Archived Policies - Prescription Drugs


Recombinant and Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions

Number:RX501.034

Effective Date:11-01-2018

End Date:04-14-2019

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Recombinant platelet-derived growth factor (i.e., becaplermin) may be considered medically necessary when used as an adjunct to standard wound management for the following indications:

Neuropathic diabetic ulcers extending into the subcutaneous tissue (when used according to the U.S. Food and Drug Administration labeled indication), AND when meeting ALL of the following criteria:

o Adequate tissue oxygenation, as measured by a transcutaneous partial pressure of oxygen of 30 mm Hg or greater on the foot dorsum or at the margin of the ulcer;

o Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues; and

o Participation in a wound management program, which includes sharp debridement, pressure relief (i.e., non-weight bearing), and infection control.

Pressure ulcers extending into the subcutaneous tissue when meeting ALL the following criteria:

o Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues;

o Ulcer in an anatomic location that can be offloaded for the duration of treatment;

o Albumin concentration >2.5dL;

o Total lymphocyte count >1,000/μL; and

o Normal values of vitamins A and C.

NOTE 1: Becaplermin gel should be applied once daily to the ulcer until complete healing has occurred. If the ulcer does not decrease in size by approximately 30% after 10 weeks of treatment or complete healing has not occurred in 20 weeks, continued treatment with becaplermin gel should be reassessed.

NOTE 2: An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of becaplermin gel, therefore it should only be used when the benefits can be expected to outweigh the risks.

Other applications of recombinant platelet-derived growth factor (i.e., becaplermin) are considered experimental, investigational and/or unproven including, but not limited to, ischemic ulcers, venous stasis ulcers, and ulcers not extending through the dermis into the subcutaneous tissue.

Use of platelet-rich plasma (i.e., autologous blood-derived preparations) is considered experimental, investigational and/or unproven for the treatment of acute or chronic wounds, including surgical wounds and nonhealing ulcers.

Description:

The use of blood-derived growth factors, including recombinant platelet-derived growth factors (PDGFs) and platelet-rich plasma (PRP), has been suggested as a treatment for wounds or other miscellaneous non-orthopedic conditions, including but not limited to, diabetic ulcers, venous stasis ulcers, and surgical and traumatic wounds.

Wound Healing Treatment

A variety of growth factors have been found to play a role in wound healing, including PDGF, epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Autologous platelets are a rich source of PDGF, transforming growth factors (that function as a mitogen for fibroblasts, smooth muscle cells, and osteoblasts), and vascular endothelial growth factors. Recombinant PDGF has also been extensively investigated for clinical use in wound healing.

Autologous platelet concentrate suspended in plasma, also known as PRP, can be prepared from samples of centrifuged autologous blood. Exposure to a solution of thrombin and calcium chloride degranulates platelets, releasing various growth factors and results in the polymerization of fibrin from fibrinogen, creating a platelet gel. The platelet gel can then be applied to wounds or may be used as an adjunct to surgery to promote hemostasis and accelerate healing. In the operating room setting, PRP has been investigated as an adjunct to a variety of periodontal, reconstructive, and orthopedic procedures. For example, bone morphogenetic proteins are a type of transforming growth factors, and thus PRP has been used in conjunction with bone-replacement grafting (using either autologous grafts or bovine-derived xenograft) in periodontal and maxillofacial surgeries.

PRP is distinguished from fibrin glues or sealants, which have been used for many years as a surgical adjunct to promote local hemostasis at incision sites. Fibrin glue is created from platelet-poor plasma and consists primarily of fibrinogen. Commercial fibrin glues are created from pooled homologous human donors; Tisseel® (Baxter) and Hemaseel® (Haemacure Corp.) are examples of commercially available fibrin sealants. Autologous fibrin sealants can also be created from platelet-poor plasma. This policy does not address the use of fibrin sealants.

Wound Closure Outcomes

This policy addresses the use of recombinant PDGF products and PRP for nonorthopedic indications, which include a number of wound closure--related indications.

For this policy, the primary end points of interest for the study of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration (FDA) for the industry in developing products for the treatment of chronic cutaneous ulcer and burn wounds (1):

Incidence of complete wound closure;

Time to complete wound closure (reflecting accelerated wound closure);

Incidence of complete wound closure following surgical wound closure; and

Pain control.

