OBSERVED COMPLICATIONS FROM DEXAMETHASONE INTRAVITREAL IMPLANT FOR THE TREATMENT OF MACULAR EDEMA IN RETINAL VEIN OCCLUSION OVER 3 TREATMENT ROUNDS GERARD A. REID, MB, BCH, BAO, MSC, DILRAJ S. SAHOTA, BA (OXON), MBBS, MAHMOUD SARHAN, FRCS ED, MRCOPHTH Purpose: To report adverse events after treatment of macular edema secondary to retinal vein occlusion with intravitreal dexamethasone implant (IDI) in a UK center across three treatment rounds. Methods: A review of 61 eyes receiving IDI treatment (1 implant [n = 61], 2 implants [n = 17], 3 implants [n = 6]). Data were collected at initiation and 2 and 6 months. Outcomes were intraocular pressure (IOP) (mean IOP, IOP .25 mmHg and IOP rise .10 mmHg) and cataract surgery. Other adverse events were recorded as they occurred. An adverse event incidence in central retinal vein occlusion versus branch retinal vein occlusion and glaucoma/ocular hypertension versus nonglaucoma/ocular hypertension subgroups was analyzed. Results: Ten eyes (12%) had IOP .25 mmHg, whereas 11% required medical and 1.2% required surgical IOP management. No significant IOP change was observed during the second/third implant rounds. The IOP was higher in the glaucoma/ocular hypertension and central retinal vein occlusion subgroups. Twenty-four percent of treated phakic eyes required cataract surgery, and the incidence increased with repeated implants. The mean time to cataract surgery from IDI initiation was 377 days. Conclusion: Intraocular pressure rise is greatest 2 months after implant. In the absence of IOP complications after initial IDI exposure, repeated treatments do not represent an increased IOP risk profile. Central retinal vein occlusion and glaucoma/ocular hypertension subgroups are more likely to experience IOP-related side effects. The incidence of cataract surgery significantly increases with repeated IDI treatments. RETINA 35:1647–1655, 2015
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tion of MO.2–4 The use of intravitreal dexamethasone implant (IDI) has been indicated for the treatment of MO after central and branch retinal vein occlusion (BRVO) in the United Kingdom since 2010 when it received NICE approval.5 The efficacy of IDI was demonstrated through the GENEVA study with a significant increase in the bestcorrected visual acuity versus the sham group. The peak in efficacy was seen at day 60, whereas by day 180, no statistical difference between intervention versus sham groups remained.4 Therefore, retreatment with IDI implants may be required at 6 months, although this can be reduced to 4 months if felt clinically indicated.3
oss of vision in retinal vein occlusion is most commonly secondary to macular edema (MO).1,2 Corticosteroids suppress inflammation and have antiangiogenic properties including the inhibition of vascular endothelial growth factor (VEGF) and other cytokines and prostaglandins involved in the mediaFrom the Calderdale Royal Hospital, Halifax, West Yorkshire, United Kingdom. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Mahmoud Sarhan, Ophthalmology Department, Huddersfield Royal Infirmary, Huddersfield, HD3 3EA; e-mail: [email protected]
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1648 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Previously reported complications from IDI include accelerated cataract development and raised intraocular pressure (IOP). GENEVA quotes cataract progression of 29.8% in the treatment group at 12 months, but with only 1.3% having cataract extraction. Of note, 32.8% of the dexamethasone-treated group experienced raised IOP .10 mmHg from baseline during the 12-month study, most of which had resolved at day 180 after IDI.2,3,6 Less common complications include lens injury, vitreous detachment, vitreous hemorrhage, retinal detachment, and infection/endophthalmitis.2–4 Steroid-induced IOP rise is caused by increased outflow resistance to aqueous at the trabecular meshwork and has been recognized since 1950s.7,8 Similarly, the role of steroid inducing cataract formation is well established.9,10 This article comments on complications observed during the treatment of MO secondary to RVO with IDI over multiple implant cycles. Materials and Methods Procedure Implants were performed in a clean room using a standardized sterile technique under local anesthetic (topical tetracaine 1% and subconjunctival lignocaine 2%). After preparation with povidone–iodine 5%, a single-use applicator was used to administer the 0.7 mg dexamethasone implant intravitreally through a pars plana insertion. Patients were prescribed a course of topical levofloxacin 0.5% for 5 days after the procedure. Treatment and Retreatment The treatment criteria was the presence of MO on optical coherence tomography (central macular thickness .250 mm) as a result of RVO within 2 years of onset, visual acuity of 6/96 (24 letter logMAR) or better, and the absence of a relative afferent pupillary defect. Retreatment was indicated unless the best-corrected visual acuity was .6/7.5 (80 letters logMAR) or if there was resolution of MO (central macular thickness ,250 mm). Treatment was stopped if there was no benefit from treatment, if best-corrected visual acuity failed to stabilize after two consecutive treatments, if intolerable adverse events occurred during the previous treatment round, in favor of another treatment (photocoagulation or anti-VEGF agent), or if the patient wished to stop. Inclusion and Exclusion Criteria Eligible patients had a diagnosis of BRVO/central retinal vein occlusion (CRVO) associated with MO and had received treatment with an IDI. All patients were required to have completed a 6-month follow-up
