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CMS covers autologous platelet-rich plasma (PRP) only for patients who have chronic non-healing diabetic, pressure, and/or venous wounds and when all the following conditions are met:
The patient is enrolled in a clinical research study 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, pressure, and/or venous wounds. The clinical study must address:
Prospectively, 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 as indicated by addressing at least one of the following:
The study of PRP must adhere to the following standards of scientific integrity and relevance to the Medicare population:
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.
To: Administrative File: CAG-00190R3
Autologous Blood-Derived Products for Chronic Non-Healing Wounds (Third Reconsideration)
From: Louis Jacques, MD
Director, Coverage and Analysis Group
Tamara Syrek Jensen, JD
Deputy Director, Coverage and Analysis Group
James Rollins, MD, MSHA, PhD
Director, Division of Items and Devices
Medical Officer
Lisa Eggleston, RN, MS
Cheryl Gilbreath, PharmD, MBA, RPh
Rosemarie Hakim, PhD
Leslye K. Fitterman, PhD
Subject: Decision Memorandum for CAG-00190R3
Autologous Blood-Derived Products for Chronic Non-Healing Wounds
Date: August 2, 2012
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.
A. 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 2000).
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. Additionally, newer techniques such as negative pressure dressings, radiant heat, electrical stimulation and hyperbaric oxygen are also being investigated.
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).
B. 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 platelet-derived angiogenesis factor that causes new capillary formation from the existing microvasculature (Knighton et al. 1982). 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.
With this knowledge, a system was developed in 1985 to obtain multiple growth factors from platelets and started treating patients at the University of Minnesota. 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 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. This decision memorandum is primarily focused on autologous products, and since becaplermin is not an autologous product, it is not addressed in this memorandum.
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 that has been used in the treatment of acute wounds as well as 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 include:
In an attempt to improve the healing process, wound specialists have become more interested in autologous PRP produced by an apheresis process first developed by Charles Worden in 1998. In this process, autologous blood (blood donated by the patient) 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. 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. 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 or surgical setting. 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. In this decision memorandum as in previous ones, CMS is evaluating PRP as a service, and not a specific system for administrating PRP.
In 1992, CMS issued a national non-coverage determination for platelet-derived wound healing formulas intended to treat patients with chronic, non-healing wounds.
On December 15, 2003, CMS issued a national non-coverage determination for use of autologous PRP for the treatment of chronic non-healing cutaneous wounds except for routine costs when used in accordance with the clinical trial policy defined in section 310.1 of the National Coverage Determinations Manual.
On April 27, 2006, CMS issued an NCD to correct the erroneous potential for local coverage of becaplermin, printed in section 270.3 of the National Coverage Determinations Manual, entitled "Blood-Derived Products for Chronic Non-Healing Wounds." CMS deleted the erroneous sentences and inserted the correct statement that "Coverage for treatments utilizing becaplermin, a non-autologous growth factor for chronic non-healing subcutaneous wounds, will remain nationally non-covered under Part B based on §1861(s)(2)(A) and (B) because this product is usually administered by the patient."
On March 19, 2008, CMS issued a non-coverage determination for the use of autologous blood-derived products for the treatment of acute wounds where PRP is applied directly to the closed incision site, and for dehiscent wounds. Current non-coverage for chronic, non-healing cutaneous wounds was maintained.
A. Current Request
On October 4, 2011, Cytomedix submitted a formal request to reopen and revise section 270.3 of the Medicare National Coverage Determinations Manual, which addresses Autologous Blood-Derived Products for Chronic Non-Healing Wounds. They stated that PRP is the prevalent blood-derived therapeutic product used for treating chronic non-healing wounds.
Cytomedix submitted new studies and requested that CMS re-evaluate the coverage of autologous PRP gel for the treatment of the following chronic wounds: diabetic, pressure, and/or venous ulcers.
Alternatively, Cytomedix requested that CMS cover PRP gel through an NCD with data collection as a condition of coverage; and requested that this would provide a practical means by which CMS could obtain the necessary data to evaluate the performance of PRP gel and to confirm the outcomes presented in their request.
B. Benefit Category
For an item or service to be covered by the Medicare program, among other things, it must meet one of the statutorily defined benefit categories outlined in the Act.
There is no specific Medicare benefit category for autologous blood-derived products for treatment of chronic non-healing wounds. However, these services, at a minimum, fall within the benefit categories of physician's service (§1861(s)(1) of the Act) and "incident to" a physician's service (§1861(s)(2)(A) of the Act).
This may not be an exhaustive list of all applicable Medicare benefit categories for this item or service.
The initial 30-day public comment period opened.
The AutoloGel™ System has been cleared by the FDA under Section 510(k). It is important to note that the FDA has only issued a 510(k) device clearance for the equipment in the AutoloGel™ System, to manufacture a gel that can be used to promote moisture retention at a wound site. The gel is intended for use in conjunction with standard of care procedures as one component of a more comprehensive wound management plan. This clearance does not represent a premarket or biological license approval for the PRP gel produced by this device. The device has not been cleared or approved to produce a biologicallyactive wound healing agent.
According to FDA documents a "510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent (SE), to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to premarket approval (PMA). Submitters must compare their device to one or more similar legally marketed devices and make and support their substantial equivalency claims. A legally marketed device, as described in 21 CFR 807.92(a)(3), is a device that was legally marketed prior to May 28, 1976 (preamendments device), for which a PMA is not required, or a device which has been reclassified from Class III to Class II or I, or a device which has been found SE through the 510(k) process. The legally marketed device(s) to which equivalence is drawn is commonly known as the "predicate." Although devices recently cleared under 510(k) are often selected as the predicate to which equivalence is claimed, any legally marketed device may be used as a predicate." (FDA 2010)
Cytomedix's 510(k) submission to FDA described the AutoloGel™ System as "a device consisting of a tabletop centrifuge… and a wound dressing convenience kit…comprised of legally-marketed products…" Their Indications for Use enclosure, included in FDA's clearance letter, states the device "is intended to be used at point-of-care for the safe and rapid preparation of PRP gel from a small sample of a patient's own blood. Under the supervision of a healthcare professional, the PRP gel produced by the AutoloGel™ System is suitable for exuding wounds, such as leg ulcers, pressure ulcers and for the management of mechanically or surgically-debrided wounds." The posted 510(k) summary concluded, "Based on the clinical performance information, it can be concluded that AutoloGel is substantially equivalent to the marketed wound dressing IPM Wound Gel." (510(k) BK060007 Sponsor-provided 510(k) summary and FDA-issued clearance letter)
It is also important to emphasize that the clinical data summarized in the 510(k) clearance show the wound response rate based on ulcer size and the recommended duration of use. All of the wounds that closed in this trial were less than 7.0cm2 at the start of PRP administration and responded within 8.5 weeks of the first application. This trial did not evaluate the safety or effectiveness of repeat courses of PRP gel applications.
In general, when making NCDs under §1862(a)(1)(A), CMS evaluates relevant clinical evidence to determine whether or not the evidence supports 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 improves 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 Medicare beneficiaries. An improved health outcome is one of several considerations in determining whether an item or service is reasonable and necessary under §1862(a)(1)(A) of the Act.
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 the published clinical evidence and provide CMS with useful information. Public comments that provide information based 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 comment period to inform the public of its proposed decision. CMS responds in detail to the public comments that were received in response to the proposed decision when it issues the final decision memorandum.
A. Introduction
This section provides a summary of the evidence that CMS considered during the review. There were a number of systematic reviews and meta-analyses found in the medical literature that investigated the use of PRP in patients with acute as well as chronic wounds. Though results of both types of wounds were reported, the primary focus of this NCD is the effects of PRP on chronic wounds. A number of prospective studies such as comparative studies, and cohort studies, as well as retrospective studies were also found. They also were reviewed for this analysis.
B. Discussion of Evidence Reviewed
1. Question and Outcomes
Is the evidence sufficient to determine that Medicare beneficiaries who have chronic non-healing diabetic, pressure, and/or venous wounds that receive PRP therapy experience clinically significant health outcomes as indicated by at least one of the following:
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 that will lead to resumption of normal activities and improved quality of life.
2. External Technology Assessment
CMS did not request an external technology assessment (TA) on this topic.
On June 15, 2012, the Cochrane database, the NICE database, the Blue Cross/Blue Shield TEC database, and the Canadian Agency for Drugs and Technologies in Health database were searched using the terms "wound care," "platelet gel," "platelet lysate," "platelet-derived wound healing factor" and "platelet-rich plasma." No technology assessments were found.
AHRQ released a TA dated March 8, 2005 titled "Usual Care in the Management of Chronic Wounds: A Review of the Recent Literature." This technology assessment presented a broad review of the products, techniques, and protocols used in wound management but did not address autologous PRP specifically except to state that growth factors "show promise but need further, more rigorous evaluation." (AHRQ 2005)
AHRQ also released a TA dated May 26, 2009, which evaluated the use of Negative-Pressure Wound Therapy; however, this TA did not address the use of PRP in patients with chronic non-healing diabetic, pressure,
and/or venous wounds. Currently, AHRQ is performing a TA on Skin Substitutes for Treating Chronic Wounds. We will determine whether the use of PRP is addressed in this TA when it is publicly available.
3. Internal Technology Assessment
Literature search methods
The reviewed evidence was gathered from articles submitted by the NCD requester, submitted during the public comment period, and from a literature search of Pub Med, Cochrane Library, EMBASE as well as other
sources, such as the TRIP Database, performed by CMS staff.