Regulatory Status

Regranex®

In 1997, becaplermin gel (Regranex®, Smith & Nephew), a recombinant PDGF product, was approved by the FDA for the following labeled indication:

"Regranex Gel is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond and have an adequate blood supply. When used as an adjunct to, and not a substitute for, good ulcer care practices including initial sharp debridement, pressure relief and infection control, Regranex Gel increases the complete healing of diabetic ulcers.

The efficacy of Regranex Gel for the treatment of diabetic neuropathic ulcers that do not extend through the dermis into subcutaneous tissue or ischemic diabetic ulcers…has not been evaluated...."

In 2008, the manufacturer added the following black box warning to the labeling for Regranex: “An increased rate of mortality secondary to malignancy was observed in patients treated with three or more tubes of Regranex Gel in a postmarketing retrospective cohort study. Regranex Gel should only be used when the benefits can be expected to outweigh the risks. Regranex Gel should be used with caution in patients with known malignancy.”

Patients are typically treated once daily for up to 20 weeks or until complete healing. Application of the gel may be performed by the patient in the home.

Regranex is available in 2-, 7.5-, and 15-g tubes and is applied in a thin continuous layer, about 1/16 of an inch thick (i.e., 1.6 mm or the thickness of a dime). The amount of the gel used will depend on the size of the ulcer, measured in square centimeters. However, an average-sized ulcer, measuring 3 cm2, treated for an average length of time of 85 days, will require a little more than one 15-g tube. If the ulcer is treated for the maximum length of time of 140 days, 1.75 of the 15-g tubes would be required.

Platelet-Rich Plasma

The FDA regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research under the Code of Federal Regulation, title 21, parts 1270 and 1271. Blood products such as PRP are included in these regulations.

Under these regulations, certain products including blood products such as PRP are exempt and therefore do not follow the traditional FDA regulatory pathway. To date, the FDA has not attempted to regulate activated PRP. (2)

Numerous PRP preparation systems have been cleared for marketing by the FDA through the 510(k) process. These devices are intended to concentrate patient plasma at the point of care during bone grafting procedures. The use of different devices and procedures can lead to variable concentrations of active platelets and associated proteins, increasing variability between studies of clinical efficacy.

Rationale:

This policy was originally developed in 1993 and has been updated with searches of the MEDLINE database. The most recent literature update was performed through December 21, 2017.

Medical policies assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function--including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Recombinant Platelet-Derived Growth Factor

Diabetic Lower Extremity Ulcers

The portion of this medical policy on the use of recombinant platelet-derived growth factor (PDGF; becaplermin gel) was informed by a 1999 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, which found that the evidence supported the conclusion that becaplermin gel, in conjunction with good wound care, improves the health outcomes of patients with chronic neuropathic diabetic ulcers that meet the patient selection criteria defined therein. (3) Becaplermin gel plus good wound care resulted in a 43% complete wound-closure rate, compared with 28% for patients treated with good wound care alone. Becaplermin gel also appeared to reduce the average time to complete wound closure. A 2014 systematic review identified 6 RCTs (total N=992 patients) that compared recombinant PDGFs with placebo or standard care. (4) There was a combined odds ratio of 1.53 (95% confidence interval [CI], 1.14 to 2.04; p=0.004) favoring recombinant PDGF for complete healing rate.

A 2005 industry-sponsored study assessed the effectiveness of recombinant PDGF for diabetic neuropathic foot ulcers in actual clinical practice. (5) Among a cohort of 24,898 patients in wound-care centers, those subjects whose wounds did not heal over an 8-week observation period were eligible for the study and were retrospectively assessed over 20 weeks or until they healed. Any subject with an open wound who was lost to follow-up was considered unhealed. Of the nearly 25,000 patients treated for foot ulcers, 2,394 (9.6%) received recombinant PDGF. A propensity score method with covariates to statistically model treatment selection was used to adjust for selection bias; results were stratified by 5 propensity score groups. Overall, the rate of healing was 26.5% in the control group and 33.5% in patients treated with recombinant PDGF. The relative risk (RR), controlling for the propensity to receive PDGF, was 1.32 (95% CI, 1.22 to 1.38) for healing and 0.65 (95% CI, 0.54 to 0.78) for amputation (6.4% in controls vs 4.9%, in the PDGF group). The analysis also indicated that those who received PDGF were more likely to be younger, male, and have older wounds--factors not known to affect wound healing. These results support clinical utility of recombinant PDGF for treatment of diabetic neuropathic foot ulcers in actual clinical practice.

