Predictors of Success With Ocriplasmin in VMT and FTMH
In cases of vitreomacular traction and macular hole, choice of treatment can make a big difference.
MICHELLE C. LIANG, MD • JAY S. DUKER, MD
Advances in OCT imaging over the last two decades have significantly enhanced our understanding of the vitreomacular interface in both health and disease. Vitreomacular adhesion (VMA), now more accurately identified by anatomical features on OCT, is typically an asymptomatic stage in normal vitreous aging.1,2
Pathology in the aging process, however, can lead to an anomalous posterior vitreous detachment (PVD), which in turn results in vitreomacular traction (VMT) or macular hole formation. These disease states often cause patients distress due to symptoms of decreased vision, metamorphopsia, and central vision loss.
With the introduction of ocriplasmin (Jetrea, ThromboGenics, Inc., Leuven, Belgium), the reality of pharmacologic vitreolysis has given clinicians an office-based, nonvitrectomy option for the treatment of “symptomatic VMA” — a clinical diagnosis that is contingent on the presence of an OCT showing vitreous traction resulting in abnormal macular architecture (VMT), with or without macular hole formation.
Before the FDA approved ocriplasmin in 2012, observation and vitrectomy surgery were the only options for these patients. For those with central distortion but relatively preserved visual acuity, the risks of vitrectomy and postoperative face-down positioning for macular hole repair often outweighed the benefits.
Michelle C. Liang, MD, is a vitreoretinal fellow at the New England Eye Center and Ophthalmic Consultants of Boston and a clinical associate at Tufts University School of Medicine in Boston. Jay S. Duker, MD, is the director of the New England Eye Center and professor and chair of ophthalmology at Tufts University School of Medicine. Neither author reports any financial interests in any products mentioned in this article. Dr. Duker’s e-mail is email@example.com.
Ocriplasmin has since revolutionized the management of select cases of VMT and macular holes associated with VMT.
Ocriplasmin is the first pharmacologic agent approved by the FDA for the treatment of symptomatic VMA. Produced by recombinant DNA, ocriplasmin is a truncated form of the human serine protease plasmin, and it has proteolytic activity against fibronectin, laminin, and collagen, components of the vitreous body and vitreomacular interface.3-5
If successful, this intervention allows patients to avoid the mechanical manipulation of vitrectomy and potentially to achieve improved macular anatomy and function.9
Clinical Trials Data
The MIVI-TRUST trials combined the analysis of two multicenter, randomized, double-blind, phase 3 clinical trials comparing a single intravitreal injection of ocriplasmin with placebo injection in patients with symptomatic VMA.
Six hundred fifty-two patients were treated: 464 with ocriplasmin (125 µg/0.1 mL) and 188 with placebo injection. The primary endpoint was resolution of VMA at day 28.
Twenty-six percent of patients in the ocriplasmin-injected eyes had resolution of VMA, in contrast to 10.1% of the patients with placebo-injected eyes. One secondary endpoint was the nonsurgical closure of a macular hole at day 28. Forty percent of ocriplasmin-treated eyes achieved this endpoint (N=106), compared to 10.6% of placebo-injected eyes (N=47).10
These trials showed that ocriplasmin treatment resolved traction and resulted in macular hole closure more often than placebo. However, as ocriplasmin use has increased in practice, it has become obvious that appropriate patient selection is critical to maximizing the benefits of ocriplasmin therapy.
CLASSIFICATION OF VITREOMACULAR INTERFACE DISEASE
Continued improvement in OCT technology has allowed for more detailed views of the vitreomacular interface and subsequent diagnosis of vitreomacular conditions, such as VMT and macular hole with or without VMT.
However, as technology has advanced, no single classification system or even consistent nomenclature has been used to define diseases of the vitreomacular interface. In 2012, a panel of vitreoretinal disease experts, the International Vitreomacular Traction Study (IVTS) group, convened to develop a unifying system to facilitate identification, monitoring, and management of vitreomacular interface diseases.1
This international classification system provides clinicians with an objective, OCT-based definition for diseases of the vitreomacular interface. Unlike previous staging systems, the definitions are based on anatomy, not patient symptoms or clinical findings.