Search terms used to review the medical literature include the following: platelet-rich plasma, platelet-rich plasma gels, PRP, PRP gel(s), autologous plasma rich in platelets, autologous platelet gel, autologous platelet-rich plasma gel, preparation rich in growth factors (PRGF), platelet-rich and platelet poor plasma, platelet gel, autologous platelet lysate, platelet releasate, platelet derived growth factors (PDGF), autologous platelet-derived wound healing factors (PDWHF), wounds, chronic wounds, chronic non-healing wounds, dehiscence wounds, diabetic ulcers, venous ulcers, and pressure ulcers. Only sources provided in English were used. The following terms are considered synonymous to PRP: platelet releasate, platelet lysate, PDWHF, and PDGF.
The NCD requesters provided the full text of 149 articles as part of the reconsideration materials. We also received a number of full text articles as well as references to articles from commenters during the initial comment period, much of which were duplications of full text articles submitted by the requester. Using the above mentioned search terms, over 8,000 citations were identified. Neither the Cochrane Library review nor EMBASE provided any additional studies, but the Cochrane Library currently has posted a protocol for a systematic review of autologous PRP for the treatment of chronic wounds.
A large number of these articles were excluded from this evaluation because they were clinical summary review articles that do not provide primary evidence (e.g., Akingboye et al. 2010, Everts et al. 2006, Peitramaggiori et al. 2006); addressed the use of PRP in only acute wounds (e.g., Almdahl et al. 2011, Englert et al. 2006, Fanning et al. 2007, Trowbridge et al. 2005 ); discussed PRP usage in conjunction with other treatment modalities (e.g., Cervelli et al. 2010, Gurvich et al. 2008, Klayman et al. 2006); discussed PRP used in orthopedic procedures (e.g., Christgau et al. 2006, Jenis et al. 2006, Simon et al. 2004); discussed PRP usage in dental procedures (e.g., Babbush et al. 2003, Griffin et al. 2004, Marx 2004); or discussed the use of PRP in ear, nose and throat (ENT) procedures (e.g., Kassolis et al. 2005, Pomerantz et al. 2005, Steigmann et al. 2005).
The medical literature also had a large number of studies that reported outcomes as a percentage of wound surface healing and as healing trajectory (Anitua et al. 2007, van Rijswijk & Polansky 1994, Benigni et al. 2007, Carter et al. 2011, Coerper et al. 2008, Phillips et al. 2000, Robson et al. 2000, Sheehan et al. 2003, Snyder, et al. 2010, van Rijswijk et al. 2011, van Rijswijk and Polansky 1994, de Leon et al. 2011, Frykberg et al. 2010, Sell et al. 2010). Some of these studies were designed to show that reduction in chronic wound size over a specified period of time was a good predictor of complete healing. Though these articles are of interest, they do not address the key outcomes, complete healing and/or the patient's ability to return to previous function and resumption of normal activity, which CMS considers pertinent clinical health outcomes in patients with chronic wounds. Therefore, these studies were not persuasive in this analysis and were excluded.
Other studies were excluded because they were duplicate studies, cost-effectiveness studies, case studies/series, reported outcomes not of interest to CMS, used freeze-dried PRP preparations or allogenic PRP frozen platelets, used homologous PRP, or were animal studies.
The following tables with summaries of the literature analysis can be found in Appendix B:
Systematic Review/Meta-Analysis
In a review of the medical literature, there were ultimately three pertinent systematic reviews/meta-analyses found addressing, at least tangentially, the use of PRP in the treatment of patients with chronic wounds. In the proposed decision memorandum, we included mention of a fourth meta-analysis performed by Margolis et al. (1999); since it did not include an exploration of PRP, we have therefore removed it from this final memorandum.
Carter MJ, Fylling CP, Parnell LK. Use of platelet-rich plasma gel on wound healing: a systematic review and meta-analysis. Eplasty. 2011;11:e38.
Using RCTs and comparative groups, Carter et al. performed a systematic review on the use of autologous platelet-rich plasma (intervention group) compared to standard wound care (control group) in cutaneous wounds. The systematic review looked at articles published between 2001 and 2011. Outcomes of interest included healing information such as complete or partial wound healing, time to heal, healing trajectory, velocity or rate, and wound size reduction. The assessment included publications from peer-reviewed journals (which included articles, brief articles, case studies or letters to the editor), as well as materials presented at scientific meetings (e.g., abstracts, posters). Eligible studies included investigations of patients with cutaneous ulcers or wounds (including dehisced wounds, open surgical wounds, acute or chronic wounds) that were treated with activation-processed PRP. Patients with mixed origin wounds, subsets of different wound types, surgical wounds treated with PRP prior to closure and opening, and surgical wounds treated with PRP were also included in the analysis. Inclusion eligibility required PRP studies to have a control treatment group (e.g. placebo, wound care treatment). Non-inferiority trials that involved two types of PRP treatments were also eligible for the study.
To avoid methodological confounding, studies in which the investigational group received other treatments were eligible provided that the control group also received the same treatment or care. Excluded studies were those that focused on burns, dental or jaw treatment, bone fractures, orthopedic injections, plastic surgery, or those that used homologous/allogenic PRP procedures, lysates, freezing or freeze-dried techniques to produce PRP "fibrin glue." Wound healing parameters (e.g., wound area reduction, healing rate, comparisons of clinically significant healing events) used as outcome measures, were reviewed unadjusted or adjusted for other covariates and factors using both baseline and final outcomes as well as repeated measures statistics.
Sources used to obtain studies included the Cochrane Library, Scopus, CINAHL, Pub Med database as well as the clinicaltrial.gov database, using specific search terms. Study quality was assessed using a method reported by Downs and Black (modified by Carter et al.) that evaluated quality of study data reporting, the generalizability of the study, the potential for bias and confounding, and the power of the study to discriminate the effect sizes of the outcomes.
Outcomes were categorized by type, and for each one the pre-treatment and post-treatment numbers, median, or mean values were extracted. Numbers needed to treat (NNT) were calculated and, in cases where protocol analyses were used, the data was updated to reflect an intent-to-treat (ITT) analysis. A fixed-effect model was used to calculate the 95% confidence interval and P values, but if inconsistencies arose, a random effects model was employed. The GRADE classification system was used to compare PRP treatments against standard care treatments. Statistical pooling was carried out on studies that had high homogeneity on: (1) complete wound healing; (2) superficial infection; and (3) reduction in pain, and RCTs were pooled separately from other comparative studies. Statistical heterogeneity was assessed using the I2 (inconsistency) statistic.
Based on the eligibility criteria, 21 studies (which consisted of 12 RCTs, three cohort studies, five comparative studies, and one retrospective analysis) as well as three systematic reviews were identified and used (qualitative synthesis). After further refinement of the studies, the authors found the following:
Meta-analyses were also performed based on research design, type of wound (e.g., chronic versus acute), and outcomes (e.g., complete healing, pain reduction, reduction in infection rate). The first meta-analysis found that the same four RCTs above met their criteria in evaluating chronic healed wounds (Anitua et al. 2007, Driver et al. 2006, Friese et al. 2007, Saldalamacchia et al. 2004). No evidence of significant heterogeneity was noted amongst the studies. Of the four studies, two failed to reveal any statistical difference between patients receiving PRP treatment compared to patients that received saline gel or no topical treatment. When assessing the four studies using a fixed-effect model, the results revealed findings that were significantly in favor of PRP therapy compared to control therapies of saline gauze, saline gel, or not topical treatment (Z = 2.54, P = 0.01). The authors indicate that this was due to the statistical weight of one study that was presented at a medical conference but was not published as a peer-reviewed article. A meta-analysis for RCTs in acute wounds with primary closure was not performed because only two studies were found.
Another meta-analysis, using a random-effects model was performed to evaluate reduction in infection in acute wounds. The researchers found two articles that met their criteria (Everts et al. 2006, Trowbridge et al. 2005). Results revealed that superficial infections in acute wounds with primary closure was favorable, but were not statistically significant when compared to no topical treatment (Z = 1.42, P = 0.16).
The final meta-analysis, again using the random effects model, was performed to evaluate acute wounds with primary closure for postoperative pain (Yoo et al. 2008, Buchwald et al. 2008, Englert et al. 2004). Study findings again revealed that the results were in favor of PRP therapy, but were not statistically significant when compared to saline spray or topical treatment (Z = 0.90, P = 0.37).
Martinez-Zapata MJ, Marti-Caarvajal A, Sola I, Bolivar I, et al. Efficacy and safety of the use of autologous plasma rich in platelets for tissue regeneration: a systematic review. Transfusion. 2009;49(1):44-56.
Using data sources such as MEDLINE, EMBASE, Cochrane registry of controlled trials, and the Science Citation Index, Martinez-Zapata and associates performed a systematic review to determine the safety and tissue regeneration ability of platelet-rich products. Peer-reviewed publications from 1945 to 2006 were reviewed. Inclusion criteria included RCTs that assessed the safety and/or efficacy of PRP for healing and regeneration of hard and soft tissues in any and all medical or surgical procedures. A random-effects model was used by the authors to calculate risk ratios for binary outcomes, and sensitivity analysis was performed if a high degree of heterogeneity was noted amongst the studies. Though 20 RCTs met the inclusion criteria of the study, only seven studies (six parallel designs and one crossover design) addressed the use of PRP in cutaneous ulcers, and only two studies (one parallel and one split design) addressed the use of PRP in surgical wounds.
In studies that evaluated PRP use in patients with cutaneous wounds, Jadad scores were used to assess quality: three studies were considered high quality, three studies were of moderate quality and one study was low quality. Four of the RCTs included patients with chronic ulcers of different etiologies, two studies addressed patients with chronic venous ulcers, and one study addressed patients with diabetic foot ulcers. Six of the seven studies used "complete ulcer epithelialization" as an outcome (the other study used a different definition for healing); combining these six studies resulted in a total of 122 patients in the intervention group and 105 patients in the control group (Knighton et al. 1990, Krupski et al. 1991, Stacey et al. 2000, Senet et al. 2003, Weed et al. 2004, Driver et al. 2006). Results of these combined studies revealed that complete ulcer epithelialization was not statistically significant between the intervention group and the control group (relative risk [RR], 1.40, range 0.85-2.31). Because of the high degree of heterogeneity found between studies (I2 = 56.8%), a sensitivity analysis was performed, and results were similar to the principle analysis which revealed no statistically significant difference between the two groups (RR, 1.23, range 0.90 - 1.41).
