Ocriplasmin for symptomatic vitreomacular adhesion

James E Neffendorf, Varo Kirthi, Edward Pringle, Timothy L Jackson

Symptomatic vitreomacular adhesion (sVMA) is a recognised cause of visual loss and by tradition has been managed by pars plana vitrectomy (PPV). A less invasive alternative to surgery in some people is enzymatic vitreolysis, using an intravitreal injection of ocriplasmin. To assess the efficacy and safety of ocriplasmin compared to no treatment, sham or placebo for the treatment of sVMA. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 1), MEDLINE Ovid (1946 to 24 February 2017), Embase Ovid (1947 to 24 February 2017), PubMed (1946 to 24 February 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 24 February 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 24 February 2017 and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 24 February 2017. We did not use any date or language restrictions in the electronic searches for trials. We included randomised controlled trials (RCTs) of people with sVMA. The intervention was intravitreal ocriplasmin 125 μg injection, and this was compared to placebo or sham injection (control). Placebo was defined as a single intravitreal injection of 0.10 mL placebo with identical drug vehicle diluted with saline. A sham injection was defined as the syringe hub or blunt needle touching the conjunctiva to simulate an injection. Two authors independently selected relevant trials, assessed methodological quality and extracted data. We graded the certainty of the evidence using the GRADE approach. This review included four RCTs conducted in Europe and the USA with a total of 932 eyes of 932 participants. Participants were 18 to 97 years of age, with evidence of focal vitreomacular adhesion (VMA) on optical coherence tomography (OCT) imaging, with a best corrected visual acuity (BCVA) of 20/25 or worse in the study eye and 20/400 or better in the fellow eye. The interventions compared were intravitreal ocriplasmin versus sham (two RCTs) or placebo (two RCTs) injection. Both sham and placebo injection were classified as the control group. The main outcome measures were assessed at 28 days and six months. Overall, we judged the studies to have a low or unclear risk of bias. All four RCTs were sponsored by the manufacturers of ocriplasmin.Compared with control, ocriplasmin treatment was more likely to result in VMA release within 28 days (risk ratio (RR) 3.46, 95% confidence interval (CI) 2.00 to 6.00; 859 eyes, 4 RCTs, high-certainty evidence). Approximately 97/1000 eyes will have VMA release within 28 days without treatment. An additional 237 eyes will have VMA release within 28 days for every 1000 eyes treated with ocriplasmin (95% CI 96 more to 482 more).Treatment with ocriplasmin was also more likely to result in macular hole closure (RR 2.87, 95% CI 1.50 to 5.51; 229 eyes, 3 RCTs, high-certainty evidence). Approximately 123/1000 eyes with macular holes will have closure with no treatment. An additional 231 eyes will have macular hole closure for every 1000 eyes treated with ocriplasmin (95% CI 62 more to 556 more).Eyes receiving ocriplasmin were also more likely to have complete posterior vitreous detachment (PVD) within 28 days (RR 2.94, 95% CI 1.39 to 6.24; 689 eyes, 3 RCTs, high-certainty evidence). Approximately 40/1000 eyes will have complete PVD within 28 days without treatment. An additional 78 eyes will have complete PVD within 28 days for every 1000 eyes treated with ocriplasmin (95% CI 16 more to 210 more).Eyes receiving ocriplasmin were more likely to achieve 3-line or greater improvement in BCVA at six months (RR 1.95, 95% CI 1.07 to 3.53; 674 eyes, 3 RCTs, moderate-certainty evidence). Approximately 61/1000 eyes will have a 3-line or greater improvement in BCVA at six months without treatment. An additional 58 eyes will have 3-line or greater improvement in BCVA at six months for every 1000 eyes treated with ocriplasmin (95% CI 9 more to 154 more).Receiving ocriplasmin also reduced the requirement for vitrectomy at six months (RR 0.67, 95% CI 0.50 to 0.91; 689 eyes, 3 RCTs, moderate-certainty evidence). Approximately 265/1000 eyes will require vitrectomy at six months without treatment and 87 fewer eyes will require vitrectomy for every 1000 eyes treated with ocriplasmin (95% CI 24 fewer to 132 fewer).Treatment with ocriplasmin resulted in a greater improvement in validated Visual Function Questionnaire form score at six months (mean improvement difference 2.7 points, 95% CI 0.8 to 4.6; 652 eyes, 2 RCTs, moderate-certainty evidence).Eyes receiving ocriplasmin were more likely to have an adverse event (RR 1.22, 95% CI 1.09 to 1.37, 909 eyes, 4 RCTs, moderate-certainty evidence). Approximately 571/1000 eyes will have an adverse event with sham or placebo injection and 106 more eyes will have an adverse event for every 1000 eyes treated with ocriplasmin (95% CI 52 more to 212 more). Evidence from a limited number of RCTs suggests that ocriplasmin is useful in the treatment of sVMA. However, up to 20% of eyes treated with ocriplasmin will still require additional treatment with PPV within six months. There were more ocular adverse events in eyes treated with ocriplasmin than control (sham or placebo injection) treatment. Many of these adverse events, particularly vitreous floaters and photopsia, are known to be associated with posterior vitreous detachment. At present however, there is minimal published long-term safety data on eyes treated with ocriplasmin. Further large RCTs comparing ocriplasmin with other management options for sVMA would be beneficial.