Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Initial Outcomes Following Intravitreal Ocriplasmin for Treatment of Symptomatic Vitreomacular Adhesion

Brian T. Kim, MD; Stephen G. Schwartz, MD, MBA; William E. Smiddy, MD; Rishi R. Doshi, MD; Jaclyn L. Kovach, MD; Audina M. Berrocal, MD; Andrew A. Moshfeghi, MD, MBA; Jorge A. Fortun, MD

Abstract

BACKGROUND AND OBJECTIVE:

When delivered via a single intravitreal injection, ocriplasmin can effect proteolytic resolution of symptomatic vitreomacular adhesion (VMA). The authors describe their initial clinical experience with ocriplasmin at a large academic center.

PATIENTS AND METHODS:

Retrospective review of all patients with symptomatic VMA treated with ocriplasmin from January 2013 through May 2013 at a single center.

RESULTS:

Nineteen patients with symptomatic VMA received intravitreal ocriplasmin. Eight patients (42%) exhibited resolution of VMA. Macular holes in three of six patients (50%) closed after injection. A higher proportion of VMA resolution was observed in patients with the following baseline characteristics: age less than 65 years, focal adhesions less than or equal to 1,500 μm, presence of macular hole, phakic status, and absence of epiretinal membrane.

CONCLUSION:

Initial clinical outcomes using ocriplasmin in this study are consistent with those reported in the phase 3 clinical trials. Improved clinical results can be achieved with careful case selection based on specific baseline characteristics.

[Ophthalmic Surg Lasers Imaging Retina. 2013;44:334–343.]

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.

Dr. Fortun is a consultant for ThromboGenics. Dr. Moshfeghi is a consultant and has received honoraria for non-CME speaking services for ThromboGenics. The remaining authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Jorge A. Fortun, MD, Bascom Palmer Eye Institute, 7101 Fairway Drive, Palm Beach Gardens, FL 33418; email: jfortun@med.miami.edu.

Received: July 08, 2013
Accepted: July 12, 2013

Abstract

BACKGROUND AND OBJECTIVE:

When delivered via a single intravitreal injection, ocriplasmin can effect proteolytic resolution of symptomatic vitreomacular adhesion (VMA). The authors describe their initial clinical experience with ocriplasmin at a large academic center.

PATIENTS AND METHODS:

Retrospective review of all patients with symptomatic VMA treated with ocriplasmin from January 2013 through May 2013 at a single center.

RESULTS:

Nineteen patients with symptomatic VMA received intravitreal ocriplasmin. Eight patients (42%) exhibited resolution of VMA. Macular holes in three of six patients (50%) closed after injection. A higher proportion of VMA resolution was observed in patients with the following baseline characteristics: age less than 65 years, focal adhesions less than or equal to 1,500 μm, presence of macular hole, phakic status, and absence of epiretinal membrane.

CONCLUSION:

Initial clinical outcomes using ocriplasmin in this study are consistent with those reported in the phase 3 clinical trials. Improved clinical results can be achieved with careful case selection based on specific baseline characteristics.

[Ophthalmic Surg Lasers Imaging Retina. 2013;44:334–343.]

From the Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.

Dr. Fortun is a consultant for ThromboGenics. Dr. Moshfeghi is a consultant and has received honoraria for non-CME speaking services for ThromboGenics. The remaining authors have no financial or proprietary interest in the materials presented herein.

Address correspondence to Jorge A. Fortun, MD, Bascom Palmer Eye Institute, 7101 Fairway Drive, Palm Beach Gardens, FL 33418; email: jfortun@med.miami.edu.

Received: July 08, 2013
Accepted: July 12, 2013

Introduction

The treatment of vitreomacular interface disorders, including vitreomacular adhesion (VMA), vitreomacular traction, and evolving or early full-thickness macular hole (FTMH), has traditionally been limited to either surgical or observational management. In January 2013, ocriplasmin (Jetrea; ThromboGenics, Iselin, NJ) became the first commercially available U.S. Food and Drug Administration–approved pharmacologic treatment option for symptomatic VMA.1 Ocriplasmin is a protease subunit derived from human plasmin that hydrolyzes collagen, laminin, and fibronectin in the vitreous body and at the vitreoretinal interface. When injected intravitreally, ocriplasmin induces vitreous liquefaction and separation of vitreoretinal adhesions at the macula and peripapillary retina.2 An example case can be seen in Figure 7. In pivotal phase 3 clinical trials, a one-time intravitreal injection of ocriplasmin 125 μg per 100 μL was administered in treatment for symptomatic VMA including small (less than or equal to 250 μm) and medium (250 to 400 μm) FTMH with persistent VMA. When evaluating the pooled data from the pivotal studies, the incidence of nonsurgical resolution of VMA was found to be 26.5%, compared to 10.1% with placebo injection. In the current study, we report our initial clinical experience with intravitreal ocriplasmin for the treatment of symptomatic VMA and FTMH with persistent VMA.