Similarly, the authors found two studies that evaluated the use of PRP in patients with surgical wounds (Powell et al. 2001, Englert et al. 2005). Both studies acknowledged only one treatment session with PRP therapy, and based on Jadad quality scores, both studies were considered of low quality. Outcomes for this group of studies included pain, swelling and redness. Results of the analysis revealed that though the experimental group had better relief in pain, redness and swelling compared to the control group, the degree of improvement was not statistically significant.
The authors concluded that in the treatment of skin ulcers PRP can increase the percentage of recovery but not statistically significantly, and for the treatment of surgical wounds, there was not a statistically significant difference in the outcomes (e.g., pain, redness, swelling, etc.) when compared to the control group.
Villela DL, Santos VL. Evidence on the use of platelet-rich plasma for diabetic ulcer: a systematic review. Growth Factors. Apr 2010;28(2):111-6.
Villela and Santos performed a systematic review to evaluate the use of PRP for the topical treatment of chronic diabetic leg ulcers. Using procedures adopted by the Cochrane Collaborative, articles were retrieved from the following sources: Cochrane, Lilacs, CINAHL, EMBASE, and the Pub Med databases, using July of 2008 as an ending date. Specific inclusion criteria (e.g., clinical trials, complete articles, articles from national and international journals) as well as exclusion criteria (e.g., abstracts, studies using platelet-poor-plasma in combination with PRP; studies using a recombinant or single growth factor) were used in the retrieval of articles. Specific search terms were also used. To evaluate the study quality and evidence, the authors used the scale to assess the grade of recommendation and level of evidence (SGRLE) and the scale to assess control of variables (SACV). The authors acknowledged that there was no scale to assess the intrinsic and extrinsic variables that interfere with chronic wound healing. The Jadad (Oxford) scale was used to assess study quality in cases where RCTs were evaluated. Meta-analysis was performed according to the classification of the results, and both fixed-effects as well as random-effects models were used, depending on the degree of heterogeneity between studies.
There were 18 studies found that met criteria; seven were RCTs and three were cross-sectional clinical studies. When looking at study quality based on the three scales, collectively they were moderate. Only four studies were methodologically similar (Driver et al. 2006, Knighton et al. 1990, Holloway et al. 1993, Steed et al. 1992). A meta-analysis of these four studies was performed. When graphing the four studies individually on a Forest plot, two studies (Holloway et al. 1993, Knighton et al. 1990) reported the best outcome for the treatment group (80% and 81% had healed wounds; CI 2.05-48.5 and 3.65-150 respectively), while the other two studies (Driver et al. 2006, Steed et al. 1992) failed to reveal a difference between the control and treatment group (CI 0.78-10.57 and 0.83-186 respectively). When the four studies were analyzed together, it revealed a trend towards the occurrence of healing and it remained higher in the PRP group compared to the control group (CI 2.94- 20.31). These findings were replicated in both the fixed effect as well as the random effects models. After reviewing results, the authors did acknowledge that it is practically impossible to establish a reference value of platelet concentration in PRP necessary to produce healing because each study reported different methods of preparation and concentrations of PRP.
In conclusion, the authors note that there was scientific evidence regarding favorable outcomes when using PRP in the treatment of diabetic ulcers, but this is tempered by the knowledge that all studies used different preparations of PRP.
Prospective Studies
A number of prospective studies were identified that evaluated the use of PRP in patients with chronic wounds. These include RCTs (Table 2), as well as other types of prospective studies (Table 3). A number of parameters are captured in the analysis. Most of these prospective studies were randomized, double blind, placebo controlled studies (N = 9), though some prospective trials were open-label trials without control groups. The number of participants in these studies ranged from 13 to 97.
Randomized Clinical Trials
There were nine RCTs identified that addressed the use of PRP in patients with chronic wounds. Of these, only the study performed by Knighton appeared in the meta-analyses performed by Villela and Martinez-Zapata. The primary outcome of interest in all of these studies, including the RCTs as well as the meta-analyses, was complete wound healing. Complete wound healing was defined as documentation of 100% epithelialization of the wound confirmed by inspection, photography, tracings or planimetry, which is a three dimensional measurement of the wound.
Driver VR, Hanft J, Fylling CP. Beriou JM. A Prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy Wound Manage. 2006;52(6):68-87.
The objective of this study was to evaluate the safety and incidence of complete wound healing as well as wound recidivism rates among healed wounds in the treatment of non-healing diabetic foot ulcers. To be eligible for the study, participants must have type I or type II diabetes, be between the ages of 18 and 95, and must have an ulcer that lasted for at least four weeks. A total of 72 patients met the inclusion criteria, including 40 participants in the intervention group (PRP gel) and 32 participants in the control group (saline gel). The mean age in intervention group was 56.4 years, while the mean age in the control group 57.5 years (reported as not statistically significant). The percentage of males in the intervention and control groups were 80%/81.4 respectively (reported as not statistically significant). Patients received treatment with either PRP gel or saline gel twice weekly. An Intent-to-Treat Analysis (ITT) was performed, and of the 72 participants, 13 of 40 patients (32.5%) in the PRP gel and nine of 32 patients (28.1%) in the control group had completely healed wounds after 12 weeks (P = 0.79).
Because the authors felt that the ITT analysis results did not reflect previous clinical outcomes, an independent audit was performed. This resulted in the elimination of 32 participants due to protocol violations and failure to complete treatment. The final analysis was based on 19 patients in intervention group and 21 patients in control group. Based on this new per-protocol analysis, 13 of 19 (68.4%) patients in PRP gel and nine of 21 (42.9%) patients in the control group had complete healing (P = 0.125). As part of a post-hoc analysis, results were reanalyzed based on wound size. After adjustment, more patients in the PRP group had complete healing (81.3%) compared to patients in the control group (42.1%), respectively (P = 0.036). When looking at the 40 patients in the per-protocol database subset one patient in the PRP gel group had a wound that reopened, while in the saline gel group there were no reopened wounds (not statistically significant). No treatment-related serious adverse events were noted during the study. The authors concluded that PRP gel is safe for the treatment of non-healing diabetic ulcers, and that in the most common size of diabetic ulcers (< 7.0 cm2 in area and < 2cm3 in volume), PRP gel-treated wounds also were significantly more likely to heal than control gel treated wounds.
Holloway GA, Steed DL. DeMarco MJ, Masumoto T, et al. A randomized, controlled, multicenter, dose response trial of activated platelet supernatant, topical CT-102 in chronic non-healing, diabetic wounds.
Wounds. 1993;5(4):198-206.
The purpose of this study was to evaluate the safety and efficacy of homologous platelet releasate. Patients eligible for study were diabetics with chronic, non-healing wounds that persisted for a minimum of eight weeks. The extent of wounds were graded from Grade 1 (partial thickness ulcer involving only the dermis and epidermis) to Grade 6 (full-thickness ulcer involving bone, ligament, joint and had gangrene in the surrounding tissue) based on wound characteristics. The study used a functional assessment tool that looked at the degree of epithelialization, drainage, and the need for dressing change. These parameters ranged from Level 1 (< 100% epithelialization with drainage/need to change dressing) to Level 4 (100% epithelialization with no drainage/no need to change dressing). In the study, 70 participants were randomized to either placebo group or to one of three dilution groups-0.01, 0.1, or 0.033, to be received once a day.
Baseline characteristics of patients and wounds failed to show any differences in mean age of patients between the three dilutions and placebo group. Mean ages ranged from 59 and 62 between the four groups. There was no significant difference between treatment groups concerning wound severity scores at baseline. Results of the study revealed that wound healing was higher in all groups of platelet-derived wound healing factor (PDWHF) dilution compared to the control group; 29% had complete healing in the control group, while in the PDWHF group, healing occurred in 80%, 62%, and 52% in the 0.01, 0.033 and 0.1 dilution groups respectively (P = 0.02). In terms of healing, no statistical difference was noted among the drug solutions. The median time for complete healing in the PDWHF group was 140 days, but the median time for complete healing in the control group could not be determined since less than half of the patients in this group healed by the end of the study. The authors concluded that PDWHF was more effective than placebo in healing diabetic wounds.
Knighton DR, Ciresi K, 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.
The purpose of this crossover study was to test whether or not PDWHF accelerates repair of chronic non-healing cutaneous ulcers. In this study, 32 patients with chronic, non-healing wounds of the lower extremities were randomized to eight weeks of therapy with either PDWHF or placebo (platelet-buffered solution). Total Wound Severity Scores (TWSS) were used to classify severity of wounds based on clinical as well as anatomic findings, along with measured wound and patient variables. Patients had to have a wound for at least eight weeks to be included in the study. Enrollees were placed on a twice-daily wound dressing protocol. After eight weeks, 17 out of 21 wounds (81% of patients) in PDWHF treatment group achieved epithelialization compared to two of 13 (15% of patients) in the control group (P < 0.0001). After crossover to treatment with PDWHF, all of the patients in the control group had epithelialization in an average of 7.1 weeks. The authors concluded that there is a significant increase in the rate of epithelialization of the wounds in patients treated with PDWHF.
Krupski WC, Reilly LM, Perez S, Moss KM, Crombleholme PA, Rapp JH. A prospective randomized trial of autologous platelet-derived wound healing factors for treatment of chronic non-healing wounds: A preliminary report. J Vasc Surg. 1991;14:526-36.
