Pending Policies - Surgery


Amniotic Membrane and Amniotic Fluid

Number:SUR704.011

Effective Date:08-01-2018

Coverage:

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

Treatment of nonhealing diabetic lower-extremity ulcers using the following human amniotic membrane products (AmnioBand® Membrane, Biovance®, Epifix®, Grafix™) may be considered medically necessary when there is medical record documentation of less than a 20% decrease in wound area with standard wound care for at least 2 weeks.

Sutured human amniotic membrane grafts may be considered medically necessary for the treatment of the following ophthalmic indications:

Neurotrophic keratitis,

Corneal ulcers and melts,

Pterygium repair,

Stevens-Johnson syndrome, and

Persistent epithelial defects (See NOTE 1).

NOTE 1: A persistent epithelial defect is one that failed to close completely after 5 days of conservative treatment or has failed to demonstrate a decrease in size after 2 days of conservative treatment. Conservative treatment is defined as use of topical lubricants and/or topical antibiotics and/or therapeutic contact lens and/or patching.

Sutured human amniotic membrane grafts are considered experimental, investigational and/or unproven for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem-cell deficiency, and after photorefractive keratectomy.

Human amniotic membrane without suture (e.g., Prokera®, AmbioDisk™) for ophthalmic indications is considered experimental, investigational and/or unproven.

Injection of micronized or particulated human amniotic membrane is considered experimental, investigational and/or unproven for all indications, including but not limited to treatment of osteoarthritis and plantar fasciitis.

Injection of human amniotic fluid is considered experimental, investigational and/or unproven for all indications.

All other human amniotic membrane products and indications not listed above are considered experimental, investigational and/or unproven, including but not limited to treatment of lower-extremity ulcers due to venous insufficiency.

Description:

Several commercially available forms of human amniotic membrane and amniotic fluid can be administered by patches, topical application, or injection. Amniotic membrane and amniotic fluid are being evaluated for the treatment of a variety of conditions, including chronic full-thickness diabetic lower extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions.

Human Amniotic Membrane

Human amniotic membrane (HAM) consists of 2 conjoined layers, the amnion and chorion, and forms the innermost lining of the amniotic sac or placenta. When prepared for use as an allograft, the membrane is harvested immediately after birth, cleaned, sterilized, and either cryopreserved or dehydrated. Many products available using amnion, chorion, amniotic fluid, and umbilical cord are being studied for the treatment of a variety of conditions, including chronic full-thickness diabetic lower-extremity ulcers, venous ulcers, knee osteoarthritis, plantar fasciitis, and ophthalmic conditions. The products are formulated either as patches, which can be applied as wound covers, or as suspensions or particulates, or connective tissue extractions, which can be injected or applied topically (see Table 1).

The fresh amniotic membrane contains collagen, fibronectin, and hyaluronic acid, along with a combination of growth factors, cytokines, and anti-inflammatory proteins such as interleukin-1 receptor antagonist. (1) There is evidence that the tissue has anti-inflammatory, antifibroblastic, and antimicrobial properties. HAM is considered nonimmunogenic and has not been observed to cause substantial immune response. It is believed that these properties are retained in cryopreserved HAM and dehydrated HAM products, resulting in a readily available tissue with regenerative potential. In support, 1 dehydrated HAM product has been shown to elute growth factors into saline and stimulate the migration of mesenchymal stem-cells, both in vitro and in vivo. (2)

Use of a HAM graft, which is fixated by sutures, is an established treatment for disorders of the corneal surface, including neurotrophic keratitis, corneal ulcers and melts, following pterygium repair, Stevens-Johnson syndrome, and persistent epithelial defects. Amniotic membrane products that are inserted like a contact lens have more recently been investigated for the treatment of corneal and ocular surface disorders. Amniotic membrane patches are also being evaluated for the treatment of various other conditions, including skin wounds, burns, leg ulcers, and prevention of tissue adhesion in surgical procedures. (1) Additional indications studied in preclinical models include tendonitis, tendon repair, and nerve repair. The availability of HAM opens the possibility of regenerative medicine for an array of conditions.

Amniotic Fluid

Amniotic fluid surrounds the fetus during pregnancy and provides protection and nourishment. In the second half of gestation, most of the fluid is a result of micturition and secretion from the respiratory tract and gastrointestinal tract of the fetus, along with urea. (1) The fluid contains proteins, carbohydrates, peptides, fats, amino acids, enzymes, hormones, pigments, and fetal cells. Use of human and bovine amniotic fluid for orthopedic conditions was first reported in 1927. (3) Amniotic fluid has been compared with synovial fluid, containing hyaluronan, lubrican, cholesterol, and cytokines. Injection of amniotic fluid or amniotic fluid?derived cells is currently being evaluated for the treatment of osteoarthritis and plantar fasciitis.

Amniotic membrane and amniotic fluid are also being investigated as sources of pluripotent stem-cells. (1) Pluripotent stem-cells can be cultured and are capable of differentiation toward any cell type. The use of stem-cells in orthopedic applications is addressed in medical policy SUR703.051.

Table 1. Amniotic Membrane and Amniotic Fluid Preparations: Preparation and Components

Product (Supplier)

Preparation

Components

Cryopreserved, Dehydrated, or Extracted

Amnion

Chorion

Amniotic Fluid

Umbilical Cord

Patch

Affinity™ (NuTech Medical)

C

X

AlloWrap™ (AlloSource)

NS

X

AmbioDisk® (IOP Ophthalmics)

D

AmbioDry5® (IOP Ophthalmics)

D

AmnioBand® Membrane (MTF Wound Care)

D

X

X

AmnioClear™ (Liventa Bioscience)

NS

X

X

AmnioExcel® (Derma Sciences)

D

X

AmnioFix® (MiMedx)

D

X

AmnioGraft® (Bio-Tissue)

C

Artacent® Wound (Tides Medical)

D

X

BioDDryFlex® (BioD)

D

X

BioDfence™ (BioD)

D

X

X

BioSkin (HRT)a

D

X

X

Biovance® (Alliqua Biomedical)

D

X

Clarix® (Amniox Medical)

C

X

X

Cygnus (Vivex Biomedical)

D

X

Cygnus Max (Vivex Biomedical)

D

X

EpiCord™ (MiMedx)

D

X

EpiFix® (MiMedx)

D

X

X

Dermavest™ (Aedicell)a

C

X

X

X

Grafix® (Osiris)

C

X

X

Guardian/AmnioBand® (MTF Wound Care)

D

X

X

Neox® 100 (Amniox Medical)

C

X

X

Neox® Cord (Amniox Medical)

C

X

X

Neox® Wound Allograft (Amniox Medical)

C

X

X

NuShield™ (NuTech Medical)

D

X

X

PalinGen® Membrane (Amnio ReGen Solutions)

C

X

Plurivest™ (Aedicell)a

C

X

X

X

Prokera® (Bio-Tissue)

C

Revitalon™ (Medline Industries)

D

X

X

WoundEx® (Skye Biologics)a

D

X

X

Suspension, particulate, or extraction

AmnioBand® Particulate (MTF Wound Care)

