Medicine Section - Autologous Blood-Derived Growth Factors as a Treatment for Wound Healing and Other Miscellaneous Conditions

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

Description

A variety of growth factors have been found to play a role in wound healing, including blood-platelet-derived growth factor (PDGF), epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factor. Topically applied blood autologous platelet-derived growth factors have been most extensively investigated for clinical use in wound healing. 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) or buffy coat, 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 are 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 operating room setting, PRP has been investigated as an adjunct to a variety of periodontal, reconstructive, and orthopedic procedures. In addition, platelet-rich plasma has also been proposed as a primary treatment of miscellaneous conditions such as epicondylitis, plantar fasciitis 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. Autologous fibrin glue or sealants can be created from platelet-poor plasma, and consists primarily of fibrinogen. Commercial fibrin glues are created from pooled homologous human donors; Tisseel (Baxter) and Hemaseal are examples of commercially available fibrin sealants. This policy does not address the use of fibrin sealants.

Note: This policy is not intended to address Regranex® (becaplermin gel), which is not an autologous platelet-derived growth factor..

Policy/Criteria

Autologous blood-derived growth factors (i.e. platelet rich plasma) are considered investigational for all indications including but not limited to:

1. Chronic non-healing wounds
2. Epicondylitis (e.g., tennis elbow, elbow epicondylar tendinosis)
3. Plantar fasciitis
4. Dupuytren’s contracture
5. As an adjunct to spinal fusion
6. Sinus surgery
7. Periodontal surgery
8. Injection of ligament tears with any type of blood-derived growth factor, whether from the patient or another source

Scientific Background

Wound Healing

This policy was initially derived from a 1992 TEC assessment. (2) The TEC assessment identified two randomized clinical trials that reported conflicting results such that no conclusions could be reached regarding the health benefits of autologous blood-derived wound healing formula.  Since the TEC assessment, the published clinical trial data continue to preclude scientific conclusions due to such design flaws as small size and conflicting results. For example, Stacey and colleagues randomized 86 patients with venous ulcers to autologous blood-derived wound healing formula plus conventional wound care or placebo plus conventional wound care. (3) Each patient attended clinic twice weekly for up to nine months for their designated treatment. Wounds treated with the autologous blood-derived wound healing formula did not heal at a faster rate than the wounds treated with placebo. In a prospective, double-blind, multicenter trial, Driver and colleagues randomized 72 diabetic patients with a minimum four week history of foot ulcer to one of two groups. (4) Patients in the experimental group were treated with a platelet-rich plasma (PRP) gel preparation applied to the wound bed while patients in the control group received applications of saline gel. Treatments continued for 12 weeks or until healing occurred. Several different analyses were conducted.  At the 12 week follow-up, no significant difference in healing proportion or time was found between the PRP group and the saline group (32.5% and 28.1%, respectively, p=0.79). The study sponsor subsequently commissioned an independent audit of the fourteen investigation sites which led to exclusion of 32 patients (44%) for protocol violations and failure to complete treatment. An analysis of the data from the remaining 40 patients again found no significant between-group difference in number of healed wounds and time to complete healing. At the 12 week follow-up another analysis was conducted, this time including only patients with wound size ≤7.0 cm² in area and ≤2.0 cm² in volume (n=35). Proportion of complete healing was significantly higher (p=0.0177) in the PRP group (81%) than in the control group (42%). Time to complete healing was the same for both groups.

A review by Margolis and colleagues summarized the outcomes of 6,252 patients with diabetic neuropathic ulcers from the Curative Health Services patient database. (5)  Through the database information the authors concluded that more diabetic neuropathic ulcers treated with blood-derived formula healed by 32 weeks than diabetic neuropathic ulcers that were treated with the Center's standard wound care protocol (50% versus 41%). The effect appeared to be more pronounced in more severe wounds. This was not a randomized, comparative clinical trial, neither patients nor treating health care providers were blinded to the treatment received, and it was not documented whether the difference in wounds healed by 32 weeks between the two groups reached statistical significance. Senet and colleagues published the results of a trial that randomized fifteen patients with chronic venous ulcers to receive either a preparation of frozen autologous platelets or placebo.  (6) There was no significant difference in reduction in ulcer area between the two groups.

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 six months with traditional methods. (7) Wound closure and complete epithelialization was achieved in 20 of 33 wounds in an average of eleven weeks.  Given the failure of past treatment methods in this patient group, these findings were encouraging. In a randomized study of complications at the site of saphenous vein removal for coronary artery bypass grafts, Buchwald and colleagues found no difference in complication rates during the primary stay or in the follow-up period between those patients who received PRP and those who did not. (8)

The evidence from randomized, controlled clinical trials is conflicting and therefore does not permit conclusions concerning the independent contribution of autologous blood-derived wound healing formula in the treatment of chronic non-healing wounds.  An updated search of the MEDLINE database through January 23, 2009 failed to return any articles that address the limitations noted above. Specifically, no additional randomized trials focusing on blood-derived wound healing preparations were identified.  Several articles described different methods of preparation of autologous platelet-rich plasma, and noted variability in platelet concentration and viability depending on the preparation. (9-11)

Miscellaneous Conditions

The current published literature related to the use of platelet-rich plasma as a treatment of lateral epicondylitis is limited to one article. (12) Twenty patients with severe refractory lateral epicondylitis received a single percutaneous application of platelet rich plasma (PRP treatment group) or bupivacaine (control group). The abstract does not state whether group assignment was randomized or the number of patients in each group.  Four weeks following the procedure the PRP patients noted a 46% improvement in their visual analog pain scores, versus a 17% improvement in control patients (p = 0.028).  At eight weeks follow-up the PRP patients noted a 60% improvement versus a 16% improvement in control patients (p = 0.001).  After eight weeks 60% of the control patients either formally withdrew from the study or sought other treatments; therefore, only the PRP patients were available for further evaluation.  At six months follow-up, the PRP patients noted an 81% improvement in their visual analog pain scores.  The authors conclude that this procedure should be considered prior to surgical intervention.  However, the small study size, incomplete information related to group assignment and lack of control group data after eight weeks does not permit conclusions concerning the effectiveness of PRP in the treatment of epicondylitis.

