Medical Policies - Other

Ocriplasmin for Symptomatic Vitreomacular Adhesion


Effective Date:10-01-2018



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, DrugDex (IIb strength of recommendation 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:

  1. There is vitreous adhesion within 6-mm of the fovea (center of macula); and
  2. There is elevation of the posterior vitreous cortex (outer layer of the vitreous); AND

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:

  • Proliferative diabetic retinopathy (PDR), or
  • Neovascular age-related macular degeneration (AMD), or
  • Retinal vascular occlusion (RVO), or
  • Aphakia, or
  • High myopia (more than −8 diopters), or
  • Uncontrolled glaucoma, or
  • Macular hole greater than 400 μm in diameter, or
  • Vitreous opacification, or
  • Lenticular or zonular instability, or
  • History of retinal detachment in either eye, or
  • Prior vitrectomy in the affected eye, or
  • Prior laser photocoagulation of the macula in the affected eye, or
  • Prior treatment with ocular surgery, intravitreal injection or retinal laser photocoagulation in the previous 3 months.

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, used for symptomatic vitreomacular adhesion (VMA) and vitreomacular traction (VMT). Ocriplasmin is injected into the affected eye (intravitreal) as a single dose and can induce vitreous liquefaction and separation from the retina.


Vitreous Detachment

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. 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 and 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 and 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, conducted in patients scheduled to have vitrectomy, established doses that showed some effect in inducing PVD. Studies by Benz et al. (2010), de Smet et al. (2009), and Stalmans et al. (2010) led to the design and conduct of the pivotal clinical trials described in the Rationale section below. (4-6)

Regulatory Status

In October 2012, ocriplasmin (Jetrea®; ThromboGenics) 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.


This medical policy was created in January 2014 and has been updated using the MedLine database. The most recent literature update was performed through August 19, 2018. The following is a summary of the key literature.

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.

Intravitreal Injection for Vitreomacular Adhesion (VMA) or Vitreomacular Traction (VMT)

This medical policy was originally based on a Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment (2013), which concluded that ocriplasmin is associated with higher rates of resolution of VMAs, 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. (7) The assessment concluded that use of ocriplasmin led to improvement in health outcomes.

The principal evidence supporting ocriplasmin for symptomatic VMA are the RCT results published by Stalmans et al. (2012) 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 a 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 (number needed to treat, 6.1). 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 a categorical improvement of 3 or more lines on the Early Treatment of Diabetic Retinopathy Study chart, ocriplasmin-treated subjects showed greater improvement than placebo-treated subjects. Absolute gains in both groups were modest (needed to treat, 17) – e.g., 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 (7.7%) did not differ significantly from placebo-injected eyes (10.7%). (11) The most common adverse events 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.

In a phase 2 randomized, sham-controlled trial, Novack et al. (2015) assessed 100 patients with exudative age-related macular degeneration (AMD). (12) The trial was primarily intended to evaluate the efficacy but also reported adverse events. Adverse events were higher in the ocriplasmin group, and SAEs 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 between active and sham treatments was not statistically significant (24.3% versus 12.0%, p=0.26); the phase 2 trial had insufficient power to detect a significant difference. Visual acuity was similar in both groups.

In a phase 2, sham-controlled, randomized trial, Dresner et al. (2016) evaluated 22 pediatric patients scheduled to undergo vitrectomy. (13) The trial was intended to test whether ocriplasmin would permit a faster surgical procedure and fewer complications. Use of ocriplasmin in pediatric patients is not currently recommended. The primary outcome was the proportion of eyes with posterior vitreous detachment at the beginning of vitrectomy or after suction. This outcome was observed in 50% of the ocriplasmin group and 62.5% of the placebo group. This result did not support any potential benefit of ocriplasmin.

Hahn et al. (2015), in a report commissioned by the American Society of Retina Specialists, assessed adverse events based on regulatory reports of 999 injections administered during clinical trials and voluntary reports of adverse events from 4387 doses administered postmarketing. (14) This report described the 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 could not be determined with certainty due to the voluntary and possibility incomplete nature of reporting.

Shah et al. (2016) surveyed 2465 retinal physicians about ocriplasmin use and adverse events--270 (11%) completed questionnaires (reporting on 1056 treated eyes). (15) The most common adverse events reported included acute visual acuity decline (17.0%), retinal detachment or submacular fluid (10.2%), dyschromatopsia (9.1%), progression to macular hole (8.7%), retinal detachment (2.7%), retinal tear (2.0%), and afferent pupillary defect (1.8%). Reported adverse event rates were higher than those in clinical trial data (e.g., incidence of decline in visual acuity in trials was 7.7%). However, the survey-based estimates would likely to be influenced by the high rate of physician nonresponse.

