Coverage Policy Manual
Policy #: 1997176
Category: Medicine
Initiated: January 1993
Last Review: February 2019
  Blood/Platelet-Derived Growth Factors for Wound Healing

Description:
A variety of growth factors have been found to play a role in wound healing, including platelet-derived growth factor, epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. Topically applied platelet-derived growth factors (PDGF) have been most extensively investigated for clinical use in wound healing.
 
A recombinant PDGF product, becaplermin gel (Regranex®, McNeil Pharmaceutical) has been recently approved by the U.S. Food and Drug Administration (FDA). The labeled indication is:  “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 this black box warning to the labeling for Regranex, “An increased rate of mortality secondary to malignancy was observed in patients treated with 3 or more tubes of REGRANEX Gel in a post-marketing 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.”
 
Autologous wound healing factors have also been derived from the patients’ blood. Procuren® (Curative Technologies, Inc.) is an autologous product that is derived from the patients’ own blood cells; blood is collected from the patient and sent to a specialized laboratory for processing and then returned to the patient for topical use. Originally Procuren was offered as part of a program of wound care management by Wound Care Centers, which are operated by Curative Technologies, Inc. As of 2002, Procuren is no longer marketed.
 
A number of commercially available centrifugation devices are used for the preparation of platelet-rich plasma (PRP). For example, AutoloGel™ (Cytomedix) and SafeBlood® (SafeBlood Technologies) are two related but distinct autologous blood-derived preparations that can be prepared at the bedside for immediate application. Both Autologel and SafeBlood have been specifically marketed for wound healing. Other devices may be used in the operating room setting, such as Medtronic Electromedic, Elmd-500 Autotransfusion system, the Plasma Saver device, or the Smart PreP device. The Magellan Autologous Platelet Separator System (Medtronic) includes a disposables kit designed for use with the Magellan Autologous Platelet Separator portable tabletop centrifuge. BioMet Biologics received marketing clearance through the FDA’s 510(k) process for a gravitational platelet separation system (GPSII), which uses a disposable separation tube for centrifugation and a dual cannula tip to mix the platelets and thrombin at the surgical site. Filtration or plasmapheresis may also be used to produce platelet-rich concentrates. 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.
  
Chronic non-healing ulcers of the lower extremity are a common problem and may be related to venous stasis, peripheral neuropathy, local trauma, or ischemia—the last 3 factors are common causes of ulcers in diabetic persons. Standard treatment for non-healing ulcers includes debridement, treatment of infection, avoidance of weight-bearing, and revascularization in those surgical candidates with ischemic ulcers.
 
Coding
In July 2010, a new CPT category III code for injections of platelet-rich plasma became effective:
0232T: Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed
 
The instructions issued with the code state that it is not to be reported with codes 20550, 20551, 20600-20610, 20926, 76942, 77002, 77012, 77021 and 86965. Code 0232T includes the harvesting and preparation of the platelet-rich plasma.
 
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 (unlisted transfusion medicine procedure) can be used. It has been reported that providers have used CPT code 20926 (tissue graft, other) 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.
 
There is also a HCPCS code for this treatment:
 
G0460 - Autologous platelet rich plasma for chronic wounds/ulcers, including phlebotomy, centrifugation, and all other preparatory procedures, administration and dressings, per treatment.

Policy/
Coverage:
Effective, December 2009
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Recombinant platelet-derived growth factor (i.e., becaplermin) meets primary coverage criteria that there be scientific evidence of effectiveness when used as an adjunct to standard wound management for the following indications:
 
    • When used according to the FDA-labeled indication, i.e., neuropathic diabetic ulcers extending into the subcutaneous tissue
    • As a treatment of pressure ulcers extending into the subcutaneous tissue
  
Appropriate candidates for becaplermin gel for treatment of neuropathic ulcers should meet ALL of the following criteria:
 
    • 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
    • Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues
    • Participation in a wound management program, which includes sharp debridement, pressure relief (i.e., non-weight-bearing), and infection control
  
Appropriate candidates for becaplermin gel for treatment of pressure ulcers should meet ALL of the following criteria:
 
Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues
    • Ulcer in an anatomic location that can be off loaded for the duration of treatment
    • Albumin concentration >2.5 dL
    • Total lymphocyte count > 1,000
    • Normal values of vitamins A and C
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Other applications of becaplermin, including, but not limited to, ischemic ulcers, ulcers related to venous stasis, and ulcers not extending  through the dermis into the subcutaneous tissue, do not meet member benefit certificate of coverage that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, other applications of becaplermin are considered investigational, including, but not limited to, ischemic ulcers, ulcers related to venous stasis, and ulcers not extending through the dermis into the subcutaneous tissue.  Investigational services are an exclusion in the member certificate of coverage.
  
Autologous blood-derived growth factors for chronic wound healing does not meet member benefit certificate primary coverage criteria because this treatment is currently being studied in clinical trials. (This includes but is not limited to Procuren, Autologel, and SafeBlood.)
 
