| MP 2.01.16 | Recombinant and Autologous Platelet-derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions | |
| Medical Policy | ||
| Section Medicine |
Subsection | Last Review Status/Date Reviewed with literature search/8:2009 |
| Issue 8:2009 |
Original Policy Date 3/31/96 |
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Disclaimer
Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract. Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage. Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.
Description
This policy addresses the use of blood-derived growth factors, including recombinant platelet-derived growth factors and platelet rich plasma, as a primary treatment of wounds or other musculoskeletal conditions, including but not limited to treatment of diabetic ulcers, ulcers related to venous stasis, lateral epicondylitis (i.e., tennis elbow), plantar fasciitis, or Dupuytren’s contracture.
Platelet-derived growth factors (PDGF) are frequently used as an adjunct to surgery, including but not limited to their use in periodontal, plastic/reconstructive, or orthopedic procedures; adjunctive use of PDGF is considered outside the scope of this policy. This policy only discusses use of blood-derived growth factors as a primary treatment.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. Autologous platelets are a rich source of PDGF, transforming growth factors (which 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 platelet-rich plasma (PRP), can be prepared from samples of centrifuged autologous blood. Exposure to a solution of thrombin and calcium chloride degranulates platelets, releasing the 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. Alternatively, platelet-rich plasma may be injected directly into the tissue. Injection of platelet-rich plasma for tendon and ligament pain is theoretically related to prolotherapy (discussed in policy No. 2.01.26). However, prolotherapy involves injection of chemical irritants that are intended to stimulate inflammatory responses and induce release of endogenous growth factors.
Platelet-rich plasma 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; Tissel (Baxter) and Hemaseal are examples of commercially available fibrin sealants. Autologous fibrin sealants can be created from platelet-poor plasma. This policy does not address the use of fibrin sealants. There are a number of commercially available centrifugation devices used for the preparation of PRP. For example, AutoloGel™ (Cytomedix) and SafeBlood® (SafeBlood Technologies) are 2 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. 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. In addition, PRP has also been proposed as a primary treatment of miscellaneous conditions, such as epicondylitis, plantar fasciitis, and Dupuytren’s contracture. A recombinant PDGF product, becaplermin gel (Regranex®, McNeil Pharmaceutical) has been approved by the U.S. Food and Drug Administration (FDA). The labeled indication is as follows: '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.”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 (for further information on patient selection criteria, see Policy Guidelines below.)
- 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
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.
Autologous blood-derived preparations (i.e., platelet-rich plasma) are considered investigational in the treatment of acute or chronic non-healing wounds including, but not limited to, Autologel, and SafeBlood.
Autologous blood-derived preparations (i.e., platelet-rich plasma) are considered investigational as a primary procedure for other miscellaneous conditions including, but not limited to, epicondylitis (i.e., tennis elbow), plantar fasciitis, or Dupuytren’s contracture.
Policy Guidelines
Becaplermin
Appropriate candidates for becaplermin gel for treatment of neuropathic ulcers should meet ALL of the following criteria:
1. 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
2. Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues
3. 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 the treatment of pressure ulcers should meet ALL of the following criteria:
1. Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues
2. Ulcer in an anatomic location that can be off loaded for the duration of treatment
3. Albumin concentration >2.5 dL
4. Total lymphocyte count > 1,000
5. Normal values of vitamins A and C
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.
Becaplermin 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., 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 cm-2, 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 the15-g tubes would be required.
Autologous Blood-derived Preparations (i.e., Platelet-rich Plasma)
No specific CPT codes describe the preparation of autologous blood-derived products. However, 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.
Benefit Application
BlueCard/National Account Issues
Utilization for becaplermin gel is potentially high, particularly if used for off-label indications, or if used outside the setting of adequate and diligent standard wound management. Plans may want to consider active implementation and management of this policy to ensure that becaplermin is used as part of a program of wound management, as described in the Policy Guidelines.
Rationale
Recombinant Platelet-derived Growth Factor (Becaplermin Gel)
This policy regarding the use of becaplermin gel is based on a 1999 TEC Assessment (1) that offered the following observations and conclusions:
- 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 here. 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.
- Evidence is insufficient 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.
Results of a randomized study focusing on the use of becaplermin gel as a treatment of pressure ulcers has also been published. (2) The patient selection criteria for this study are summarized in the Policy Guidelines section, 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 above100 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.
