Archived Policies - Other
Ocriplasmin for Symptomatic Vitreomacular Adhesion
Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, Hayes, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
A single intravitreal injection of ocriplasmin may be considered medically necessary for treatment of an eye with symptomatic vitreomacular adhesion (VMA) or vitreomacular traction (VMT), when the following criteria have been met:
• Individual's age is equal to or greater than 18 years; AND
• Optical coherence tomography (OCT) demonstrates all of the following:
• Individual has best-corrected visual acuity (BCVA) of 20/25 or less in the eye to be treated with ocriplasmin; AND
• Individual does not have any of the following:
The use of intravitreal ocriplasmin is considered experimental, investigational and/or unproven in all other situations, including use of repeat injections of ocriplasmin.
Ocriplasmin (Jetrea®) is a recombinant truncated form of human plasmin, a proteolytic enzyme that breaks down protein components at the vitreoretinal interface in the eye. Ocriplasmin is injected into the affected eye (intravitreal) as a single dose and can induce vitreous liquefaction and separation from the retina. Its proposed use is for the treatment of symptomatic vitreomacular adhesion (VMA) and vitreomacular traction (VMT).
Vitreous is a gel-like fluid within the eye that adheres completely to the surface of the retina. The consistency of vitreous and its adhesion to the retina are maintained by several proteins including collagen, laminin, and fibronectin. With aging, the proteins in the vitreous break down, resulting in liquefaction of vitreous and eventual separation of vitreous from the retina, a process called posterior vitreous detachment (PVD).
The process of vitreous detachment usually proceeds without incident, but sometimes the separation is incomplete. Adhesion usually remains at sites where the bonds between the vitreous and retina are the strongest. In some cases, the adhesion can cause visual symptoms. The traction caused by the adherent vitreous can cause deformation of the retina, edema, and full-thickness macular holes (FTMH). Although the terms are sometimes used synonymously, the International Vitreomacular Traction Study Group has defined VMA as adhesion at the macula without detectable changes in retinal morphology and VMT as adhesion with retinal morphologic changes but without full-thickness defect. (1) Both VMA and VMT can be focal or diffuse.
Symptoms can vary, but may include diminished visual acuity, distorted vision (metamorphopsia), and central field defect. Patients are usually observed until resolution or worsening, in which case vitrectomy is the standard treatment. Spontaneous release of VMA/VMT occurs in about 30% of cases over a period of 1 to 2 years, and observation is usually indicated because vitrectomy has risks and an almost certain occurrence of cataract in the years following the procedure. (2, 3)
Ocriplasmin is a recombinant product that is a shortened form of the protease plasmin. Early studies of ocriplasmin were conducted in patients scheduled to have vitrectomy and established doses that showed some effect in inducing PVD. Studies by Benz et al., de Smet et al., and Stalmans et al. led to the design and conduct of the pivotal clinical trials described in the Rationale section of this policy. (4-6)
In October 2012, ocriplasmin (Jetrea®; ThromboGenics, Iselin, NJ) received U.S. Food and Drug Administration (FDA) approval for the treatment of symptomatic VMA. No contraindications were noted. In the Warnings and Precautions section of the prescribing information, it was noted that a higher percentage of subjects treated with ocriplasmin in the clinical trials had worsening of visual acuity of 3 or more lines than subjects in the control group. Transient injection-associated effects such as inflammation occurred in a higher percentage of subjects treated with ocriplasmin than control subjects. Alcon has obtained exclusive distribution rights for Jetrea® in the U.S. The FDA-approved label for Jetrea® states that it is “indicated for the treatment of symptomatic vitreomacular adhesion [sVMA].” (13)
This medical policy was created in January 2014 and has been updated using the MedLine database. The most recent literature update was performed through May 2016. The following is a summary of the key literature.
The medical policy was originally based on a 2013 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment, (7) which concluded that ocriplasmin is associated with higher rates of resolution of vitreomacular adhesions (VMA), closure of macular holes, lower rates of vitrectomy, and improvement in some measures of visual acuity, without increases in major adverse events, when compared with watchful waiting with vitrectomy as indicated. This Assessment concluded that use of ocriplasmin led to improvement in health outcomes.
The principal evidence supporting ocriplasmin for symptomatic VMA is the published study by Stalmans et al. for the MIVI-TRUST study group. (8) The study presented pooled results of 2 identically designed, double-blind, placebo-controlled randomized trials. Patients enrolled in the trial met strict inclusion and exclusion criteria: they were not currently scheduled to have vitrectomy, but according to assessment by their physicians, 84% were expected to need vitrectomy if their conditions did not improve. Overall, 652 eyes were treated, 464 with ocriplasmin and 188 with placebo. The principal study end point, resolution of VMA at 28 days, was met by 26.5% of ocriplasmin-treated patients and by 10.1% of placebo-treated patients. Other 28-day secondary end points (posterior vitreal detachment, closure of macular holes) also favored ocriplasmin.
