Symptomatic vitreomacular adhesion (VMA) is an age-related condition occurring when vitreous detachment from the retina is incomplete, resulting in pulling on the macula or vitreomacular traction (VMT).1 VMT resolves spontaneously in approximately 10% to 35% of patients, but for those patients who do not experience spontaneous resolution, further anatomic damage and visual impairment may occur.2-4 Approximately 70% of patients with VMT, particularly those with full-thickness macular hole (FTMH), may develop metamorphopsia, a highly disabling visual function disturbance.5 Metamorphopsia may lead to significantly lower vision- and health-related quality of life, which has been demonstrated across validated vision- and health-related questionnaires.6 The burden of metamorphopsia on patients underscores the importance of treating VMT.
Historically, surgical intervention with pars plana vitrectomy (PPV) was the only treatment option for symptomatic stages of VMT, often when MH was already present. Delayed treatment can lead to irreversible anatomic damage, vision loss, and reduced likelihood of vision recovery.3 Watchful waiting for disease progression can result in a poorer prognosis in visual outcomes after PPV. Patients who undergo PPV may only have modest visual acuity (VA) gains,3,7 and these patients can experience complications, such as infection, development of cataracts, and retinal tears.4
THE FIRST NONSURGICAL TREATMENT FOR SYMPTOMATIC VMA
Ocriplasmin (Jetrea; ThromboGenics) is a proteolytic enzyme administered as a single 0.125-mg intravitreal injection. By dissolving the protein matrix responsible for VMA, ocriplasmin separates the vitreous from the macula, thereby releasing VMT and, in some patients, closing small MHs.8
Ocriplasmin is the only pharmacologic treatment available for symptomatic VMA/VMT. It was approved in the United States in October 2012 (symptomatic VMA) and in Europe (VMT) in March 2013.8,9 A ready-diluted form, eliminating the preparation steps for injection, was approved in the European Union in 2015 and was recently introduced in the United States.10
The introduction of a pharmacologic treatment for symptomatic VMA/VMT has provided ophthalmologists with a medical option to treat adult patients with early-stage VMT.
Brian C. Joondeph, MD, MPS, FACS, is a vitreoretinal specialist with Colorado Retina Associates in Denver, Colorado. Dr. Joondeph is a consultant for Allergan, DORC Ophthalmic USA, ThromboGenics, and Santen Pharmaceutical. Reach him at email@example.com.
Acknowledgement: Medical writing support was provided by Kelly Burns at Fishawack Communications Inc., and this service was supported by ThromboGenics.
CLINICAL DEVELOPMENT PROGRAM
Ocriplasmin has been studied in large populations with symptomatic VMA in both clinical studies and real-world settings (Table). The MIVI-TRUST trials were 2 phase 3, randomized, placebo-controlled, 6-month studies designed to assess the safety and efficacy of ocriplasmin4 in adults with symptomatic VMA. The primary endpoint of VMA resolution at day 28 was met in 26.5% of patients in the ocriplasmin group, compared with 10.1% in the placebo group (P≤.02). FTMH closure at day 28, a secondary endpoint, occurred in 40.6% in the ocriplasmin group and 10.6% in the placebo group (P<.001). The proportion of patients who had any ocular adverse event (AE) in the study eye was 68.4% in the ocriplasmin group and 53.5% in the placebo group (P<.001). The difference was largely due to AEs known to be associated with vitreous detachment. Most AEs were mild in severity and transient in nature and may have been due to patient selection for the study. Study design can be considered a limitation of the MIVI-TRUST trials, as the inclusion of a placebo arm did not allow for the distinction between natural disease history and mechanical effect in either group. Based on the results of these trials, ocriplasmin was approved in the United States and Europe.