For contracts without primary coverage criteria the use of autologous blood-derived growth factors for chronic wound healing is considered investigational.  Investigational services are exclusions in the member benefit certificate of coverage. (This includes but is not limited to Procuren, Autologel, and SafeBlood.)
 
Effective, September 2002-November 2009
Autologous platelet derived wound healing formulas are considered investigational and are not covered due to lack of medical data attesting to the effectiveness of the procedure.  
 
Platelet rich plasma mixed with bone graft material is considered investigational and is not covered due to
lack of medical data attesting to the effectiveness of the procedure. Investigational services are a benefit contract exclusion.
 
Recombinant platelet derived growth factor (becaplermin) is covered when used as an adjunct to standard wound management for patients with neuropathic diabetic ulcers extending into the subcutaneous tissue or beyond when (1) There is adequate tissue oxygenation as measured by a transcutaneous partial pressure of oxygen of at least 30 mm Hg at the edge of the tissue margin or on the dorsum of the foot; and (2) The patient is also participating in a wound care program that includes initial sharp debridement, pressure relief (no weight bearing), and infection control.
 
Becaplermin is considered investigational for other indications including, but not limited to, ischemic ulcers, ulcers related to venous stasis, pressure ulcers, and ulcers that do not extend into the subcutaneous tissue or beyond.
 
 
Effective, January 1993-August 2002
Platelet derived wound healing formulas are considered investigational and are not covered due to lack of medical data attesting to the effectiveness of the procedure.
 
Platelet rich plasma mixed with bone graft material is considered investigational and is not covered due to lack of medical data attesting to the effectiveness of the procedure.
 
  
 

Rationale:
Becaplermin Gel
    • The evidence supports the conclusion that becaplermin treatment, in conjunction with good wound care, improves the health outcomes of patients with chronic neuropathic diabetic ulcers that meet the patient selection criteria defined above. Becaplermin gel plus good wound care resulted in a 43% complete wound-closure rate, compared to 28% for patients treated with good wound care alone. Becaplermin gel also appeared to reduce the average time to complete wound closure.
    • There is insufficient evidence to determine the effect of becaplermin gel in treatment of other types of ulcers, including ischemic, chronic venous, or chronic pressure ulcers.
    • It should be emphasized that the beneficial effects of becaplermin were achieved within the setting of a controlled clinical trial protocol. Results of the clinical trials clearly tied the efficacy of becaplermin treatment to the overall intensity of the wound management effort. Variations in standard care, including infection control, debridement type and frequency, non-weight bearing compliance and methods, and patients’ glycemic control all influence ulcer healing. Whether this comprehensive degree of wound care is maintained in a community practice or home care setting is a concern. The magnitude of becaplermin effect, as demonstrated in clinical trials, can be expected only in settings that adhere to good wound care practices.
 
2002 Update on Becaplermin Gel
Results of a randomized study focusing on the use of becaplermin gel as a treatment of pressure ulcers has also been published.  The patient selection criteria for this study are summarized in the Policy / Coverage  section above, but most importantly included full-thickness ulcers and an anatomic location where pressure could be off loaded during treatment. This latter patient selection criterion may limit the number of patients with pressure ulcers who would be 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 once daily doses of becaplermin (either 100 or 300 uG/g), the incidence of complete healing was significantly improved compared to the placebo group. There was no difference in outcome between the 100 and 300 uG/g group, suggesting that there is no clinical benefit in increasing the dose above 100 uG/g. A third group of patients received becaplermin 100 uG/g twice a day. This group did not report an improved outcome compared to placebo, a finding that is unexplained.
 
Blood-Derived Wound Healing Preparations (i.e., Procuren, SafeBlood, and Autologel)
Two randomized clinical trials were identified in 1992.  These two trials reported conflicting results such that no conclusions could be reached regarding the health benefits of platelet-derived wound-healing formula.
 
A literature search extending from January 1992 to April 1999 was performed;  no additional randomized studies were identified. Glover and colleagues published a 4-year retrospective study of wound healing using platelet-derived wound-healing formula.  Although the authors stated that patients in the  treatment group reported higher healing rates compared to those treated with standard wound care alone, this uncontrolled study does not permit analysis of the independent contribution of platelet-derived wound healing formula.
 
A literature search of the MEDLINE database performed for the period of 1999 to 2003 did not identify any articles that addressed the limitations noted above. Specifically, no additional randomized trials focusing on platelet-derived wound healing formula were identified. No published peer-reviewed articles were identified that focused on the use of Autologel or SafeBlood as a distinct type of autologous platelet-derived wound-healing preparation.
 
2006-2008 Updates
Searches of the MEDLINE database were conducted through February 2007, and from March 2007 through May 2008.
 