The purpose of this study was to assess the ability of platelet factors to facilitate healing of chronic wounds. Participants included 18 patients with 26 lower extremity wounds that were refractory to conventional therapy. Wound etiology included diabetes (78% of patients), peripheral vascular disease (72% of patients), as well as venous disease (28% of patients). The treatment group (n = 10, with 17 wounds) received topical PDWHF while the control group (n = 8, with 9 wounds) received conventional therapy for type of wound. Both groups received standard surgical and supportive care. To be eligible for the study, patients needed to have at least one chronic non-healing wound of eight weeks duration or longer. Wounds were graded on a scale from one (e.g., relatively superficial robust wound) to six (e.g., deeper more complicated wound) based on wound characteristics. Participants ranged in age from 57 to 75, and on average, wounds were present for 5.5 months prior to enrollment in the study.
There were no significant differences in demographics or laboratory values between the two treatment groups. The average duration of therapy was 10.1 +/- 2.7 weeks (median 12, mode 12). Participants were to receive PDWHF or placebo solution every 12 hours. Results of the study revealed that three of nine (33%) in the control group had complete healing, while four of 17 (24%) in the PDWHF had complete healing. No significant difference was observed in comparing either wounds healed or patients healed. The author concluded that PDWHF provides no additional benefit over traditional therapy.
Saad Setta H, Elshahat A, Elsherbiny K, Massoud K, Safe I. Platelet-rich plasma versus platelet-poor plasma in the management of chronic diabetic foot ulcers: a comparative study. Int Wound J. Jun 2011;8(3):307-12.
The aim of this study was to investigate the efficiency of platelet releasate on the healing of chronic wounds. Eligible patients included type I or type II diabetics between 40 and 60 years of age with a history of non-healing diabetic ulcers of at least 12 weeks duration. Twenty-four patients participated in the study and they were equally enrolled in the PRP (platelet-rich plasma) group and PPP (platelet-poor plasma) group. Participants received PRP or PPP treatments twice weekly. Results of the study revealed that the incidence of wound healing was the same in both groups (100%); though the mean healing time for the PRP group was 11.5 weeks, while healing time in the PPP group was 17 weeks (P < 0.005). No mention was made about recurrence of ulcers after healing. The authors concluded that PRP promotes and accelerates healing of chronic diabetic foot ulcers.
Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg. Sep 2000;20(3):296-301.
The purpose of this study was to determine if topical platelet lysate sped up the healing process in patients with chronic venous ulcers. A total of 86 patients were randomized to either the experimental group (n = 42) or the placebo group (n = 44) to receive either platelet lysate or placebo buffer solution twice a week. Patient characteristics as well as age and gender distribution were similar between both groups. Results of the study revealed that 34 of 44 subjects (77%) in the placebo group had complete healing, while 33 of 42 subjects (79%) in the intervention group had complete healing. The authors noted no difference between the two groups in terms of healing. The authors concluded that the use of topical platelet lysate had no significant influence on venous ulcer healing.
Steed DL. Clinical evaluation of recombinant human platelet-derived growth factor for the treatment of lower extremity ulcers. Plast Reconstr Surg. Jun 2006;117(7 Suppl):143S-149S.
In this analysis, Steed combined data from four previous RCT studies in an attempt to determine the safety and efficacy of topically applied gel, either rhPDGF-BB30µg/g or rhPDGF-BB100µg/g, compared to placebo gel or good ulcer care. All participants received the standardized protocol of good ulcer care. Enrollment included 922 men and women, ranging in age from 23 to 93 years (median age 59) with either type I or type II diabetes. In the four trials, the combined numbers of patients in each treatment group were as follows: rhPDGF-BB30µg/g, n = 193; rhPDGF-BB100µg/g, n = 285; placebo gel, n = 254; good ulcer care, n = 190. Baseline characteristics of patients were similar between all four groups within and across studies. Of the 922 patients treated, 874 (95%) had baseline ulcer areas that were less than or equal to 10 cm2. As per protocol, patients received treatments daily. Results of the study revealed that complete healing was higher in the rhPDGF-BB100µg/g group compared to placebo gel treatment (50% versus 36%, P = 0.007), and results were similar in patients with baseline ulcer areas that were less than or equal to 10 cm2 in all four studies.
The first of the four studies was a phase II trial that assessed the efficacy of rhPDGF-BB30µg/g. It revealed a healing rate of 48% for patients treated with rhPDGF-BB30µg/g compared to a healing rate of 25% for those treated with placebo gel. The second study was a phase III trial looking at efficacy of rhPDGF-BB at 30µg/g and 100µg/g dosages, and it revealed a healing rate of 50% for patients treated with rhPDGF-BB100µg/g, 36% for patients receiving rhPDGF-BB30µg/g and those receiving placebo gel. The third study compared placebo gel with that of good ulcer care alone and revealed the overall incidence of complete healing in all patients was 44% for patients receiving rhPDGF-BB100µg/g, compared to 36% for those receiving placebo gel and 22% for those receiving good ulcer care alone. The final study assessed resource utilization and found that the incidence of complete ulcer healing in the rhPDGF-BB100µg/g group was 36% and that for the good ulcer care group alone was 32%, but the authors did not report if the findings were statistically significant.
Steed DL, Goslen JB, Holloway GA, Malone JM, Bunt TJ, Webster MW. Randomized prospective double-blind trial in healing chronic diabetic foot ulcers. Diabetes Care. 1992;15(11):1598-1604.
The purpose of this study was to determine the effect of topically applied purified platelet releasate (also known as PDWHF) on the healing of chronic diabetic neurotrophic foot ulcers. In order to be eligible for the study, the diabetic patients needed to have a non-healing neurotrophic ulcer on the lower extremity for at least eight weeks despite standard therapy consisting of antibiotics and protective devices, resting the involved region and debridement of necrotic tissue. Length, wide, and depth of ulcers were measured, and photos were taken. Ulcer dressings were changed every 12 hours and either PDWHF or placebo solution was applied. The study consisted of 13 participants (nine males, four females), seven in PDWHF group ranging in age from 39-75 (mean age of 59), and six in the control group ranging in age from 41-74 (mean age of 54). Patients in the control group received standard therapy along with placebo (normal saline), while patients in intervention group received standard therapy along with PDWHF.
Analysis of demographic data revealed that baseline characteristics were similar between both groups except the treatment group had diabetes longer than the control group (26 years versus 10 years). Results of the study revealed that one of six (17%) ulcers healed by week 20 in the control group, while five of seven ulcers healed in the PDWHF group (71%) within 15 weeks. The authors concluded that PDWHF accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic wounds.
Weed B, Davis MDP, Felty CL, Liedl DA, et al. Autologous platelet lysate product versus placebo in patients with chronic leg ulcerations: a pilot study using a randomized, double-blind, placebo-controlled trial. Wounds. 2004;16(9):1-14.
The objective of this study was to assess the ability of autologous platelet lysate to facilitate healing of chronic cutaneous ulcers. In this study (N = 26), 15 patients received autologous platelet lysate product mixed with collagen (treatment group) while 11 patients received platelet-poor plasma (PPP) mixed with collagen (placebo group). Treatments were applied twice daily for 12 weeks. After the 12 weeks, there was a washout period of two weeks, and patients whose ulcers had not healed were then assigned to receive whichever treatment they had not received in the previous 12 weeks. Results of the study revealed that during the first 12 weeks, in the treatment group, nine of 15 (60%) patients healed, while four of 11 (36%) in the control group healed. There was not a statistically significant difference between the proportion of healed wounds in these two groups at 12 weeks (P = 0.68). After a two-week washout period, in the treatment group two (29%) of the patients healed, while two (33%) of the patients in the control group healed.
There was not a statistically significant difference between the proportion healed in these two groups at the end of the second 12 week period (P = 0.99). Throughout the study, 11 patients (42%) healed with platelet lysate, six (23%) healed with placebo treatment, and nine (35%) failed to heal. In the analysis using both time periods, there was not a statistical difference between treatment groups in the proportion of wounds healed (P = 0.31). The authors concluded that autologous platelet lysate product in addition to collagen did not accelerate the rate of wound healing or significantly decrease wound size compared to platelet-poor plasma with collagen.
Other Prospective Studies
A number of other prospective studies with a limited number of participants have been performed evaluating the use of PRP in chronic wounds (Table 3).
One was an open-label trial involving 13 patients with a total of 14 venous leg wounds and diabetic foot ulcers (Gurgen 2008). After one month of PRP treatment, only one wound was completely healed. Though there was a reduction in size, the remaining 13 wounds had not healed. Over the next ten months, an additional seven ulcers healed. By the end of the study, almost a year later 35% of the wounds had not healed. A second prospective study involved the use of autologous PDGF in 24 patients with a total of 33 chronic non-healing wound in the lower extremities (McAleer et al. 2006). Wounds had a variety of etiologies including venous stasis ulcers, decubitus ulcers, arterial insufficiency ulceration, ulcers due to diabetic traumatic events, and diabetic ulcers with neuropathic pathology.
By the end of the study ten months later, 20 wounds exhibited complete epithelialization, eight wounds showed reduction in size with no healing, and the remaining five wounds showed no improvement. One final prospective study evaluated the use of autologous platelet-rich fibrin matrix in 21 patients with non-healing lower extremity ulcers (O'Connell et al. 2008). In the study, 12 patients with 17 venous ulcers and nine patients with 13 non-venous ulcers were treated with platelet-rich fibrin matrix along with the appropriate standard wound care. By the conclusion of the study, a little more than half of patients with venous leg ulcers treated with autologous platelet-rich fibrin, and less than half of patients with non-venous ulcers treated with autologous platelet-rich fibrin had complete closure.
Retrospective Studies
A number of retrospective studies were also found. Some were comparative in nature and contained a control group while others studies had a limited number of participants. These were described in the proposed decision, and are summarized in Table 4 for the convenience of the reader.