|Study Description||Phase 3, randomized, placebo-controlled, double-masked, multicenter trials of ocriplasmin intravitreal injection for nonsurgical treatment of symptomatic VMA||Phase 3b, randomized, double-masked, sham-controlled, 24-month study to investigate the efficacy and safety profile of ocriplasmin in symptomatic VMA|
|Number of Eyes/Patients||N=652 eyes
|Study Measures||Primary endpoint: Resolution of VMA by day 28 after injection with either 0.125 mg of ocriplasmin or placebo
Secondary endpoints: PVD, Nonsurgical closure of MH at day 28, avoidance of PPV, change in BCVA
|Primary endpoint: Proportion of patients with VMA resolution at day 28 determined by SD-OCT read by a CRC
Secondary endpoints (assessed at month 24): Proportion of subjects with ≥2-line BCVA gain from baseline, nonsurgical FTMH closure, progression to PPV, VFQ-25 outcomes
|Key Inclusion/Exclusion Criteria||Inclusion: ≥18 years of age Focal VMA, BCVA of 20/25 or less in study eye and 20/800 or more in nonstudy eye
Exclusion: History/current proliferative DR, neovascular AMD, aphakia, and uncontrolled glaucoma, MH >400 µm, prior vitrectomy, intravitreal injection within previous 3 months
|Inclusion: ≥18 years of age Focal VMA, BCVA of 20/32 or less in study eye and 20/800 or more in nonstudy eye
Exclusion: History/current proliferative DR, neovascular AMD, aphakia, and uncontrolled glaucoma,MH >400 µm, presence of ERM, prior vitrectomy
|VMA Resolution at Day 28/Month 1||Ocriplasmin||26.5%||41.7%|
|Key Results||Efficacy: Rate of PVD among phakic eyes: 13.4% ocriplasmin vs 3% placebo (P<.001) Nonsurgical closure of MH: 40.6% ocriplasmin vs 10.6% placebo (P<0.001); BCVA more likely to improve by ≥3 lines with ocriplasmin than placebo
Safety: Any AE: 68.4% ocriplasmin vs 53.5% placebo (P<0.001); most common AEs: vitreous floaters (16.8% ocriplasmin vs 7.5% placebo, P=.01), photopsia (11.8% ocriplasmin vs 2.7% placebo, P<0.001)
|Efficacy: Nonsurgical FTMH closure: 30% ocriplasmin vs 15.4% sham at month 24 (P=.163 for 14.6% treatment difference), all secondary endpoints favored ocriplasmin over sham
Safety: Any AE: 68.4% ocriplasmin vs 53.5% sham (P<0.001); most common AEs: Vitreous floaters (37.7% ocriplasmin vs 8.1% placebo), photopsia (29.5% ocriplasmin vs 6.8% sham)
|Clinical Relevance||Patient characteristics identified as variables that could increase the efficacy of ocriplasmin included: No presence of ERM, focal adhesions ≤1,500 µm, and FTMH ≤400 µm.There was a higher incidence of AEs with ocriplasmin, most of which were transient.||This study used SD-OCT imaging to assess VMA resolution. FTMH closure rate was achieved by month 3 and was maintained throughout trial. Patients with presence of ERM, phakic lens status, FTMH >400 µm, and focal lesions >1,500 µm were excluded from the study. No new safety signals were identified. These data highlight the need for careful patient selection.|
|Study Description||Phase 4, prospective, observational study to collect real-world data on ocriplasmin use in the United States||Phase 4, multicenter, prospective, single-arm, open-label, interventional|
|Number of Eyes/Patients||N=539 patients||N=628 patients|
|Study Measures||Primary outcome measures (assessed over 12 months): Resolution of VMA and FTMH using SD-OCT read by a CRC at month 1; mean change in VA from baseline over 12 months; occurrence and time to vitrectomy.||Primary endpoint: Proportion of patients with VMA resolution at day 28, determined by SD-OCT read by a CRC
Secondary endpoint: Proportion of patients with MH closure at days 28, 90, and 180
|Key Inclusion/Exclusion Criteria||Inclusion: ≥18 years of age who had received ocriplasmin
Exclusion: Treatment outside US, Participation in concurrent study
|Inclusion: ≥18 years of age at the time of informed consent; diagnosed with VMT/sVMA; evidence of focal; VMT visible on SD-OCT
Exclusion: Active or suspected intraocular or periocular infection; participation in any interventional clinical trial within 30 days prior to baseline; ERM; broad VMT/sVMA >1,500 µm; history of vitrectomy, laser photocoagulation, retinal detachment, MH >400 µm; proliferative DR; ischemic retinopathies; retinal vein occlusions; AMD; vitreous hemorrhage.