D

X

X

AmnioMatrix® (Derma Sciences)

D

X

X

AmnioVisc™ (Lattice Biologics)

NS

X

BioSkin® Flow (HRT)b

E

X

X

X

X

Clarix® Flo (Amniox Medical)

C

X

X

Interfyl™ (Alliqua Biomedical)

NS

X

X

Neox® Flo (Amniox Medical)

C

X

X

OrthoFlo™ (MiMedx)

D

X

PalinGen® Flow (Amnio ReGen Solutions)

C

X

X

PalinGen® SportFlow (Amnio ReGen Solutions)

C

X

X

ProMatrX™ ACF (Amnio ReGen Solutions)

C

X

X

ReNu™ (NuTech Medical)

D

X

X

WoundEx® Flow (Skye Biologics)b

E

X

X

X

X

C: cryopreserved; D: dehydrated; E: extracted connective tissue; HRT: Human Regenerative Technologies; MTF: Musculoskeletal Transplant Foundation; NS: not specified.

a, b Processed by HRT and marketed by under different tradenames.

AmnioClip (FORTECH GmbH) is a ring designed to hold amniotic membrane in the eye without sutures or glue fixation. A mounting device is used to secure the amniotic membrane within the AmnioClip. The AmnioClip currently has CE approval in Europe.

Regulatory Status

The U.S. Food and Drug Administration (FDA) regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation (CFR) title 21, parts 1270 and 1271. Human amniotic membrane products and amniotic fluid products are included in these regulations.

In 2003, Prokera™ was cleared for marketing by the FDA through the 510(k) process for the ophthalmic conformer that incorporates amniotic membrane (K032104). The FDA determined that this device was substantially equivalent to the Symblepharon Ring. The Prokera™ device is intended “for use in eyes in which the ocular surface cells have been damaged, or underlying stroma is inflamed and scarred.” (4)

Rationale:

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

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

The primary end points of interest for trials of wound closure are as follows, consistent with guidance from the U.S. Food and Drug Administration for industry in developing products for treatment of chronic cutaneous ulcer and burn wounds:

1. Incidence of complete wound closure.

2. Time to complete wound closure (reflecting accelerated wound closure).

3. Incidence of complete wound closure following surgical wound closure.

4. Pain control.

Diabetic Lower-Extremity Ulcers

Dehydrated Amniotic Membrane or Placental Membrane

AmnioBand vs Standard Care

AmnioBand Membrane was compared with standard of care (SOC) for the treatment of nonhealing (minimum 4 weeks) diabetic foot ulcers in an industry-sponsored, multicenter trial by DiDomenico et al. (2016). (5) Forty patients were randomized to SOC or to SOC plus weekly applications of the dehydrated placental allograft for up to 12 weeks. Healing was determined by the principal investigator at each institution and confirmed by an independent and blinded panel of 6 physicians. This trial was adequately powered to detect a difference of 45% between groups in the primary outcome (the proportion of wounds healed at 6 weeks). Complete healing by 6 weeks was observed for 70% (14/20) of wounds treated with the dehydrated placental matrix compared with 15% (3/20) of wounds treated by SOC alone (p=0.001). The odds ratio for healing was 17 (95% confidence interval [CI], 3.1 to 93; p=0.001). At 12 weeks, complete healing was observed for 85% (17/20) of wounds in the AmnioBand group compared with 25% (5/20) in the SOC group. Mean time to heal for wounds treated with amniotic membrane was 36 days (95% CI, 27 to 46 days) compared to 70 days (95% CI, 59 to 81 days; p<0.001) with standard care. The number needed to treat to achieve healing at 12 weeks was 1.7 (95% CI, 1.2 to 2.8). Strengths of this trial included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and intention-to-treat (ITT) analysis.

AmnioExcel vs Standard Care

AmnioExcel dehydrated human amniotic membrane (d-HAM) was compared with standard care in an industry-sponsored, open-label multicenter RCT (n=29) by Snyder et al. (2016). (6) Randomization was performed by computer module and stratified by site and wound area. The primary outcome was the percentage of patients with complete wound closure at 6 weeks. The per protocol population included 11 patients in the AmnioExcel group and 10 in the SOC group. For the ITT population, 33% (95% CI, 25.0% to 46.4%) of patients in the AmnioExcel group achieved wound closure by 6 weeks compared to 0% of the SOC group (p=0.017). In the per protocol analysis, 45.5% of patients treated with AmnioExcel achieved wound closure by 6 weeks compared to 0% in the SOC arm (p=0.008) with a 95% confidence interval of the responder ratio of 32.9% to 58.0% (p=0.014). Power analysis was not described and 8 patients withdrew early (4 in each group), raising questions about the reliability of the effect size.

Biovance Registry

Smiell et al. (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types, including 47 diabetic foot wounds, 20 pressure ulcers, and 89 venous ulcers. (7) This study showed the effectiveness of d-HAM in a real-world setting. The size of the wounds at baseline ranged from less than 2 cm2 (35.4% of wounds) to over 25 cm2 (9.0% of wounds). Ninety-eight percent were on the lower extremities. Twenty-eight ulcers had failed prior treatment with advanced biologic therapies (Apligraf, Dermagraft, or Regranex), including 10 diabetic foot wounds. For all wound types, 41.6% closed, with a mean time to closure of 8 weeks and a mean of 2.4 amniotic membrane applications. In the subgroup of 112 patients who practiced good wound care, including offloading or compression therapy as indicated, 49.6% of wounds closed by a mean of 7.4 weeks. Wounds that had not closed during the observation period decreased in size by a mean of 46.6%.

EpiFix vs Standard Care

Zelen et al. (2013) reported an industry-sponsored, nonblinded, RCT comparing use of EpiFix d-HAM (n=13) with SOC (n=12) for diabetic foot ulcers of at least 4 weeks in duration. (8) EpiFix was applied every 2 weeks if the wound had not healed, with weekly dressing changes comprised of nonadherent dressing, moisture retentive dressing, and a compression dressing. Standard moist wound dressing was changed daily. After 4 weeks of treatment, EpiFix-treated wounds had reduced in size by a mean of 97% compared with 32% for the SOC group. Healing rate, defined as complete epithelialization of the open area of the wound, was 77% for EpiFix compared with 0% for SOC. After 6 weeks of treatment, wound sizes were reduced by 98.4% with EpiFix treatment compared with -1.8% for SOC. The healing rate was 92% with EpiFix compared with 8% with SOC alone. At trial conclusion, unhealed wounds from the control group were treated with EpiFix. (9) The mean duration of foot ulcers at the beginning of treatment was 19.4 weeks (range, 6.0-54 weeks) for the combined group. Follow-up was available at 9 to 12 months after primary healing in 18 of 22 eligible patients. Examination of these 18 patients found that 17 (94.4%) wounds remained fully healed. In a subsequent report by Zelen et al. (2014), weekly application of EpiFix resulted in significantly faster healing (n=20; mean, 2.4 weeks) compared with biweekly application (n=20; mean, 4.1 weeks; p=0.039). (10) All wounds treated weekly had healed by week 8 compared with 75% of wounds treated biweekly (p=0.047).