Secondary outcomes measured beyond 28 days were also better in ocriplasmin-treated eyes. By 6 months, 17.7% of ocriplasmin-treated subjects had undergone vitrectomy versus 26.6% of placebo-treated subjects. Visual improvement varied depending on how data were analyzed, but generally favored ocriplasmin. Measured as categorical improvement of 3 or more lines on the Early Treatment of Diabetic Retinopathy chart, ocriplasmin-treated subjects showed greater improvement than placebo-treated subjects. Absolute gains in both groups were modest, particularly in the analysis that only considered those who did not undergo vitrectomy (9.7% and 3.7%, respectively). A higher proportion of patients in the ocriplasmin group had a clinically meaningful (≥5 point) improvement on 25-item National Eye Institute Visual Function Questionnaire scores (36.0% versus 27.2%, p=0.03), and fewer ocriplasmin-treated patients had a clinically meaningful worsening in their visual function compared with the placebo group (15.0% versus 24.3%, p=0.005). (9) Resolution of VMA at 28 days, regardless of treatment group, was associated with greater improvement in visual acuity at all-time points (7.5-letter improvement versus 2.1-letter improvement, p<0.001). (10) Serious adverse events (SAEs) in ocriplasmin-injected eyes did not differ significantly from placebo-injected eyes (7.7% ocriplasmin versus 10.7% placebo). (11) The most common adverse effects reported in patients treated with ocriplasmin include eye floaters, bleeding of the conjunctiva, eye pain, flashes of light (photopsia), blurred vision, vision loss, retinal edema (swelling), and macular edema.
A phase 2 randomized, sham-controlled trial in 100 patients with age-related macular degeneration (AMD) was primarily intended to evaluate adverse effects, but also reported efficacy results. (12) Adverse events were higher in the ocriplasmin group, and serious adverse events in the study eye were observed in 10.7% of ocriplasmin-injected eyes compared with 0% sham-treated eyes. The efficacy in releasing VMAs was numerically similar to the MIVI-TRUST trial, but the difference was not statistically significant (24.3% versus 12.0%, p=0.26). Visual acuity was similar for the 2 groups.
A phase 2, sham-controlled, randomized trial of 22 pediatric patients scheduled to undergo vitrectomy was intended to demonstrate whether ocriplasmin might permit a faster surgical procedure and fewer complications. (13) Use of ocriplasmin in pediatric patients is not currently recommended. The primary study outcome was the proportion of eyes with posterior vitreous detachment at the beginning of vitrectomy or after suction. This outcome might indicate a vitrectomy procedure that is easier to complete. The primary outcome was observed in 50% of the ocriplasmin group and 62.5% of the placebo group. This result does not reveal any potential benefit of ocriplasmin.
A 2015 report for the American Society of Retina Specialists Therapeutic Surveillance Committee assessed adverse events from regulatory reports of 999 injections administered during clinical trials and voluntary reports of adverse events from 4387 doses administered postmarketing. (14) This report described incidence, in a small percentage of patients, of significant and permanent vision loss, electroretinogram changes, dyschromatopsia, retinal tear/detachment, lens subluxation, impaired pupillary reflex, loss or disruption of the ellipsoid zone, vascular attenuation or vasoconstriction, and nyctalopia (night blindness). The rates of these adverse events cannot be determined with certainty due to the voluntary and possibility incomplete nature of reporting.
Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 1.
Table 1. Summary of Key Trials
Ocriplasmin Research to Better Inform Treatment (ORBIT)
Assessment of Anatomical and Functional Outcomes in Subjects Treated With Ocriplasmin for Vitreomacular Traction/Symptomatic Vitreomacular Adhesion (VMT/sVMA)
Assessment of Anatomical and Functional Outcomes in Patients Treated With Ocriplasmin for Vitreomacular/Symptomatic Vitreomacular Adhesion (VMT/sVMA)
Sep 2015 (completed)
NCT: National Clinical Trial.
a: Denotes industry-sponsored or cosponsored trial.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In 2013 Blue Cross Blue Shield Association requested and received clinical input from 1 physician specialty society and 1 academic medical center while their policy was under review in 2013. Clinical input suggested that not all of the trial exclusion criteria should be absolute exclusions. However, there was no consensus on which exclusion criteria should be removed. Individual reviewers suggested removing the following criteria: macular hole greater than 400 μm, PDR, vitreous opacification, aphakia, high myopia, neovascular AMD, history of retinal detachment, and uncontrolled glaucoma. In addition, it was suggested that ocriplasmin may be beneficial for the treatment of macular holes and vitreous hemorrhage.
Practice Guidelines and Position Statements
National Institute for Health and Care Excellence (NICE)
In 2013, NICE issued guidance on ocriplasmin for treating VMT. (15) NICE recommended ocriplasmin as an option for treating VMT in adults, only if:
• “An epiretinal membrane is not present and
• They have a stage II full-thickness macular hole with a diameter of 400 micrometers or less and/or
• They have severe symptoms.”