Section Summary: Diabetic Lower-Extremity Ulcers

Results from RCTs have shown improved rates of healing with use of recombinant PDGF for diabetic lower-extremity ulcers. The increase in the rate of healing must be balanced with the potential for increased risk from cancer. Overall the evidence is sufficient that use of recombinant PDGF improves health outcomes.

Pressure Ulcers

Rees et al. (1999) conducted an RCT focusing on the use of becaplermin gel as a treatment of pressure ulcers. (6) Patient selection criteria included full-thickness ulcers and an anatomic location where pressure could be off-loaded during treatment. This latter patient selection criterion might have limited the number of patients with pressure ulcers who would have been considered candidates for becaplermin therapy. Patients were randomized to 1 of 4 parallel treatment groups and received either a placebo or 1 of 3 doses of becaplermin. All patients received a standardized program of good wound care. In the 2 groups of patients treated with the once daily doses (becaplermin 0.01% or 0.03%), the incidence of complete healing was significantly improved compared with the placebo group. There was no difference in outcome between the 0.01% and 0.03% groups, suggesting that there is no clinical benefit in increasing the potency above 0.01%. A third group received becaplermin 0.01% twice daily. That group did not report improved outcomes compared with placebo, a finding that is unexplained.

Section Summary: Pressure Ulcers

Results from RCTs have shown improved rates of healing with use of recombinant PDGF for diabetic pressure ulcers. The increase in the rate of healing must be balanced with the potential for increased risk from cancer. Overall the evidence is sufficient that use of recombinant PDGF improves health outcomes.

Venous Leg Ulcers

In 2011, Senet et al. in France published a multicenter, double-blind RCT of becaplermin gel for venous leg ulcers. (7) There was no significant difference between the becaplermin (n=28) and control hydrogel (n=31) groups for any of the outcome measures, which included complete closure rates after 8 and 12 weeks, changed ulcer area, and changed ulcer-related pain and quality of life.

Section Summary: Venous Leg Ulcers

The evidence is insufficient to determine whether becaplermin gel improves health outcomes when used to treat venous leg ulcers.

Acute Surgical or Traumatic Wounds:

Topical recombinant PDGF has also been investigated for repair of work-related fingertip injuries. A 2005 prospective controlled trial alternately assigned 50 patients (fingertip wound area of ≥1.5 cm, with or without phalangeal exposure) to daily treatment with PDGF (n=25) or surgical reconstruction (n=25). (8) Statistical analysis showed that the baseline characteristics of the two groups were similar for patient age, wound area (2.2–2.4 cm), and distribution of fingertip injuries across the digits. Assessment by an independent physician showed that, compared with the surgical intervention, treatment with recombinant PDGF resulted in faster return to work (10 days vs 38 days) and wound healing (25 days vs 35 days), less functional impairment (10% vs 22%) and less need for physical therapy (20% vs 56%), respectively. Fingertips treated with PDGF were also reported to have satisfactory aesthetic results, while surgically treated fingertips were shorter and often unsightly. These results, if confirmed in additional RCTs, could lead to improvement in health outcomes for patients with fingertip injuries. However, this trial was limited by its small sample size, method of randomization, and potential for investigator bias (although examining physicians were blinded to treatment allocation, actual treatment might have been obvious).

Section Summary: Acute Surgical or Traumatic Wounds

The evidence is insufficient to determine whether becaplermin gel improves health outcomes when used to treat acute or traumatic wounds.

Adverse Events

Growth factors cause cells to divide more rapidly. For this reason, the manufacturer of Regranex continued to monitor studies that started before its approval (in December 1997) for any evidence of adverse effects, such as increased numbers of cancers. In a long-term safety study completed in 2001, more deaths from cancer occurred among patients who used Regranex than in those who did not use it. A subsequent study was performed using a health insurance database that covered the period from January 1998 through June 2003. This trial identified two groups of patients with similar diagnoses, drug use, and use of health services: one group used Regranex, and the other group did not. Results showed that there were more deaths from cancer among patients who were given 3 or more prescriptions for Regranex than deaths for those not treated with Regranex. No single type of cancer was identified; deaths from all types of cancer were observed. In 2008, the U.S. Food and Drug Administration (FDA) concluded that the increased risk of death from cancer in patients who used 3 or more tubes of Regranex was 5 times higher compared with those who did not use Regranex, prompting the manufacturer to add a black box warning to the labeling for Regranex. The risk of new cancers among Regranex users was not increased compared with nonusers, although the duration of follow-up of patients in this study was not long enough to detect new cancers.