Recombinant platelet-derived growth factors
An industry-sponsored study assessed the effectiveness of recombinant PDGF on diabetic neuropathic foot ulcers in actual clinical practice. Subjects (from a cohort of 24,898 patients in wound-care centers) whose wounds did not heal over a 8-week observation period were eligible for the study and assessed over a period of 20 weeks or until they healed. Any individual with an open wound who was lost to follow-up was considered unhealed. Out 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 the patients treated with recombinant PDGF. The relative risk, controlling for the propensity to receive PDGF, was 1.32 for healing and 0.65 for amputation (6.4% vs. 4.9%). 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 effectiveness of recombinant PDGF for treatment of diabetic neuropathic foot ulcers in actual clinical practice. Also identified in the literature search was a small multicenter randomized controlled trial from the OASIS Diabetic Ulcer Study Group that compared an acellular biomaterial from pig small intestine submucosa (OAISIS wound matrix) with recombinant PDGF.  This industry-sponsored trial found 49% healing in 37 OASIS-treated patients in comparison with 28% in 36 PDGF-treated patients (p = 0.55). Additional studies with a greater number of subjects are needed to compare efficacy between these 2 wound-healing agents.
 
Topical recombinant PDGF has also been investigated for repair of work-related fingertip injuries. One study used alternate assignment to “randomize” 50 patients (fingertip wound area of 1.5 cm or more, with or without phalangeal exposure) to daily treatment with PDGF or surgical reconstruction. (10) Statistical analysis showed that the baseline characteristics of the 2 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 in comparison with the surgical intervention, treatment with recombinant PDGF resulted in faster return to work (10 vs. 38 days) and wound healing (25 vs. 35 days), and a reduction in functional impairment (10% vs. 22%) and need for physiotherapy (20% vs. 56%). Fingertips treated with PDGF were also reported to have satisfactory esthetic results, while surgically treated fingertips were shorter and often unsightly. These results, if confirmed, could lead to improvement in health outcomes for patients with finger tip injury. However, the present study is limited by the small sample size, the method of randomization, and the potential for investigator bias (although the investigators did blind the examining physician from treatment allocation, the actual treatment may have been obvious). Additional randomized controlled trials are needed.
Growth factors cause cells to divide more rapidly. It is for this reason that the manufacturer continued to monitor studies begun before Regranex was approved in December 1997 for any evidence of adverse effects such as increased numbers of cancers. In a long-term safety study completed in 2001, there were more deaths from cancer in people who used Regranex than in those who did not use it.
 
Following the report of the study completed in 2001, an additional study was performed using a health insurance database that covered the period from January 1998 through June 2003. This study used the database to identify two groups of patients with similar diagnoses, drug use, and use of health services, one of which used Regranex and one group that did not. The results of this study showed that deaths from cancer were higher for patients who were given 3 or more prescriptions for treatment with Regranex than those who were not treated with Regranex. No single type of cancer was identified, but rather deaths from all types of cancer combined were observed. In 2008, the FDA concluded that the increase in the risk of death from cancer in patients who used 3 or more tubes of Regranex was 5 times higher than in those patients who did not use Regranex. The risk of getting new cancers among Regranex users was not increased compared to non-users, although the duration of follow-up of patients in this study was not long enough to detect new cancers.
 
Autologous platelet-derived growth factors
One case series reported efficacy of concentrated autologous platelet-derived growth factors in 24 patients with lower extremity wounds that had been treated previously for at least 6 months with traditional methods.  Wound closure and complete epithelialization was achieved in 20 of 33 wounds in an average of 11 weeks. Given the failure of past treatment methods in this patient group, these findings are encouraging.
 
Use of autologous PDGF as a primary treatment of soft-tissue injuries is in an early stage. Evidence is insufficient to permit conclusions concerning the effect of this technology on health outcomes. Therefore, the policy statements are unchanged.
 
2009 Update
A 2009 systematic review identified 42 controlled trials on PRP, 20 of these were randomized controlled trials (RCTs) and included in the systematic review (Martinez-Zapata, 2009). The 20 RCTs comprised 11 studies on oral and maxillofacial surgery, 7 on chronic skin ulcers, and 2 on surgery wounds. Four of the 11 studies on oral and maxillofacial (dental) surgery were combined to analyze the efficacy of PRP in patients with chronic periodontitis. The mean effect showed a greater reduction in patients in the PRP group for depth reduction of gingival recession of 0.54 mm. The mean effect for 3 studies assessing the clinical attachment level was not significant, although the studies were heterogeneous. When only the 2 studies including patients at severe stages were considered, there was a 0.89 mm advantage for the PRP group. Of the 7 RCTs assessing PRP for skin ulcers, 6 could be combined for the measure of complete ulcer epithelialization. The observed relative risk ratio of 1.40 was not significant between the experimental and controls groups. Two low quality RCTs assessed the use of PRP in surgery wounds; both studies tended to favor the PRP group, but were not statistically significant. The authors concluded that PRP improved the gingival recession but not the clinical attachment level in chronic periodontitis. Results were inconclusive for the healing of skin ulcers, and there were little safety data.
 