(A) This patient had a decrease in vision to 20/60 for 1 week due to this full-thickness macular hole with focal adhesion. (B) Two days after ocriplasmin injection, the vitreomacular adhesion had resolved and the hole closed. (C) Smaller subretinal fluid at day 7. (D) At 5 weeks, further reduction in subretinal fluid and vision improvement to 20/25.

Figure 7. (A) This patient had a decrease in vision to 20/60 for 1 week due to this full-thickness macular hole with focal adhesion. (B) Two days after ocriplasmin injection, the vitreomacular adhesion had resolved and the hole closed. (C) Smaller subretinal fluid at day 7. (D) At 5 weeks, further reduction in subretinal fluid and vision improvement to 20/25.

Patients and Methods

This is an IRB-approved, retrospective case review series of all patients who received intravitreal ocriplasmin for symptomatic VMA at all of the campuses of the Bascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, between January 14 and June 1, 2013. Spectral-domain optical coherence tomography (OCT) was performed with either Cirrus HD-OCT (Carl Zeiss Med-itec, Dublin, CA) or Spectralis (Heidelberg Engineering, Heidelberg, Germany) systems as part of routine pre- and post-injection follow-up visits. At baseline and all follow-up visits, patient demographics and examination findings were collected. OCT images were reviewed at these visits for VMA, epiretinal membrane (ERM), and FTMH status. OCT measurements were taken using the respective companies’ proprietary software. Snellen visual acuity was converted to an ETDRS equivalent3 to calculate and compare changes.

Results

A total of 19 consecutive patients with a spectrum of symptomatic VMA were treated with intravitreal ocriplasmin injections by eight retina specialists. Seventeen had greater than 28 days of follow-up, with a mean of 56 days (range: 6 to 133 days). Of the two patients with shorter follow-up duration, one patient achieved complete resolution of VMA by 2 weeks after injection (Figure 1), while the other’s VMA persisted at 1 week post-injection before the patient was lost to follow-up (Figure 18). Eight patients were male, and 11 were female. The average age was 71 years (range: 57 to 81 years), with only two patients aged less than 65 years. Fifteen patients were phakic, and the remaining four patients had posterior chamber intraocular lenses. Eight patients showed OCT evidence of ERM at baseline.

(A) This is a patient with 20/25 vision who is functionally monocular due to full-thickness macular hole in the contralateral eye. (B) One day and (C) 16 days after ocriplasmin injection.

Figure 1. (A) This is a patient with 20/25 vision who is functionally monocular due to full-thickness macular hole in the contralateral eye. (B) One day and (C) 16 days after ocriplasmin injection.

(A) This patient had retinal detachment in the contralateral eye and has a thick posterior hyaloid with a central 878 μm adhesion diameter. Multiple adhesions can be seen in the peripheral macula and nerve head. (B) At 1 week, there was no improvement on OCT. This patient was lost to follow-up.

Figure 18. (A) This patient had retinal detachment in the contralateral eye and has a thick posterior hyaloid with a central 878 μm adhesion diameter. Multiple adhesions can be seen in the peripheral macula and nerve head. (B) At 1 week, there was no improvement on OCT. This patient was lost to follow-up.

Overall, eight of 19 patients (42.1%) achieved successful nonsurgical release of VMA following intravitreal ocriplasmin injection (Figures 1 to 8). Of the phakic patients, eight (53.3%) achieved nonsurgical release of VMA compared to none in the pseudophakic group. Two of eight patients (25%) with ERM versus five of 11 (45.5%) without baseline ERM achieved nonsurgical VMA resolution. Four of six FTMH patients (66.7%) had successful VMA resolution, with three (50%) achieving hole closure. In the remaining 13 patients without macular holes, there was resolution of VMA in four (31%).

(A) Focal vitreomacular adhesion with epiretinal membrane and early lamellar defect that persisted at 1 month but (B) released late at day 68.

Figure 2. (A) Focal vitreomacular adhesion with epiretinal membrane and early lamellar defect that persisted at 1 month but (B) released late at day 68.

(A) This is a patient with micro-full-thickness macular hole and stringy vitreomacular adhesion attached focally to the edges of the hole and epiretinal membrane. (B) One month after ocriplasmin with release of vitreomacular adhesion and closure of full-thickness macular hole.

