Archived Policies - Prescription Drugs


Recombinant and Autologous Platelet-Derived Growth Factors as a Primary Treatment of Wound Healing and Other Miscellaneous Conditions

Number:RX501.034

Effective Date:11-15-2006

End Date:07-14-2008

Coverage:

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 FDA-labeled indication), AND when meeting 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.    
  • Pressure ulcers extending into the subcutaneous tissue when meeting all the following criteria:
    1. Full-thickness ulcer (i.e., Stage III or IV), extending through dermis into subcutaneous tissues, and
    2. Ulcer in an anatomic location that can be offloaded for the duration of treatment
    3. Albumin concentration >2.5dL, and
    4. Total lymphocyte count >1,000, and
    5. Normal values of vitamins A and C.

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

All other applications of recombinant platelet-derived growth factor (i.e. becaplermin) are considered experimental, investigational, and unproven.

Autologous blood-derived preparations (i.e., platelet-rich plasma) are considered experimental, investigational and unproven for the following:

  • As a treatment of chronic non-healing wounds including, but not limited to, Procuren, AutoloGel, and SafeBlood.
  • As a primary procedure for other miscellaneous conditions including, but not limited to, epicondylitis (i.e., tennis elbow), plantar fascitis, or Dupuytren’s contracture.

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) is 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."

Autologous (related to self) PDGFs have also been investigated as wound healing products. For example, platelets are a rich source of PDGFs, transforming growth factors (which function as a mitogen for fibroblasts, smooth muscle cells, and osteoblasts), and vascular endothelial growth factors. 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 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. Activated platelets then degranulate, releasing the various growth factors. There is a number of commercially available centrifugation devices used for the preparation of 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. In the OR 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, platelet-rich plasma has also been proposed as a primary treatment of miscellaneous conditions, such as epicondylitis, plantar fascitis, and Dupuytren’s contracture.

Platelet-rich plasma must be 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.

Note:  This policy only addresses the use of blood-derived growth factors, including platelet-rich plasma, as a primary treatment of wounds or other conditions, including but not limited to treatment of lateral epicondylitis (i.e., tennis elbow), plantar fascitis, or Dupuytren’s contracture. This policy does NOT address the use of blood-derived growth factors as an adjunct to surgery, including but not limited to their use in periodontal, plastic/reconstructive, or orthopedic procedures.

Rationale:

This policy regarding the use of becaplemin gel is based on a 1999 Technology Evaluation Center (TEC) Assessment that offered the following observations and conclusions.

  • The evidence supports the conclusion that becaplemin 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.  Becaplemin gel plus good wound care resulted in a 43% complete wound-closure rate, compared to 28% for patients treated with good wound care alone.  Becaplemin 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.

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 coverage section of this policy, but most importantly include 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 becaplemin therapy.  Patients were randomized to one of four parallel treatment groups, and received either a placebo or one of three doses of becaplemin.  All patients received a standardized program of good wound care.  In the two 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 becaplemin 100ug/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®)

The policy on platelet-derived wound healing formula is derived from a 1992 TEC Assessment.  The TEC Assessment identified two randomized clinical trials that 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 four-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.

2006 Update of blood-Derived Wound Healing Formula:

A literature search of the MEDLINE database performed for the period of 1999 to March 2006 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.

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:

None


Medicare Coverage:

“The CMS issued a national Medicare non coverage determination in 1992 related to platelet-derived wound healing formulas containing growth factors to treat non healing wounds based on a lack of sufficient published data to determine its efficacy and safety. Upon reconsideration, CMS continues to believe that the clinical effectiveness of autologous blood derived products, both platelet derived growth factor in a platelet poor plasma, and platelet rich plasma (PRP) are not adequately proven in scientific literature. Therefore, autologous blood derived products remain nationally noncovered for chronic non healing cutaneous wounds as not reasonable and necessary under section 1861(a) of the Social Security Act.”

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.

References:

Growth Factors for Wound Healing.  Chicago, Illinois: Blue Cross Blue shield Association – Technology Evaluation Center Assessment Program, (1992 December) 352-377.

Growth Factors for Wound Healing - Becaplermin.  Chicago, Illinois: Blue Cross Blue shield Association – Technology Evaluation Center Assessment Program, (1999 June) 14(5):

Rees R.S., Robson M.C., et al.  Becaplermin gel in the treatment of pressure ulcers: a phase II randomized, double-blind, placebo-controlled study.  Wound Repair Regan (1999) 7(3): 141-7.

Glover J.L., Weingarten M.S., et al.  A 4-year outcome-based retrospective study of wound healing and limb salvage in patients with chronic wounds.  Advanced Wound Care (1997) 10(1): 33-8

Ebbley, B.L., Woodell, J.E., et al.  Platelet quantification and growth factor analysis from platelet-rich plasma:  implications for wound healing.  Plastic Reconstructive Surgery (2004) 114(6):1502-8. 

Crovetti G, Martinelli G., et al.  Platelet gel for healing cutaneous chronic wounds.  Transfusion and Aphaeresis Science (2004) 30(2):  145-51.

Kevy S.V., Jacobson M.S.,   Comparison of methods for point of care preparation of autologous platelet gel.  Journal of Extra-Corporeal Technology (2004) 36(1): 28-35

Mishra A.K.  Treatment of chronic severe elbow tendinosis with platelet rich plasma. Annual Meeting American Academy of Orthopedic Surgeons.  (2005)  Paper #203    

Hardikar, J. V., Chiranjeev, R., et al.  Efficacy of Recombinant Human Platelet-Derived Growth factor (rhPDGF) Based Gel in diabetic foot Ulcers:  A Randomized, Multicenter, Double-Blind, Placebo-Controlled Study in India.  Wounds (2005) 17(6):141-152.

Policy History:

Archived Document(s):

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