An industry-sponsored study assessed the effectiveness of recombinant PDGF on diabetic neuropathic foot ulcers in actual clinical practice. (3) 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. (4) 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. (5) 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 Blood-derived Preparations (i.e., Platelet-rich Plasma)
The policy on platelet-derived wound-healing formula was originally derived from a 1992 TEC Assessment (6), which primarily focused on the Procuren process, referred to platelet-derived wound-healing formula. This preparation is no longer commercially available. A literature search for different preparations of platelet-derived growth factors was performed for the period of 1999 to June 2005 using the MEDLINE database. No controlled clinical trials were identified. Several articles described different methods of preparation of autologous PRP and noted variability in platelet concentration and viability depending on the preparation. (7-9)
Acute and Chronic Wounds
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. (10) Wound closure and complete epithelialization was achieved in 20 of 33 wounds in an average of 11 weeks. 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). (11) Conventional treatment consisted of topical washing and cleaning of the wounds, removal of the necrotic tissues, 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, began 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 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 (visual analog scale [VAS] score of 58 PRP vs. 80 control). Although these results are encouraging, additional study with a larger number of subjects is needed. Tendon, Ligament and Muscle One abstract was identified from a 2005 meeting presentation that described the use of percutaneous injection of PRP as a treatment of lateral epicondylitis in a prospective controlled study of 20 patients; a full report was published by Mishra and Pavelko in 2006. (12, 13) Criteria for participation included elbow epicondylar pain for longer than 3 months and at least 60 out of 100 on a visual analog scale (VAS) with failure of conservative therapy (a standardized stretching and strengthening protocol, and sosme combination of non-steroidal medication, bracing, or corticosteroid injections). Twenty (15%) of the 140 patients evaluated met the inclusion/exclusion criteria. Fifteen patients were treated with PRP and 5 patients were injected only with bupivacaine with epinephrine into the skin, subcutaneous tissue and directly into the area of maximum tenderness. Either 2 - 3 mL PRP or 2 - 3 mL bupivacaine with epinephrine was injected into the common extensor or flexor tendon using a single skin portal with 5 penetrations of the tendon (peppering technique). Although drawing of 55 mL of blood in control patients (to conceal the treatment allocation) was not permitted by the institutional review board, participants were informed that the needling alone was expected to improve symptoms. All participants were given a standardized post-treatment stretching and strengthening program. At 4 weeks after the procedure, PRP-treated patients reported a mean 46% improvement (80 to 43) in VAS pain scores and a 42% improvement (50 to 71) in Mayo elbow scores. Control patients reported a mean 17% improvement (86 to 71) in VAS and 20% improvement (50 to 60) in Mayo elbow scores. The PRP-treated patients continued to improve over follow-up. At a mean of 26 months’ follow-up PRP-treated patients reported a 93% reduction in pain compared with before the procedure. Follow-up was limited in the control patients as 3 of 5 (60%) had either sought treatment outside of the protocol or had formally withdrawn from the study by 8 weeks. No complications were noted in either group at any time. Mishra and colleagues report that a double-blind prospective trial with 230 patients has been initiated in the United States using this protocol. (14) No additional studies of PRP treatment of lateral epicondylitis were identified in a 2009 systematic review of injection therapies. (15) Anecdotally, PRP has also been investigated as a treatment of plantar fasciitis or Dupuytren’s contracture, but no published studies were identified. 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.Medicare National Coverage
In 2004, Medicare announced the following policy regarding autologous blood-derived products for chronic non-healing cutaneous wounds:
- Upon reconsideration, the clinical effectiveness of autologous PDGF products continues to not be adequately proven in scientific literature. As the evidence is insufficient to conclude that autologous PDGF in a platelet-poor plasma is reasonable and necessary, it remains non-covered for treatment of chronic, non-healing cutaneous wounds.
- Additionally, the evidence is not adequate to determine that autologous platelet rich plasma (PRP) is reasonable and necessary for the treatment of chronic non-healing cutaneous wounds, acute surgical wounds when the autologous PRP is applied directly to the closed incision, or dehiscent wounds.
- Coverage for treatments utilizing becaplermin, a non-autologous growth factor for chronic, non-healing subcutaneous wounds, will remain nationally non-covered under Part B based on §1861(s)(2)(A) and (B) of the Social Security Act because this product is usually administered by the patient.
References:
- 1999 TEC Assessment: Tab 5
- 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.
- 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.
- Niezgoda JA, Van Gils CC, Frykberg RG et al. Randomized clinical trial comparing OASIS Wound Matrix to Regranex Gel for diabetic ulcers. Adv Skin Wound Care 2005; 18(5 pt 1):258-66.