Kazakos and colleagues reported a prospective controlled study of the treatment of acute traumatic wounds with platelet gel in 59 consecutive patients (27 PRP and 32 controls) (Kazakos, 2008).  Conventional treatment consisted of topical washing and cleaning of the wounds, removal of the necrotic tissue, and dressing with Vaseline gauze every 2 days. In all patients with open tibial fractures, an external fixation system was applied. PRP gel, prepared with specialized tubes and a bench-top centrifuge, was applied to the wounds after surgical debridement and placement of the external fixation system. The time needed for preparation and application of the PRP gel was 52 minutes. PRP gel was then applied to the wounds once weekly in the outpatient clinic until there was adequate tissue regeneration (mean of 21 days) 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 the PRP treated patients at 2 and 3 weeks (VAS score of 58 PRP vs. 80 controls). Although these results are encouraging, additional study with a larger number of subjects is needed.
 
In summary, the available evidence does not prompt a change in the coverage statement.
 
2012 Update
This policy is being updated with a search of the MEDLINE database. There were no trials identified that would prompt a change in the coverage statement. Several articles, summarized below, were identified that relate to the use of autologous blood-derived preparations (i.e.,platelet-rich plasma) for the treatment of wounds and other conditions.
 
A 2010 systematic review of autologous growth factor injections in chronic tendinopathy found no high-quality studies using PRP (de Vos, 2010).  
 
An industry-funded systematic review included 21 studies on PRP gel for cutaneous wound healing, 12 of which were RCTs (Carter, 2011). 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 was found to vary 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. The primary outcome measure for this meta-analysis was complete wound healing. Overall, results from the RCTs are mixed, i.e. some trials report a benefit but others do not. Of 4 RCTs that evaluated complete healing of chronic wounds, 2 reported a statistically significant benefit for PRP, and meta-analysis of the 4 RCTs showed a significant combined effect of PRP for complete healing of chronic wounds. However, 2 of the 4 studies were rated as low quality and the other 2 could not be rated because they were presented only in abstract or letter form. Meta-analysis could not be conducted for complete healing of acute primary or secondary closure wounds. The meta-analysis of the effect of PRP on complete wound healing of chronic wounds is limited by the inclusion of poor quality studies. There are no high-quality RCTs that show an improvement in complete healing with PRP.
 
A 2012 systematic review included 23 randomized trials and 10 prospective cohort studies that compared PRP to placebo, corticosteroid, or a standard procedure (Sheth, 2012). Of 22 RCTs that evaluated functional outcomes, 6 showed a functional benefit of PRP, 15 showed no difference between PRP and the control, and 1 showed a significant functional advantage for the control group. For most of the studies the outcome measures differed, but 6 RCTs (n=358) and 3 prospective cohort studies (n=88) reported results of PRP using a visual analog score (VAS) and were combined for analysis. These studies assessed injuries to the acromion, rotator cuff, lateral humeral epicondyle, anterior cruciate ligament (ACL), patella, tibia, and spine. Follow-up ranged from 6 weeks to 24 months. No significant benefit of PRP was found for the 6 RCTs or the 3 prospective cohort studies. Interpretation of this systematic review is limited by the combination of a wide variety of conditions, as well as the lack of standardization of platelet-separation techniques and outcome measures in the primary literature.
 
Key references on platelet-rich plasma for specific indications are described below.
 
 
Achilles Tendinopathy: A single center, randomized, double-blind, placebo-controlled trial of PRP injection in patients with chronic midportion Achilles tendinopathy was reported by de Vos et al. in 2010 (de Vos, 2010). Fifty-four patients were randomized to receive PRP or saline injection, and all patients performed eccentric exercises. The Victorian Institute of Sports Assessment-Achilles (VISA-A) questionnaire evaluating pain score and activity level was completed at baseline and at 6, 12, and 24 weeks. The mean VISA-A score improved significantly after 24 weeks in both groups, and the between-group difference was not statistically significant. There were no significant differences on secondary measures of patient satisfaction and number of patients returning to their desired sport. The authors conclude that “in patients treated with an eccentric exercise program, a PRP injection compared with saline injection did not result in greater improvement in pain and activity.”
 
Lateral Epicondylitis (Tennis Elbow): A double-blind randomized trial of PRP for lateral epicondylitis was reported by Peerbooms and colleagues in 2010, with 2-year follow-up reported by Gosens et al. in 2011 (Peerbooms, 2010) (Gosens, 2011). One hundred patients with chronic (longer than 6 months) epicondylitis were randomized, 49 to receive corticosteroid injection and 51 to receive PRP injection. Stretching and exercise protocols were followed by each group, and normal sport or recreational activities were allowed as tolerated 4 weeks after injection. Eight patients were lost to follow-up, and their last scores were carried forward. Success was defined as 25% reduction in pain on VAS or Disabilities of the Arm, Shoulder, and Hand (DASH) outcomes measure score after 1 year without a re-intervention. Initially, mean VAS was 70.1 in the PRP-treated patients and 65.8 in the corticosteroid group. DASH scores were 161.3 and 131.2, respectively (p<0.001). At 4 and 8 weeks after injection, outcomes on VAS and DASH scores were significantly better in the corticosteroid group. At 12 weeks, between-group differences were not significant. After 1 year, 73% of PRP and 49% of corticosteroid-treated patients met criteria for success on pain VAS; 73% of the PRP group and 51% the steroid group were successful using DASH outcome measures (P=0.005). At 2 years, both VAS and DASH scores were significantly better in the PRP group (21.3 and 17.6, respectively) compared to the corticosteroid group (42.4 and 36.5). Success on the DASH was achieved by 73% of the PRP group and 39% of the corticosteroid group, while more patients in the corticosteroid group (47% vs. 14%) had deteriorated at 2 years. Additional studies are needed to evaluate PRP in this condition.
 