2015 VOLUME 35 NUMBER 8
period after the procedure. Patients with other ocular conditions, that is, glaucoma, diabetes, and age-related macular degeneration were included in this study. This was appropriate as the best-corrected visual acuity was not an outcome measure and patients with glaucoma/ ocular hypertension (Glau/OHT) are an important patient subgroup. Patients were deemed ineligible if they had had another intervention within the 6-month follow-up period (i.e., photocoagulation or intravitreal antiVEGF treatment) or they failed to attend all followup appointments within the 6 months after the procedure period. It should be noted that some patients had other interventions before starting IDI treatment, but this did not result in exclusion from the study. All patients were IDI-treatment naive at initiation. Data Collection Data were collected retrospectively from a single center over 2 years. During this period, consecutive patients receiving IDI for treatment of MO due to retinal vein occlusion were identified. A follow-up period of 6 months was observed after each implantation, at which point treatment was stopped or a further implant cycle was undertaken. Each 6-month implant cycle represents an individual treatment episode. Intraocular pressure was assessed by applanation tonometry and was recorded periprocedure and at 2-month and 6-month follow-ups. When an instance of raised IOP was recorded, so was the medical or surgical management if required. Patients were identified as phakic or pseudophakic on entry. If cataract surgery was required after initiation of IDI treatment, this was recorded, as well as the elapsed time between initial treatment and the cataract surgery date. Other significant adverse outcomes were recorded as they occurred. Outcome Measures Outcome measures were the mean IOP at initiation, 2 months, and 6 months, the incidence of cases with an IOP .25 mmHg and cases experiencing .10 mmHg rise from baseline, the requirement of treatment for raised IOP, and the nature of treatment (medical vs. surgical), the incidence of cataract surgery in the ipsilateral eye after initiation of IDI treatment, the time elapsed from the first IDI exposure to the cataract surgery date. The above measures were analyzed overall and between subgroups of one implant versus two implants versus three implants, CRVO versus BRVO, and Glau/OHT versus nonglaucoma/ocular hypertension (non-Glau/OHT). Other adverse events were recorded as they occurred.
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
Medical Statistics For statistical analysis, the Student’s t-test was performed to quantify the significance of differences observed between groups. Because of a small sample size, nonparametric analysis using the Mann–Whitney rank-sum test was performed to corroborate P value of the IOP implant subgroups and glaucoma/nonglaucoma subgroups. A P value of ,0.05 was considered to represent statistically significant difference throughout. The Pearson correlation coefficient was used in the evaluation of rate of progression to cataract surgery. Results Study Population A total of 84 treatment episodes were recorded over 3 treatment rounds. Sixty-one patients entered the first IDI round. All were treatment naive on initiation. Of the 84 treatment episodes, 13 (15.5%) were from the Glau/OHT group of patients. Patients who had previous treatments before IDI are as follows. Laser: 18 (29.5%) patients at an average of 7.39 months before initiation of IDI therapy. Anti-VEGF: 13 (21.3%) patients 5.17 months before IDI therapy and intravitreal triamcinolone: 3 (4.9%) patients at an average of 21.0 months before IDI therapy (Table 1). Intraocular Pressure The overall mean IOP of 84 treatment episodes is displayed in Figure 1A. At initiation, the mean IOP was 15.48 mmHg. At 2 months, follow-up mean IOP was 18.02 mmHg, a rise of +2.54 mmHg, which was statistically significant. At 6 months, postimplant mean IOP was 16.11 mmHg; this demonstrated an insignificant rise of +0.63 mmHg from baseline (Table 2). An IOP recording .25 mmHg occurred in 10 episodes (12%), and .10 mmHg rise from baseline occurred in 8 episodes (10%) (Table 2). Of the raised IOP recordings, 9 events were at 2 months of followup and 1 event was at 6 months of follow-up. Treatment of these events was medical in 9 cases (11%), with 1 patient (1.2%), a case of CRVO, requiring deep sclerectomy for OHT refractory to medication. Another patient developed neovascular glaucoma and was excluded from the study as IOP rise was not a direct complication of intravitreal dexamethasone. Implant Groups In the 1 implant group (n = 61), there was a significant mean IOP rise at 2 months (+2.92 mmHg), which remained significant at 6 months (+1.07 mmHg). The