Platelet-Rich Plasma (PRP) (i.e., Autologous Blood-Derived Preparations)

This portion of this medical policy on platelet-derived wound healing formulae was informed by a 1992 BCBSA TEC Assessment that primarily focused on the Procuren process. (9) This preparation method is no longer commercially available. Currently, a large number of devices are available for the preparation of PRP or PRP gel. The amount and mixture of growth factors produced by different cell-separating systems vary, and it is unknown whether platelet activation before injection is necessary. (10-14)

Mixed Wound Types (Chronic and Surgical)

Systematic Reviews

A number of systematic reviews of the evidence on PRP have been published. A 2012 Cochrane review included 9 RCTs (total N=325 participants) of PRP for treating chronic wounds. (15) This review was restricted to trials comparing PRP with no additional treatment or placebo. Four RCTs included patients with mixed chronic wounds, 3 included patients with venous leg ulcers, and 2 included patients with diabetic foot ulcers. Only 1 trial was considered to be at low risk of bias. After a median treatment duration of 12 weeks, there was no significant difference between the PRP and control groups in complete healing of diabetic foot ulcers, venous leg ulcers, or mixed chronic wounds. There was no significant difference in the area epithelialized in 3 RCTs of mixed chronic wounds. In 2 RCTs of mixed chronic wounds, there was a significant difference favoring PRP in the wound area that was healed. Reviewers concluded that there was no current evidence to suggest that autologous PRP would be of value for treating chronic wounds, given the small number of RCTs included, most of which were either at high or unclear risk of bias.

This Cochrane review was updated in 2016; it added a new RCT, for a total of 10 RCTs (total N=442 patients). (16) Conclusions about the quality of the overall body of evidence were similar to the 2012 review. For the outcome of overall wound healing, autologous PRP did not significantly increase healing compared with standard treatment (RR=1.19; 95% CI, 0.95 to 1.50; I2=27%, low-quality evidence). For wound healing in foot ulcers in people with diabetes, the evidence suggested that autologous PRP might increase healing compared with standard care (RR=1.22; 95% CI, 1.01 to 1.49; I2=0%, low-quality evidence). It was unclear whether autologous PRP increased wound healing compared with standard care for venous leg ulcers (RR=1.05; 95% CI, 0.29 to 3.88; I2=0%, low-quality evidence).

Other systematic reviews reached similar conclusions. For example, one from 2009 identified 42 controlled trials on PRP; of these, 20 were RCTs and were included in the systematic review, which found results to be inconclusive. (17) The 20 RCTs comprised 11 trials on oral and maxillofacial surgery, 7 on chronic skin ulcers, and 2 on surgery wounds. An industry-funded systematic review from 2011 included 21 studies of PRP gel for cutaneous wound healing, 12 of which were RCTs. (18) There were 3 main types of wounds, including open chronic wounds, acute surgical wounds with primary closure, and acute surgical wound with secondary closure. Study quality varied considerably, with 3 studies rated as high quality and 6 rated as poor quality. Two additional studies could not be rated because they were published only as an abstract and letter. Meta-analysis of the effect of PRP on complete wound healing of chronic wounds was limited by the inclusion of poor-quality studies. No high-quality RCTs showed improvement in complete healing with PRP. A 2015 systematic review of PRP for diabetic foot ulcers identified 6 small RCTs published between 1992 and 2011. (19) Although 5 of the studies reported positive results with PRP, the studies were small, and the possibility of selective publication bias was not assessed.

Chronic Wounds

Since the publication of the 2015 update to the Cochrane review on PRP for wounds, Escamilla Cardenosa et al. (2017) reported on an unblinded RCT comparing PRP and saline for venous ulcer treatment. (20) The trial included 61 patients (102 ulcers) who were randomized to the weekly application of a PRP dressing (31 patients, 55 ulcers) or weekly wet-to-dry dressing changes with saline (30 patients, 47 ulcers) over a 24-week period. The average percentage healed area in the PRP group was 67.7% and 11.2% in the control group (p<0.001). PRP group members had greater reductions in pain with the intervention.

Section Summary: Chronic Wounds

The evidence for autologous PRP for a variety of chronic wounds includes RCTs, which have been summarized in a systematic review. For chronic wounds, including diabetic ulcers, pressure ulcers, and vascular ulcers, the systematic review of RCTs did not find that PRP was associated with improved outcomes.