The evidence for intravitreal injection of ocriplasmin in individuals who have VMA or VMT includes 2 large, double-blind, placebo-controlled, trials and other supporting studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of the principal randomized controlled trial (MIVI-TRUST) demonstrated an improvement in the resolution of VMA and VMT at 28 days (26.5% of patients versus 10.1% of patients) and a modest reduction in the proportion of patients undergoing vitrectomy (17.7% of patients versus 26.6% of patients). Results of this and other trials have also showed a modest increase in the proportion of patients who had clinically significant gains in visual acuity and visual function. The randomized controlled trials did not find higher rates of important complications; however, postmarketing surveillance has identified some previously unknown adverse effects for this novel enzymatic treatment. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.
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1. Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. Dec 2013; 120(12):2611-9. PMID 24053995
2. Tzu JH, John VJ, Flynn HW, Jr., et al. Clinical course of vitreomacular traction managed initially by observation. Ophthalmic Surg Lasers Imaging Retina. May 1 2015; 46(5):571-6. PMID 26057761
3. Jackson TL, Donachie PH, Sparrow JM, et al. United Kingdom National Ophthalmology Database Study of Vitreoretinal Surgery: Report 1; Case mix, complications, and cataract. Eye (Lond). May 2013; 27(5):644-51. PMID 23449509
4. Benz MS, Packo KH, Gonzalez V, et al. A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy. Ophthalmology. Apr 2010; 117(4):791-7. PMID 20138368
5. de Smet MD, Gandorfer A, Stalmans P, et al. Microplasmin intravitreal administration in patients with vitreomacular traction scheduled for vitrectomy: the MIVI I trial. Ophthalmology. Jul 2009; 116(7):1349-55, 55 e1-2. PMID 19447497
6. Stalmans P, Delaey C, de Smet MD, et al. Intravitreal injection of microplasmin for treatment of vitreomacular adhesion: results of a prospective, randomized, sham-controlled phase II trial (the MIVI-IIT trial). Retina. Jul-Aug 2010; 30(7):1122-7. PMID 20616687
7. Ocriplasmin for Symptomatic Vitreomacular Adhesion. Chicago, Illinois: Blue Cross Blue Shield Association Technology Evaluation Center. (August 2013) Volume 28, Tab 5.
8. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. Aug 16 2012; 367(7):606-15. PMID 22894573
9. Varma R, Haller JA, Kaiser PK. Improvement in patient-reported visual function after ocriplasmin for vitreomacular adhesion: results of the Microplasmin for Intravitreous Injection-Traction Release Without Surgical Treatment (MIVI-TRUST) Trials. JAMA Ophthalmol. Sep 2015; 133(9):997-1004. PMID 26068086
10. Gandorfer A, Benz MS, Haller JA, et al. Association between anatomical resolution and functional outcomes in the mivi-trust studies using ocriplasmin to treat symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with macular hole. Retina. Jun 2015; 35(6):1151-7. PMID 25741816
11. Kaiser PK, Kampik A, Kuppermann BD, et al. Safety profile of ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina. Jun 2015; 35(6):1111-27. PMID 25635577
12. Novack RL, Staurenghi G, Girach A, et al. Safety of intravitreal ocriplasmin for focal vitreomacular adhesion in patients with exudative age-related macular degeneration. Ophthalmology. Apr 2015; 122(4):796-802. PMID 25435217
13. Drugs @ FDA – Drug Approval Package: Jetrea (ocriplasmin) Intravitreal Injection. Food and Drug Administration (2012 December 4). Available at <http://www.fda.gov> (accessed – 2016 June 18).
14. Ocriplasmin for Symptomatic Vitreomacular Adhesion. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (March 2016) Other/Vision 9.03.30.
|8/1/2016||Document updated with literature review. The following condition was added to the medically necessary coverage statement: “vitreomacular traction (VMT).” “VMA” acronym removed from title.|
|11/1/2015||Reviewed. No changes.|
|1/1/2014||New medical document. A single intravitreal injection of ocriplasmin may be considered medically necessary for treatment of an eye with symptomatic vitreomacular adhesion (VMA), when specified clinical criteria has been met. Otherwise, the use of intravitreal ocriplasmin is considered experimental, investigational and/or unproven in all other situations, including use of repeat injections of ocriplasmin.|
|Title:||Effective Date:||End Date:|
|Ocriplasmin for Symptomatic Vitreomacular Adhesion||07-15-2017||09-30-2018|
|Ocriplasmin for Symptomatic Vitreomacular Adhesion||08-01-2016||07-14-2017|
|Ocriplasmin for Symptomatic Vitreomacular Adhesion (VMA)||11-01-2015||07-31-2016|
|Ocriplasmin for Symptomatic Vitreomacular Adhesion (VMA)||01-01-2014||10-31-2015|