During the proposed comment period, we received an additional retrospective study conducted by Sakata and associates (Sakata et al. 2012). The purpose of this retrospective, longitudinal study was to assess treatment outcomes in Japanese patients with complex and severe ulcerations who were treated in wound care centers (WCC) with standard wound care treatments and PRP gel. In the study, standard wound care treatments consisted of medical history and physical, wound and infection assessment, diagnostic test and noninvasive and invasive vascular studies. Based on the results of the assessment, the need for infection control intervention, revascularization, excision and debridement, growth factor (PRP) gel therapy, skin grafts/flaps, wound protection, and education was determined, and used if needed. Standard formulations of PRP gel was made from 20cc of the patient's own blood, and was applied as a thin primary wound contact layer once a week or twice-weekly, at the discretion of the clinician. Wound outcomes of 39 patients with 40 chronic, non-healing wounds of the lower extremity were evaluated between two time periods:
On average, patients were 66.8 (10.6 SD) years of life, and a mean wound duration of 99.7 (108 SD) days before treatment; most of the patients in the study had diabetes mellitus (85%). Wounds were classified as the following:
Patients with diabetic foot ulcers had either Wagner III or IV lesions. All participants had infections and they were treated according to treatment protocol. Results of the study revealed that the first treatment period (T1 to T2) lasted 75 days, none of the wounds healed, and the average wound area increased in size. Following topical PRP gel treatment, 83% of wounds healed within 145 days (T2 to T3) (P < 0.00002). Only one patient receiving PRP required a lower extremity amputation. The authors concluded that the use of a protocol of supportive care (including revascularization procedures) and the use of PRP gel treatments could result in good healing outcomes and a low amputation rate.
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 was found during a search of the National Guideline Clearinghouse database. 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.
In 2006, the Wound Healing Society 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.
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.
7. Expert Opinion
We did not receive any expert opinions during the comment periods.
8. Public Comments
CMS uses the initial public comments to inform its proposed decision. 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 is redacted and protected and are not made available to the public. CMS responds in detail to the second set of public comments on a proposed decision when issuing the final decision memorandum. On the tracking sheet for this NCD, CMS requested public comments on the evidence speaking to the health outcomes attributable to the use of PRP products in the treatment of chronic non-healing diabetic, pressure, and/or venous wounds. CMS also encouraged the submission of comments that would pertain to clinical studies falling under the Coverage with Evidence Development (CED) paradigm.
Initial Comment Period (11/09/2011 – 12/08/2011)
CMS received a total of 126 comments. Most comments were generally in favor of coverage, however a few comments strongly opposed coverage, and one expressed no clear indication for coverage.
CMS received a total of 15 comments that referred to evidence that was either already received from the requestor or considered later in the analysis. Two of these comments were non-supportive of coverage stating that there is insufficient clinical data demonstrating the safety and efficacy of PRP for treating chronic cutaneous ulcers.
CMS received a number of comments from physicians, surgeons and perfusionists. One perfusionist expressed opposition of national coverage and emphasized that too much money is spent on PRP with no substantial scientific evidence of its safety.
CMS received a number of comments from other individuals within the healthcare industry, such as nurses, podiatrists, physical therapists, professors, hospital administrators, professional societies, healthcare insurers, etc. CMS also received comments from representatives of manufacturing companies and other businesses and consulting firms. These commenters include lawyers, sales representatives, consultants and executives. One commenter suggested that CED is better than national non-coverage.
CMS received seven comments from various public organizations and patients. Many commenters stated that PRP treatment yielded positive results such as improved wound healing time, less pain after surgery, and in one instance avoided amputation.
Comment period on the proposed decision (05/09/2012- 06/08/2012)
CMS received a total of 37 timely comments.
There were nine comments in favor of the proposed decision for CED. Reasons given for support included the need for further general knowledge and evidence about PRP as a relatively novel device for use in the various types of chronic wounds, and more specifically, the need for additional studies to determine the appropriate preparation and use of PRP where applicable.
CMS appreciates the supportive comments.
A number of commenters recommended that CMS allow a registry to fulfill the CED requirement instead of restricting CED to randomized clinical trials, arguing that there are significant difficulties in the design of RCTs and that RCTs are by necessity smaller and less generalizable.
CMS recognizes that while RCTs may be more challenging to accomplish and may have limited generalizability, the use of less methodologically rigorous study designs or registries significantly limits the persuasiveness of their reported conclusions, particularly when assessing the clinical impact of a therapeutic intervention. We believe that a comprehensive investigational strategy can appropriately encompass practical study designs where RCTs and other methodologies are integrated to complement each other. Though registries in and of themselves are not appropriate research designs for the attribution of causality, and will not be considered to be appropriate to meet the CED requirement in this NCD, we acknowledge that a registry infrastructure may be useful to obtain information in the context of a larger investigation.
CMS believes that a research study that uses data collected by a registry can enhance its persuasiveness if it has the following attributes.
One commenter recommended that the CMS require entry into the U.S. Wound Registry, which is based on data from electronic health records (EHR).
CMS understands that the U.S. Wound registry is a high quality data collection designed for benchmarking among wound care centers. Despite this, CMS cannot support the use of a CED research study that uses registry data based on EHR alone for the following reasons.
However, this or other registries may be adapted to become data collection platforms for research as discussed in the previous response. The adaptations would have to include, at minimum: informed consent;
prospective design with contemporaneous controls; uniform data collection of the treatment and control groups; consistent and relevant data elements; control and monitoring of the treatment and control interventions; adequate follow up; standardization of wound measurement; inclusion of validated survey instruments; and a description of appropriate statistical methods (note: statistical modeling and propensity scoring or other risk stratification method may be needed even if randomization is performed).
One commenter recommended that CMS continue non-coverage of PRP and not finalize the proposed decision. One reason cited is the availability of other products for usage in chronic wounds. The commenter feels that the existing evidence regarding PRP does not support the use of CED. The commenter also said that, if CED is finalized CMS should establish additional trial design requirements to address a number of data validity issues in order to increase the chance that the results of any clinical trials performed under CED would provide CMS with valid clinical data.
CMS has reviewed the medical literature on autologous PRP in patients with chronic wounds and believes that CED is appropriate for PRP treatment. Although a number of studies have limitations as we have described in the analysis section, when reviewed as a body of evidence, it does indicate that PRP shows promise in the populations of interest to CMS.
As noted in the analysis section, there is marked variation in a number of parameters including wound duration, preparation of PRP, application of PRP as well as other parameters. In reviewing the CED research proposals, CMS will address whether or not they have adequate safeguards to make sure that data validity issues are addressed, including standardization of preparation, adequate documentation of concentration, quantity and quality of platelets as well as other bioactive substances, and clearly defined health outcomes. Any approved clinical study must adhere to the standards of scientific integrity and relevance to the Medicare population; specifically elements (f), "the research study is in compliance with all applicable Federal regulations concerning the protection of human subjects found at 45 CFR Part 46," and (g), "all aspects of the research study are conducted according to appropriate standards of scientific integrity."
One commenter disagreed with CMS' initial statements regarding the FDA clearance of only the equipment included in the AutoloGel™ System and not the PRP gel produced by the system. They asserted that, "by clearing the gel as the end product, FDA automatically cleared the equipment, processing kit, applicator, reagents, and standard formulation of the gel needed to produce the PRP gel as well as the application to the wounds."
CMS consulted with FDA regarding this comment and has confirmed that FDA has not issued a biological license or premarket approval for the PRP gel to be used as a biologically active wound healing agent; but has only issued a 510(k) clearance for the device to produce a PRP gel that is intended for use in conjunction with standard of care procedures as one component of a more comprehensive wound management plan.
The same commenter submitted for inclusion in this analysis a recently published article by Sakata, Sasaki, Handa, Uchino, Sasaki et al. entitled, A retrospective, longitudinal study to evaluate healing lower extremity wounds in patients with diabetes mellitus and ischemia using standard protocols of care and platelet-rich plasma get in a Japanese wound care program. (Sakata et al. 2012).
We have discussed this study elsewhere in this decision memorandum. Though the results reveal that 83% of wounds healed within 145 days following the application of PRP during the second time period, there are a number of limitations with the study. Retrospective study designs are generally not persuasive evidence when attributing causality to a therapeutic intervention.
The same commenter suggested the two articles by Stacey et al. (2000) and Weed et al. (2004) should not be included in this NCD because these authors used platelet lysate, which is a freeze-dried preparation of PRP, and freeze-dried PRP preparations were excluded from our analysis. The commenter also suggested the two articles by Holloway et al. (1993) and Steed et al. (1992) should not be included in the NCD because these authors used homologous preparations of PRP, and homologous PRP preparations were excluded from our analysis. The commenter suggested the article by Steed (2006) which describes the use of becaplermin, a form of recombinant human platelet derived growth factor, for the treatment of lower extremity ulcers should not be included in the NCD because recombinant human platelet derived growth factors were excluded from our analysis. The same commenter also writes that the article by Margolis et al. (1999) should not be included in the analysis because PRP was not one of the treatments explored or considered in this study.
We recognize the limitations of the persuasiveness of these articles as evidence for PRP. For the convenience of the reader we discussed the articles by Stacey et al., Weed et al., Holloway et al., Steed et al., and Steed because they all had been cited in the three systematic reviews/meta-analyses that were included in our analysis. However, since the meta-analysis performed by Margolis did not include an exploration of PRP, we have removed it from this final memorandum.
The same commenter mentioned that a 2008 study by Dougherty, entitled An evidence-based model comparing the cost-effectiveness of platelet-rich plasma gel to alternative therapies for patients with nonhealing diabetic foot ulcers, included a quality of life analysis; so it should be included in the analysis.