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second and third implant groups (n = 17 and 6, respectively) did not demonstrate a significant rise in IOP at either 2 months (+1.12 and +2.83 mmHg) or 6 months of follow-up (−0.41 and −0.67 mmHg, respectively). A comparison of the mean IOP across groups demonstrated no statistically significant difference between the first implant and the second or third implant groups at initiation (P = 0.188 and 0.881) at 2 months (P = 0.267 and 0.926) or 6 months (P = 0.244 and 0.292) (Table 2). After 1 IDI treatment round, 5 patients (8%) dropped out because of IOP-related complications. The mean IOP of these 5 cases was 15.50 mmHg at initiation, 31.33 mmHg at 2 months and 18.80 mmHg at 6 months of follow-up. This compares to a mean IOP of 15.33 mmHg, 16.84 mmHg, and 16.19 mmHg for the remaining 56 patients at the respective follow-up intervals. The 2-month follow-up mean IOP reading was significantly greater in these five drop-out patients than those who continued to the second treatment round (P = 0.037). Initial and 6-month follow-up readings were not significantly different. No patients dropped out because of IOP complications between the second and third treatment rounds (Table 3). Glaucoma/Ocular Hypertension Subgroup Data were separated into Glau/OHT (n = 13) and non-Glau/OHT (n = 71) subgroups. Within each subgroup, there was a significant mean IOP rise at 2 months, which resolved, becoming insignificant at 6 months of follow-up. This pattern mirrors the overall group findings (Figure 1B). There was no significant difference between the mean IOP of the non-Glau/OHT versus Glau/OHT subgroups at initiation of treatment (16.62 mmHg vs. 15.27 mmHg, respectively). However, there was a significant increase in the mean IOP of the Glau/ OHT subgroup compared with the non-Glau/OHT subgroup at 2 months (+6.15 mmHg vs. +1.88 mmHg) and 6 months (+2.00 mmHg vs. +0.47 mmHg). Thirtyone percent of the Glau/OHT subgroup recorded a raised IOP .25 mmHg compared with 8% in the non-Glau/OHT group (Table 2), again, this difference was significant. Central Retinal Vein Occlusion Versus Branch Retinal Vein Occlusion The mean IOP was significantly raised in the CRVO subgroup (n = 39) relative to the BRVO subgroup (n = 45) at initiation, 2 months, and 6 months (Table 2). The mean rise in IOP was also greater at 2 months (3.31 vs. 1.89 mmHg) and 6 months (1.21 vs 0.13 mmHg) of follow-up in the CRVO subgroup (Figure 1C). Of the
Pommier et al11
Moisseiev et al12
Joshi et al13
Querques et al14
Coscas et al15
Capone et al16
220
17
51
33
128
289
97/123 — —
3/14 — —
28/23 8 (15.7%) —
26/7 — 18 (54.5%)
58/70 — 68 (53.1%)
—
—
6 (11.8%)
2 (6.1%)
9 (7%)
—
—
—
18 (54.5%)
39 (30.2%)
Previous IVTA
—
—
—
0
10 (7.8%)
Number of IDI treatment rounds Follow-up period per IDI Retreatment interval (mean) 1st/2nd IDI 2nd/3rd IDI IOP .10 mmHg rise
$1
1–2
$1
2
$2
132/157 91 (31.5%) 248 (85.8%) 112 (38.8%) 205 (70.9%) 115 (39.8%) 2–9
0, 1, 3, 6 months
0, 1, 2, 3, 6 months
Monthly review, 0–12 months
0, 1, 4, 5, 6 months
0, 2, 3, 4, 5, 6 months
— .21 mmHg (5.9%)
6.3 months
4.7 months 5.1 months Total: 12 (36%) Mean rise 9.6 mmHg
5.9 months 8.7 months
5.6 months
5.3 months
6.7 months 7.1 months
9 (7%)
91 (32.6%)
8 (9.5%)
9 (7%) 21 (16.4%)
97 (33.7%) 84 (29.1%)
10 (11.9%) 9 (10.7%)
0 5 (3.9%) 0 0
9 (3.1%) 4 (1.4%) 5 (1.7%) 28 (9.7%) 46 (15.9%) 0
1 (1.2%) 0 1 (1.2%) — 13 (24.1%) 0
Overall, N CRVO/BRVO Glau/OHT Previous treatment total Previous Macular argon laser Previous anti-VEGF
34 (15.8%) —
1 (5.9%)
14 (27%) 14 (27%)
12 (36.4%)
84 injections, 61 patients 39/45 13 (15.5%) 26 (42.6%) 18 (29.5%) 13 (21.3%) 3 (4.9%) 3 0, 2, 6 months
— — — Vitreous hemorrhage: 6 (3%)
— 10 (58.8%) 6 (35.2%) Vitreous hemorrhage: 1 (5.9%)
IVTA, intravitreal triamcinolone; IDI, Intravitreal Dexamethasone Implant.
0 1 (2.0%) — 0
0 8 (24.2%) 2 (6.1%) 0
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.25 mmHg recorded Medical IOP management Surgical IOP management Total Laser Incisional Cataract progression Cataract surgery Other adverse events
—
13 (5.9%)
0, 3, 6 months
Reid et al 2015
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Table 1. Comparison of Study Population and Adverse Effects of IDI in Retinal Vein Occlusion Against Published Data
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
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Fig 1. A. Mean IOP overall and in each implant round. B. Glau/ OHT versus non-Glau/OHT subgroups. C. CRVO versus BRVO subgroups.
CRVO cases, 7 (18%) experienced an IOP recording .25 mmHg compared with 3 (7%) BRVO cases (Table 2). This difference was not statistically significant (P = 0.057). A statistically significant increase in eyes experiencing IOP rise .10 mmHg was seen in CRVO eyes versus BRVO eyes, that is, 6 (15%) versus 2 (4%) (P = 0.041).
Cataract The overall incidence of cataract surgery was 24.1%. The 1 implant group had an incidence of progression to cataract surgery of 13.2%. In the second implant group, an incidence of 45% was observed, and in the third implant group, there was an incidence of 60% (Figure 2A). This rise in cataract surgery rates of the second and third implant groups was significant relative to the first implant group. The mean time overall for progression to cataract surgery in the ipsilateral eye after the first dexamethasone exposure was 377 days (Table 4).