With this new system, VMT is defined as a perifoveal vitreous cortex detachment from the retinal surface, with macular attachment of the vitreous cortex within a 3-mm radius of the fovea.
Unlike VMA, associated distortion of the foveal surface, intraretinal structural changes, and/or elevation of the fovea above the RPE may be present. VMT can be further subclassified by the size of the attachment area, as focal (≤1,500 µm) or broad (>1,500 µm), and by the absence (isolated) or presence of concurrent retinal conditions (Figure 1).
Figure 1. OCT scans demonstrating VMA and VMT, according to the IVTS classification system. A) Broad VMA with attachment >1,500 µm and no detectable change in foveal contour. B) Focal VMT with attachment ≤1,500 µm and distortion of the foveal surface. C) Focal VMT with foveal cystic changes.
Full-thickness Macular Holes
Full-thickness macular holes (FTMHs) are defined by their OCT characteristics and the factors associated with surgical success. In this classification, a FTMH is a full-thickness foveal lesion that interrupts all of the macular layers from the internal limiting membrane to the retinal pigment epithelium.
Full-thickness macular hole can be further subclassified by the aperture size of the hole into:
• small, ≤250 µm;
• medium, >250 µm and ≤400 µm; and
• large >400 µm.
Aperture size is defined as the minimum width measured at the narrowest hole point in the mid-retina, a measurement drawn roughly parallel to the RPE.1 This aperture size is significant because it can be used to help predict anatomic success with both medication and surgery. In addition, FTMH can be subclassified based on whether or not VMT is present (Figure 2).
Figure 2. OCT scans illustrating examples of FTMH according to the IVTS classification system. A) Small FTMH with aperture size ≤250 µm. Note the overlying vitreous attachment. B) Medium FTMH with aperture size >250 µm and ≤400 µm. There is no associated vitreous attachment. C) Large FTMH with aperture size >400 µm. Persistent vitreous attachment is visible at the edge of the hole.
Finally, the term “idiopathic” has been abandoned, because it is clear that such holes are created by VMT. Holes resulting from VMT should be referred to as primary macular holes, while those that occur as a result of other processes (eg, trauma, macular telangiectasia type II) should be referred to as secondary macular holes.
According to the MIVI-TRUST trials, success (ie, the primary endpoint) was release of VMA as assessed by the post-treatment OCT. While improvement in BCVA was a secondary endpoint, it can be difficult to correlate visual acuity with improvement in symptoms, especially metamorphopsia. This correlation has become more evident as use of ocriplasmin in clinical practice has increased.
In addition, while “phase 3 success,” ie, “release of adhesion,” may occur, a visually significant underlying macular hole may persist. Failure of the macular hole to close despite PVD would not likely be considered a success by either the clinician or the patient.
Specific patient factors, as well as OCT findings, can help physicians to maximize success in treating patients with VMT and FTMH. First, they must confirm on OCT that VMT is in fact present.
While either time-domain, as used in the MIVI-TRUST trials, or spectral-domain OCT can be utilized to diagnose VMT, SD-OCT has better resolution and theoretically allows for better identification of fine areas of VMT. In addition, once determined to be present, the physician must conclude that the VMT aspect of the scan is an active part of the pathology.
Subgroup analysis of the MIVI-TRUST trials demonstrated certain factors, including age <65 years, absence of epiretinal membrane (ERM), VMA ≤1,500 µm, and phakic lens status, were more associated with VMA release after treatment with ocriplasmin. In addition, smaller macular holes, those ≤250 µm, were more likely to close than medium-sized ones.10-12
For patients with focal VMA (≤1,500 µm), a 34.7% success rate was found for VMA release with ocriplasmin, compared to 14.6% in placebo-injected eyes. In addition, while significant ERMs were excluded from the phase 3 trials, the presence of any ERM was associated with a lower rate of release of VMA.