EpiFix vs Apligraf

EpiFix d-HAM was compared with Apligraf (living cell therapy) in a multicenter RCT published by Zelen et al. (2015, 2016). (11, 12) Sixty patients with less than 20% wound reduction during a 2-week run-in period were randomized to treatment with Epifix, Apligraf, or standard wound care. Although patients and site investigators could not be blinded due to differences in products, wound healing was verified by 3 independent physicians who evaluated photographic images. Median wound size was 2.0 cm2 (range, 1.0-9.0 cm2) and median duration of the index ulcer was 11 weeks (range, 5-54 weeks). After 6 weekly treatments, the mean percent wound area healed was 97.1% for EpiFix, 80.9% for Apligraf, and 27.7% for SOC; 95% of wounds had healed completely in the EpiFix group compared with 45% treated with Apligraf and 35% who received standard wound care (p=0.003). The estimated median time to wound closure, based on Kaplan-Meier analysis, was 13 days for EpiFix compared with 49 days for both Apligraf and SOC (p<0.001). This study was extended to 12 weeks with 100 patients who were treated with either Epifix (n=32), Apligraf (n=33), or standard wound care (n=35). (12) Patients whose wound failed to heal by at least 50% by 6 weeks exited the study; this included 4 patients in the Apligraf group and 13 in the SOC group. An additional 5 SOC patients withdrew from the study. Patients treated with EpiFix had a higher probability of wound healing (hazard ratio, 5.66; 95% CI, 3.03 to 10.57; p<0.001) compared with SOC and required fewer weekly treatments (3.4) compared with wounds treated with Apligraf (5.9; p=0.003).

Kirsner et al. (2015) reported an industry-sponsored observational study comparing the effectiveness of Apligraf and EpiFix in a real-world setting. (13) Data were obtained from a wound care-specific database from 3000 wound care facilities. The database included 1458 diabetic ulcers treated for the first time in 2014 with Apligraf (n=994) or EpiFix (n=464). Using the same criteria as the 2015 study by Zelen (2015; described above), data were included on the treatment of 226 diabetic foot ulcers from 99 wound care centers. Selection criteria for foot wounds included size between 1 cm2 and 25 cm2, duration of 1 year or less, and wound reduction of 20% or less in the 14 days prior to treatment. Although wounds for the 2 groups were comparable at baseline, the rationale for using a particular product was not reported. One hundred sixty-three wounds were treated with Apligraf (mean, 2.5 applications) and 63 were treated with EpiFix (mean, 3.5 applications, p=0.003). By week 24, 72% of wounds treated with Apligraf and 47% of wounds treated with EpiFix had closed (p=0.01). Median time to closure was 13.3 weeks for Apligraf and 26.0 weeks for EpiFix (p=0.01). This study is at risk of selection bias in determining treatment assignment.

Cryopreserved Placental Membrane

Grafix vs Standard Care

Grafix cryopreserved placental membrane was compared with standard wound care in a 2014 multicenter RCT. (14) Strengths of this trial included power analysis, blinded assessment of wound healing, evaluation of wound closure as the primary outcome measure, and ITT analysis. Ninety-seven patients with chronic diabetic foot ulcers were randomized to Grafix or to standard wound therapy, both administered once a week for up to 12 weeks. Power analysis indicated that 94 patients per arm would be needed. However, after prespecified interim analysis at 50% enrollment, the blinded review committee recommended that the trial be stopped due to efficacy of the treatment. ITT analysis from the blinded evaluation phase showed a significant increase in the proportion of patients achieving the primary outcome of wound closure by 12 weeks (62.0% vs 21.3%, p<0.001) and a decrease in the median time to complete wound closure (42.0 days vs 69.5 days, p=0.019). Safety evaluation found that fewer Grafix-treated patients experienced at least 1 adverse event (44.0% vs 66.0%, p=0.031) or had wound-related infections (18.0% vs 36.2%, p=0.044), with a trend toward fewer hospitalizations related to infections (6% vs 15%, p=0.15).

Section Summary: Diabetic Lower-Extremity Ulcers

The evidence on amniotic and placental membrane products for the treatment of diabetic lower-extremity ulcers includes several RCTs comparing HAM with SOC or with an established advanced wound care product. All of these industry-sponsored studies included evaluation of wound closure as the primary outcome measure, and some included power analysis, blinded assessment of wound healing, and ITT analysis. For the amniotic membrane products evaluated in RCTs (e.g., AmnioBand Membrane, EpiFix, Grafix), results indicated improved outcomes compared with SOC, and outcomes that are at least as good as the advanced wound care product Apligraf. Also, a registry study for Biovance showed improved health outcomes, with a magnitude of benefit similar to that observed in the RCTs for other products.

Lower-Extremity Ulcers Due to Venous Insufficiency

Dehydrated Amniotic Membrane

EpiFix

Serena et al. (2014) reported on an industry-sponsored multicenter open-label RCT that compared EpiFix d-HAM plus compression therapy with compression therapy alone for venous leg ulcers (see Table 2). (15) The primary outcome in this trial was the proportion of patients with 40% wound closure at 4 weeks, which was achieved by about twice as many patients in the combined EpiFix group compared with the control group (see Table 3). However, a similar percentage of patients in the combined EpiFix group and the control group achieved complete wound closure during the 4-week study. There was no significant difference in healing for wounds given 1 vs 2 applications of amniotic membrane (62% vs 63%, respectively). Strengths of this trial included adequate power and ITT analysis with last observation carried forward. Limitations included the lack of blinding for wound evaluation and use of 40% closure rather than complete closure. A 2015 retrospective study of 44 patients from this RCT (31 treated with amniotic membrane) found that wounds with at least 40% closure at 4 weeks (n=20) had a closure rate of 80% by 24 weeks; however, this analysis did not take into account additional treatments after the 4-week randomized trial period. (16)

A second industry-sponsored multicenter open-label RCT (Bianchi et al., 2017) evaluated the time to complete ulcer healing following weekly treatment with EpiFix d-HAM and compression therapy or compression therapy with standard dressing (see Table 2). (17) Patients treated with EpiFix had a higher probability of complete healing by 12 weeks, as adjudicated by blinded outcome assessors (hazard ratio, 2.26; 95% CI, 1.25 to 4.10; p=0.01), and improved time to complete healing, as assessed by Kaplan-Meier analysis. Healing within 12 weeks was reported for 60% of patients in the EpiFix group and 35% of patients in the control group (see Table 3). There were several limitations of this trial. Nineteen (15%) patients were excluded from the analysis, and the proportion of patients excluded differed between groups (19% from the EpiFix group vs 11% from the control group). Also, the trial did not use ITT analysis. Had all excluded patients been considered treatment failures, the difference between groups would have been 17% (48% wound healing for EpiFix vs 31% for controls). There was also a difference between the groups in how treatment failures at 8 weeks were handled. Patients in the control group who did not have a 40% decrease in wound area at 8 weeks were considered study failures and treated with advanced wound therapies. Although the trialists noted that only 1 patient from this group had healed by weeks 12 and 16, reporting is unclear about how many patients from the d-HAM group would have been considered treatment failures at 8 weeks using the same cutoff.