A weak negative correlation (R = −0.3522) existed between implant rounds 1 and 2 in terms of time to cataract surgery. When round three was included, a weak positive correlation (R = +0.352) was calculated (Figure 2B). From these contradictory correlations, no relationship can be extrapolated regarding the number of dexamethasone implants and time to cataract surgery. No significant differences between CRVO versus BRVO or Glau/OHT versus nonglaucoma subgroups were present in terms of cataract surgery incidence after first IDI exposure. Other Adverse Events No other serious adverse events were recorded. Withdrawals Between Treatment Rounds There was a significant dropout rate between rounds. Sixty-one patients entered round 1, with 17 patients completing 2 rounds and 6 patients completing 3 implant rounds. Reasons for dropout/withdrawal are listed in Table 3. After the first round, 13 patients
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Table 2. Mean IOP at Initiation, 2 Months, and 6 Months of Follow-up Mean IOP
Group
No. of Implants
Overall
84
1 implant
61
2 implants
17
P value 1 versus 2 implants 3 implants
6
P value 1 versus 3 implants Nonglaucoma
71
Glau/OHT
13
P value Glau versus nonGlau CRVO
39
BRVO
45
P value CRVO versus BRVO
Initiation
P Initiation Versus 2 Months
2 Months
15.48 (±2.86) 15.34 (±2.82) 16.06 (±3.29) 0.118
18.02 (±6.20) 18.26 (±6.68) 17.18 (±4.77) 0.267
15.17 (±2.04) 0.881
18.00 (±5.18) 0.926
0.177
15.27 (±2.69) 16.62 (±3.57) 0.108
17.15 (±5.41) 22.77 (±8.17) 0.015
0.004
16.18 (±3.14) 14.87 (±2.46) 0.035
19.49 (±7.67) 16.76 (±4.26) 0.043
chose not to continue, although treatment was indicated and no adverse event had been experienced. These patients were not included in later calculations on the complication rate. Discussion This study consists of 84 IDI of 61 patients over 3 treatment rounds. Of these 84 implants, there was approximately a 50:50 ratio of CRVO and BRVO Table 3. Number of Patients Withdrawing After Each Treatment Round Reason for Withdrawal Resolution of MO Failure to respond/other treatment pursued IOP complications Patient choice not to continue treatment (although indicated) Excluded Total number
After 1st Implant
After 2nd Implant
11 (18%) 14 (23%)
2 (12%) 7 (41%)
5 (8%) 13 (21%)
0 0
1 (2%)* 44 (72%)
2 (12%)† 11 (65%)
*Neovascular glaucoma. †Macular argon laser during follow-up period.
0.0002 0.001 0.217
0.008
0.006 0.005
6 Months 16.11 (±3.87) 16.41 (±4.31) 15.65 (±2.32) 0.244
P Initiation Versus 6 Months
IOP .25 mmHg
IOP Rise .10 mmHg
0.079
10 (12%) 8 (10%)
0.0308
7 (11%)
7 (11%)
0.2935
2 (12%)
0 (0%)
0.974
0.147
1 (17%)
1 (17%)
0.713
0.713
14.50 (±2.35) 0.292
0.2829
15.74 (±3.43) 18.62 (±5.12) 0.032
0.21
6 (8%)
5 (7%)
0.087
4 (31%)
3 (23%)
0.011
0.018
0.064
7 (18%)
6 (15%)
0.402
3 (7%)
2 (4%)
0.057
0.041
17.39 (±4.92) 15.00 (±2.17) 0.005
cases, and 15.5% of total implants were in the Glau/ OHT subgroup. A number of cases underwent previous interventions, and this introduces a degree of confounding to this study (Table 1). The proportion of patients with previous interventions is less than that in comparable studies. The fact that patients were treatment naive on entry helps to minimize confounding. Previous laser and anti-VEGF therapies were on average 7.39 and 5.17 months before IDI therapy initiation, respectively. It would be expected that any effect on IOP would be minimal after this period. These previous therapies could of course continue to influence cataract development. In total, 3 (3.6%) cases previously had intravitreal triamcinolone therapy at an average of 21 months before IDI initiation. Intravitreal triamcinolone is more likely to cause IOP rises and cataract. After 21 months, the effect of intravitreal triamcinolone on IOP should be stable/minimized. Intraocular Pressure The greatest mean IOP rise in the overall group was observed at 2 months of (day 60) follow-up and was statistically significant (+2.54 mmHg). The mean IOP
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
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Fig 2. A. Incidence of cataract surgery across implant groups. B. Time to cataract surgery event after first dexamethasone exposure. pts, patients.
returned to near baseline by 6 months where the mean IOP rise was not significant (+0.63 mmHg). This pattern of IOP change correlates with findings from the GENEVA studies, which demonstrated a maximal dexamethasone effect at day 60, returning to near baseline by 180 days.2,4 Proportionally, the number of implants causing IOP rises is similar to that reported in comparable studies listed in Table 1, with the exception of the SHASTA study.16 All IOP complications (11%) were managed medically but for 1 case (1.2%), which required surgical intervention (deep sclerectomy) after failure of maximal medical management. This figure for surgical intervention is comparable with other studies of IDI in retinal vein occlusion at approximately 1% or less (again excluding the SHASTA study).3,15 The SHASTA study (n = 289) quotes IOP rises in approximately 30% of cases and a surgical management requirement of IOP in 3.1%.16 It should be noted that SHASTA had a large Glau/OHT group (31.5%) relative to comparable publications (Table 1). During the first implant round, an IOP rise of +2.92 mmHg at 2 months and +1.07 mmHg at 6 months were statistically significant. The second and third implant rounds demonstrated a rise at 2 months that were not significant and no mean IOP rise at 6 months. Table 4. Cataract Surgery Incidence Over Three Treatment Rounds Cataract Surgery Required After IDI No. Patients Exposure 1 implant 38 5 2 implants 11 5 P of 1 versus 2 implants = 0.019 3 implants 5 3 P of 1 versus 2 implants = 0.011 Overall 54 13
%
Average Time to Cataract Surgery After IDI Exposure
13.2 374.20 (±92.87) 45 298.20 (±129.85) 60
514.00 (±16.52)
24.1 377.23 (±125.79)