As noted in the article, the purpose of the study was to perform a cost-effectiveness analysis to compare the potential economic benefit of autologous platelet-rich plasma gel to alternative therapies in the treatment of nonhealing diabetic foot ulcers. Outcome measures of the study included cost as well as quality adjusted life years (QALY). While we agree that the results are relevant to a broader consideration of this topic, CMS generally has not relied on cost effectiveness analyses or QALY
information when making national coverage determinations.
The same commenter disagreed with our exclusion of the de Leon et al. (2010) and Frykberg (2012) articles because they studied predictors of complete healing. The commenter suggested that these, as well as the article by Carter et al. should be included because they demonstrated changes in the healing trajectory.
The articles by de Leon and Frykberg were excluded because these articles looked only at predictors of complete healing and evaluated increased healing trajectory specifically related to chronic wounds. The
article by Carter was also excluded because it looked at the impact of PRP on healing trajectory. These articles do not address the key outcomes important to CMS as stated in this NCD, which are complete wound healing, the patient's ability to return to previous function, and resumption of normal activity. The research questions posed as part of CED will however, take into consideration the outcomes which look at healing trajectory and reduction in wound size and how they relate to a patient's ability to return to previous function, and resumption of normal activity.
All comments that were submitted via CMS coverage website may be viewed by using the following link:
National Coverage Determinations (NCDs) are determinations by the Secretary with respect to whether or not a particular item of service is covered nationally by Medicare (§1869 (f)(1)(B) of the Act).
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, §1862(a)(1) of the Act in part states that, with limited exceptions, no payment may be made under Part A or part B for any expenses incurred for items or services:
Section 1142 of the Act describes the authority of the AHRQ. Under section 1142, research may be conducted and supported on the outcomes, effectiveness, and appropriateness of health care services and procedures to identify the manner in which diseases, disorders, and other health conditions can be prevented, diagnosed, treated, and managed clinically.
Section 1862(a)(1)(E) allows Medicare to cover under CED certain items or services where additional data gathered in the context of clinical care would further clarify the impact of these items and services on the health of Medicare beneficiaries. For your convenience, the 2006 CED guidance document is available at www.cms.gov/Medicare/Coverage/DeterminationProcess/downloads/ced.pdf.
A. §1862(a)(1)(A) Analysis
Is the evidence adequate to conclude that Medicare beneficiaries who have chronic non-healing diabetic, pressure, and/or venous wounds that receive PRP therapy experience clinically significant health outcomes as indicated by at least one of the following:
In analyzing the medical literature, CMS focused on evidence that PRP provides patient-centered health benefits (e.g. complete healing, less recurrent wounds, improved quality of life) in patients with chronic diabetic, pressure, and/or venous wounds.
Increased healing trajectory is often mentioned in the medical literature as a surrogate for complete wound healing, especially in acute wounds (Carter et al. 2011). It also has been noted that the use of a dynamic healing trajectory or healing time curve may allow the prediction of healing of an individual wound (Robson, Hill, Woodshe, and Steed 2000). But because the healing process differs between acute and chronic wounds, the use of healing trajectory may not be appropriate for chronic wounds. Studies that emphasize percentage of surface wound healings are also often touted as predictable or reliable indicators for healing. However, acute wounds that often start healing well can stop in mid-course and become chronic non-healing wounds. Though healing trajectory and percentage of surface wound reduction might be useful efficacy endpoints, as noted in the questions and outcomes section, CMS underscores the importance of complete wound healing or the ability to return to previous function and resumption of normal activities when considering patient-centered health outcomes.
Systematic Reviews/Meta-Analysis
Using RCTs and comparative group studies, Carter et al. performed a systematic review and meta-analysis on the use of platelet-rich plasma gel in wound healing. Based on their analysis, they felt that the studies confirmed that PRP was effective in healing wounds. A number of concerns were identified.
Using RCTs, Martinez-Zapata et al. performed a systematic review to determine tissue regeneration among patients with chronic skin ulcers. Results of the study revealed that there was no statistical difference between patients receiving PRP compared to patients in the control group. However, as noted by the author there was a number of limitations of the study.
Villela and Santos also performed a systematic review to evaluate the use of PRP for the topical treatment of chronic diabetic leg ulcers (Villela & Santos 2010). They concluded that there was sufficient evidence to conclude that the use of PRP for the treatment of diabetic ulcers was better than comparison treatment. The authors acknowledged a number of limitations of the study.
In summary, in addition to the limitations listed for each systematic review/meta-analysis, all three studies used different tools to measure study quality. Carter et al. used the Downs and Black reporting method, Martinez-Zapata et al. used the Jadad (Oxford) quality tool, and Villela et al. used the SGRLE scale, the SACV scale, as well as the Jadad (Oxford) scale when needed. Though all three meta-analyses used quality tools to assess studies, each meta-analysis used a different tool so there was very little agreement in terms of studies which were defined as high quality, moderate quality or low quality studies. All meta-analyses used a fixed effect model; and if a high degree of heterogeneity was found among the studies, a random-effects model was performed. But each study used a different cut-off point to identify heterogeneity. Though the studies considered wound healing, they did not address other relevant patient outcomes such as resumption of normal activities and improved quality of life.
Driver VR, Hanft J, Fylling CP. Beriou JM. A prospective, randomized, controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic foot ulcers. Ostomy/Wound Manage. 2006;52(6):68–87.
This study evaluated the use of PRP in patients with diabetic foot ulcers. Using an intent to treat analysis based on the 72 patients originally enrolled in the study, the researchers found no difference between the PRP group and the control group (P = 0.79). A later audit and analysis was performed because the findings of the original study did not reflect previous clinical outcomes. This resulted in the exclusion of 32 participants. A new analysis of the data was performed, after adjusting for wound size. It showed that patients treated with PRP had a higher complete healing rate compared to patients in the control group. Some issues and concerns were noted.
Holloway GA, Steed DL, DeMarco MJ, Masumoto T, et al. A randomized, controlled, multicenter, dose response trial of activated platelet supernatant, topical CT-102 in chronic non-healing, diabetic wounds.
Wounds. 1993;5(4):198-206.
The authors of this study concluded that PDWHF was more effective than placebo in healing wounds. But the primary concern of this study was the variation in comparators within the same study. At the beginning of the study, 14 patients were given either 0.01 dilution of CD-102 or a placebo consisting of physiologic normal saline. Later, the study was revised to include two additional dilutions of CT-102 at 0.1 and 0.03, and the placebo solution changed to an isotonic platelet buffer. It is unclear whether the final results were consistent among the study groups due to these changes during the study.
This study demonstrated that patients who received the platelet-derived wound healing formula that was derived from autologous platelets have a higher healing rate compared to patients who received placebo. The main concerns of this study are noted below.
The study performed by Krupski et al. showed that there was no difference in the healing rate of chronic wounds between experimental group and control group. The authors noted potential flaws in the study.
This RCT was able to demonstrate that patients who received PRP preparations had a higher healing rate than patients that received PPP preparations. The main concerns of this study are noted below.
Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomised double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg. Sep 2000; 20(3):296-301.
This study assessed the effect of topical platelet lysate on chronic venous ulcers, and showed that PRP had no influence on the healing. However, one potential confounding factor in the design of this study was the lack of data on deep vein reflux and post-thrombotic changes. If there was an uneven distribution of deep vein abnormalities between the two groups, this could theoretically influence the outcome of the study.
In this study, Steed combined data from four previous RCT studies and found that both rhPDGF-BB30µg/g and rhPDGF-BB100µg/g were more effective in healing wounds compared with placebo gel or good ulcer care alone. Concerns of this study include the following points.
The authors concluded that PRP significantly accelerated wound closure in diabetic leg ulcers when administered as part of a comprehensive program for the healing of chronic ulcers. But as noted by other authors, this study leaves a couple of concerns.
Though the results of this study revealed that topical autologous platelets had no significant effect on the healing of chronic wounds, there were some areas of concern.
Overarching Concerns
When looking at these RCTs, there were significant variations noted among these study designs, which make it difficult to reach a harmonious and generalizable conclusion for our beneficiary population. The following parameters were reviewed.
Duration of wound
To be consistent, all studies should have the same operational definition when defining wound duration in order to participate in the study. All studies except one (Driver et al. 2006) required patients to have a wound for a minimum of eight weeks in order to participate in the study. Driver required the wounds to last a minimum of four weeks while all the other studies required a minimum of eight weeks. Even though all the patients met the general definition of a chronic wound, Driver's results may have been more favorable because on average the wounds had a shorter duration. If the studies were consistent with an operational definition of wound duration, then we would be able to see a true relationship between PRP and wound healing.
Of the nine RCTs reviewed, two studies evaluated the use of homologous PRP (Steed et al. 1992, Holloway et al. 1993) while the other studies evaluated the use of autologous PRP. CMS believes that it is important to include reviews of articles using homologous PRP preparations because one of the meta-analysis used in this assessment included a study in which the intervention group received homologous PRP (Villela et al. 2010). In this study, the homologous preparation of PRP was found to be more effective in healing diabetic foot ulcers than the comparator group (Holloway et al. 1993). There were no head-to-head comparisons between homologous and autologous preparations, and studies that did use the homologous preparations did not have any complications due to the pooling of serum needed to make this type of preparation.
In addition, studies documented different amounts of venous blood used to make the PRP preparation. One study required as little as 10cc of venous blood (Saad Setta 2011) while other studies required as much as 240cc of venous blood (Weed et al. 2004). Variance in the amount of venous blood used to make PRP could result in differences in concentrations that could ultimately affect results. And as noted before, some studies performed an analysis to make sure that the collected specimen had an adequate amount of mitogenic activity (Steed et al. 1992, Stacey et al. 2000, Krupski et al. 1991, Knighton et al. 1990), while other studies made no mention of confirming mitogenic activities (Saad Setta et al. 2011, Driver et al. 2006, Holloway et al. 1993, Weed et al. 2004, Steed 2006). The lack of samples containing an adequate amount of mitogenic activity could account for the failure of PRP preparations and the failure of wound closure.