|VMA Resolution at Day 28/Month 1||Ocriplasmin||45.8%||47.4%|
|Key Results||Efficacy: VMA resolution and FTMH closure rates improved over time (up to 3 months), The proportion of patients with improved BCVA increased at each follow-up visit
Safety: Most common AEs: photopsia (30.6%), vitreous floaters (13.5%)
|Efficacy: For patients with VMT at baseline, VMA resolution was 43.4% at day 28, Nonsurgical closure of MH at day 28 was 39.5% and was greater (57.1%) in patients with small MH (≤250 µm), The proportion of patients with improved BCVA increased at each follow-up visit,
Safety: No new safety signals identified
|Clinical Relevance||This study confirmed safety and efficacy results from MIVI-TRUST and OASIS. No new safety signals were identified. VMA resolution rates at month 1 in ORBIT were higher than results reported in MIVI-TRUST, further demonstrating the importance of patient selection.||These results confirm previous rates of VMA resolution and FTMH closure and further characterize patient selection.|
|Study Description||Phase 4, multicenter, prospective, single-arm, open-label, interventional||Noninterventional prospective study of VMT in patients treated with ocriplasmin|
|Study Location||Multinational (Eurasia)||EU/Canada|
|Number of Eyes/Patients||N=52 patients||N=105 patients|
|Study Measures||Primary endpoint: Proportion of patients with VMA resolution at day 28 determined by SD-OCT read by a CRC
Secondary endpoint: Proportion of patients with MH closure at days 28, 90, and 180
|Primary outcome measures: Evaluated safety, clinical effectiveness, and HRQoL|
|Key Inclusion/Exclusion Criteria||Inclusion: ≥18 years of age at the time of informed consent; diagnosed with VMT/sVMA; evidence of focal; VMT visible on SD-OCT
Exclusion: Active or suspected intraocular or periocular infection; participation in any interventional clinical trial within 30 days prior to baseline ERM, Broad VMT/sVMA >1,500 µm; history of vitrectomy, laser photocoagulation, retinal detachment; MH >400 µm; proliferative DR, ischemic retinopathies; retinal vein occlusions; AMD; vitreous hemorrhage
|Inclusion: ≥18 years of age who had received ocriplasmin
Exclusion: Patients who are treated with ocriplasmin for medical conditions outside the product labeling; participation in concurrent study; patients presenting with any contraindications to ocriplasmin used as per local, approved label
|VMA Resolution at Day 28/Month 1||Ocriplasmin||26.9%||Study ongoing|
|Key Results||Efficacy: For patients with VMT at baseline, VMA resolution was 26.9% at day 28. The proportion of patients with VMT resolution increased to 40.4% by day 180. Patients had a mean increase of 3.3 ETDRS letters at day 180.
Safety: No new safety signals identified
|Clinical Relevance||These results confirm previous rates of VMA resolution and FTMH closure. Further characterizes patient selection as this population was somewhat older than OVIID-I (74.5 vs 71.7 years of age). There were fewer MHs in OVIID-II than OVIID-I.|
|AE, adverse event; AMD, age-related macular degeneration; BCVA, best-corrected visual acuity; CRC, central reading center; DR, diabetic retinopathy; ERM, epiretinal membrane; FTMH, full-thickness macular hole; HRQoL, health-related quality of life; MH, macular hole; N/A, not applicable; PPV, pars plana vitrectomy; PVD, posterior vitreous detachment; SD-OCT, spectral-domain optical coherence tomography; VA, visual acuity; VFQ-25, Visual Function Questionnaire-25; VMA, vitreomacular adhesion; VMT, vitreomacular traction.