For patients without ERMs, the rate of VMA release was 37.4% in ocriplasmin-treated patients, compared to 14.3% of placebo-injected patients. Notably, only 8.7% of patients with an ERM treated with ocriplasmin had VMA release.
For those patients with macular holes, the overall closure rate was 40.6% in the ocriplasmin-treated group. Subgroup analysis demonstrated that the rate of closure was 58.3% in small holes (those 250 µm or less) and 36.8% in medium-sized holes (those between 250 and 400 µm in size).
Large macular holes (>400 µm) were excluded from the study; nevertheless, the trial inadvertently enrolled 22 such eyes. None closed with either ocriplasmin (N=19) or placebo (N=3).
A combination of these predictive factors was also correlated with an increased release of VMA. Specifically, patients age <65 years with VMA ≤1,500 µm and no ERM had a 70% success rate for VMA release, compared with 23.1% of placebo-injected patients.10-12
In a recent retrospective case series performed by Singh et al, the authors found that the percentage of VMA release increased with more positive predictive factors. Of 17 patients, 47.1% (eight patients) experienced VMA release.
Subgroup analysis showed a 50% response rate in patients with three of four predictive factors (seven of 14 eyes) and 75% in patients with four criteria (3/4 eyes).13
While these characteristics can help clinicians optimize results in the office, vitrectomy remains the gold standard and likely a better option if a large area of VMA, large macular hole size, or associated ERM is present (Table).
|Presence of VMT on OCT||Focal adhesion (≤1,500 μm)|
|Macular hole aperture <400 μm||No epiretinal membrane (ERM)|
|No diabetic retinopathy|
For patients with symptomatic VMA, ocriplasmin is a welcome addition to the physician’s armamentarium for treatment of VMT and FTMH associated with VMT. More recent experience with ocriplasmin has identified certain factors associated with an increased likelihood of success.
Ideal patients most likely to benefit are those with focal VMT, no ERM, and a small macular hole size. Other factors, including associations with macular degeneration and diabetes, have yet to be investigated fully. With prudent selection of patients, physicians can maximize visual results and minimize both the risk and cost to their patients. RP
1. Duker JS, Kaiser PK, Binder S, et al. The International Vitreomacular Traction Study Group classification of vitreomacular adhesion, traction, and macular hole. Ophthalmology. 2013;120:2611-2619.
2. Stalmans P, Duker JS, Kaiser PK, et al. OCT-based interpretation of the vitreomacular interface and indications for pharmacologic vitreolysis. Retina. 2013;33:2003-2011.
3. JETREA (package insert). Iselin, NJ; ThromboGenics Inc.; 2012.
4. Schneider EW, Johnson MW. Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review. Clin Ophthalmol. 2011;5:1151-1165.
5. Gandorfer A. Enzymatic vitreous disruption. Eye. 2008;1273-1277.
6. Sebag J. Pharmacologic vitreolysis. Retina. 1998;18:1-3.
7. de Smet MD, Valmaggia C, Zarrantz J, Willekens B: Microplasmin: ex vivo characterization of its activity in porcine vitreous. Invest Ophthalmol Vis Sci. 2009;50:814-819
8. Aerts F, Noppen B, Fonteyn L, Derua R, Waelkens E, de Smet MD, Vanhove M: Mechanism of inactivation of ocriplasmin in porcine vitreous. Biophysical Chemistry 2012;165-166:30-38.
9. Trese M. Enzymatic-assisted vitrectomy. Eye. 2002;16:365-368.
10. Stalmans P, Benz MS, Gandorfer A, et al; MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367:606-615.
11. Kaiser PK. Medical management with pharmacologic agents: rationale and clinical trials. Paper presented at: Contemporary Management of Diseases of the Vitreomacular Interface; Boston, MA; July 13, 2013.
12. Regillo CD. Ocriplasmin in clinical practice: how and when to use it. Paper presented at: Contemporary Management of Diseases of the Vitreomacular Interface; Boston, MA; July 13, 2013.
13. Singh RP, Li A, Bedi R, et al. Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome. Br J Ophthalmol. 2013 Dec 19. [Epub ahead of print]