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Ocriplasmin for Symptomatic Vitreomacular Adhesion

Policy Number: MP-535


Latest Review Date:  March 2019

Category:  Surgery  

Policy Grade: C   

Description of Procedure or Service:

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 and vitreomacular traction. 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 the 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 the vitreous and eventual separation of the 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 vitreomacular adhesion (VMA) as adhesion at the macula without detectable changes in retinal morphology and vitreomacular traction as adhesion with retinal morphologic changes but without full-thickness defect. Both VMA and vitreomacular traction 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/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.

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 posterior vitreous detachment. 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 Key Points section of this policy.


A single intravitreal injection of ocriplasmin may be considered medically necessary for treatment of an eye with symptomatic vitreomacular adhesion (VMA) when the following are met:

  • Individual's age is equal to or greater than 18 years;
  • Optical coherence tomography (OCT) demonstrates all of the following:
    • There is vitreous adhesion within 6-mm of the fovea (center of macula); and
    • There is elevation of the posterior vitreous cortex (outer layer of the vitreous).
  • Individual has best-corrected visual acuity of 20/25 or less in the eye to be treated with ocriplasmin
  • Individual does not have any of the following:
    • Proliferative diabetic retinopathy;
    • Neovascular age-related macular degeneration;
    • Retinal vascular occlusion;
    • Aphakia;
    • High myopia (> −8 diopters);
    • Uncontrolled glaucoma;
    • Macular hole greater than 400 μm in diameter;
    • Vitreous opacification;
    • Lenticular or zonular instability;
    • History of retinal detachment in either eye;
    • Prior vitrectomy in the affected eye;
    • Prior laser photocoagulation of the macula in the affected eye;
    • Prior treatment with ocular surgery, intravitreal injection or retinal laser photocoagulation in the previous three months.

The use of intravitreal ocriplasmin is not medically necessary and is considered investigational in all other situations, including use of repeat injections of ocriplasmin.

Key Points:

This policy is updated periodically with literature review using the MEDLINE database. The most recent literature update was performed through January 09, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the 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 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 technology, two 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 or Vitreomacular Traction

The evidence review was informed by a 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. 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. The study presented pooled results of 2 identically designed, double-blind, placebo-controlled randomized trials. Patients enrolled in the study 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 results varied depending on how the 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 had higher success rates than placebo-treated subjects. Absolute gains in both groups were modest (NNT=17), for example in the analysis where improvement was only counted in 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% vs 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% vs 24.3%, p=0.005). 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 vs 2.1-letter improvement, p<0.001). Serious adverse events (SAEs) in ocriplasmin-injected eyes did not differ significantly from placebo-injected eyes (7.7% ocriplasmin vs 10.7% placebo).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.

In a Phase 2 randomized, sham-controlled trial, Novack et al (2015) assessed 100 patients with exudative agerelated macular degeneration. The trial was primarily intended to evaluate the efficacy but also reported adverse events. 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 between active and sham treatments was not statistically significant (24.3% vs 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. 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 for 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 post-marketing. This publication 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 cannot be determined with certainty due to the voluntary nature of reporting, raising the possibility of incomplete reporting.

Shah et al (2016) surveyed 2465 retinal physicians regarding ocriplasmin use and adverse events—270 (11%) completed questionnaires (reporting on 1056 treated eyes). 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 are likely to be impacted by the high rate of physician nonresponse.

Finally, Chatziralli et al (2016) conducted a meta-analysis ocriplasmin for VMT. 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 VMT 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% CI, 326 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 et al survey. While some factors were associated with response, implications are limited by the study-level nature of the meta-analysis.

Summary of Evidence

For individuals who have symptomatic vitreomacular adhesion or vitreomacular traction who receive intravitreal injection of ocriplasmin, the evidence includes 2 large, double-blind, placebo-controlled, clinical trials and other supporting studies. Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life, and treatment-related morbidity. Results of randomized controlled trials (RCTs) demonstrate an improvement in the resolution of VMA/VMT at 28 days (26.5% vs 10.1% of patients, NNT=6) and a lesser reduction in the proportion of patients undergoing vitrectomy (17.7% vs 26.6%, NNT=11). Results of these trials also showed a modest increase in the proportion of patients who had clinically significant gains in visual acuity (NNT=17) and visual function. The RCTs did not find a higher rate of important complications; however, post-marketing surveillance has identified some previously unknown adverse effects with this novel enzymatic treatment. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Clinical input obtained in 2013 has suggested that not all of the MIVI-TRUST exclusion criteria should be absolute. However, there was no consensus on which criteria should be removed.