Osteochondral Lesions: In 2012, Mei-Dan et al. reported a quasi-randomized trial of 29 patients with 30 osteochondral lesions of the talus assigned to 3 intra-articular injections of hyaluronate or PRP (Mei-Dan, 2012). At 28-week follow-up, scores on the American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Scale (AHFS) improved to a greater extent in the PRP group (from 68 to 92) than the hyaluronate group (from 66 to 78). Subjective global function also improved to a greater extent in the PRP group (from 58 to 91) than the hyaluronate group (from 56 to 73). Interpretation of the composite measures of VAS pain and VAS function is limited by differences in the groups at baseline. Neither the patients nor the evaluators were blinded to treatment in this small study.
 
Osteoarthritis: A 2009 report from Europe described a prospective study of intra-articular injection of PRP in 100 consecutive patients affected by chronic degenerative cartilage lesions (Kon, 2010). Patients had a history of pain or swelling of the knee for at least 4 months and imaging findings on radiograph or magnetic resonance imaging (MR) of degenerative changes in the joint; 58 knees presented with a degenerative chondral lesion, 33 with early osteoarthritis, and 24 had advanced osteoarthritis. Exclusion criteria included systemic disorders, axial malalignment, severe cardiovascular diseases, infections, or immunodepression. Three injections were administered at 21-day intervals. During the treatment period, rest or mild activities such as an exercise bike or mild exercises in a pool were indicated. Gradual resumption of normal sport or recreational activities was allowed as tolerated. Five patients were lost to follow-up, and 4 did not complete treatment (1 patient had swelling after the first treatment). Evaluation was conducted in 91 patients (91% follow-up) before and at the end of the 3 treatments and at 6 and 12 months after treatment. The International Knee Documentation Committee (IKDC) objective score improved from 46% (of normal and nearly normal knees) to 78% at the end of therapy, declining to 67% at 12-month follow-up. The IKDC subjective score improved from 41 to 63 after treatment, with a score of 61 at 12-month follow-up. Treatment was less effective in older, heavier, and more advanced osteoarthritis patients than in younger patients with less severe chondral damage. Controlled studies are needed to evaluate this relatively simple, low cost, and minimally invasive method of applying growth factors.
 
Plantar Fasciitis: The 2012 systematic review by Sheth et al. identified 3 studies that evaluated the effect of autologous blood injections (Sheth, 2012). No controlled trials have been identified that evaluated the effect of PRP for plantar fasciitis.
 
Rotator Cuff Repair: Castricini et al randomized 88 patients with a rotator cuff tear to arthroscopic repair without (n=45) or with (n=43) augmentation with platelet-rich fibrin matrix (Castricini, 2011). At average follow-up of 20.2 months (range, 16-30 months), both groups demonstrated statistically significant improvement in the primary endpoint (Constant Scores evaluating pain, activities of daily living, range of movement, and power), but the between-group difference was not significant.
 
Randelli et al. randomized 53 patients in a double-blind study to activated PRP or to no treatment after arthroscopic rotator cuff repair. (24) VAS pain scores in the PRP group were lower than controls at baseline (4.8 vs. 6.4) through 30 days after surgery (1.1 vs. 2.4). At 3 months after surgery, the PRP group had higher scores on Constant scores (65.0 vs. 57.8) and the Simple Shoulder Test (8.9 vs. 7.1), University of California (UCLA, 26.9 vs. 24.2) and strength in external rotation (3.0 vs. 2.1). There was no difference in functional outcomes between the groups at 6, 12, and 24 months after surgery and no difference in the healing rate measured by magntic resonance imaging (MRI) at 1 year or more after surgery. This study is limited by the difference in VAS between the groups at baseline.
 
Spinal Fusion: No randomized trials on PRP in spinal fusion were identified; however, 2 controlled studies found no difference in fusion rates with use of a platelet gel or platelet glue (Carreon, 2005) (Tsai, 2009).
 