The smaller (insignificant) mean IOP rise in the second and third implant groups may be attributable to the dropout of patients of greater steroid sensitivity after one treatment round. After 1 IDI round, 5 patients (8%) dropped out because of IOP complications compared with none after 2 implant rounds (Table 3). After exclusion of those patients with IOP complications, no statistically significant rise was present in the second or third treatment rounds. Therefore, if intravitreal dexamethasone is initially tolerated in treatment-naive patients, it seems that repeated treatment does not lead to further/progressive IOP complications. A reduced IOP complication rate has been noted elsewhere after the first IDI implant round.13 This may demonstrate clinical selection of patients not experiencing IOP adverse events into the later IDI treatment rounds. The mean IOP was investigated in two further subgroups. In the Glau/OHT versus non-Glau/OHT subgroups, no significant difference between the mean IOP was present at initiation. This suggests a wellcontrolled Glau/OHT subgroup on entry. At 2 months of follow-up, a significantly greater mean IOP rise in the Glau/OHT subgroup was seen. At 6 months, a significant difference in the mean IOP rise remained where the Glau/OHT subgroup was +2.00 mmHg from baseline compared with the non-Glau/OHT subgroup at +0.47 mmHG. Glaucoma is a recognized risk factor for steroid-induced OHT.8,17 A comparison with the SHASTA study (which had a relatively larger Glau/ OHT population) seems to corroborate this relationship (Table 1). In the CRVO subgroup, the mean IOP recorded at initiation was significantly greater compared with the BRVO subgroup. The mean IOP rise from baseline was also significantly greater at 2 months and at 6 months in the CRVO subgroup relative to the BRVO subgroup. This is not surprising as increased IOP is associated with CRVO.18,19 Glaucoma or OHT may be the primary event in CRVO, and there is increased risk
1654 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
of developing neovascular glaucoma in cases of CRVO versus BRVO.19–21 It is also worth noting that the surgically managed case in this study was from the CRVO subgroup as was the one excluded case of neovascular glaucoma. Cataract Cataract development is a well-documented consequence of intravitreal steroid treatment.9,22,23 The overall incidence of cataract surgery after IDI in this study was 24.1%. This value is similar to those reported in the published literature on intravitreal triamcinolone but higher than many similar IDI publications (Table 1).14,16,21 After 12 months (2 treatment cycles), GENEVA reported a positive correlation between IDI and cataract progression, which was proportional to the number of IDI treatments.6 An increase in the incidence of cataract surgery was observed with the second and third implant groups relative to the 1 implant group. This is a significant finding but is confounded to some extent by an increased follow-up duration in the later groups (i.e., 1 implant cycle = 6 months vs. 3 implant cycles = 18 months). Previously, it has been suggested that cataract surgery is an event expected much later than 12 months.12 However, time to cataract surgery after the first IDI exposure in this study was an average of 377 days. No other adverse events were identified, which suggests that the insertion technique is safe and did not lead to complications and that the local effect of dexamethasone causes the recorded complications (i.e., IOP rise and cataract formation).
Conclusion This study confirms previous findings for IDI treatment regarding its safety profile. Rise in IOP was greatest at 2 months, and surgical management of IOP was required in 1.2% of cases. After the exclusion of 5 patients (8%) who were sensitive to intravitreal steroid, no significant rise in the mean IOP rise was demonstrated in the subsequent IDI treatment rounds (i.e., second or third exposures). Intravitreal dexamethasone implant offers the benefits of longer action and reduced clinical load when compared with anti-VEGF alternatives. For patients with no IOP complications after the first IDI exposure, further implants remain a safe treatment option over multiple treatment rounds. Alternative intravitreal agents should be considered if patients experience IOP complications after one exposure to IDI.
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The CRVO and Glau/OHT subgroups experienced greater IOP complications compared with the general study population prompting consideration of alternatives treatments (i.e., anti-VEGF agents) in such cases. Cataract development remains an unavoidable consequence of intravitreal steroid treatment, and the incidence of cataract surgery did significantly increase with multiple IDI exposures. Key words: intavitreal implant, dexamethasone, adverse effects, macular edema, retinal vein occlusion. References 1. Yau J, Lee P, Wong T, Best J. Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management. Intern Med J 2008;38:904–910. 2. Glanville J, Patterson J, McCool R, et al. Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review. BMC Ophthalmol 2014;14:7. 3. Shyangdan D, Cummins E, Lois N, Royle P. Evidence review: dexamethasone implants (Ozurdex) for macular oedema after retinal vein occlusion. Single technology appraisal (STA) AbHTAG. 2010. Available at: http://www.nice.org.uk/ nicemedia/live/13037/52883/52883.pdf. Accessed July 2014. 4. Haller JA, Bandello F, Belfort R Jr., et al. Randomized, shamcontrolled Trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146.e3. 5. National Institute for Health and Care Excellence. Dexamethasone Intravitreal Implant for the Treatment of Macular Oedema Secondary to Retinal Vein Occlusion. [TA229]. London, England: National Institute for Health and Care Excellence; 2011. Available at: http://www.nice.org.uk/ nicemedia/live/13541/55590/55590.pdf. Accessed July 2014. 6. Haller JA, Bandello F, Belfort R Jr., et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453–2460. 7. McLean JM, Woods AC. Clinical and experimental observation on the use of ACTH and cortisone in ocular inflammatory disease. Trans Am Ophthalmol Soc 1950;48:293–294. 8. Jones R, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol 2006;17:163–167. 9. James ER. The etiology of steroid cataract. J Ocul Pharmacol Ther 2007;23:403–420. 10. Jonas JB, Kreissig I, Degenring RF. Cataract surgery after intravitreal injection of triamcinolone acetonide. Eye (Lond) 2004;18:361–364. 11. Pommier S, Meyer F. RE-MI-DO Study: results of a multicenter study of dexamethasone implantation in eyes with macular oedema in retinal vein occlusion. Acta Ophthalmol 2012;90:1755–3768. 12. Moisseiev E, Goldstein M, Waisbourd M, et al. Long-term evaluation of patients treated with dexamethasone intravitreal implant for macular edema due to retinal vein occlusion. Eye (Lond) 2013;27:65–71. 13. Joshi L, Yaganti S, Gemenetzi M, et al. Dexamethasone implants in retinal vein occlusion: 12-month clinical effectiveness using repeat injections as-needed. Br J Ophthalmol 2013;97: 1040–1044.