Table 2. Summary of Key RCT Characteristics

 

Interventions

Study

Countries

Sites

Dates

Participants

Active

Comparator

Serena et al. (2014) (15)

U.S.

8

2012-2014

84 patients with a full-thickness chronic VLU between 2 and 20 cm2 treated for at least 14 days

1 (n=26) or 2 (n=27)

applications of EpiFix plus compression (n=53)

Compression therapy alone (n=31)

Bianchi et al. (2017) (17)

U.S.

15

2015-2017

128 patients with a full-thickness VLU of at least 30-days duration

Weekly EpiFix plus moist wound therapy plus compression (n=64; 52 analyzed)

Moist wound therapy plus compression (n=64; 57 analyzed)

RCT: randomized controlled trial; VLU: venous leg ulcer.

Table 3. Summary of Key RCT Results

Study

Percent With 40% Wound Closure at 4 Weeks

Percent With Complete Wound Closure at 4 Weeks

Percent With Complete Wound Closure at 12 Weeks

Percent With Complete Wound Closure at 16 Weeks

Serena et al. (2014) (15)

EpiFix

62

11.3

   

Control

32

12.9

   

p

0.005

     

Bianchi et al. (2017) (17)

EpiFix

   

60

71

Control

   

35

44

p

   

0.013

0.007

RCT: randomized controlled trial.

Biovance

As described above, Smiell et al. (2015) reported on an industry-sponsored, multicenter registry study of Biovance d-HAM for the treatment of various chronic wound types; about half (n=89) were venous ulcers. (7) Of the 179 treated, 28 (16%) ulcers had failed prior treatment with advanced biologic therapies. For all wound types, 41.6% closed within a mean time of 8 weeks and a mean of 2.4 amniotic membrane applications. However, without a control group, the percentage of wounds that would have healed with SOC is unknown.

Section Summary: Lower-Extremity Ulcers due to Venous Insufficiency

Well-designed and well-conducted RCTs are comparing HAM with SOC for venous lower-extremity ulcers and evaluating the outcome of complete wound closure are needed to demonstrate efficacy. The evidence on HAM for the treatment of venous leg ulcers includes 2 multicenter RCTs with EpiFix. The RCT by Serena (2014) reported a larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure at 4 weeks did not differ between EpiFix and SOC. The study by Bianchi (2017) evaluated complete wound closure at 12 weeks after weekly application of EpiFix or standard dressings with compression. Although a significant difference in complete healing was reported, data interpretation is limited by the differential loss to follow-up and exclusions between groups and the lack of ITT analysis. Corroboration with well-designed and well-conducted RCTs evaluating wound healing is needed to demonstrate efficacy. The corroborating RCTs should report ITT analysis, with analysis of all patients, including those who were off treatment or had protocol deviations and exclusions. While per protocol analysis can supplement the results, it is not sufficient to determine the effect of the treatment on health outcomes.

Osteoarthritis

ReNu

A feasibility study (n=6) of cryopreserved human amniotic membrane (c-HAM) suspension with amniotic fluid?derived cells (ReNu) for the treatment of knee osteoarthritis was reported in 2016. (18) A single intra-articular injection of the suspension was used, with follow-up at 1 and 2 weeks and at 3, 6, and 12 months posttreatment. Outcomes included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee scale, and a numeric pain scale. Statistical analyses were not performed for this small sample. No adverse effects, aside from a transient increase in pain, were noted. An RCT is in progress.

Section Summary: Osteoarthritis

Current evidence is insufficient to support definitive conclusions on the utility of c-HAM in the treatment of knee osteoarthritis.

Plantar Fasciitis

One systematic review and 2 randomized pilot studies were identified on the treatment of plantar fasciitis using injection of micronized HAM.

Systematic Review

A 2016 network meta-analysis of 22 RCTs (total n=1216 patients) compared injection therapies for plantar fasciitis. (19) In addition to c-HAM and micronized d-HAM/chorionic membrane, treatments included corticosteroids, botulinum toxin type A, autologous whole blood, platelet-rich plasma (PRP), nonsteroidal anti-inflammatory drugs, dry needling, dextrose prolotherapy, and polydeoxyribonucleotide. Placebo arms included normal saline, local anesthetic, sham dry needling, and tibial nerve block. The minimum clinically important difference (MCID) was defined as -9 mm on a visual analog scale (VAS), which is substantially lower than the 30% or 20-mm decrease in VAS score for pain more typically used. Secondary outcomes included total and subscores for the Foot Health Status Questionnaire (FHSQ), with an MCID defined as 7 on the FHSQ function and 9 on the FHSQ general foot health subscales. Overall, risk of bias was low for randomization and blinding of participants, high for blinding of personnel, and uncertain for allocation concealment and outcome reporting. Analysis found d-HAM had the highest probability for improvement in pain and composite outcomes in the short term. However, this finding was based only on a single RCT. When the efficacy of d-HAM was compared to corticosteroid injections, the mean difference in VAS score was a modest at -7.32 out of 100 (95% CI, -11.2 to -3.38) and the mean difference in the FHSQ score was 31.2 (95% CI, 13.9 to 48.6). Outcomes at 2-to-6 months (7 RCTs) favored botulinum toxin for pain and PRP for composite outcomes.

Clarix Flo

One small (n=23), industry-sponsored, double-blind study (2015) found similar improvements with injection of c-HAM (Clarix Flo) compared with corticosteroid injection. (20) Another industry-sponsored, patient-blinded study (2013) by Zelen et al. (n=45) compared injection of saline to d-HAM (AmnioFix) 0.5 mL or 1.25 mL in patients with symptoms recalcitrant to conservative treatment. (21) In the 2 d-HAM groups, scores on the American Orthopaedic Foot and Ankle Society hindfoot scale improved by about 50 points over the 8 weeks of the study compared with 10 points for controls (p<0.001). FACES pain scores decreased from 8.7 out of 10 at baseline to 0.8 at 8 weeks with d-HAM, compared with a decrease from 8.1 to 4.6 for controls (p<0.001).

Section Summary: Plantar Fasciitis

The evidence on injection of particulated amniotic membrane and amniotic fluid for the treatment of plantar fasciitis is limited. Evidence includes a small (n=23) double-blind comparison with corticosteroid and a patient-blinded (n=45) comparison of 2 different doses of d-HAM with saline. Power analyses were not reported. A network meta-analysis, which identified only the Zelen et al. trial, concluded that d-HAM was more effective than corticosteroid. However, these 2 small trials are not sufficient to demonstrate an improvement in health outcomes for this common condition. Additional study in a larger number of patients is needed to demonstrate consistency in results.

Sutured HAM Graft for Ophthalmologic Conditions

Sutured HAM graft has been evaluated for a variety of ophthalmologic conditions.