Acute Surgical or Traumatic Wounds

Surgical Wounds-Aortic Arch Repair

In 2015, Zhou et al. reported a double-blind RCT with 80 patients that assessed the effect of PRP on the amount of blood transfused in the perioperative period for elective ascending and transverse aortic arch repair. (21) The anesthesiologist prepared the PRP so that the surgeon was unaware of the treatment group. The volume of PRP transfused was 726 mL, and led to a reduction in transfusion rates for red blood cells, frozen plasma, cryoprecipitate, and platelets by 34% to 70% (p<0.02). Hospital length of stay was also reduced (9.4 days vs 12.7 days). There was no difference in mortality between the 2 groups (1 patient in each group) and no significant difference in postoperative complications or other outcome measures. Corroboration of the effect of PRP on perioperative blood transfusion is needed.

Surgical Wounds-Sternotomy Wounds

In 2015, Serraino et al. reported on a large series with historical controls that assessed the occurrence of deep sternal wound infections in patients who underwent cardiac surgery either with (2010-2012, 422 consecutive patients) or without (2007-2009, 671 consecutive patients) application of PRP. (22) The 2 groups were comparable at baseline. At the end of cardiac surgery, PRP gel was applied on the sternum before the closure of subcutaneous tissue. Rates of both deep and superficial wound infection were reduced in the patients treated with PRP (deep: 0.2% vs 1.5%, superficial: 0.5% vs 2.8%). Interpretation of these results is limited by likely differences in treatments over time. RCTs are needed to evaluate this potential use of PRP.

Surgical Wounds-Otolaryngology

In 2016, El-Anwar et al. reported on an RCT that evaluated PRP in 44 children (age range, 12-23 months) undergoing repair of a complete cleft palate. (23) Speech and velopharyngeal valve movement on follow-up were evaluated by 3 judges who “usually assessed every patient blindly,” physical examination, video nasoendoscopy, and audio recording of audio perceptual assessment. At 6 months, PRP-treated patients had better nasality grade on audio perceptual assessment (p=0.024) and better velopharyngeal closure on endoscopy (p=0.016).

A 2008 double-blind RCT assessed the efficacy of PRP following tonsillectomy in 70 children (age range, 4-15 years). (24) PRP was placed into the tonsil beds of half of the children, where it was directly visible. To compare pain symptoms and recovery, a daily diary was completed by the patient or a family member for 10 days after surgery. A FACES Pain Scale was used for children ages 4 to 7 years, while a numeric pain rating scale was used for children older than 7 years. Diaries from 83% of patients showed no differences in pain, medication doses, activity, and days eating solid foods between the 2 conditions.

Surgical Wounds-Other Wounds

A 2011 Norwegian trial of PRP applied to saphenous vein harvest sites after wound closure found no differences in the incidence of wound infection or cosmetic result. (25)

Traumatic Wounds

Kazakos et al. (2009) reported a prospective RCT that evaluated treatment of acute traumatic wounds (open fractures, closed fractures with skin necrosis, and friction burns) with platelet gel in 59 consecutive patients (27 PRP, 32 controls). (26) Conventional treatment consisted of topical washing and cleaning of the wounds, removal of the necrotic tissue, and dressing with petroleum jelly gauze every 2 days. In all patients with open tibial fractures, an external fixation system was applied. PRP gel was applied to the wounds after surgical débridement and placement of the external fixation system. The time needed for preparation and application of the PRP gel was 52 minutes. Thereafter, PRP gel was applied to the wounds once weekly in the outpatient clinic until there was adequate tissue regeneration (mean, 21 days) sufficient to undergo reconstructive plastic surgery. Control patients receiving conventional treatment required a mean of 41 days for adequate tissue regeneration. Pain scores were significantly lower in PRP-treated patients at 2 and 3 weeks (visual analog scale score, 58 PRP vs 80 controls). Although these results are encouraging, additional study with a larger number of patients is needed.

In 2016, Marck et al. reported on a randomized, double-blind, within-patient-controlled study in patients with deep dermal to full-thickness burns undergoing split-skin graft, comparing PRP with usual care. (27) The study randomized 52 patients, 50 of whom received the allocated PRP intervention. There were no significant differences in short-term (5-7 days) rates in graft take in the intervention and control areas on each patient. At 3, 6, and 12 months, there were no significant differences in skin appearance or epithelialization scores.