The application of PRP varied between studies. In some studies, PRP and placebo were applied as often as every 12 hours (Krupski et al. 1991, Steed et al. 1992, Weed et al. 2004, Knighton et al. 1990), once a day (Holloway et al. 1993, Steed 2006) or twice weekly (Stacey 2000, Saad Setta et al. 2011, Driver et al. 2006). Also in studies that used a platelet gel preparation, there were different ways of applying it. Man et al. (2001) used a dual syringe method; one syringe to deliver PRP gel and the other syringe to deliver bovine thrombin and calcium chloride. Driver et al. poured platelet gel directly into the wound and then covered it with a dressing. Different schedules of PRP application could make comparisons between studies difficult.
There were a myriad of comparators used in the different studies. In the control group, some studies used physiologic (normal/buffered) saline solution (Krupski et al. 1991, Steed et al. 1992, Holloway et al. 1993, Stacey et al. 2000); and some studies used a saline gel dressing (Driver 2006) or a placebo gel (Steed 2006). In addition, some comparator groups received platelet buffered solution (Knighton et al. 1990) while others received PPP (Saad Setta et al. 2011) or PPP plus collagen (Weed et al. 2004). It is difficult to determine if PRP therapy improved wound healing if different comparators are used.
Type of Wound
A number of RCTs addressed patients with only neurotrophic diabetic ulcers (Steed et al. 1992, Holloway et al. 1993, Driver et al. 2006, Saad Setta et al. 2011, Steed 2006), and one study addressed patients with only venous ulcers (Stacey et al. 2000). But in the remaining studies, patients in both the experimental and control group suffered with diabetes, peripheral vascular disease, and venous stasis (Knighton et al. 1990, Krupski et al. 1991, Weed et al. 2004). If there was a disproportionate small amount of one type of wound compared to other types of wounds in the studies that evaluated multiple wounds of different etiologies, stratification of the wound by type should have been performed. If stratification by wound type did not occur, it might lead to a wrong conclusion. Few studies addressed the use of PRP in patients with pressure ulcers.
After reviewing the results on these nine RCTs, some studies showed that PRP increased complete wound healing rates (Knighton et al. 1990, Steed et al.1992, Holloway et al. 1993, Driver et al. 2006, Saad Setta et al. 2011, Steed 2006) while other RCTs studies revealed that PRP did not increase healing rate in the treatment of chronic wounds (Krupski et al. 1991, Stacey et al. 2000, Weed et al. 2004).
When looking at all of these RCTs collectively, there is little standardization in the parameters being studied. In addition to variation in study design and components, little information was provided on recurrence of ulcers after wound healing, return to previous function, resumption of normal activities as well as improved quality of life. Overall, we conclude that this is a conflicted body of evidence.
Gurgen M. Treatment of chronic wounds with platelet-rich plasma. EWMA Journal. 2008;8(2):5-10.
This open-label prospective study evaluated the use of PRP in patients with recalcitrant wounds. A number of issues were identified.
McAleer JP, Kaplan E, Persich GJ. Efficacy of autologous platelet-derived growth factors in chronic lower extremity wounds. J Am Podiatr Med Assoc. Nov-Dec 2006;96(6):482-8.
This prospective cohort study evaluated the efficacy of concentrated autologous PDGF s in chronic lower-extremity wounds. There was a lack of randomization and controls.
O'Connell SM, Impeduglia T, Hessler K, Wang XJ, Carroll RJ, Dardik H. Autologous platelet-rich fibrin matrix as cell therapy in the healing of chronic wounds. Wound Rep Reg. Nov-Dec 2008;16(6):749-56.
This prospective pilot trial demonstrated that patients with venous as well as non-venous wounds healed with the use of autologous platelet-rich fibrin matrix as cell therapy. Concerns of this study include the following points.
Overall, the biggest flaws of this group of studies are the lack of randomization and control groups, as well as small sample sizes. Like systematic reviews/meta-analysis, little information was provided on recurrence of ulcer after wound healing, resumption of normal activities as well as improved quality of life.
Retrospective studies are inherently inadequate methodologically to reach persuasive conclusions about the causal impact of these therapeutic interventions. Beyond that, we summarize some other limitations of these studies.
Glover JL, Weingarter MS, Buchbinder DS, Poucher RL, Deitrick GA, Fylling CP. A 4-year outcome-based retrospective study of wound healing and limb salvage in patients with chronic wounds. Adv Wound Care. Jan-Feb 1997;10(1):33-8.
This retrospective study revealed that comprehensive wound care in combination with platelet releasate had higher healing rates and lower amputation rates compared a comprehensive wound care alone. Concerns of this study include the following points.
Keyser JE. Diabetic wound healing and limb salvage in an outpatient wound care program. South Med J. Mar 1993;86(3):311-7.
This retrospective study showed that diabetic patients who participated in a comprehensive program including a topical growth factor solution of PDWHF had a higher healing rate and were less likely to have amputations compared to diabetic patients who participated in a comprehensive group alone. Concerns of this study include the following points.
Margolis DJ, Kantor J, Santanna J, Strom BL, Berlin J. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care. 2001; 24(3):483-488.
In this study, the authors concluded that by using propensity scores, they were able to demonstrate that PRP was more effective than standard therapy in the treatment of diabetic neuropathic foot ulcers. There are a number of issues noted in this research.
Mazzucco L, Medici D, Serra M, Panizza R, et al. The use of autologous platelet gel to treat difficult-to-heal wounds: a pilot study. Transfusion. July 2004;44(7):1013-18.
In this pilot study, the authors concluded that patients with chronic non-healing wounds showed substantial improvement in autologous platelet gel compared to patients treated with conventional therapy. Concerns of this study include the following points.
Sakata J, Sasaki S, Handa K, Uchino T, et al. A retrospective, longitudinal study to evaluate healing lower extremity wounds in patients with diabetes mellitus and ischemia using standard protocols
of care and platelet-rich plasma gel in a Japanese wound care program. Ostomy Wound Management. 2012; 58(4):36-49.
Sakata and associates performed a retrospective, longitudinal study to assess treatment outcomes in Japanese patients with complex ulcerations who were treated with standard wound care treatments and PRP gel. The results of the study revealed that, following application of PRP during the second time period, 83% of wounds healed within 145 days, and only one patient required a lower extremity amputation. There were a number of issues associated with this study.
Steenvoorde P, van Doorn LP, Naves C, Oskam J. Use of autologous platelet-rich fibrin on hard-to-heal wounds. J Wound Care. Feb 2008; 17(2):60-3.
This study demonstrated that the use of autologous platelet-rich fibrin improved healing rates in patients with chronic wounds. However, this study leaves a couple of issues.
In summary, we conclude that PRP for Medicare beneficiaries with chronic non-diabetic, pressure, and/or venous wounds is not reasonable and necessary under §1862(a)(1)(A). The available evidence does not allow us to conclude that PRP improves health outcomes in Medicare beneficiaries who have chronic wounds as described in our analytic question above. We also emphasize that the very nature of a retrospective study design makes it prone to confounding and bias. Some of these studies used propensity scores as a method to attempt to provide an unbiased estimation of the treatment effect. However, as noted above, the use of propensity scores presents its own methodological issues. And like the systematic reviews/meta-analysis and RCTs and other prospective studies included in this analysis, little information was provided on recurrence of ulcer after wound healing, return to previous function, resumption of normal activities and improved quality of life.
The systematic reviews/meta-analysis had moderate to severe quality limitations. The RCTs had a marked degree of variation between studies, including type of PRP preparation, production of PRP, documentation of mitogenic activity, lack of standardization of PRP concentration, as well as lack of standardization of the application of PRP. There also was variation in the definition of chronic wounds, as well as choice of comparators. The degree of heterogeneity among the studies questions the validity of the findings, especially those of the systematic reviews and the meta-analyses since they combine multiple RCTs. Findings in other prospective studies were limited due to the lack of randomization and controls. Retrospective studies suffered from selection bias and confounding. The use of propensity scores could potentially negate the findings. Lacci et al. reviewed the literature on PRP treatment of chronic wounds and found that few studies that evaluated the use of PRP on chronic wounds were performed with scientific rigor, although the safety of PRP appears to be validated (Lacci et al. 2010). The retrospective study performed by Sakata that was submitted to us during the second comment period also does not provide definitive evidence that PRP is effective in the treatment of chronic wounds. Notable issues such as the lack of control groups, small number of participants, as well as marked variability between time periods, makes this study limited in providing evidentiary weight.
When looking at the literature, most of the studies did not address recurrence of wounds. And though improved quality of life as well as ability to return to previous function and resumption of normal activity were often mentioned in the medical literature as an objective that can be achieved by treating chronic wounds, the evidence does not confirm this. One study does discuss improved quality of life as an outcome of PRP therapy (Mazzucco et al. 2004). In the study the authors allude to this by mentioning that "almost all patients treated with platelet gel reported significant pain relief, thus bettering their quality of life." However, no measurement tools were used to assess quality of life, nor was there any attempt to include these parameters in the design of the studies. Other RCTs as well as studies with other designs have made similar statements, but have not provided any evidence that successful treatment of chronic wounds results in improved quality of life, return to previous function or resumption of normal activities (Saad Setta et al. 2011, Villela et al. 2010, Trowbridge et al. 2005). A study performed by Spyridakis et al. did show that patients with pilonidal sinus disease who undergo open excision (resulting in an acute wound) and secondary closure using PRP do have a higher quality of life as well as resumption of normal activities. However, this NCD concerns PRP treatment of chronic wounds not acute wounds. Also in reference to acute wounds, the charge of this NCD was the evaluation of chronic wounds, so a surveillance of studies on acute wounds was not performed, though a number of studies seemed to indicate that PRP has a positive impact on acute wounds. So, this poses a question of whether this therapy may also be beneficial in chronic wounds.