OASIS was a phase 3b, randomized, double-masked, sham-controlled, 24-month study to further characterize the efficacy and safety of ocriplasmin in patients with symptomatic VMA.11 Results from the OASIS study confirmed the efficacy and safety results of MIVI-TRUST over a longer follow-up period. In contrast to the MIVI-TRUST studies, results from OASIS characterized drug-related effects (including volume effects) from natural disease history. The primary outcome was VMA resolution at day 28, assessed by spectral-domain optical coherence tomography (SD-OCT) read by a central reading center (CRC) — technology that had not been widely available when the MIVI-TRUST studies were conducted. Use of high-resolution SD-OCT allows for the detection of changes to individual cellular layers, providing additional information about the anatomic response to ocriplasmin.12 The study further highlighted the importance of patient selection for ocriplasmin treatment, as 41.7% of patients in the ocriplasmin group experienced VMA resolution at day 28, compared with 6.2% in the sham group (P<.001). The nonsurgical FTMH closure rate was 30.0% in the ocriplasmin group, compared with 15.4% in the placebo group (95% CI: -4.2, 33.4; P=.163 for treatment difference). The increase in patients experiencing VMA resolution with ocriplasmin compared with the rates in the MIVI-TRUST trials was likely due to the more stringent inclusion criteria, specifically smaller MHs and the absence of an epiretinal membrane (ERM). This study allowed the investigators to characterize previously identified risks, such as electroretinogram (ERG) changes and dyschromatopsia,13 and to address the perception of new-onset MH and VMT related to ocriplasmin treatment. In MIVI-TRUST, the use of a placebo injection could have increased VMA release, whereas having a sham arm reduced that possibility and provided more insight into the natural history of VMT. No new safety signals were identified in the 24-month follow-up. AE resolution continued to improve after day 28.
ORBIT was a prospective, noncontrolled, observational study designed to collect real-world clinical data on ocriplasmin use in the United States as part of the ongoing phase 4 program.14 Using SD-OCT read by a CRC, the primary endpoint of VMA resolution at day 28 was 45.8% in the ocriplasmin group (95% CI: 41.3, 50.4). Nonsurgical FTMH closure was achieved by month 3 in 32.2% of patients and was maintained through the end of the trial. VMA resolution rates for ocriplasmin in a real-world setting were higher than those reported in the MIVI-TRUST studies, likely due to the clinicians having insights into the prognostic factors for successful traction release with ocriplasmin and the widespread use of SD-OCT to better define macular pathology. No new safety signals were identified.
OVIID-I, a phase 4, multicenter, prospective, single-arm, interventional study, assessed the anatomic and functional outcomes of ocriplasmin over a 6-month period.15 Using SD-OCT imaging read by a CRC, the overall percentage of patients with nonsurgical VMT resolution at day 28 was 43.4% in the ocriplasmin group. The overall percentage of nonsurgical MH closure at day 28 was 39.5%; this rate was higher (57.1%) in patients with MH ≤250 µm.
Preliminary results of OVIID-II, which was conducted in a Eurasian population (N=52) using the OVIID-I trial design, showed that 26.9% had resolution of VMT at day 28. This proportion increased to 40.4% at day 180.16
The ongoing INJECT study will also assess the efficacy of ocriplasmin in a real-world setting and will further identify baseline characteristics contributing to best outcomes with ocriplasmin treatment.17
Efficacy results from these studies highlight the importance of patient selection for successful treatment with ocriplasmin. Ideal candidates for ocriplasmin treatment include patients with the following characteristics: FTMH ≤400 µm, focal adhesion ≤1,500 µm, no presence of ERM, phakic lens status, no previous retinal surgery, and ≤65 years of age.18,19 Other studies have shown varying results in VMA resolution, FTMH closure, and visual improvements with ocriplasmin, but these variations may be due to differences in patient selection and the limitations of retrospective case reviews.20-23
As data from the clinical studies have shown, a long-term (>24 months) view should be taken when evaluating patients after ocriplasmin injection because VMA resolution has been demonstrated at 28 days in some patients, but it can take up to 6 months in others. Although it is unclear whether the variations in time needed for VMA resolution are due to the effects of ocriplasmin or the natural course of disease, clinicians have the option of waiting longer than 28 days to delay or avoid PPV, particularly if the patient is mildly symptomatic.