Subacromial Decompression Surgery: Everts and colleagues reported a rigorously conducted, small (n=40) double-blinded RCT of platelet and leukocyte-rich plasma (PLRP) gel following open subacromial decompression surgery in a carefully selected patient population (Everts, 2008). Blood was drawn from all patients after induction of anesthesia to maintain blinding. PLRP with autologous thrombin was injected into both the subacrominal intracapsular space and the subcutaneous layer covering the incision during wound closure. Postoperative examinations at 1, 2, 4, and 6 weeks were performed by independent evaluators; unique patient identifier codes were used to maintain patient and investigator blinding. Neither self-assessed nor physician-assessed instability were improved. Both subjective pain and use of pain medication were lower in the PLRP group across the 6 weeks of measurements. For example, at 2 weeks after surgery, VAS scores for pain were lower by about 50% in the PLRP group (close to 4 in the control group and close to 2 in the PLRP group) and only 1 patient (5%) was taking pain medication compared to 10 (50%) control patients. Objective measures of range of motion showed clinically significant improvement in the PLRP group across the 6-week assessment period, while patients reported improvements in activities of daily living such as ability to sleep on the operated shoulder at 4 weeks after surgery and earlier return to work.
 
Tonsillectomy: A double-blind RCT assessed the efficacy of PRP following tonsillectomy in 70 children, aged 4 to 15 years of age (Sidman, 2008). The PRP was prepared during the surgery and 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 either the patient or family member for 10 days after surgery. A FACES pain scale was used for the children aged 4 to 7 years, while a numbered pain scale was used for children older than 7 years. Diaries from 83% of the patients showed no differences in pain, medication doses, activity, and days eating solid foods between the two conditions.
 
Wound Closure: A study of PRP applied to saphenous vein harvest sites after wound closure found no difference in the incidence of wound infection or cosmetic result (Almdahl, 2011).
 
As of March 2012, CMS is reviewing new evidence and reconsidering its National Coverage Decision (NCD 270.3) to determine if the use of autologous platelet rich gel in patients with chronic non-healing pressure ulcers, venous ulcers, and diabetic foot ulcers is reasonable and necessary under the Medicare program.  In May, 2012, a proposed decision  memo was released  proposing that platelet-rich plasma (PRP) will be covered only for the treatment of chronic non-healing diabetic, venous and/or pressure wounds when the patient is enrolled in a randomized clinical trial that meets the required criteria established in the memo.
   
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
A 2015 systematic review of PRP for diabetic foot ulcers identified 6 small RCTs published between 1992 and 2011 (Picard, 2015). Although 5 of the studies reported positive results with PRP, the studies were small and the possibility of selective publication bias was not assessed.
 
Aortic Arch Repair
In 2015, Zhou and colleagues 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 (Zhou, 2015). The anesthesiologist prepared the PRP behind the surgical curtain and 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 vs 12.7 days). There was no difference in mortality between the 2 groups (1 patient in each group) and no significant difference in post-operative complications or other outcome measures. Corroboration of the effect of PRP on perioperative blood transfusion is needed.
 
Sternotomy Wounds
Serraino and colleagues reported 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 (Serraino, 2015).  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. The occurrence 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 this study is limited by likely differences in treatments over time. RCTs are needed to evaluate this potential use of PRP.
 
2018 Update
A literature search conducted through January 2018 revealed no new information that would prompt a change in the coverage statement.  
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Other Wounds
Alamdari et al published a clinical trial evaluating the efficacy of pleurodesis with a combination of PRP and fibrin glue compared with surgical intervention. The study population consisted of 52 esophageal cancer patients with postoperative chylothorax who did not respond to conservative management. Each member of the population was consecutively and randomly allocated to either a PRP fibrin glue pleurodesis arm or a surgical thoracic duct ligation arm. Twenty-six in each arm were treated with their respective intervention. The patients were distributed into the intervention arms in a way that made each group similar in terms of tumor size and patient demographics. This distribution procedure was not described. All patients (26) in the PRP treatment arm and 20 (76.9%) in the surgery arm were successfully treated (p=0.009). Seven patients (26.92%) of the PRP required a second application of the PRP fibrin glue after a week. The mean length of hospital stay was higher in the surgery group (53.50 ± 16.662 days) than the PRP group (36.04 ± 8.224 days; p < 0.001). The study was limited due to the fact the procedure for randomization was not described and, thus, its efficacy cannot be evaluated (Alamdari, 2018).https://www.evidencepositioningsystem.com/_w_1985646703e69442087b4411f05a9ef225be82b4b8f87d49/
 
Traumatic Wounds
Kazakos et al reported on a prospective RCT that evaluated treatment of acute traumatic wounds (open fractures, closed fractures with skin necrosis, friction burns) with platelet gel in 59 consecutive patients (27 PRP, 32 controls) (Kazakos, 2009). Conventional treatment consisted of topical washing and cleaning of the wounds, removal of the necrotic tissue, and dressing in petroleum jelly gauze every two 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. After that, 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.
 
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 (Marck, 2016). 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.
 