Section Summary: Acute Surgical or Traumatic Wounds

The evidence for autologous PRP for a variety of acute and traumatic wounds includes RCTs, which have been summarized in several systematic reviews. For a variety of conditions, studies have either not demonstrated a benefit or have demonstrated small benefits in studies with methodologic limitations.

Summary of Evidence

Recombinant PDGFs (Platelet-Derived Growth Factors)

For individuals who have diabetic lower-extremity ulcers or pressure ulcers who receive recombinant PDGF, the evidence includes randomized controlled trials and systematic reviews. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. Results have shown improved rates of healing with use of recombinant PDGF for diabetic neuropathic ulcers and pressure ulcers. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have venous stasis leg ulcers or acute surgical or traumatic wounds who receive recombinant PDGF, the evidence includes small randomized controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. The level of evidence does not permit conclusions whether recombinant PDGF is effective in treating other wound types, including chronic venous ulcers or acute traumatic wounds. The evidence is insufficient to determine the effects of the technology on health outcomes.

Platelet-Rich Plasma (PRP)

For individuals who have chronic wounds or acute surgical or traumatic wounds who receive PRP, the evidence includes a number of small controlled trials. Relevant outcomes are symptoms, change in disease status, morbid events, quality of life, and treatment-related morbidity. Current results of trials using PRP are mixed, and the studies are limited in both size and quality. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American College of Physicians

In 2015, the American College of Physicians (ACP) published guidelines on treatment of pressure ulcers. (28) The guidelines noted that “although low quality evidence suggests that dressings containing PDGF [platelet-derived growth factors] promote healing, ACP supports the use of other dressings such as hydrocolloid and foam dressings, which are effective at promoting healing and cost less than PDGF dressings.”

Association for the Advancement of Wound Care

The Association for the Advancement of Wound Care developed guideline recommendations for the management of pressure ulcers (2010) and venous ulcers (2015) (29,30):

Pressure ulcer: “Growth factors are not indicated for PU [pressure ulcers] at this time” (level C evidence – no RCTs available comparing growth factors with A-level dressings)

Venous ulcer: “Platelet derived growth factor has shown no significant effects on VU [venous ulcer healing or recurrence]” (level A evidence).

National Institute for Health and Care Excellence

In 2016, the National Institute for Health and Care Excellence updated its guidance on the prevention and management of diabetic foot problems. (31) The guidance stated that neither autologous platelet-rich plasma (PRP) gel nor platelet-derived growth factors should be offered in the treatment of diabetic foot ulcers.

Ongoing and Unpublished Clinical Trials

Some larger studies that might influence this policy are listed in Table 1.

Table 1. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT03037970a

A Prospective Randomized Controlled Blinded Study to Evaluate the Safety and Efficacy of rhPDGF-BB Saturated Collagen Wound Dressings on Diabetic Foot Ulcers

40

Oct 2017 (ongoing)

NCT02213952

Efficacy of Autologous Platelet-Rich Plasma in the Treatment of Vascular Ulcers in Primary Care: Clinical Trial Phase III

150

Dec 2017 (ongoing)

NCT02312596a

A Prospective, Randomized Clinical Trial of ECLIPSE PRP™ Wound Biomatrix in Non-Healing Diabetic Foot Ulcers

250

Jul 2018

NCT02312570a

Clinical Trial of ECLIPSE PRP™ Wound Biomatrix in Chronic Non- Healing Pressure Ulcers

250

Jul 2018

NCT02402374a

Randomized, Placebo-controlled, Blind-assessor Study to Evaluate the Safety and Efficacy of Autologous Platelet Rich Plasma Gel Prepared With the RegenKit-BCT Plus Family of Kits for the Treatment of Diabetic Foot Ulcer

192

Dec 2018

NCT02071979a

Registry Trial of the Effectiveness of Platelet Rich Plasma for Chronic Non-Healing Wounds (CMS)

1500

Dec 2021

Unpublished

NCT02209662a

A Multi-Center, Randomized Trial Comparing the Effectiveness of APIC-PRP to Control, When Added to Standard of Care in the Treatment of Non-healing Diabetic Foot Ulcers

274

Dec 2015 (unknown)

NCT02307448a

Effectiveness of Autologous Platelet Rich Plasma in the Treatment of Chronic Non-Healing Wounds

1500

Mar 2016 (unknown)

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

For situations other than injection (when 0232T would be reported), no specific CPT codes describe the preparation of autologous blood-derived products but CPT code 86999 can be used. It has been reported that providers have used CPT code 20926 to describe the overall procedure. It is questionable whether platelet-rich plasma is appropriately considered a tissue graft.