A long-term view of VMA resolution should be taken following ocriplasmin injection and when evaluating BCVA outcomes. Improvements in BCVA also have been demonstrated over a long-term follow-up period. A subanalysis of the MIVI-TRUST trials showed that the proportion of patients demonstrating BCVA improvements at 6 months was greater with ocriplasmin than with placebo in both the ≥2-line and ≥3-line subgroups (28.0% vs 17.1%, P=.003, and 12.3% vs 6.4%, P=.024, respectively).24 In the OASIS study, which evaluated BCVA improvements at 24 months, 50.5% of patients in the ocriplasmin group had a ≥2-line improvement from baseline, compared with 39.1% in the sham group (95% CI: -2.1, 24.8; P=.114).11 The differences in BCVA improvement may be linked to the presence of FTMH at baseline. Of the patients with FTMH at baseline, those in the ocriplasmin group gained a mean of 12.2 letters, compared with 13.0 letters in the sham group (P=.765). However, of the patients without FTMH at baseline, the ocriplasmin group gained a mean of 7.7 letters, compared with 3.2 letters in the sham group (P=.016).11 These results suggest that BCVA may continue to improve over time, and baseline characteristics and patient selection for the use of ocriplasmin may impact BCVA outcomes. Preliminary results from ORBIT showed a similar trend of long-term BCVA improvement following ocriplasmin injection, with 13.1% of patients achieving a ≥2-line improvement at week 1, 18.7% at month 1, 30.0% at month 6, and 32.5% at month 12.14 Further analyses of long-term BCVA improvements and their potential correlations with anatomic changes associated with ocriplasmin are ongoing.
SAFETY OF OCRIPLASMIN
The safety profile of ocriplasmin has been studied carefully in clinical studies using patient-reported data, physician assessments, and SD-OCT imaging to identify AEs (Table).4,11,13-15 Broader analysis of 19 ocriplasmin studies (874 treated eyes) identified vitreous floaters (17.5%), decreased VA (17.4%), and photopsia (17.3%) as the most common AEs. These AEs mostly occurred in the first week following treatment and resolved with time.18 These events were generally transient and self-limited; nonetheless, patients should be aware of these potential AEs before consenting to ocriplasmin treatment.25-27 In a small number of patients, alterations may persist, but their occurrence could be related to underlying anatomic conditions.28-30 Patient- and physician-reported AEs are subjective, and it is unclear whether the AE is related to the natural disease course or to treatment. In addition, in the process of posterior vitreous detachment, photopsia and vitreous floaters are likely to occur and may indicate that ocriplasmin is having the desired vitreolytic effect. Additional changes may include the appearance of subretinal fluid,28 breaks in the ellipsoid zone visualized by SD-OCT,28 and ERG alterations,11,31 but these changes generally resolve over time and may be followed by improvements in BCVA. Ultimately, SD-OCT imaging could be used to verify the effects of ocriplasmin.
VISUAL FUNCTION ANALYSES
Further study of ocriplasmin has shown a clinically meaningful visual function benefit, in addition to the anatomic effects on VMT in these patients. A retrospective analysis using the MIVI-TRUST dataset assessed the effects of ocriplasmin on visual function response (VFR) using VA and vision-related quality-of-life measurements to quantify the association between VFR and resolution of VMA.32 At 6 months, 55.1% of patients in the ocriplasmin group had clinically meaningful visual benefits, compared with 34.2% in the placebo group (P<.0001). These visual function benefits were maintained over the 24-month study period.
An analysis of the MIVI-TRUST studies assessing the National Eye Institute Visual Function Questionnaire-25 (VFQ-25) showed that mean change in VFQ-25 scores was greater in the ocriplasmin group (3.4) than in the placebo group (0.7) (P=.005).33 Additionally, the patients in the ocriplasmin group who did not have VMA resolution at day 28 still had improvements in subscale scores at 6 months, compared with patients in the placebo arm. These results suggest that partial VMA release was sufficient to improve traction and related effects on vision. Given the significant impact on quality of life that patients with VMT experience, analysis of visual function response provides further support for the early treatment of the disease.
The cost-effectiveness of ocriplasmin has been comprehensively evaluated using clinical data from the MIVI-TRUST and OASIS trials to compare ocriplasmin with the standard of care in the United States and European Union. Widely accepted modeling techniques using national and international data have demonstrated that ocriplasmin is a cost-effective option for patients without ERM (irrespective of MH status), based on quality-adjusted life years gained34,35 and the impact on healthcare plans compared with standard of care.36
Patient selection and clinical insight are important factors when considering ocriplasmin for treatment of VMA/VMT. The following 2 case studies illustrate how ocriplasmin can successfully resolve VMA/VMT with sustained results when using good clinical judgment to identify patients likely to respond to vitreolysis.