Figure 3. (A) This is a patient with micro-full-thickness macular hole and stringy vitreomacular adhesion attached focally to the edges of the hole and epiretinal membrane. (B) One month after ocriplasmin with release of vitreomacular adhesion and closure of full-thickness macular hole.

(A) Traction-related subretinal fluid due to focal vitreomacular adhesion. (B) Vitreomacular adhesion release with small area of persistent fluid at 1 month.

Figure 4. (A) Traction-related subretinal fluid due to focal vitreomacular adhesion. (B) Vitreomacular adhesion release with small area of persistent fluid at 1 month.

(A) Micro-full-thickness macular hole due to focal adhesion seen here in the setting of dry macular degeneration treated with ocriplasmin, (B) showing late anatomic improvement at day 42.

Figure 5. (A) Micro-full-thickness macular hole due to focal adhesion seen here in the setting of dry macular degeneration treated with ocriplasmin, (B) showing late anatomic improvement at day 42.

(A) Wet macular degeneration controlled with regular aflibercept injections was treated with ocriplasmin. (B) At day 14, the vitreomacular adhesion released but the subretinal fluid recurred and was treated with repeat aflibercept and (C) had subsequent resolution of subretinal fluid 8 weeks later.

Figure 6. (A) Wet macular degeneration controlled with regular aflibercept injections was treated with ocriplasmin. (B) At day 14, the vitreomacular adhesion released but the subretinal fluid recurred and was treated with repeat aflibercept and (C) had subsequent resolution of subretinal fluid 8 weeks later.

(A) Full-thickness macular hole with focal adhesion (B) released vitreomacular adhesion at 1 month, but (C) a persistent hole at 2 months after ocriplasmin required surgical closure.

Figure 8. (A) Full-thickness macular hole with focal adhesion (B) released vitreomacular adhesion at 1 month, but (C) a persistent hole at 2 months after ocriplasmin required surgical closure.

The average baseline visual acuity was equivalent to 63 ETDRS letters, which is approximately 20/50 to 20/60 Snellen. Eight of 19 (42.1%) patients had no change in baseline vision. An additional eight patients showed mild visual improvement of less than two ETDRS lines. Two of 19 patients had a significant gain in vision of at least three ETDRS lines after nonsurgical closure of full-thickness macular holes. Only one patient experienced loss of vision, from 20/70 to 20/200 (at least three ETDRS lines) due to progression of vitreomacular traction to a full-thickness macular hole. Individual patient data are detailed in Table 1.

Baseline and Follow-up Characteristics of Study Population

Table 1: Baseline and Follow-up Characteristics of Study Population

There were no cases of post-injection uveitis, endophthalmitis, retinal tears, or retinal detachment throughout the follow-up period.

Discussion

Intravitreal injection of ocriplasmin represents a novel treatment option supplementing observation and vitrectomy in the management of patients with symptomatic vitreomacular interface disorders. In the current study, representing a case series of the initial experience of an academic center using ocriplasmin, the overall incidence of successful VMA release (42%) was comparable to the results of the MIVI-TRUST (MIVI-006, MIVI-007) clinical trials (26.5%).1 Post hoc subgroup analysis of the phase 3 clinical trial data established that successful outcomes were more likely in patients with certain independent baseline characteristics, specifically absence of ERM, adhesion diameter less than 1,500 μm, presence of FTMH, presence of crystalline lens, and age less than 65 years.4 Despite a small sample size that did not allow for statistical significance, outcomes in our series were consistent with these results (Table 2).

Comaprison of Rates of Vitreomacular Adhesion Resolution in Current Study and Ocriplasmin Clinical Trials

Table 2: Comaprison of Rates of Vitreomacular Adhesion Resolution in Current Study and Ocriplasmin Clinical Trials

Visual acuity improvement in our study was modest overall. Eight of 19 patients had no change in baseline vision. An additional eight patients showed mild visual improvement (less than two ETDRS lines). Two patients had a significant gain in vision (three or more ETDRS lines), and both involved nonsurgical closure of full-thickness macular holes (Table 1, patients 3 and 7; Figures 3 and 7). Only one patient experienced loss of vision (two or more ETDRS lines), from 20/70 to 20/200 due to the progression of vitreomacular traction to a full-thickness macular hole (Table 1, patient 17; Figure 17).

(A) Pocket of subretinal fluid from vitreomacular adhesion. (B) Persistent vitreomacular adhesion 28 days after intravitreal ocriplasmin with a secondary opening of full-thickness macular hole.

Figure 17. (A) Pocket of subretinal fluid from vitreomacular adhesion. (B) Persistent vitreomacular adhesion 28 days after intravitreal ocriplasmin with a secondary opening of full-thickness macular hole.