Neurotrophic Keratitis

Khokhar et al. (2005) reported on an RCT of 30 patients (30 eyes) with refractory neurotrophic corneal ulcers who were randomized to HAM transplantation (n=15) or to conventional treatment with tarsorrhaphy or bandage contact lens. (22) At the 3-month follow-up, 11 (73.3%) of 15 patients in the HAM group showed complete epithelialization compared to 10 (66.7%) of 15 in the conventional group. This difference was not significantly significant.

Following Pterygium Repair

A number of RCTs have been reported on use of amniotic membrane following pterygium repair. In 2013, the American Academy of Ophthalmology published a technology assessment on options and adjuvants for pterygium surgery. (23) Reviewers identified 4 RCTs comparing conjunctival or limbal autograft procedure with amniotic membrane graft, finding that conjunctival or limbal autograft was more effective than HAM graft in reducing the rate of pterygium recurrence. A 2016 Cochrane review of 20 RCTs (total n=1866 patients) arrived at the same conclusion. (24)

Stevens-Johnson Syndrome

One RCT from India by Sharma et al. (2016) assigned 25 patients (50 eyes) with acute ocular Stevens-Johnson syndrome to c-HAM plus medical therapy (antibiotics, steroids, or lubricants) or to medical therapy alone. (25) The c-HAM was prepared locally and applied with fibrin glue rather than sutures. Application of c-HAM in the early stages of Stevens-Johnson syndrome resulted in improved visual acuity (p=0.042), better tear breakup time (p=0.015), improved Schirmer test results (p<0.001), and less conjunctival congestion (p=0.03). In the c-HAM group at 180 days, there were no cases of corneal haze, limbal stem-cell deficiency, symblepharon, ankyloblepharon, or lid-related complications. These outcomes are dramatically better than those in the medical therapy alone group, which had 11 (44%) of 25 cases with corneal haze (p=0.001), 6 (24%) cases of corneal vascularization and conjunctivalization (p=0.03), and 6 (24%) cases of trichiasis and metaplastic lashes.

Persistent Epithelial Defects and Ulceration

Bouchard and John (2004) reviewed the use of amniotic membrane transplantation in the management of severe ocular surface disease. (26) They noted that c-HAM has been available since 1995, and has become an established treatment for persistent epithelial defects and ulceration refractory to conventional therapy. However, there was a lack of controlled studies due to rarity of the diseases and the absence of a standard therapy. They identified 661 reported cases in the peer-reviewed literature. Most cases reported assessed the conjunctival indications of pterygium, scars and symblepharon, and corneal indications of acute chemical injury and postinfectious keratitis.

Ocular Burns

A 2012 Cochrane review evaluated the evidence on HAM graft for acute ocular burns. (27) Included in the review was a single RCT from India of 68 patients with acute ocular burns who were randomized to c-HAM plus medical therapy or to medical therapy alone. In the subset of 36 patients with moderate ocular burns treated within 7 days, 13 (65.0%) of 20 control eyes and 14 (87.5%) of 16 eyes treated with amniotic membrane transplantation had complete epithelialization by 21 days. There was a trend (p=0.09) toward a reduced relative risk of failure of epithelization in the treatment group. Mean logarithm of the minimum angle of resolution (logMAR) final visual acuities were 0.06 in the treatment group and 0.38 in the control group. In the subset of patients with severe ocular burns treated within 7 days, 1 (5.9%) of 17 eyes treated with amniotic membrane transplantation and 1 (6.7%) of 15 control eyes were epithelialized by day 21. There was no significant difference in final visual acuity (1.77 logMAR in eyes treated with amniotic membrane transplantation vs 1.64 in control eyes (p=0.79). The risk of bias was considered high because of differences between the groups at baseline and because outcome assessors could not be masked to treatment. Reviewers determined that conclusive evidence supporting the treatment of acute ocular surface burns with amniotic membrane transplantation was lacking.

Bullous Keratopathy

Bullous keratopathy is characterized by stromal edema and epithelial and subepithelial bulla formation. Dos Santos Paris et al. (2013) published an RCT that compared fresh HAM to stromal puncture for the management of pain in patients with bullous keratopathy. (28) Forty patients with pain from bullous keratopathy who were either waiting for a corneal transplant or had no potential for sight in the affected eye were randomized to the 2 treatments. Symptoms had been present for approximately 2 years. HAM resulted in a more regular epithelial surface at up to 180 days follow-up, but there was no difference between the treatments related to the presence of bullae or the severity or duration of pain. Because of the similar effects on pain, the authors recommended initial use of the simpler stromal puncture procedure, with use of HAM only if pain did not resolve.

Dry Eye Syndrome, Corneal Perforation, and Limbus Stem-Cell Deficiency

No RCTs were identified on these other ophthalmic indications.

Section Summary: Sutured HAM Graft for Ophthalmic Conditions

The most widely studied condition with a technology assessment evaluating RCT evidence is the use of HAM following pterygium repair. The assessment concluded, based on 4 RCTs, that conjunctival or limbal autograft was more effective than HAM. An RCT on HAM for refractory neurotrophic corneal ulcers found that outcomes following HAM graft were similar to those for conventional therapy. One RCT has shown that application of c-HAM in the early stages of Stevens-Johnson syndrome leads to clinically significant improvement compared to medical therapy alone. A 2012 Cochrane review found 1 RCT evaluating HAM graft for acute ocular burns. The trial suggested a benefit for HAM in the healing rate for ocular burns, but it was considered at high or uncertain risk of bias due to unequal baseline scores and lack of masking to treatment condition. A trial on HAM for the treatment of bullous keratopathy reported that there was no difference in clinical outcomes between HAM and stromal puncture. Other indications have been studied only in case series.

HAM Without Suture for Ophthalmic Conditions

Traditionally, amniotic membrane has been fixed onto the eye with sutures or glue or placed under a bandage contact lens for a variety of ocular surface disorders. Several devices have been reported that use a ring around a c-HAM allograft that allows it to be inserted under topical anesthesia similar to insertion of a contact lens. The easier insertion may lead to more widespread use, such as dry eye disease and for healing after photorefractive keratectomy (PRK). The development of Prokera, a commercially available product, was supported in part by the National Institute of Health and the National Eye Institute.

Dry Eye Disease

John et al. (2017) reported on an RCT with 20 patients with moderate-to-severe dry eye disease who were treated with Prokera c-HAM or maximal conventional treatment. (29) The c-HAM was applied for an average of 3.4 days (range, 3-5 days), while the control group continued treatment with artificial tears, cyclosporine A, serum tears, antibiotics, steroids, and nonsteroidal anti-inflammatory medications. The primary outcome was an increase in corneal nerve density. Signs and symptoms of dry eye disease improved at both 1-month and 3-month follow-ups in the c-HAM group but not in the conventional treatment group. For example, pain scores decreased from 7.1 at baseline to 2.2 at 1 month and 1.0 at 3 months in the c-HAM group. In vivo confocal microscopy, reviewed by masked readers, showed a significant increase in corneal nerve density in the study group at 3 months, with no change in nerve density in the controls. Corneal sensitivity was similarly increased in the c-HAM group but not in controls.