As mentioned earlier in the analysis section of this NCD, a number of researchers have equated wound size reduction and wound healing trajectory as indirect efficacy measures. A review of the number of studies that looked at these measures failed to show any association with clinically significant health outcomes. CMS is interested in demonstrating that reduction in wound size or healing trajectory does result in some type of patient centered clinically significant health outcomes such as the patient's ability to return to previous function or resumption of normal activity.
Generally, the FDA clears many wound care products, specifically wound dressing devices, under the 510(k) clearance pathway. As mentioned earlier in this NCD under the FDA Status section, the AutoloGel™ System has the FDA's 510(k) clearance as a wound dressing device that is intended for the safe and rapid preparation of PRP gel at the point-of-care. While the FDA has stated the PRP gel produced from the AutoloGel™ System is suitable for the management of exuding wounds, the FDA did not make a determination regarding effectiveness of the actual gel in regards to the active promotion of wound healing. As stated in the posted 510(k) summary, the PRP gel produced by theAutoloGel™ System may assist the body's own natural healing process by keeping the wound site moist. This is a passive effect of a moist wound dressing and should not be confused with active wound healing associated with biological factors such as cytokines and growth factors.
CMS is aware that various stakeholders claim certain benefits related to their product, however the clinical claims related to active promotion of wound healing were not reviewed by the FDA as a condition of this clearance, thus CMS did not find them to be credible. The FDA's clearance for wound care products actually has a narrow indication as part of wound management. Thus, the broader claims of wound healing and other clinical utility measures are not supported by the FDA clearance, and in fact represent gaps in the current evidence. The current FDA cleared indication for AutoloGel™ did not answer the relevant question as to if this wound care product does indeed help in the promotion of healing. Understanding that it is nearly impossible to generalize clinical trial data for one type of wound to other types of wounds, the FDA has issued guidance to the general wound-care industry noting that separate safety and efficacy data should be submitted for each wound type for which a product's indication is sought. (FDA 2000)
Health Disparities
A review of articles discussed above in this decision memorandum reveals no analysis of PRP clinical outcome by racial or ethnic categories. Any inference about relative benefits of PRP for management of chronic wounds in patients with diabetic, pressure, and/or venous ulcers in specific racial or ethnic groups would be, at best, speculative. CMS also notes the absence of evidence about benefits or harms related to other population classifiers that have been associated historically with healthcare access or outcome disparities, such as gender, sexual orientation, religion, and age, and encourages additional studies in which such associations might be studied.
This lack of evidence about racial and ethnic factors and the response to PRP treatment represents in our view an evidence gap that we encourage trial designers to consider when proposing clinical trial designs for PRP under this NCD. While recognizing that this consideration may complicate the design of appropriate clinical studies, we will nevertheless prefer clinical study proposals in which data on racial and ethnic factors are specifically collected and analyzed.
B. §1862(a)(1)(E) Analysis
When looking at the different types of studies reviewed in this analysis, there are issues that must be addressed. CMS recognizes that the absence of conclusive evidence of benefit does not equate to conclusive evidence of no benefit. CMS also appreciates the significant burden of chronic non-healing wounds on the beneficiary population, which may lead to frustration on the part of patients, their treating practitioners and their caregivers.
We believe that it is appropriate to use CED to support the generation of more informative evidence. As explained in the 2006 CED guidance document cited above, CED facilitates development of additional evidence from approved clinical studies in order to clarify the impact of an item or service on the health outcomes of Medicare beneficiaries. CED enables this additional development of evidence within a research setting where there are added safety, patient protections, monitoring and clinical expertise.
As a foundation for CED, CMS has emphasized three factors relevant to the appropriateness of a CED coverage determination. The first is that the basic safety of the proposed item or service must be assured. In the case of PRP for the treatment of chronic non-healing diabetic, pressure, and/or venous wounds, the medical literature has failed to show that adverse event rates are higher or more severe in the PRP treated group compared to the control group.
Second, CMS believes that PRP has the potential to benefit Medicare beneficiaries. As noted above, PRP has been used in attempts to treat chronic non-healing diabetic, pressure, and/or venous wounds. If PRP can be shown that it provides a meaningful clinical benefit for the treatment of chronic wounds, it could potentially lead to improved patient function, and decreased patient dependence on other aspects of the health care system. While we have stated that the evidence as yet is insufficient to confidently support these claims, we agree with the importance of further study and want to encourage research on these topics through the use of CED.
The third factor is the difficulty of conducting adequate trials. CMS acknowledges the difficulties that have plagued the development of a better body of evidence on wound care, and believes that an opportunity should be afforded to address the limitations of previous studies. As noted before, a number of RCTs, prospective cohort studies as well as retrospective reviews have been performed. Each of these has a number of flaws that challenge the validity of their reported conclusions. A number of systematic reviews/meta-analyses have been performed, but since these studies were based on the same RCTs, they would also be subject to the same criticism as RCTs. By identifying issues and concerns of the studies, CMS can support initiatives to address these shortcomings.
CMS will expand coverage for PRP for this indication only when PRP is provided under a clinical research study that meets the requirements specified below to assess the effect of PRP for the treatment of chronic non-healing diabetic, pressure, and/or venous wounds. The research study must address the following questions:
Duration of CED coverage for PRP
CMS requires that any applications for coverage of PRP for chronic non-healing diabetic, pressure, and/or venous wounds in CED studies must be received and approved by August 2, 2014. If there are no approved clinical studies on this date, this NCD will expire.
CMS considers the results of all CED clinical studies critical in the evolution of medical technology and in the evaluation of the benefit of items and services covered under CED. Because of this, CMS does not consider an NCD that requires CED as a condition of payment to be a permanent policy. In the past, CMS has not put time limitations on NCDs that require enrollment in clinical studies for coverage. This has led to a number of circumstances that could have been avoided by establishing time limits, including having a standing NCD without any CED clinical studies being conducted and allowing payment for services provided in studies that have never produced evidence. In order to avoid these circumstances for this CED NCD, CMS proposes setting the specific time limits described below.
This CED decision will require that all clinical studies under which there is CED coverage for PRP for chronic non-healing diabetic, pressure, and/or venous wounds must be approved within two years of the date on which this final NCD is issued. If there are no approved clinical studies on that date, this NCD will expire. We base this time period on CMS' experience with earlier CED decisions in which approval processes for CED clinical trials have been completed within two years after the NCD date. Any clinical study approved within two years of the date on which this final NCD is issued will adhere to the timeframe designated in the approved clinical study protocol.
For each approved study of PRP for chronic non-healing diabetic, pressure, and/or venous wounds, we will allow enough time, based on the study protocol, for the expected number of patients to be enrolled and for the treatment to be administered to the last patient in the study. After that, coverage for PRP for chronic non-healing diabetic, pressure, and/or venous for the particular clinical study will no longer be available. The time period will be based on the following factors:
This NCD will then expire with the expiration of the latest allowed time frame for a clinical study approved for CED under this NCD.
Studies performed in the United States should also 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. We find it 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.
The Centers for Medicare & Medicare Services (CMS) believes, based on its review, that the available evidence does not permit us to conclude that use of autologous PRP improves health outcomes in beneficiaries with chronic diabetic, pressure, and/or venous wounds. We therefore have determined that PRP used to treat chronic non-healing diabetic, pressure, and/or venous wounds be covered under Coverage with Evidence Development (CED) under §1862(a)(1)(E) of the Act.
CMS recognizes that chronic non-healing diabetic, pressure, and/or venous wounds are an important cause of disability and burden for beneficiaries and society. More rigorous study of PRP therapy may yet produce evidence of improved health benefit for patients with chronic non-healing diabetic, pressure, and/or venous wounds.
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 falling within a benefit category is reasonable and necessary for the diagnosis or treatment of an illness or injury or to improve the functioning of a malformed body member. 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.
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 the extent to which 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:
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-RCTs 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 which have alternative names) ranked from most to least methodologically rigorous in their potential ability to minimize systematic bias.
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 which 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 which 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. We are interested in the results of changed patient management not just altered management. 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. For most determinations, CMS evaluates whether reported benefits translate into improved health outcomes. 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.
Table 2: Randomized Clinical Trials
2. Holloway, Steed, DeMarco, Masumoto, et al. 1993.
3. Knighton, Ciresi, Fiegl, Schumerth, Butler, Cerra 1990.
4. Krupski, Reilly, Perez, Moss, Crombleholme, Rapp 1991.
5. Saad Setta, Elshahat, Elsherbiny, Massoud, Safe 2011.
6. Stacey, Mata, Trengove, Mather 2000.
7. Steed. 2006.
8. Steed, Goslen, Holloway, Malone, Bunt, Webster 1992.
9. Weed, Davis, Felty, Liedl, et al. 2004.
Table 3: Other Prospective Studies
1. Gurgen, 2008.
2. McAleer, Kaplan, Persich, 2006.
3. O'Connell, Impeduglia, Hessler, Wang, Carroll, Dardik 2008.
4. Scevola, Nicoletti, Brenta, Isernia, Maestri, Faga 2010.
Table 4: Retrospective Studies
1. Margolis, Kantor, Santanna, Strom, Berlin, 2001
2. Glover, Weingarten, Buchbinder, Poucher, Deitrick, Fylling
3. Keyser. 1993.
4. Mazzucco, Medici, Serra, Panizza, Rivara, Orecchia, et al. 2004.
5. Steenvoorde, van Door, Naves, Oskar, 2008.
6. Sakata J, Sasaki S, Handa K, Uchino T, Sasaki T, Higashita R, et al. 2012.
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