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL 14. Querques L, Querques G, Lattanzio R, et al. Repeated intravitreal dexamethasone implant (Ozurdex) for retinal vein occlusion. Ophthalmologica 2013;229:21–25. 15. Coscas G, Augustin A, Bandello F, et al. Retreatment with ozurdex for macular edema secondary to retinal vein occlusion. Eur J Ophthalmol 2014;24:1–9. 16. Capone A Jr., Singer MA, Dodwell DG, et al. Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (Shasta Study). Retina 2014;34:342–351. 17. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol 2004;138:740–743. 18. Frucht J, Shapiro A, Merin S. Intraocular pressure in retinal vein occlusion. Br J Ophthalmol 1984;68:26–28.
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19. Lindblom B. Open angle glaucoma and non-central retinal vein occlusion—the chicken or the egg? Acta Ophthalmol Scand 1998;76:329–333. 20. Hayreh SS, Zimmerman MB, Beri M, et al. Intraocular pressure abnormalities associated with central and hemicentral retinal vein occlusion. Ophthalmology 2004;111: 133–141. 21. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005;24: 493–519. 22. Jonas JB. Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Res 2006;38:218–245. 23. Petersen A, Carlsson T, Karlsson J-O, et al. Effects of dexamethasone on human lens epithelial cells in culture. Mol Vis 2008;14:1344–1352.
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tion of MO.2–4 The use of intravitreal dexamethasone implant (IDI) has been indicated for the treatment of MO after central and branch retinal vein occlusion (BRVO) in the United Kingdom since 2010 when it received NICE approval.5 The efficacy of IDI was demonstrated through the GENEVA study with a significant increase in the bestcorrected visual acuity versus the sham group. The peak in efficacy was seen at day 60, whereas by day 180, no statistical difference between intervention versus sham groups remained.4 Therefore, retreatment with IDI implants may be required at 6 months, although this can be reduced to 4 months if felt clinically indicated.3
oss of vision in retinal vein occlusion is most commonly secondary to macular edema (MO).1,2 Corticosteroids suppress inflammation and have antiangiogenic properties including the inhibition of vascular endothelial growth factor (VEGF) and other cytokines and prostaglandins involved in the mediaFrom the Calderdale Royal Hospital, Halifax, West Yorkshire, United Kingdom. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Mahmoud Sarhan, Ophthalmology Department, Huddersfield Royal Infirmary, Huddersfield, HD3 3EA; e-mail: [email protected]
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1648 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Previously reported complications from IDI include accelerated cataract development and raised intraocular pressure (IOP). GENEVA quotes cataract progression of 29.8% in the treatment group at 12 months, but with only 1.3% having cataract extraction. Of note, 32.8% of the dexamethasone-treated group experienced raised IOP .10 mmHg from baseline during the 12-month study, most of which had resolved at day 180 after IDI.2,3,6 Less common complications include lens injury, vitreous detachment, vitreous hemorrhage, retinal detachment, and infection/endophthalmitis.2–4 Steroid-induced IOP rise is caused by increased outflow resistance to aqueous at the trabecular meshwork and has been recognized since 1950s.7,8 Similarly, the role of steroid inducing cataract formation is well established.9,10 This article comments on complications observed during the treatment of MO secondary to RVO with IDI over multiple implant cycles. Materials and Methods Procedure Implants were performed in a clean room using a standardized sterile technique under local anesthetic (topical tetracaine 1% and subconjunctival lignocaine 2%). After preparation with povidone–iodine 5%, a single-use applicator was used to administer the 0.7 mg dexamethasone implant intravitreally through a pars plana insertion. Patients were prescribed a course of topical levofloxacin 0.5% for 5 days after the procedure. Treatment and Retreatment The treatment criteria was the presence of MO on optical coherence tomography (central macular thickness .250 mm) as a result of RVO within 2 years of onset, visual acuity of 6/96 (24 letter logMAR) or better, and the absence of a relative afferent pupillary defect. Retreatment was indicated unless the best-corrected visual acuity was .6/7.5 (80 letters logMAR) or if there was resolution of MO (central macular thickness ,250 mm). Treatment was stopped if there was no benefit from treatment, if best-corrected visual acuity failed to stabilize after two consecutive treatments, if intolerable adverse events occurred during the previous treatment round, in favor of another treatment (photocoagulation or anti-VEGF agent), or if the patient wished to stop. Inclusion and Exclusion Criteria Eligible patients had a diagnosis of BRVO/central retinal vein occlusion (CRVO) associated with MO and had received treatment with an IDI. All patients were required to have completed a 6-month follow-up
2015 VOLUME 35 NUMBER 8