Practice Guidelines and Position Statements

In 2013, the National Institute for Health and Care Excellence (NICE) issued guidance on ocriplasmin for treating vitreomacular traction. NICE recommends 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 micrometres or less and/or
  • they have severe symptoms

As of February 2017, this guidance was placed on the “static guidance list.”

American Academy of Ophthalmology

The American Academy of Ophthalmology’s 2016 preferred practice pattern on idiopathic epiretinal membrane and vitreomacular traction 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)”

U.S. Preventive Services Task Force Recommendations

Not applicable.

Key Words:

Intravitreal Injection, Ocriplasmin, Jetrea


Approved by Governing Bodies:

In October 2012, ocriplasmin (Jetrea®, ThromboGenics Inc., Iselin, NJ) received U.S. Food and Drug Administration (FDA) approval for the treatment of symptomatic vitreomacular adhesion (VMA). There were no contraindications 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 three 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.

Benefit Application:

Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

Current Coding:

CPT Codes


Intravitreal injection of a pharmacologic agent (separate procedure)



Injection, ocriplasmin, 0.125 mg



  1. Benz MS, Packo KH, Gonzalez V et al. A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy. Ophthalmology 2010; 117(4):791-7.

  2. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Ocriplasmin for symptomatic vitreomacular adhesion. TEC Assessments 2013; Volume 28, Tab TBA.

  3. 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 2009; 116(7):1349-1355, 1355 e1341-1342.

  4. 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):1247-1256.

  5. Drenser K, Girach A, Capone A, Jr. A randomized, placebo-controlled study of intravitreal ocriplasmin in pediatric patients scheduled for vitrectomy. Retina. Sep 21 2015.

  6. 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):2611-2619.

  7. Folk JC, Adelman RA, Flaxel CJ, et al. Idiopathic epiretinal membrane and vitreomacular traction Preferred Practice Pattern® guidelines. Ophthalmology. Jan 2016; 123(1):P152-181.

  8. 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):1151-1157.

  9. Hahn P, Chung MM, Flynn HW, Jr., et al. Safety profile of ocriplasmin for symptomatic vitreomacular adhesion: A comprehensive analysis of premarketing and post-marketing experiences. Retina. Jun 2015; 35(6):1128-1134.

  10. Hikichi T, Yoshida A, Trempe CL. Course of vitreomacular traction syndrome. Am J Ophthalmol 1995; 119(1):55-61.

  11. 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) 2013; 27(5):644-51.

  12. 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):1111-1127.

  13. National Institute of Health and Care Excellence (NICE). Ocriplasmin for treating vitreomacular traction. 2013; TA297: // Accessed February 16, 2018.

  14. 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.

  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):156-160.

  16. 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 2010; 30(7):1122-7.

  17. Stalmans P, Benz MS, Gandorfer A et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012; 367(7):606-15.

  18. 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):571-576.

  19. 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. Jun 11 2015.

Policy History:

Medical Policy Panel, July & August 2013

Medical Policy Group, August 2013 (2): New policy

Medical Policy Administration Committee, August 2013

Available for comment August 22 through October 5, 2013

Medical Policy Group, January 2014 (1): 2014 Coding Update: new HCPCS code, J7316, added to coding section, effective 01/01/2014; deleted code C9298 moved to previous coding section, effective 01/01/2014

Medical Policy Panel, August 2014

Medical Policy Group, August 2014 (1): Update to Key Points and References; no change to policy statement

Medical Policy Panel, March 2016

Medical Policy Group, March 2016 (6): Updates to Description, Key Points and References; no change to policy statement

Medical Policy Panel, March 2017

Medical Policy Group, March 2017 (6): Updates to Description, Key points, Summary, Practice Guidelines and References. No change to policy intent.

Medical Policy Panel, March 2018

Medical Policy Group, March 2018 (6): Updates to Description, Key points, Practice Guidelines and References. No change to policy intent.

Medical Policy Panel, March 2019

Medical Policy Group, March 2019 (6): Updates to Description and Key Points. No change to policy statement.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.