The Prokera c-HAM device was also evaluated in a series by Cheng et al. (2016) (30) The senior author of the study holds the patent on Prokera. This retrospective review assessed 10 patients treated with the self-retained device for moderate-to-severe dry eye disease. In this study, these 10 patients had moderate-to-severe dry eye syndrome despite conventional medical treatment. The c-HAM device was placed in 15 eyes (1 eye at a time) for a mean of 4.9 days (range, 2-8 days), after which the c-HAM was either dissolved or cloudy. Treatment resulted in symptomatic relief for a mean of 4.2 months (range, 0.3 to 6.8 months) after a single treatment. Symptomatic improvement was accompanied by statistically significant reductions of Ocular Surface Disease Index scores, use of topical medications, conjunctival hyperemia, corneal staining (all p<0.001), and a trend toward improved visual acuity (p=0.06).

Photorefractive Keratectomy

Vlasov et al. (2016) reported on a prospective, nonrandomized controlled trial evaluating the effect of sutureless amniotic membrane (Prokera) on corneal wound healing after PRK. (31) Forty patients (80 eyes) had PRK for myopia. After surgery, a high-oxygen-transmissible bandage contact lens was applied on the dominant eye and cryopreserved amniotic membrane on the nondominant eye. Patients were assessed daily until complete corneal re-epithelialization occurred in both eyes and then at 2 weeks and 1, 3, 6, and 12 months thereafter. The primary outcome was re-epithelialization, which was assessed daily with slitlamp examination, fluorescein staining, and photography. The time to complete reepithelization was faster in eyes treated with a bandage contact lens (3.7 days; range, 3-7 days) than with the amniotic membrane product (4.6 days; range, 3-16 days). Initially, patients reported greater discomfort and dryness with amniotic membrane. Visual and clarity and optical quality of the cornea were similar between the amniotic membrane graft eyes and bandage contact lens eyes.

Other Indications

Use of Prokera has also been reported for refractory ulcerative keratitis, neurotrophic keratitis, recurrent epithelial erosion, high-risk corneal grafts, acute chemical and thermal burns, acute Stevens-Johnson syndrome, necrotizing scleritis, and limbal stem-cell deficiency. (30)

Section Summary: HAM Without Suture for Ophthalmic Conditions

Current evidence on use of the Prokera device includes an RCT with 20 patients, a within-subject comparative study, and case series. The RCT with 20 patients found a benefit of Prokera in patients with dry eye disease, but the prospective comparative trial identified found no benefit of HAM compared with a bandage contact lens when used for wound healing after PRK. While the studies reported generally positive effects, high-quality RCTs are needed to determine the effect of sutureless self-contained HAM on corneal healing.

Summary of Evidence

Diabetic Lower-Extremity Ulcers

For individuals who have nonhealing diabetic lower-extremity ulcers who receive a patch or flowable formulation of human amniotic membrane (HAM) (i.e., AmnioBand Membrane, Biovance, Epifix, Grafix), the evidence includes randomized controlled trials (RCTs). Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The RCTs evaluating amniotic and placental membrane products for the treatment of nonhealing (<20% healing with ≥2 weeks of standard care) diabetic lower-extremity ulcers have compared HAM to standard care or to an established advanced wound care product. These trials used wound closure as the primary outcome measure, and some used power analysis, blinded assessment of wound healing, and intention-to-treat analysis. For the HAM products that have been sufficiently evaluated (i.e., AmnioBand Membrane, Biovance, Epifix, Grafix), results have shown improved outcomes compared to standard care, and outcomes that are at least as good as an established advanced wound care product. Improved health outcomes in the RCTs are supported by multicenter registries. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Lower-Extremity Ulcers due to Venous Insufficiency

For individuals who have lower-extremity ulcers due to venous insufficiency who receive a patch or flowable formulation of HAM, the evidence includes two RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The evidence on HAM for the treatment of lower-extremity venous ulcers includes 2 multicenter RCTs with EpiFix. One RCT reported larger percent wound closure at 4 weeks, but the percentage of patients with complete wound closure did not differ between EpiFix and standard of care. A second multicenter RCT reported a significant difference in complete healing at 12 weeks, but the interpretation is limited by methodologic concerns. Well-designed and well-conducted RCTs that compare HAM with the standard of care for venous insufficiency ulcers are needed. The evidence is insufficient to determine the effects of the technology on health outcomes.

Osteoarthritis

For individuals who have knee osteoarthritis who receive injection of suspension or particulate formulation of HAM or amniotic fluid, the evidence includes a feasibility study. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. The pilot study assessed the feasibility of a larger RCT evaluating HAM injection. Additional trials, which will have a larger sample sizes and longer follow-up, are needed to permit conclusions on the effect of this treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

Plantar Fasciitis

For individuals who have plantar fasciitis who receive injection of suspension or particulate formulation of HAM or amniotic fluid, the evidence includes 2 small RCTs. Relevant outcomes are symptoms, functional outcomes, quality of life, and treatment-related morbidity. Research on HAM injections for plantar fasciitis is at an early stage. The evidence includes a small (n=23) double-blind comparison with corticosteroid and a patient-blinded (n=45) comparison of 2 different doses of dehydrated HAM with saline. Additional controlled trials with larger sample sizes and longer follow-up are needed to permit conclusions on the effect of HAM and amniotic fluid injections on plantar fasciitis pain. The evidence is insufficient to determine the effects of the technology on health outcomes.

Ophthalmic Conditions

For individuals who have neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, or persistent epithelial defects who receive sutured HAM graft, the evidence incudes several RCTs and a technology assessment. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. The most widely studied condition with a technology assessment of RCT evidence is the use of HAM following pterygium repair. The technology assessment concluded, based on 4 RCTs, that conjunctival or limbal autograft was more effective than HAM. An RCT evaluating HAM for refractory neurotrophic corneal ulcers found that outcomes following HAM graft were similar to conventional therapy. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have ophthalmic disorders other than neurotrophic keratitis, corneal ulcers and melts, pterygium repair, Stevens-Johnson syndrome, or persistent epithelial defects who receive sutured HAM graft, the evidence includes a systematic review article and RCTs. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. A 2012 Cochrane review found a single RCT on HAM graft for acute ocular burns. The trial suggested a benefit in the healing rate for ocular burns, but it was considered at high or uncertain risk of bias due to unequal baseline scores and the lack of masking of the treatment condition. A trial assessing HAM for the treatment of bullous keratopathy reported no difference in clinical outcomes between HAM and stromal puncture. RCTs are needed to evaluate the benefit of HAM for these indications. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have ophthalmic conditions who receive HAM without suture, the evidence includes an RCT (n=20), a within-subject comparative study and case series. Relevant outcomes are symptoms, morbid events, functional outcomes, and quality of life. Traditionally, amniotic membrane has been sutured onto the eye for a variety of severe ocular surface disorders. The Prokera device is novel because it has a ring around the cryopreserved HAM allograft that permits it to be inserted under topical anesthesia, similar to insertion of a contact lens, allowing for more widespread use. Use of Prokera has been reported for refractory dry eye syndrome, ulcerative keratitis, neurotrophic keratitis, recurrent epithelial erosion, high-risk corneal grafts, acute chemical and thermal burns, acute Stevens-Johnson syndrome, necrotizing scleritis, and limbal stem-cell deficiency. Current evidence on its use is limited. While the small RCT and case series reported generally positive effects, the prospective comparative trial found no benefit of HAM compared to a bandage contact lens for healing a wound after photorefractive keratectomy. RCTs are needed to determine whether HAM improves healing for the various ophthalmic disorders. The evidence is insufficient to determine the effects of the technology on health outcomes.