A 68-year-old woman presented with a small MH, symptomatic VMA, and 20/200 VA. After 1 month of observation, there was no improvement. She was phakic, and SD-OCT showed no ERM (Figure 1A). The patient was administered ocriplasmin according to the labeling instructions; 6 weeks after injection, the VMT released, the MH closed, and her VA improved to 20/40 (Figure 1B). SD-OCT images revealed the presence of a small subfoveal fluid pocket, as is commonly seen after MH closure, regardless of whether the treatment was with ocriplasmin or PPV. The fluid pocket resolved 6 months post injection. Three years post injection, her VA was 20/25, and she had normal SD-OCT imaging (Figure 1C).
A 72-year-old woman presented with symptomatic VMA, MH, and mild intraretinal fluid with 20/150 VA. She was phakic, and SD-OCT showed no ERM (Figure 2A). The decision was made to treat her with ocriplasmin according to the labeling instructions. At 1 week post injection, the traction released, the MH closed, and the VA improved to 20/70. A small subfoveal fluid pocket (Figure 2B) was observed, but 3 months later, the subfoveal fluid pocket showed continued resolution, with the VA improving to 20/30 (Figure 2C). At 15 months post injection, her VA was 20/40 with no traction or subfoveal fluid and only a small ellipsoid zone defect, as seen on SD-OCT (Figure 2D).
THE FUTURE OF OCRIPLASMIN
Ocriplasmin is the only pharmacologic treatment approved for symptomatic VMA, providing a potential alternative to PPV. Ocriplasmin has a well-established efficacy and safety profile, as reported in clinical and postmarketing studies. Ocriplasmin has proven to be a cost-effective treatment option with improved, sustained visual outcomes in select patient populations. Ocriplasmin is currently being studied for other potential indications, including age-related macular degeneration and diabetic retinopathy, as VMA and subsequent traction could influence the course of these diseases.37,38 These studies represent an important area of investigation moving forward. RP
- Kuppermann BD. Ocriplasmin for the treatment of symptomatic vitreomacular adhesion/traction. US Ophthalmic Rev. 2015;8:55-59.
- Almeida D, Chin EK, Folk JC, Rahim K, Russell SR. Predictive factors for the spontaneous resolution of vitreomacular traction. Invest Ophthalmol Vis Sci. 2014;55(13):327.
- Stalmans P. A retrospective cohort study in patients with tractional diseases of the vitreomacular interface (ReCoVit). Graefes Arch Clin Exp Ophthalmol. 2016;254:617-628.
- Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367:606-615.
- Patel PJ, Brazier J, Hirneiß C, Tangelder M, Lescrauwaet B; MeMo Study Group. Prevalence of metamorphopsia in patients with vitreomacular traction and its impact on quality of life: the MeMo study. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; Seattle, WA; May 1-5, 2016.
- Brazier J, Hirneiß C, Tangelder M, Lescrauwaet B, Patel PJ. Prevalence of metamorphopsia in patients with vitreomacular traction (VMT), with or without macular hole (MH) and its impact on quality of life: the MeMo study. Paper presented at: 21st annual international meeting of ISPOR; Washington, DC; May 21-25, 2016.
- Jackson TL, Donachie PH, Johnston RL. Electronic medical record database study of vitrectomy and observation for vitreomacular traction. Retina. 2016;36:1897-1905.
- Jetrea [package insert]. Iselin, NJ: ThromboGenics; 2016.
- Annex I: Survey of Product Characteristics. European Medicines Agency. 2017. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002381/WC500142158.pdf . Accessed August 25, 2017.
- ThromboGenics. ThromboGenics successfully introduces new ‘already-diluted’ formulation of JETREA(R) (ocriplasmin) in the US [press release]; 2017.
- Dugel PU, Tolentino M, Feiner L, Kozma P, Leroy A. Results of the 2-Year Ocriplasmin for Treatment for Symptomatic Vitreomacular Adhesion Including Macular Hole (OASIS) randomized trial. Ophthalmology. 2016;123:2232-2247.
- Wu L, Zas M, Berrocal MH, et al. Anatomical and functional outcomes of symptomatic idiopathic vitreomacular traction: A natural history study from the Pan American Collaborative Retina Study Group. Retina. 2016;36:1913-1918.