period after the procedure. Patients with other ocular conditions, that is, glaucoma, diabetes, and age-related macular degeneration were included in this study. This was appropriate as the best-corrected visual acuity was not an outcome measure and patients with glaucoma/ ocular hypertension (Glau/OHT) are an important patient subgroup. Patients were deemed ineligible if they had had another intervention within the 6-month follow-up period (i.e., photocoagulation or intravitreal antiVEGF treatment) or they failed to attend all followup appointments within the 6 months after the procedure period. It should be noted that some patients had other interventions before starting IDI treatment, but this did not result in exclusion from the study. All patients were IDI-treatment naive at initiation. Data Collection Data were collected retrospectively from a single center over 2 years. During this period, consecutive patients receiving IDI for treatment of MO due to retinal vein occlusion were identified. A follow-up period of 6 months was observed after each implantation, at which point treatment was stopped or a further implant cycle was undertaken. Each 6-month implant cycle represents an individual treatment episode. Intraocular pressure was assessed by applanation tonometry and was recorded periprocedure and at 2-month and 6-month follow-ups. When an instance of raised IOP was recorded, so was the medical or surgical management if required. Patients were identified as phakic or pseudophakic on entry. If cataract surgery was required after initiation of IDI treatment, this was recorded, as well as the elapsed time between initial treatment and the cataract surgery date. Other significant adverse outcomes were recorded as they occurred. Outcome Measures Outcome measures were the mean IOP at initiation, 2 months, and 6 months, the incidence of cases with an IOP .25 mmHg and cases experiencing .10 mmHg rise from baseline, the requirement of treatment for raised IOP, and the nature of treatment (medical vs. surgical), the incidence of cataract surgery in the ipsilateral eye after initiation of IDI treatment, the time elapsed from the first IDI exposure to the cataract surgery date. The above measures were analyzed overall and between subgroups of one implant versus two implants versus three implants, CRVO versus BRVO, and Glau/OHT versus nonglaucoma/ocular hypertension (non-Glau/OHT). Other adverse events were recorded as they occurred.
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
Medical Statistics For statistical analysis, the Student’s t-test was performed to quantify the significance of differences observed between groups. Because of a small sample size, nonparametric analysis using the Mann–Whitney rank-sum test was performed to corroborate P value of the IOP implant subgroups and glaucoma/nonglaucoma subgroups. A P value of ,0.05 was considered to represent statistically significant difference throughout. The Pearson correlation coefficient was used in the evaluation of rate of progression to cataract surgery. Results Study Population A total of 84 treatment episodes were recorded over 3 treatment rounds. Sixty-one patients entered the first IDI round. All were treatment naive on initiation. Of the 84 treatment episodes, 13 (15.5%) were from the Glau/OHT group of patients. Patients who had previous treatments before IDI are as follows. Laser: 18 (29.5%) patients at an average of 7.39 months before initiation of IDI therapy. Anti-VEGF: 13 (21.3%) patients 5.17 months before IDI therapy and intravitreal triamcinolone: 3 (4.9%) patients at an average of 21.0 months before IDI therapy (Table 1). Intraocular Pressure The overall mean IOP of 84 treatment episodes is displayed in Figure 1A. At initiation, the mean IOP was 15.48 mmHg. At 2 months, follow-up mean IOP was 18.02 mmHg, a rise of +2.54 mmHg, which was statistically significant. At 6 months, postimplant mean IOP was 16.11 mmHg; this demonstrated an insignificant rise of +0.63 mmHg from baseline (Table 2). An IOP recording .25 mmHg occurred in 10 episodes (12%), and .10 mmHg rise from baseline occurred in 8 episodes (10%) (Table 2). Of the raised IOP recordings, 9 events were at 2 months of followup and 1 event was at 6 months of follow-up. Treatment of these events was medical in 9 cases (11%), with 1 patient (1.2%), a case of CRVO, requiring deep sclerectomy for OHT refractory to medication. Another patient developed neovascular glaucoma and was excluded from the study as IOP rise was not a direct complication of intravitreal dexamethasone. Implant Groups In the 1 implant group (n = 61), there was a significant mean IOP rise at 2 months (+2.92 mmHg), which remained significant at 6 months (+1.07 mmHg). The