Yeung et al performed a prospective RCT to test the efficacy of lyophilized platelet-rich plasma powder (LPRP) on the healing rate of wounds in patients with deep, second-degree burn injuries in comparison with a control group using a placebo. LPRP was dissolved in a solution and applied on deep second-degree burn wounds once per day for four consecutive days. Twenty-seven patients with deep second-degree burns were recruited and then those that met eligibility criteria were randomized into two groups. The LRPR group received the intervention (n = 15) and the control group received a placebo application (n = 12). A concentration of 1.0 x 107 platelets/cm2 (wound area) was sprayed on the wound evenly. Function was assessed by the percentage of wound closure and bacteria picking out rate at weeks two and three. The mean burn area of control for the LPRP was 75.65 ± 50.72 cm2 and 99.73 ± 70.17 cm2 (p=0013), respectively. In the control group, the original wound area was 25.49 cm2 at baseline, 23.79 cm2 (6.67% healed) at week 2, and 4.34 cm2 (86.40% healed) at week 3. In the LPRP group, the original wound area was 84.36 cm2, followed by 23.96 cm2 (71.59% healed) at week 2, and 0.63 cm2 (99.24% healed) at week 3. The wound closure rate at week 2 in the LPRP group reached nearly 80% and was greater than 90% by week 3, showing a significant difference (p<0.05). Alternatively, in the control group, the wound closure rates were 60% and 80% in 2 and 3 weeks, respectively. The postoperative infection rate in the LPRP (26.67%) was lower than the control group (33.33%). Neither was significant, statistically. One limitation of this study is that the powder is made by an independent lab and dissolved in a specified amount of water. This provides an opportunity for accidental error-this may also be the case with some liquid PRP (Yeung, 2018).

CPT/HCPCS:
0232TInjection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed
G0460Autologous platelet rich plasma for chronic wounds/ulcers, including phlebotomy, centrifugation, and all other preparatory procedures, administration and dressings, per treatment
S0157Becaplermin gel 0.01%, 0.5 gm
S9055Procuren or other growth factor preparation to promote wound healing

References: Kazakos K, Lyras DN, Verettas D et al.(2008) The use of autologous PRP gel as an aid in the management of acute trauma wounds. . Injury 2008 Aug 12. [Epub ahead of print]

Association for the Advancement of Wound Care (AAWC).(2016) AAWC Guideline: Pressure Ulcer. http://aawconline.org/wp-content/uploads/2015/11/AAWCPressureUlcerGuidelineofGuidelinesAug11.pdf. Accessed December 12, 2016.

Association for the Advancement of Wound Care (AAWC).(2016) AAWC Venous Ulcer Guideline. http://aawconline.org/wp-content/uploads/2015/11/AAWC-Venous-Ulcer-Guideline-Update-Algorithm-v28-updated-11Feb2014.pdf. Accessed December 12, 2016.

Alamdari DH AM, Rahim AN, et al.(2018) Efficacy and Safety of Pleurodesis Using Platelet-Rich Plasma and Fibrin Glue in Management of Postoperative Chylothorax After Esophagectomy. World J Surg. 2018;42(4):1046-1055. PMID: 28986682

Almdahl SM, Veel T, Halvorsen P et al.(2011) 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 2011; 39(1):44-8.

Becaplermin. FDA approved labeling 1999.

Carreon LY, Glassman SD, Anekstein Y et al.(2005) Platelet gel (AGF) fails to increase fusion rates in instrumented posterolateral fusions. Spine (Phila Pa 1976) 2005; 30(9):E243-6; discussion E47.

Carter MJ, Fylling CP, Parnell LK.(2011) Use of platelet rich plasma gel on wound healing: a systematic review and meta-analysis. Eplasty 2011; 11:e38.

Castillo TN, Pouliot MA, Kim HJ et al.(2011) Comparison of growth factor and platelet concentration from commercial platelet-rich plasma separation systems. Am J Sports Med 2011; 39(2):266-71.

Castricini R, Longo UG, De Benedetto M et al.(2011) Platelet-rich plasma augmentation for arthroscopic rotator cuff repair: a randomized controlled trial. Am J Sports Med 2011; 39(2):258-65.

CMS Manual System. Autologous blood derived products for chronic non-healing wounds. CAG-00190R3. Available online at: https://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=208. Last accessed March 2012.

CMS Manual System. Proposed Decision Memo for Autologous Blood-Derived Products for chronic non-Healing Wounds (CAG-00190R3). Available at http://www.cms.gov/medicare-coverage-database/details/nca-proposed-decision-memo.aspx?NCAId=260. Last accessed June 2012.

de Vos RJ, van Veldhoven PL, Moen MH et al.(2010) Autologous growth factor injections in chronic tendinopathy: a systematic review. Br Med Bull 2010; 95:63-77.

de Vos RJ, Weir A, van Schie HT et al.(2010) Platelet-rich plasma injection for chronic Achilles tendinopathy: a randomized controlled trial. JAMA 2010; 303(2):144-9.

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

Embil JM, Nagai MK.(2002) Becaplermin: recombinant platelet derived growth factor, a new treatment for healing diabetic foot ulcers. Expert Opin Biol Ther 2002; 2:211-8.

Embil JM, Papp K, Sibbald G, et al.(2000) Recombinant human platelet-derived growth factor-BB (becaplermin) for healing chronic lower extremity diabetic ulcers: an open-label clinical evaluation of efficacy. Wound Repair Regen 2000; 8:162-8.