Finally, Chatziralli et al. (2016) conducted a meta-analysis ocriplasmin for VMT. (16) Results from 19 studies were pooled--RCT, cohort, case-control, or cross-sectional designs were included. No study quality (risk of bias) appraisal was performed. Factors predictive for vitreomacular traction release were adhesion diameter, age less than 65 years, female, and lack of a phakic lens. The pooled rate of macular hole closure was 33% (95% confidence interval, 26% to 39%; I2=0%; 13 studies). Adverse event rates were summarized for 874 eyes, including acute decrease in visual acuity (17.4%), subretinal fluid (8.8%), dyschromatopsia (0.9%), progression to macular hole (5.0%), retinal detachment/tear (1.8%), and afferent pupillary defect (0.1%). Except for decreased acute visual acuity, adverse event rates were considerably lower than those from the Shah survey. While some factors were associated with response, implications are limited by the study-level nature of the meta-analysis.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this medical policy are listed in Table 1.

Table 1. Summary of Key Trials


Trial Name

Planned Enrollment

Completion Date



Assessment of Anatomical and Functional Outcomes in Patients Treated with Ocriplasmin for Vitreomacular/Symptomatic Vitreomacular Adhesion (VMT/sVMA)


Sep 2015 (completed)


Assessment of Anatomical and Functional Outcomes in Subjects Treated with Ocriplasmin for Vitreomacular Traction/Symptomatic Vitreomacular Adhesion (VMT/sVMA)


May 2016 (completed)


Ocriplasmin Research to Better Inform Treatment (ORBIT)


May 2016 (completed)

Table Key:

NCT: National Clinical Trial.

No.: number.

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. 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. (17) 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.”

American Academy of Ophthalmology (AAO)

The AAO’s 2016 preferred practice pattern on the idiopathic epiretinal membrane and VMT offered the following recommendations:

“The treating physician should discuss the option of treating patients who have VMT with ocriplasmin and compare the treatment with observation, a gas bubble injected into the vitreous, or vitrectomy surgery (good quality, strong recommendation). The discussion should include the relevant risks versus benefits for each of these options (good quality, strong recommendation).” (18)

Summary of Evidence

For individuals who have symptomatic vitreomacular adhesion (VMA) or vitreomacular traction (VMT) who receive intravitreal injection of ocriplasmin, the evidence 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 ocriplasmin patients versus 10.1% of placebo patients; number needed to treat, 6) and a lesser reduction in the proportion of patients undergoing vitrectomy (17.7% of patients versus 26.6% of patients; needed to treat, 11). Results of this and other trials have also shown an increase in the proportion of patients who had clinically significant gains in visual acuity (needed to treat, 17) and visual function. The randomized controlled trials did not find higher rates of important complications; however, postmarketing surveillance has identified some previously unknown adverse events for this enzymatic treatment. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.


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

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ICD-9 Diagnosis Codes

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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 <>.


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 Assessment. (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. Drenser K, Girach A, Capone A, Jr. A randomized, placebo-controlled study of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. Retina. Mar 2016; 36(3):565-75. PMID 26398685

14. Hahn P, Chung MM, Flynn HW, Jr., et al. Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: A comprehensive analysis of premarketing and postmarketing experiences. Retina. Jun 2015; 35(6):1128-34. PMID 25635575

15. Shah SP, Jeng-Miller KW, Fine HF, et al. Post-marketing survey of adverse events following ocriplasmin. Ophthalmic Surg Lasers Imaging Retina. Feb 2016; 47(2):156-60. PMID 26878449

16. Chatziralli I, Theodossiadis G, Xanthopoulou P, et al. Ocriplasmin use for vitreomacular traction and macular hole: A meta-analysis and comprehensive review on predictive factors for vitreous release and potential complications. Graefes Arch Clin Exp Ophthalmol. Jul 2016; 254(7):1247-56. PMID 27137631

17. National Institute for Health and Care Excellence (NICE). Ocriplasmin for treating vitreomacular traction [TA297] (2013). Available at <> (accessed August 19, 2018).

18. Folk JC, Adelman RA, Flaxel CJ, et al. Idiopathic epiretinal membrane and vitreomacular traction Preferred Practice Pattern® guidelines. Ophthalmology. Jan 2016; 123(1):P152-81. PMID 26578445

19. Drugs @ FDA – Drug Approval Package: Jetrea (ocriplasmin) Intravitreal Injection. Food and Drug Administration (2017 February 22). Available at <> (accessed – August 19, 2018).

20. Ocriplasmin for Symptomatic Vitreomacular Adhesion. Chicago, Illinois: Blue Cross Blue Shield Association Medical Policy Reference Manual (March 2018) Other/Vision 9.03.30.

Policy History:

10/1/2018 Document updated with literature review. Coverage unchanged. References 13-18 added; none removed.
7/15/2017 Reviewed. No changes.
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.

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