The American Medical Association’s Department of Coding instructs that placement of platelet-rich plasma into an operative site is an inclusive component of the operative procedure performed and not separately reported.

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

0232T, 0481T

HCPCS Codes

G0460, P9020, S0157, S9055

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position.

A national coverage position for Medicare may have been changed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. U.S. Food and Drug Administration. Guidance for Industry: Chronic Cutaneous Ulcer and Burn Wounds -- Developing Products for Treatment. Rockville, MD: Food and Drug Administration; 2006 June. Available at: <http://www.fda.gov> (accessed June 5, 2018).

2. U.S. Food and Drug Administration (FDA). Tissue and Tissue Products. 2016. Available at: <http://www.fda.gov> (accessed December 21, 2017).

3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Becaplermin for wound healing. TEC Assessments 1999; Volume 14, Tab 5.

4. Zhao XH, Gu HF, Xu ZR, et al. Efficacy of topical recombinant human platelet-derived growth factor for treatment of diabetic lower-extremity ulcers: Systematic review and meta-analysis. Metabolism. Oct 2014; 63(10):1304-1313. PMID 25060693

5. Margolis DJ, Bartus C, Hoffstad O, et al. Effectiveness of recombinant human platelet-derived growth factor for the treatment of diabetic neuropathic foot ulcers. Wound Repair Regen. 2005; 13(6):531-6. PMID 16283867

6. Rees RS, Robson MC, Smiell JM, et al. Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study. Wound Repair Regen. 1999; 7(3):141-7. PMID 10417749

7. Senet P, Vicaut E, Beneton N, et al. Topical treatment of hypertensive leg ulcers with platelet-derived growth factor-BB: a randomized controlled trial. Arch Dermatol. 2011; 147(8):926-30. PMID 21482863

8. Freedman BM, Oplinger EH, Freedman IS. Topical becaplermin improves outcomes in work related fingertip injuries. J Trauma. 2005; 59(4):965-8. PMID 16374289

9. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Growth factors for wound healing. TEC Evaluations. 1992; Volume 7, Pages 352-77.

10. Crovetti G, Martinelli G, Issi M, et al. Platelet gel for healing cutaneous chronic wounds. Transfus Apher Sci. Apr 2004; 30(2):145-151. PMID 15062754

11. Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstr Surg. Nov 2004; 114(6):1502-1508. PMID 15509939

12. Kevy SV, Jacobson MS. Comparison of methods for point of care preparation of autologous platelet gel. J Extra Corpor Technol. Mar 2004; 36(1):28-35. PMID 15095838

13. Castillo TN, Pouliot MA, Kim HJ, et al. Comparison of growth factor and platelet concentration from commercial platelet-rich plasma separation systems. Am J Sports Med. Feb 2011; 39(2):266-271. PMID 21051428

14. Mazzucco L, Balbo V, Cattana E, et al. Not every PRP-gel is born equal. Evaluation of growth factor availability for tissues through four PRP-gel preparations: Fibrinet, RegenPRP-Kit, Plateltex and one manual procedure. Vox Sang. Aug 2009; 97(2):110-118. PMID 19392780

15. Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. 2012; 10:CD006899. PMID 23076929

16. Martinez-Zapata MJ, Marti-Carvajal AJ, Sola I, et al. Autologous platelet-rich plasma for treating chronic wounds. Cochrane Database Syst Rev. May 25 2016(5):CD006899. PMID 27223580

17. Martinez-Zapata MJ, Marti-Carvajal A, Sola 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. PMID 27223580

18. 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. PMID 22028946

19. Picard F, Hersant B, Bosc R, et al. The growing evidence for the use of platelet-rich plasma on diabetic chronic wounds: A review and a proposal for a new standard care. Wound Repair Regen. Sep 2015; 23(5):638-643. PMID 26019054

20. Escamilla Cardenosa M, Dominguez-Maldonado G, Cordoba-Fernandez A. Efficacy and safety of the use of platelet-rich plasma to manage venous ulcers. J Tissue Viability. Nov 29 2016. PMID 27955807

21. Zhou SF, Estrera AL, Loubser P, et al. Autologous platelet-rich plasma reduces transfusions during ascending aortic arch repair: a prospective, randomized, controlled trial. Ann Thorac Surg. Apr 2015; 99(4):1282-1290. PMID 25661906