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

Everts PA, Devilee RJ, Brown Mahoney C et al.(2008) Exogenous application of platelet-leukocyte gel during open subacromial decompression contributes to improved patient outcome. A prospective randomized double-blind study. Eur Surg Res 2008; 40(2):203-10.

Glover JL, Weingarten MS, et al.(1997) A 4-year outcome-based retrospective study of wound healing and limb salvage in patients with chronic wounds. Adv Wound Care 1997; 10:33-38.

Gosens T, Peerbooms JC, van Laar W et al.(2011) Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med 2011; 39(6):1200-8.

Kazakos K, Lyras DN, Verettas D, et al.(2009) The use of autologous PRP gel as an aid in the management of acute trauma wounds. Injury. Aug 2009;40(8):801-805. PMID 18703188

Kon E, Buda R, Filardo G et al.(2010) Platelet-rich plasma: intra-articular knee injections produced favorable results on degenerative cartilage lesions. Knee Surg Sports Traumatol Arthrosc 2010; 18(4):472-9.

Ladin D.(2000) Becaplermin gel (PDGF-BB) as topical wound therapy. Plast Reconstr Surg 2000; 105:1230-1.

Landesberg R, Roy M, Glickman RS.(2000) Quantification of growth factor levels using a simplified method of platelet-rich plasma gel preparation. J Oral Maxillofac Surg 2000; 58:297-300; discussion 300-1.

Marck RE, Gardien KL, Stekelenburg CM, et al.(2016) 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

Marck RE, Gardien KL, Stekelenburg CM, et al.(2016) 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

Martínez-Zapata MJ, Martí-Carvajal A, Solà I et al.(2009) Efficacy and safety of the use of autologous plasma rich in platelets for tissue regeneration: a systematic review. Transfusion 2009; 49(1):44-56.

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

Mazzucco L, Balbo V, Cattana E, et al(2009) 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

Mei-Dan O, Carmont MR, Laver L et al.(2012) Platelet-rich plasma or hyaluronate in the management of osteochondral lesions of the talus. Am J Sports Med 2012; 40(3):534-41.

National Institute for Health and Clinical Excellence (NICE).(2016) Diabetic foot problems: prevention and management [NG19]. https://www.nice.org.uk/guidance/ng19. Accessed December 15, 2016.

Par YJ, et al.(2000) Platelet derived growth factor releasing chitosan sponge for periodontal bone regeneration. Biomaterials 2000; 21:153-9.

Peerbooms JC, Sluimer J, Bruijn DJ et al.(2010) Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. Am J Sports Med 2010; 38(2):255-62.

Picard F, Hersant B, Bosc R, et al.(2015) 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

Qaseem A, Humphrey LL, Forciea MA, et al.(2015) 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

Randelli P, Arrigoni P, Ragone V et al.(2011) Platelet rich plasma in arthroscopic rotator cuff repair: a prospective RCT study, 2-year follow-up. J Shoulder Elbow Surg 2011; 20(4):518-28.

Rees RS, Robson MC, Smiell, et al.(1999) Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo controlled study. Wound Rep Reg 1999; 7:141-7.

Sandhee HS.(2000) Anterior lumbar interbody fusion with osteoinductive growth factors. Clin Orthop 2000; 371:56-60.

Serraino GF, Dominijanni A, Jiritano F, et al.(2015) 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

Sheth U, Simunovic N, Klein G et al.(2012) Efficacy of autologous platelet-rich plasma use for orthopaedic indications: a meta-analysis. J Bone Joint Surg Am 2012; 94(4):298-307.

Sidman JD, Lander TA, Finkelstein M.(2008) Platelet-rich plasma for pediatric tonsillectomy patients. Laryngoscope 2008; 118(10):1765-7.

Smiell JM, Wieman TJ, Steed DL, et al.(1999) Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies. Wound Repair Regen 1999; 7:335-46.

Sonnleitner D, Huemer P, Sullivan DY.(2000) A simplified technique for producing platelet rich plasma and platelet concentrate for intraoral bone grafting techniques: A technical note. Int J Oral Maxillofac Implants 2000; 15:879-82.

Spiro RC, Thompson AY, Poser JW.(2001) Spinal fusion with recombinant human growth and differentiation factor -5 combined with a mineralized collagen matrix. Anat Rec 2001; 263:388-95.

Stephan EB, Renjen R, Lynch SE, et al.(2000) Platelet-derived growth factor enhancement of a mineral-collagen bone substitute. J Periodontol 2000; 71:1887-92.

Temple ME, Nahata MC.(2000) Pharmacotherapy of lower limb diabetic ulcers. J Am Geriat Soc 2000; 48:822-8.

Tsai CH, Hsu HC, Chen YJ et al.(2009) Using the growth factors-enriched platelet glue in spinal fusion and its efficiency. J Spinal Disord Tech 2009; 22(4):246-50.

Zhou SF, Estrera AL, Loubser P, et al.(2015) 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


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2019 American Medical Association.