- Shah SP, Jeng-Miller KW, Fine HF, Wheatley HM, Roth DB, Prenner JL. Post-marketing survey of adverse events following ocriplasmin. Ophthalmic Surg Lasers Imaging Retina. 2016;47:156-160.
- Joondeph BC, Khanani AM, Duker JS, et al. Efficacy and safety outcomes from the ORBIT phase IV clinical study. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; Baltimore, MD; May 7-11, 2017.
- Tadayoni R, Carr DC, Zhao Z. The ocriplasmin for vitreomacular traction intravitreal injection decisions (OVIID-I) trial: full study results. Invest Ophthalmol Vis Sci. 2016;57:4045.
- Lui K GJ, Chang A, Ho I. Assessment of anatomical and functional outcomes in subjects treated with ocriplasmin for vitreomacular traction -- OVIID-II. Paper presented at: Annual meeting of EURETINA; Barcelona, Spain; September 7-10, 2017.
- Stalmans P, Masin F, Spera C, Durier S, Rasouliyan L. Interim results from INJECT: investigation of Jetrea in patients with confirmed vitreomacular traction. Invest Ophthalmol Vis Sci. 2015;56:1237.
- Chatziralli I, Theodossiadis G, Xanthopoulou P, Miligkos M, Sivaprasad S, Theodossiadis P. 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. 2016;254:1247-1256.
- Figueira J, Martins D, Pessoa B, et al. The Portuguese experience with ocriplasmin in clinical practice. Ophthalmic Res. 2016;56:186-192.
- Schumann RG, Langer J, Compera D, et al. Assessment of intravitreal ocriplasmin treatment for vitreomacular traction in clinical practice. Graefes Arch Clin Exp Ophthalmol. 2017;255(11):2081-2089.
- Chaudhary K, Mak MY, Gizicki R, et al. Proportion of patients with macular hole surgery who would have been favorable ocriplasmin candidates: A retrospective analysis. Retina. 2017;37:76-79.
- Haynes RJ, Yorston D, Laidlaw DA, Keller J, Steel DH. Real world outcomes of ocriplasmin use by members of the British and Eire Association of Vitreoretinal Surgeons. Eye (Lond). 2017;31:107-112.
- Cacciamani A, Gelso A, Simonett JM, et al. Longitudinal microperimetry evaluation after intravitreal ocriplasmin injection for vitreomacular traction. Retina. 2017;37:1832-1838.
- Haller JA, Stalmans P, Benz MS, et al. Efficacy of intravitreal ocriplasmin for treatment of vitreomacular adhesion: subgroup analyses from two randomized trials. Ophthalmology. 2015;122:117-122.
- Kaiser PK, Kampik A, Kuppermann BD, Girach A, Rizzo S, Sergott RC. Safety profile of ocriplasmin for the pharmacologic treatment of symptomatic vitreomacular adhesion/traction. Retina. 2015;35:1111-1127.
- 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. 2015;35:1128-1134.
- Khan MA, Haller JA. Ocriplasmin for treatment of vitreomacular traction: An update. Ophthalmol Ther. 2016;5:147-159.
- Chatziralli IP, Theodossiadis GP, Parikakis E, Datseris I, Theodossiadis P. Complications of intravitreal ocriplasmin for vitreomacular traction and macular hole: a prospective spectral-domain optical coherence tomography study. Cutan Ocul Toxicol. 2016;35:263-269.
- Neffendorf JE, Lim LT, Gout II, El-Amir A. Widespread macular neurosensory detachment after ocriplasmin intravitreal injection. Retin Cases Brief Rep. 2016;10:354-356.
- Margo JA, Schocket LS, Klima K, Johnson MA. Persistent retinal changes after intravitreal ocriplasmin. Retin Cases Brief Rep. 2016;10:48-51.
- Rossi S, Testa F, Melillo P, Orrico A, Della Corte M, Simonelli F. Functional improvement assessed by multifocal electroretinogram after ocriplasmin treatment for vitreomacular traction. BMC Ophthalmol. 2016;16:110.
- Jackson TL, Verstraeten T, Duchateau L, Lescrauwaet B. Visual function response to ocriplasmin for the treatment of vitreomacular traction and macular hole. Acta Ophthalmol. 2017;95(8):e740-e745.
- 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. 2015;133:997-1004.
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