Clinical Input

In 2017, the Blue Cross Blue Shield Association (BCBSA) received the following clinical input on use of human amniotic membrane for ophthalmic disorders.

Based on the evidence and independent clinical input, the clinical input supports that the following indications provide a clinically meaningful improvement in the net health outcome and are consistent with generally accepted medical practice:

Use of sutured human amniotic membrane (also described as amniotic membrane graft [AMG]) for individuals with:

o Neurotrophic keratitis,

o Corneal ulcers and melts,

o Following pterygium repair,

o Stevens-Johnson syndrome, and

o Persistent epithelial defects.

Based on the evidence and independent clinical input, the clinical input does not support whether the following indications provide a clinically meaningful improvement in the net health outcome or are consistent with generally accepted medical practice:

Use of sutured AMG for individuals with:

o Corneal perforation,

o Bullous keratopathy,

o Limbus stem-cell deficiency, and

o Severe dry eye.

Based on the evidence and independent clinical input, the clinical input does not support whether the following indication provides a clinically meaningful improvement in the net health outcome or is consistent with generally accepted medical practice:

Use of sutureless AMG (e.g., Prokera) instead of sutured AMG.

Practice Guidelines and Position Statements

No guidelines or statements were identified.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 4.

Table 4. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT02318511a

An Investigation of ReNu™ Knee Injection: Monitoring the Response of Knee Function and Pain in Patients With Osteoarthritis

200

Mar 2018

NCT02609594a

A Multi-center Randomized Controlled Clinical Trial Evaluating Two Application Regimens of Amnioband Dehydrated Human Amniotic Membrane and Standard of Care vs. Standard of Care Alone in the Treatment of Venous Leg Ulcers

240

Nov 2018

NCT02880592a

A Multi-center, Randomized Controlled Clinical Trial Evaluating the Effect of Fresh Amniotic Membrane in the Treatment of Diabetic Foot Ulcers

100

Nov 2018

NCT02427191a

A Prospective, Single-Blinded, Randomized Controlled Trial of the Micronized dHACM Injection as Compared to the Saline Placebo Injection in the Treatment of Plantar Fasciitis (AmnioFix Injectable)

146

Dec 2018

NCT02838784a

The Efficacy and Safety of Artacent™ for Treatment Resistant Lower Extremity Venous and Diabetic Ulcers: A Prospective Randomized Study

134

Dec 2018

NCT03379324a

A Prospective, Randomized Study Comparing Outcomes Following Arthroscopic Double-row Rotator Cuff Repair With and Without the Addition of a Cryopreserved, Liquid, Injectable Amnion Allograft

260

Sep 2019

NCT02322554

The Registry of Cellular and Tissue Based Therapies for Chronic Wounds and Ulcers

50,000

Jan 2020

NCT03390920

Evaluation of Outcomes With Amniotic Fluid for Musculoskeletal Conditions Musculoskeletal Conditions

200

Jun 2022

NCT: national clinical trial.

a Denotes industry-sponsored or cosponsored trial.

Contract:

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

Coding:

CODING:

Disclaimer for coding information on Medical Policies

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

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

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

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

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

CPT Codes

None

HCPCS Codes

Q4131, Q4132, Q4133, Q4137, Q4138, Q4139, Q4140, Q4145, Q4148, Q4150, Q4151, Q4153, Q4154, Q4155, Q4156, Q4157, Q4159, Q4160, Q4162, Q4163, Q4168, Q4169, Q4170, Q4171, Q4173, Q4174, Q4176, Q4177, Q4178, Q4180, Q4181, Q4182, Q4185, Q4186, Q4187, Q4188, Q4189, Q4190, Q4191, Q4192, Q4194, Q4198, Q4201, Q4204

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

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

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

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

References:

1. Parolini O, Soncini M, Evangelista M, et al. Amniotic membrane and amniotic fluid-derived cells: potential tools for regenerative medicine? Regen Med. Mar 2009; 4(2):275-291. PMID 19317646

2. Koob TJ, Rennert R, Zabek N, et al. Biological properties of dehydrated human amnion/chorion composite graft: implications for chronic wound healing. Int Wound J. Oct 2013; 10(5):493-500. PMID 23902526

3. Shimberg M, Wadsworth K. The use of amniotic-fluid concentrate in orthopaedic conditions. J Bone Joint Surg. 1938; 20(I):167-177.

4. Food and Drug Administration. 510Ik) Summary: ProKera(TM) Bio-Tissue Inc. 2003; Available at <https://www.accessdata.fda.gov> (accessed May 19, 2017).

5. DiDomenico LA, Orgill DP, Galiano RD, et al. Aseptically processed placental membrane improves healing of diabetic foot ulcerations: prospective, randomized clinical trial. Plast Reconstr Surg Glob Open. Oct 2016; 4(10):e1095. PMID 27826487

6. Snyder RJ, Shimozaki K, Tallis A, et al. A prospective, randomized, multicenter, controlled evaluation of the use of dehydrated amniotic membrane allograft compared to standard of care for the closure of chronic diabetic foot ulcer. Wounds. Mar 2016; 28(3):70-77. PMID 26978860

7. Smiell JM, Treadwell T, Hahn HD, et al. Real-world experience with a decellularized dehydrated human amniotic membrane allograft. Wounds. Jun 2015; 27(6):158-169. PMID 26061491

8. Zelen CM, Serena TE, Denoziere G, et al. A prospective randomised comparative parallel study of amniotic membrane wound graft in the management of diabetic foot ulcers. Int Wound J. Oct 2013; 10(5):502-507. PMID 23742102

9. Zelen CM, Serena TE, Fetterolf DE. Dehydrated human amnion/chorion membrane allografts in patients with chronic diabetic foot ulcers: a long term follow-up study. Wound Med. 2014; 4:1-4. PMID

10. Zelen CM, Serena TE, Snyder RJ. A prospective, randomised comparative study of weekly vs biweekly application of dehydrated human amnion/chorion membrane allograft in the management of diabetic foot ulcers. Int Wound J. Apr 2014; 11(2):122-128. PMID 24618401

11. Zelen CM, Gould L, Serena TE, et al. A prospective, randomised, controlled, multi-centre comparative effectiveness study of healing using dehydrated human amnion/chorion membrane allograft, bioengineered skin substitute or standard of care for treatment of chronic lower extremity diabetic ulcers. Int Wound J. Dec 2015; 12(6):724-732. PMID 25424146