Although this was a small series with a limited follow-up interval, no major adverse effects were encountered following intravitreal injection of ocriplasmin — specifically, no retinal tears, retinal detachment, or post-injection inflammation. Patients were not systematically questioned regarding subjective visual symptoms, but one patient self-reported a transient increase in floaters and photopsias (Table 1, patient 7). However, other tests and measures of visual function such as electroretinogram, visual fields, and color vision testing were not performed.

This study is an initial look at the real-world clinical outcomes of ocriplasmin and is limited by its retrospective nature and small number of subjects. Our patient population was slightly dissimilar to those of the clinical trials because two patients who would not have met clinical trial inclusion criteria were included here. The first of these two patients was receiving regular intravitreal aflibercept injections for exudative macular degeneration, and the VMA resolved after an intravitreal ocriplasmin injection. Ocriplasmin injection did not appear clinically to alter the short-term course of macular degeneration or responsiveness to aflibercept (Table 1, patient 6; Figure 6). The second patient had quiescent proliferative diabetic retinopathy and prior macular laser and did not respond to ocriplasmin; vitrectomy was subsequently performed (Table 1, patient 11; Figure 11). Imaging modalities were not always consistently obtained at each visit, allowing for a small possibility of inconsistent clinical assessment of macular hole presence or closures. Thus, it should be emphasized that these results, while helpful in the assessment of a practical clinical setting, cannot be strictly compared to the results seen in the clinical trials.

(A) Baseline OCT in a patient with proliferative diabetic retinopathy and prior focal macular laser treated for focal symptomatic vitreomacular adhesion. (B) Two months later, there were no anatomic changes.

Figure 11. (A) Baseline OCT in a patient with proliferative diabetic retinopathy and prior focal macular laser treated for focal symptomatic vitreomacular adhesion. (B) Two months later, there were no anatomic changes.

Injection of intravitreal ocriplasmin represents a new option to be considered along with expectant management and surgical intervention in select patients with symptomatic VMA and VMA-associated macular hole. Neither this small retrospective series nor the MIVI-TRUST trials directly compared in a randomized fashion the outcomes and safety of intravitreal ocriplasmin to those of surgery or observation alone. These other treatment options should be considered in each case and discussed with the patient. Patients should be counseled regarding the realistically modest rates of anatomic and functional success with intravitreal ocriplasmin, along with the non-negligible risks of treatment and intravitreal injection. The results of the current study — a limited, retrospective, initial-experience case series — do not justify any additional, definitive claims regarding the safety and efficacy of intravitreal ocriplasmin beyond the already available data. However, the results suggest comparable efficacy, particularly with adequate patient selection, to that seen in larger clinical trials.

References

  1. 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 doi:10.1056/NEJMoa1110823 [CrossRef].
  2. Kuppermann BD. Ocriplasmin for pharmacologic vitreolysis. Retina. 2012;32:S225–S228 doi:10.1097/IAE.0b013e31825bc593 [CrossRef].
  3. Gregori NZ, Feuer W, Rosenfeld PJ. Novel method for analyzing snellen visual acuity measurements. Retina. 2010;30(7):1046–1050 doi:10.1097/IAE.0b013e3181d87e04 [CrossRef].
  4. Ray S. Baseline anatomic features predictive of pharmacologic VMA resolution in the phase III ocriplasmin clinical trial program. Paper presented at: American Academy of Ophthalmology Retina Subspecialty Day. ; November 2012. ; Chicago, IL. .

Baseline and Follow-up Characteristics of Study Population

PatientAge (years)GenderLens StatusBaseline VAFinal VA*Baseline FTMHFTMH Diameter (μm)Baseline ERMVMA Diameter (μm)VMA ReleaseDay of VMA ResolutionFollow-up Duration (days)Surgical Treatment NeededComments
168Fphakic20/2520/2000435+1160
270Fphakic20/5020/400+282+68700
371Mphakic20/10020/30+150+250+28290
457Fphakic20/4020/3000450+211330
574Mphakic20/6020/40+1500391+42400dry AMD
676Mphakic20/2520/2500600+14600wet AMD, aflibercept
768Mphakic20/6020/25+960115+2350
868Fphakic20/6020/60+1000300+2870+Persistent FTMH
965Mphakic20/3020/2500377028+
1062Fphakic20/5020/40+383+120055+
1175FPCIOL20/8020/6000250063+PDR, macular laser
1277Fphakic20/5020/5000497036+
1376Mphakic20/20020/2000+> 1,500060+
1468Fphakic20/6020/60+101+1000118+
1579MPCIOL20/8020/800+> 1,500091+CACG s/p trab
1681Fphakic20/6020/600+> 1,500084+
1770Fphakic20/7020/20000400037+LASIK
1881MPCIOL20/5020/400087806+
1967FPCIOL20/4020/400+398038+