22. Serraino GF, Dominijanni A, Jiritano F, et al. Platelet-rich plasma inside the sternotomy wound reduces the incidence of sternal wound infections. Int Wound J. Jun 2015; 12(3):260-264. PMID 23692143

23. El-Anwar MW, Nofal AA, Khalifa M, et al. Use of autologous platelet-rich plasma in complete cleft palate repair. Laryngoscope. Jul 2016; 126(7):1524-1528. PMID 27075516

24. Sidman JD, Lander TA, Finkelstein M. Platelet-rich plasma for pediatric tonsillectomy patients. Laryngoscope. Oct 2008; 118(10):1765-1767. PMID 18622315

25. Almdahl SM, Veel T, Halvorsen P, et al. Randomized prospective trial of saphenous vein harvest site infection after wound closure with and without topical application of autologous platelet-rich plasma. Eur J Cardiothorac Surg. Jan 2011; 39(1):44-48. PMID 20634084

26. Kazakos K, Lyras DN, Verettas D, et al. The use of autologous PRP gel as an aid in the management of acute trauma wounds. Injury. 2009; 40(8):801-5. PMID 18703188

27. Marck RE, Gardien KL, Stekelenburg CM, et al. The application of platelet-rich plasma in the treatment of deep dermal burns: A randomized, double-blind, intra-patient controlled study. Wound Repair Regen. Jul 2016; 24(4):712-720. PMID 27169627

28. Qaseem A, Humphrey LL, Forciea MA, et al. Treatment of pressure ulcers: a clinical practice guideline from the American College of Physicians. Ann Intern Med. Mar 03 2015; 162(5):370-379. PMID 25732279

29. Association for the Advancement of Wound Care (AAWC). Guideline of Pressure Ulcer Guidelines. Malvern, PA: AAWC; 2010. Available at: <https://aawconline.memberclicks.net> (accessed December 21, 2017).

30. Association for the Advancement of Wound Care (AAWC). International Consolidated Venous Ulcer Guideline (ICVUG). 2015. Available at: <https://aawconline.memberclicks.net> (accessed December 21, 2017).

31. National Institute for Health and Clinical Excellence (NICE). Diabetic foot problems: prevention and management [NG19]. 2016. Available at: <https://www.nice.org.uk> (accessed December 21, 2017).

32. Recombinant and Autologous Platelet-Derived Growth Factors for Wound Healing and Other Non-Orthopedic Conditions. Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 January) Medicine 2.01.16.

Policy History:

Date Reason
11/1/2018 Document updated with literature review. Coverage modified to remove language specific to use of recombinant and autologous platelet-derived growth factors for orthopedic conditions; content moved to RX501.101. Document title changed from: Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions. References 1-2, 16, 20, 23-25, 27-31 added.
7/15/2017 Reviewed. No changes.
6/1/2016 Document updated with literature review. 1) The following was added the experimental, investigational and/or unproven listing of indications for becaplermin: “ulcers not extending through the dermis into the subcutaneous tissue”. 2) The following was added to the experimental, investigational and/or unproven listing of autologous blood-derived preparations (i.e., platelet-rich plasma): surgical wounds. 3) The following orthopedic indications for primary use were added to the experimental, investigational and/or unproven listing: achilles tendinopathy, lateral epicondylitis, osteochondral lesions and osteoarthritis. 3) The following orthopedic indications for adjunctive use in the following surgical procedures were added to the experimental, investigational and/or unproven listing: ACL reconstruction, hip fracture, long-bone nonunion, patellar tendon repair, rotator cuff repair, spinal fusion and subacromial decompression surgery.
8/1/2015 Reviewed. No changes.
2/15/2014 Document updated with literature review. The following was added to the experimental, investigational and unproven coverage statement for autologous blood-derived preparations (i.e., platelet-rich plasma): “Experimental, investigational and unproven for all indications including but not limited to”. In addition, the following was also added to the listing of examples of experimental investigational and unproven indications for autologous blood-derived preparations (i.e., platelet-rich plasma): “adjunctive use in surgical procedures (e.g. orthopedic, reconstructive)”.
7/15/2008 Revised/updated entire document; this policy is no longer scheduled for routine literature review and update.
11/15/2006 Revised/updated entire document
6/1/2001 Revised/updated entire document
11/1/2000 Revised/updated entire document
4/1/1999 Revised/updated entire document
6/1/1998 Revised/updated entire document
7/1/1995 Revised/updated entire document
4/1/1993 Revised/updated entire document
1/1/1993 New medical document

Archived Document(s):

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