Anecdotally, platelet-rich plasma has also been investigated as a treatment of plantar fasciitis or Dupuytren’s contracture, but no published studies were identified. In studies of PRP use in sinus surgery (13), periodontal surgery (14) and blepharoplasty (15), no difference was found between the treatment and control groups.

Autologous growth factor concentrate (AGF) has been investigated as an adjunct to lumbar fusion.  Carreon and colleagues retrospectively identified 76 patients who underwent 1-, 2- or 3-level instrumented posterolateral lumbar fusion with iliac crest bone graft mixed with AGF for treatment of lumbar stenosis, degenerative disc disease or spondylolisthesis.  (16) A case control group of 76 patients were retrospectively selected, matched for age, gender, smoking history, and number of levels fused.  At a minimum 24 month followup, there was no statistically significant difference in the nonunion rate between the AGF and the control group (19 and 13 nonunions, respectively).  The authors conclude that AGF did not enhance fusion rate and did not recommend the use of platelet gel as a supplement in posterolateral spinal fusion.  Similarly, Hee and colleagues found no significant difference in nonunions between their iliac crest autograft fusion + AGF group of 23 patients and an historical control group of 111 patients who underwent fusion without AGF.  (17) Nor was a significant difference found in pseudoarthrosis rates.  However, in patients who did achieve fusion, a significantly faster healing rate (p<0.05) was found in the treatment group, though this effect did not last longer than six months.  The authors concluded that, although the use of AGF may have demonstrated faster fusions, it did not result in overall increase in spinal fusion rates.  Finally, Weiner and Walker found inferior results in 32 consecutive patients who underwent single-level intertransverse lumbar fusion using iliac crest bone graft + AGF when compared with 27 patients who underwent an identical procedure without AGF. (18) Fusions were assessed radiographically at one and two years postoperatively.  The fusion rate for the AGF group was 18 of 32 (62%) while the fusion rate for the control group was 24 of 27 (91%).  The authors did not recommend AGF as an adjunct to lumbar fusion.

In summary, the lack of data in the current published literature on the use of PRP for the treatment of any condition does not permit conclusions related to health outcomes.

References

1. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No. 2.01.16
2. TEC Assessment, Growth Factors for Wound Healing, 1992; pp. 352-377
3. Stacey MC, Mata SD, Trengove NJ, Mather CA. Randomized double-blind placebo controlled trial of topical autologous platelet lysate in venous ulcer healing. Eur J Vasc Endovasc Surg, 2000;20:296-301
4. Driver VR, Hanft J, Fylling C, et al. A prospective, randomized controlled trial of autologous platelet-rich plasma gel for the treatment of diabetic ulcers.  Ostomy Wound Manage 2006;52(6):68-87
5. Margolis DJ, Kantor J, Santana J, Strom BL, Berlin JA. Effectiveness of platelet releasate for the treatment of diabetic neuropathic foot ulcers. Diabetes Care 2001;24:483-488
6. Senet P, Bon FX, Benbunan M et al. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J Vasc Surg 2003;38:1342-8
7. 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
8. Buchwald D, Kaltschmidt C, Haardt H, et al. Autologous platelet gel fails to show beneficial effects on wound healing after saphenectomy in CABG patients. J Extra Corpor Technol. 2008;40(3):196-202
9. 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
10. Crovetti G, Martinelli G, Issi M et al. Platelet gel for healing cutaneous chronic wounds. Transfus Apher Sci 2004;30(2):145-51
11. 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
12. Mishra AK, Pavelko T. Treatment of chronic severe elbow tendinosis with platelet rich plasma. Am J Sports Med 2006;34:1774-8
13. Rice DH. Platelet-rich plasma in endoscopic sinus surgery. Ear Nose Throat J 2006;85(8):516
14. Yassibag-Berkman Z, Tuncer O, Subasioglu T, et al. Combined use of platelet-rich plasma and bone grafting with or without guided tissue regeneration in the treatment of anterior interproximal defects. J Periodontol. 2007;78(5):801-9
15. Vick VL, Hols JB, Hartstein ME, et al. Use of autologous platelet concentrate in blepharoplasty surgery. Ophthal Plast Reconstr Surg 2006;22(2):102-4
16. Carreon LY, Glassman ST, Anekstein Y, et al. Platelet gel (AGF) fails to increase fusion rates in instrumented posterolateral fusions. Spine 2005;30(9):E243-6
17. Hee HT, Majd ME, Holt RT, et al. Do autologous growth factors enhance transforaminal lumbar interbody fusion? Eur Spine J 2003;12:400-7
18. Weiner BK, Walker M. Efficacy of autologous growth factors in lumbar intertransverse fusions. Spine 2003;28(17):1968-70

Cross References

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