Comaprison of Rates of Vitreomacular Adhesion Resolution in Current Study and Ocriplasmin Clinical Trials

Baseline CharacteristicsCurrent StudyOcriplasmin Clinical Trials
Overall42% (n = 8/19)26.5% (n = 123/464)*
Age < 65 years50% (n = 1/2)47.5% (n = 38/80)**
Age ≥ 65 years41.2% (n = 7/17)22.1% (n = 85/464)**
FTMH present67% (n = 4/6)50.0% (n = 53/106)**
FTMH absence30.8% (n = 4/13)19.6% (n = 70/358)**
**Overall FTMH closure50% (n = 3/6)40.6% (n = 43/106)*
ERM present25.0% (n = 2/8)8.7% (n = 16/184)*
ERM absent45% (n = 5/11)37.4% (n = 101/270)*
VMA diameter ≤ 1,500 μm50% (n = 8/16)34.7% (n = 109/314)**
VMA diameter > 1,500 μm0.0% (n = 0/3)5.9% (n = 6/102)**
Phakic53% (n = 8/15)34.2% (n = 100/292)*
Pseudophakic0.0% (n = 0/3)13.4% (n = 23/172)*
(A) Despite having a focal adhesion and absence of epiretinal membrane, this patient did not respond to ocriplasmin but (B) had some improvement in lamellar defect.

Figure 9. (A) Despite having a focal adhesion and absence of epiretinal membrane, this patient did not respond to ocriplasmin but (B) had some improvement in lamellar defect.

(A) Full-thickness macular hole and epiretinal membrane with (B) paracentral focal adhesion at the time of ocriplasmin injection. (C) At month 2, the full-thickness macular hole and (D) vitreomacular adhesion persisted.

Figure 10. (A) Full-thickness macular hole and epiretinal membrane with (B) paracentral focal adhesion at the time of ocriplasmin injection. (C) At month 2, the full-thickness macular hole and (D) vitreomacular adhesion persisted.

(A) A focal lamellar defect due to vitreomacular adhesion, (B) unchanged at 36 days.

Figure 12. (A) A focal lamellar defect due to vitreomacular adhesion, (B) unchanged at 36 days.

(A) Thick epiretinal membrane with a broad vitreomacular adhesion extending beyond the raster border had (B) progression of vitreomacular adhesion with worsening subretinal fluid at month 1. This patient required surgical treatment.

Figure 13. (A) Thick epiretinal membrane with a broad vitreomacular adhesion extending beyond the raster border had (B) progression of vitreomacular adhesion with worsening subretinal fluid at month 1. This patient required surgical treatment.

(A) Micro-full-thickness macular hole with epiretinal membrane and a marginal adhesion that (B) persisted at 1 month. This patient had anatomic resolution of vitreomacular adhesion and full-thickness macular hole with surgery.

Figure 14. (A) Micro-full-thickness macular hole with epiretinal membrane and a marginal adhesion that (B) persisted at 1 month. This patient had anatomic resolution of vitreomacular adhesion and full-thickness macular hole with surgery.

(A) A thick epiretinal membrane with a broad vitreomacular adhesion extending beyond the OCT boundary treated with ocriplasmin. (B) Some worsening of intraretinal cysts and retinal thickening 1 month later.

Figure 15. (A) A thick epiretinal membrane with a broad vitreomacular adhesion extending beyond the OCT boundary treated with ocriplasmin. (B) Some worsening of intraretinal cysts and retinal thickening 1 month later.

(A) Distorted inner retinal lamellae due to a thick epiretinal membrane and broad adhesion. (B) Unchanged OCT at 1 month after ocriplasmin.

Figure 16. (A) Distorted inner retinal lamellae due to a thick epiretinal membrane and broad adhesion. (B) Unchanged OCT at 1 month after ocriplasmin.

(A) Focal vitreomacular adhesion with epiretinal membrane adjacent to the adhesion point. The contour of the posterior hyaloid may be suggestive of the presence of fibroglial proliferation. (B) No change on OCT at 1 month after ocriplasmin injection.

Figure 19. (A) Focal vitreomacular adhesion with epiretinal membrane adjacent to the adhesion point. The contour of the posterior hyaloid may be suggestive of the presence of fibroglial proliferation. (B) No change on OCT at 1 month after ocriplasmin injection.

10.3928/23258160-20130715-05

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