12. Zelen CM, Serena TE, Gould L, et al. Treatment of chronic diabetic lower extremity ulcers with advanced therapies: a prospective, randomised, controlled, multi-centre comparative study examining clinical efficacy and cost. Int Wound J. Apr 2016; 13(2):272-282. PMID 26695998

13. Kirsner RS, Sabolinski ML, Parsons NB, et al. Comparative effectiveness of a bioengineered living cellular construct vs. a dehydrated human amniotic membrane allograft for the treatment of diabetic foot ulcers in a real world setting. Wound Repair Regen. Sep 2015; 23(5):737-744. PMID 26100572

14. Lavery LA, Fulmer J, Shebetka KA, et al. The efficacy and safety of Grafix((R)) for the treatment of chronic diabetic foot ulcers: results of a multi-centre, controlled, randomised, blinded, clinical trial. Int Wound J. Oct 2014; 11(5):554-560. PMID 25048468

15. Serena TE, Carter MJ, Le LT, et al. A multicenter, randomized, controlled clinical trial evaluating the use of dehydrated human amnion/chorion membrane allografts and multilayer compression therapy vs. multilayer compression therapy alone in the treatment of venous leg ulcers. Wound Repair and Regeneration. Nov-Dec 2014; 22(6):688-693. PMID 25224019

16. Serena TE, Yaakov R, DiMarco D, et al. Dehydrated human amnion/chorion membrane treatment of venous leg ulcers: correlation between 4-week and 24-week outcomes. J Wound Care. Nov 2015; 24(11):530-534. PMID 26551645

17. Bianchi C, Cazzell S, Vayser D, et al. A multicentre randomised controlled trial evaluating the efficacy of dehydrated human amnion/chorion membrane (EpiFix(R)) allograft for the treatment of venous leg ulcers. Int Wound J. Oct 11 2017. PMID 29024419

18. Vines JB, Aliprantis AO, Gomoll AH, et al. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. Aug 2016; 29(6):443-450. PMID 26683979

19. Tsikopoulos K, Vasiliadis HS, Mavridis D. Injection therapies for plantar fasciopathy ('plantar fasciitis'): a systematic review and network meta-analysis of 22 randomised controlled trials. Br J Sports Med. Nov 2016; 50(22):1367-1375. PMID 27143138

20. Hanselman AE, Tidwell JE, Santrock RD. Cryopreserved human amniotic membrane injection for plantar fasciitis: a randomized, controlled, double-blind pilot study. Foot Ankle Int. Feb 2015; 36(2):151-158. PMID 25249320

21. Zelen CM, Poka A, Andrews J. Prospective, randomized, blinded, comparative study of injectable micronized dehydrated amniotic/chorionic membrane allograft for plantar fasciitis--a feasibility study. Foot Ankle Int. Oct 2013; 34(10):1332-1339. PMID 23945520

22. Khokhar S, Natung T, Sony P, et al. Amniotic membrane transplantation in refractory neurotrophic corneal ulcers: a randomized, controlled clinical trial. Cornea. Aug 2005; 24(6):654-660. PMID 16015082

23. Kaufman SC, Jacobs DS, Lee WB, et al. Options and adjuvants in surgery for pterygium: a report by the American Academy of Ophthalmology. Ophthalmology. Jan 2013; 120(1):201-208. PMID 23062647

24. Clearfield E, Muthappan V, Wang X, et al. Conjunctival autograft for pterygium. Cochrane Database Syst Rev. Feb 11 2016; 2:CD011349. PMID 26867004

25. Sharma N, Thenarasun SA, Kaur M, et al. Adjuvant role of amniotic membrane transplantation in acute ocular Stevens-Johnson syndrome: a randomized control trial. Ophthalmology. Mar 2016;123(3):484-491. PMID 26686968

26. Bouchard CS, John T. Amniotic membrane transplantation in the management of severe ocular surface disease: indications and outcomes. Ocul Surf. Jul 2004; 2(3):201-211. PMID 17216092

27. Clare G, Suleman H, Bunce C, et al. Amniotic membrane transplantation for acute ocular burns. Cochrane Database Syst Rev. 2012; 9:CD009379. PMID 22972141

28. Paris Fdos S, Goncalves ED, Campos MS, et al. Amniotic membrane transplantation vs anterior stromal puncture in bullous keratopathy: a comparative study. Br J Ophthalmol. Aug 2013; 97(8):980-984. PMID 23723410

29. John T, Tighe S, Sheha H, et al. Corneal nerve regeneration after self-retained cryopreserved amniotic membrane in dry eye disease. J Ophthalmol. Aug 15 2017; 2017:6404918. PMID 28894606

30. Cheng AM, Zhao D, Chen R, et al. Accelerated restoration of ocular surface health in dry eye disease by self-retained cryopreserved amniotic membrane. Ocul Surf. Jan 2016; 14(1):56-63. PMID 26387870

31. Vlasov A, Sia RK, Ryan DS, et al. Sutureless cryopreserved amniotic membrane graft and wound healing after photorefractive keratectomy. J Cataract Refract Surg. Mar 2016; 42(3):435-443. PMID 27063525

32. Amniotic Membrane and Amniotic Fluid. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (2018 February) Surgery 7.01.149

Policy History:

Date Reason
8/1/2018 New medical document. Treatment of nonhealing diabetic lower-extremity ulcers using the following human amniotic membrane products (AmnioBand® Membrane, Biovance®, Epifix®, Grafix™) may be considered medically necessary when there is medical record documentation of less than a 20% decrease in wound area with standard wound care for at least 2 weeks. Sutured human amniotic membrane grafts may be considered medically necessary for the treatment of the following ophthalmic indications: Neurotrophic keratitis, Corneal ulcers and melts, Pterygium repair, Stevens-Johnson syndrome, and Persistent epithelial defects (See NOTE 1). NOTE 1: A persistent epithelial defect is one that failed to close completely after 5 days of conservative treatment or has failed to demonstrate a decrease in size after 2 days of conservative treatment. Conservative treatment is defined as use of topical lubricants and/or topical antibiotics and/or therapeutic contact lens and/or patching. Sutured human amniotic membrane grafts are considered experimental, investigational and/or unproven for the treatment of all other ophthalmic conditions including but not limited to dry eye syndrome, burns, corneal perforation, bullous keratopathy, limbus stem-cell deficiency, and after photorefractive keratectomy. Human amniotic membrane without suture (e.g., Prokera®, AmbioDisk™) for ophthalmic indications is considered experimental, investigational and/or unproven. Injection of micronized or particulated human amniotic membrane is considered experimental, investigational and/or unproven for all indications, including but not limited to treatment of osteoarthritis and plantar fasciitis. Injection of human amniotic fluid is considered experimental, investigational and/or unproven for all indications. All other human amniotic membrane products and indications not listed above are considered experimental, investigational and/or unproven, including but not limited to treatment of lower-extremity ulcers due to venous insufficiency.

Archived Document(s):

Title:Effective Date:End Date:
Amniotic Membrane and Amniotic Fluid11-15-202012-14-2020
Amniotic Membrane and Amniotic Fluid05-01-202011-14-2020
Amniotic Membrane and Amniotic Fluid08-01-201804-30-2020
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