- Freedman BM, Oplinger EH, Freedman IS. Topical becaplermin improves outcomes in work related fingertip injuries. J Trauma 2005; 59(4):965-8.
- 1992 TEC Evaluations; pages 352-77.
- Eppley BL, Woodell JE, Higgins J. Platelet quantification and growth factor analysis from platelet-rich plasma: implications for wound healing. Plast Reconstr Surg 2004; 114(6):1502-8.
- Crovetti G, Martinelli G, Issi M et al. Platelet gel for healing cutaneous chronic wounds. Transfus Apher Sci 2004; 30(2):145-51.
- Kevy SV, Jacobson MS. Comparison of methods for point of care preparation of autologous platelet gel. J Extra Corpor Technol 2004; 36(1):28-35.
- McAleer JP, Kaplan E, Persich G. Efficacy of concentrated autologous platelet-derived growth factors in chronic lower-extremity wounds. J Am Podiatr Med Assoc 2006; 96(6):482-8.
- 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 2008 Aug 12. [Epub ahead of print]
- Mishra AK. Treatment of chronic severe elbow tendinosis with platelet rich plasma. 2005 Annual Meeting, American Academy of Orthopaedic Surgeons. Paper 203 (accessible at http://www.aaos.org/wordhtml/anmt2005/sciprog/203.htm).
- Mishra A, Pavelko T. Treatment of chronic elbow tendinosis with buffered platelet-rich plasma. Am J Sports Med 2006; 34(11):1774-8.
- Mishra A, Woodall J Jr Vieira A. Treatment of tendon and muscle using platelet-rich plasma. Clin Sports Med 2009; 28(1):113-25.
- Rabago D, Best TM, Zgierska A et al. A systematic review of four injection therapies for lateral epicondylosis: prolotherapy, polidocanol, whole blood and platelet rich plasma. Br J Sports Med 2009 Jan 21. [Epub ahead of print]
- CMS Manual System. Pub. 100-03 Medicare National Coverage Determinations, July 30, 2004.
- CMS Manual System Decision memo on autologous blood derived products for chronic non-healing wounds. CAG-00190R2. Posted March 19, 2008. Available at: https://www.cms.hhs.gov/mcd/viewdecisionmemo.asp?id=208 Last viewed July 2009.
Codes |
Number |
Description |
| CPT | See Policy Guidelines section | |
| ICD-9 Diagnosis | 250.60 – 250.63 | Diabetes with neurological manifestations code range. |
| 250.80 – 250.83 | Diabetes with other specified manifestations code range. | |
| 707.0 | Decubitus ulcer | |
| 707.1 | Ulcer of lower limbs, except decubitus | |
| 707.8 | Chronic ulcer of other specified sites | |
| 707.9 | Chronic ulcer of unspecified site | |
| HCPCS | P9020 | Platelet rich plasma, each unit |
| S0157 | Becaplermin gel 0.01%, 0.5 gm | |
| S9055 | Procuren or other growth factor preparation to promote wound healing | |
| Type of Service | Medical | |
| Place of Service | Inpatient, outpatient, home | |
Index
Autologel
Becaplermin
Growth Factors for Wound Healing
Platelet-rich Plasma
Regranex
Safeblood
Wound Healing, Growth Factors
Policy History
| Date | Action | Reason |
| 03/31/96 | Add to Medicine section | New policy |
| 07/16/99 | Replace policy | Revised policy; addresses becaplermin gel |
| 07/12/02 | Replace policy | Policy reviewed with changes: new policy statement on becaplermin gel for treatment of pressure ulcers |
| 07/17/03 | Replace policy | Policy updated; no change in policy statement. Information regarding Autologel and Safeblood provided |
| 11/9/04 | Replace policy | Policy updated; no change in policy statement. Reference added to Medicare national non-coverage policy for autologous platelet-derived products for chronic non- healing wounds |
| 09/27/05 | Replace policy | Policy revised; policy statement added regarding miscellaneous use of platelet-rich plasma as a primary procedure. Description and rationale now include discussion of platelet-rich plasma. Reference numbers 4 through 7 added. |
| 04/17/07 | Replace policy | Policy updated with literature search; reference numbers 9-12 added; policy statement unchanged |
| 07/10/08 | Replace policy | Policy updated with literature search; references reordered; policy statements unchanged |
| 08/13/09 | Replace policy | Policy updated with literature search through June 2009; references added and reordered; acute wounds added for PRP, other policy statements unchanged |
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