be an abstract that meets the requirements of the International Committee of Medical Journal Editors (http://www.icmje.org). However a full report of the outcomes must be made public no later than three (3) years after the end of data collection.
12. The CLINICAL STUDY protocol must explicitly discuss subpopulations affected by the treatment under investigation, particularly traditionally underrepresented groups in clinical studies, how the inclusion and exclusion criteria effect enrollment of these populations, and a plan for the retention and reporting of said populations on the trial. If the inclusion and exclusion criteria are expected to have a negative effect on the recruitment or retention of underrepresented populations, the protocol must discuss why these criteria are necessary.
13. The CLINICAL STUDY protocol explicitly discusses how the results are or are not expected to be generalizable to the Medicare population to infer whether Medicare patients may benefit from the intervention. Separate discussions in the protocol may be necessary for populations eligible for Medicare due to age, disability or Medicaid eligibility.

Consistent with §1142 of the Social Security Act (the Act), the Agency for Healthcare Research and Quality (AHRQ) supports clinical research studies that CMS determines meet the above-listed standards and address the above-listed research questions.

Any clinical study undertaken pursuant to this NCD must be approved no later than August 2, 2014. If there are no approved clinical studies on or before August 2, 2014, this CED will expire. Any clinical study approved will adhere to the timeframe designated in the approved clinical study protocol.

C. Nationally Non-Covered Indications

     1. Effective December 28, 1992, the Centers for Medicare & Medicaid Services (CMS) issued a national non-coverage determination for platelet-derived wound-healing formulas intended to treat patients with chronic, non-healing wounds. This decision was based on a lack of sufficient published data to determine safety and efficacy, and a public health service technology assessment.

     2. Effective July 23, 2004, upon reconsideration, the clinical effectiveness of autologous PDGF products continues to not be adequately proven in scientific literature. As the evidence is insufficient to conclude that autologous PDGF in a platelet-poor plasma is reasonable and necessary, it remains non-covered for treatment of chronic, non- healing cutaneous wounds. Also, the clinical evidence does not support a benefit in the application of autologous PRP for the treatment of chronic, non-healing, cutaneous wounds. Therefore, CMS determines it is not reasonable and necessary and is nationally non-covered.

    3. Effective April 27, 2006, coverage for treatments utilizing becaplermin, a non-autologous growth factor for chronic, non-healing subcutaneous wounds, remains nationally non-covered under Part B based on section 1861(s)(2)(A) and (B) of the Social Security Act because this product is usually administered by the patient.

    4. Effective March 19, 2008, upon reconsideration, the evidence is not adequate to conclude that autologous PRP is reasonable and necessary and remains non-covered for the treatment of chronic non-healing, cutaneous wounds. Additionally, upon reconsideration, the evidence is not adequate to conclude that autologous PRP is reasonable and necessary for the treatment of acute surgical wounds when the autologous PRP is applied directly to the closed incision, or for dehiscent wounds.

D. Other
In accordance with section 310.1 of the National Coverage Determinations Manual, the routine costs in Federally sponsored or approved clinical trials assessing the efficacy of autologous PRP in treating chronic, non-healing cutaneous wounds are covered by Medicare.

APPENDIX D
Summary of Evidence

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Karimi R, Afshar M, Salimian M, et al. The Effect of Platelet Rich Plasma Dressing on Healing Diabetic Foot Ulcers. Nurs Midwifery Stud. 2016 September; 5(3):e30314.

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Knighton DR, Ciresi KF, Fiegel VD, Austin LL, Butler EL. Classification and treatment of chronic non-healing wounds. Ann Surg. 1986;204(3):322-330.

Knighton DR, Ciresi KF, Fiegel VD, Schumerth S, Butler E, Cerra F. Stimulation of repair in chronic, non-healing, cutaneous ulcers using platelet-derived wound healing formula. Surg Gynecol Obstet. Jan 1990;1701(1):56-60.

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