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second and third implant groups (n = 17 and 6, respectively) did not demonstrate a significant rise in IOP at either 2 months (+1.12 and +2.83 mmHg) or 6 months of follow-up (−0.41 and −0.67 mmHg, respectively). A comparison of the mean IOP across groups demonstrated no statistically significant difference between the first implant and the second or third implant groups at initiation (P = 0.188 and 0.881) at 2 months (P = 0.267 and 0.926) or 6 months (P = 0.244 and 0.292) (Table 2). After 1 IDI treatment round, 5 patients (8%) dropped out because of IOP-related complications. The mean IOP of these 5 cases was 15.50 mmHg at initiation, 31.33 mmHg at 2 months and 18.80 mmHg at 6 months of follow-up. This compares to a mean IOP of 15.33 mmHg, 16.84 mmHg, and 16.19 mmHg for the remaining 56 patients at the respective follow-up intervals. The 2-month follow-up mean IOP reading was significantly greater in these five drop-out patients than those who continued to the second treatment round (P = 0.037). Initial and 6-month follow-up readings were not significantly different. No patients dropped out because of IOP complications between the second and third treatment rounds (Table 3). Glaucoma/Ocular Hypertension Subgroup Data were separated into Glau/OHT (n = 13) and non-Glau/OHT (n = 71) subgroups. Within each subgroup, there was a significant mean IOP rise at 2 months, which resolved, becoming insignificant at 6 months of follow-up. This pattern mirrors the overall group findings (Figure 1B). There was no significant difference between the mean IOP of the non-Glau/OHT versus Glau/OHT subgroups at initiation of treatment (16.62 mmHg vs. 15.27 mmHg, respectively). However, there was a significant increase in the mean IOP of the Glau/ OHT subgroup compared with the non-Glau/OHT subgroup at 2 months (+6.15 mmHg vs. +1.88 mmHg) and 6 months (+2.00 mmHg vs. +0.47 mmHg). Thirtyone percent of the Glau/OHT subgroup recorded a raised IOP .25 mmHg compared with 8% in the non-Glau/OHT group (Table 2), again, this difference was significant. Central Retinal Vein Occlusion Versus Branch Retinal Vein Occlusion The mean IOP was significantly raised in the CRVO subgroup (n = 39) relative to the BRVO subgroup (n = 45) at initiation, 2 months, and 6 months (Table 2). The mean rise in IOP was also greater at 2 months (3.31 vs. 1.89 mmHg) and 6 months (1.21 vs 0.13 mmHg) of follow-up in the CRVO subgroup (Figure 1C). Of the
Pommier et al11
Moisseiev et al12
Joshi et al13
Querques et al14
Coscas et al15
Capone et al16
220
17
51
33
128
289
97/123 — —
3/14 — —
28/23 8 (15.7%) —
26/7 — 18 (54.5%)
58/70 — 68 (53.1%)
—
—
6 (11.8%)
2 (6.1%)
9 (7%)
—
—
—
18 (54.5%)
39 (30.2%)
Previous IVTA
—
—
—
0
10 (7.8%)
Number of IDI treatment rounds Follow-up period per IDI Retreatment interval (mean) 1st/2nd IDI 2nd/3rd IDI IOP .10 mmHg rise
$1
1–2
$1
2
$2
132/157 91 (31.5%) 248 (85.8%) 112 (38.8%) 205 (70.9%) 115 (39.8%) 2–9
0, 1, 3, 6 months
0, 1, 2, 3, 6 months
Monthly review, 0–12 months
0, 1, 4, 5, 6 months
0, 2, 3, 4, 5, 6 months
— .21 mmHg (5.9%)
6.3 months
4.7 months 5.1 months Total: 12 (36%) Mean rise 9.6 mmHg
5.9 months 8.7 months
5.6 months
5.3 months
6.7 months 7.1 months
9 (7%)
91 (32.6%)
8 (9.5%)
9 (7%) 21 (16.4%)
97 (33.7%) 84 (29.1%)
10 (11.9%) 9 (10.7%)
0 5 (3.9%) 0 0
9 (3.1%) 4 (1.4%) 5 (1.7%) 28 (9.7%) 46 (15.9%) 0
1 (1.2%) 0 1 (1.2%) — 13 (24.1%) 0
Overall, N CRVO/BRVO Glau/OHT Previous treatment total Previous Macular argon laser Previous anti-VEGF
34 (15.8%) —
1 (5.9%)
14 (27%) 14 (27%)
12 (36.4%)
84 injections, 61 patients 39/45 13 (15.5%) 26 (42.6%) 18 (29.5%) 13 (21.3%) 3 (4.9%) 3 0, 2, 6 months
— — — Vitreous hemorrhage: 6 (3%)
— 10 (58.8%) 6 (35.2%) Vitreous hemorrhage: 1 (5.9%)
IVTA, intravitreal triamcinolone; IDI, Intravitreal Dexamethasone Implant.
0 1 (2.0%) — 0
0 8 (24.2%) 2 (6.1%) 0
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.25 mmHg recorded Medical IOP management Surgical IOP management Total Laser Incisional Cataract progression Cataract surgery Other adverse events
—
13 (5.9%)
0, 3, 6 months
Reid et al 2015
1650 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Table 1. Comparison of Study Population and Adverse Effects of IDI in Retinal Vein Occlusion Against Published Data
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
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Fig 1. A. Mean IOP overall and in each implant round. B. Glau/ OHT versus non-Glau/OHT subgroups. C. CRVO versus BRVO subgroups.
CRVO cases, 7 (18%) experienced an IOP recording .25 mmHg compared with 3 (7%) BRVO cases (Table 2). This difference was not statistically significant (P = 0.057). A statistically significant increase in eyes experiencing IOP rise .10 mmHg was seen in CRVO eyes versus BRVO eyes, that is, 6 (15%) versus 2 (4%) (P = 0.041).
Cataract The overall incidence of cataract surgery was 24.1%. The 1 implant group had an incidence of progression to cataract surgery of 13.2%. In the second implant group, an incidence of 45% was observed, and in the third implant group, there was an incidence of 60% (Figure 2A). This rise in cataract surgery rates of the second and third implant groups was significant relative to the first implant group. The mean time overall for progression to cataract surgery in the ipsilateral eye after the first dexamethasone exposure was 377 days (Table 4).
A weak negative correlation (R = −0.3522) existed between implant rounds 1 and 2 in terms of time to cataract surgery. When round three was included, a weak positive correlation (R = +0.352) was calculated (Figure 2B). From these contradictory correlations, no relationship can be extrapolated regarding the number of dexamethasone implants and time to cataract surgery. No significant differences between CRVO versus BRVO or Glau/OHT versus nonglaucoma subgroups were present in terms of cataract surgery incidence after first IDI exposure. Other Adverse Events No other serious adverse events were recorded. Withdrawals Between Treatment Rounds There was a significant dropout rate between rounds. Sixty-one patients entered round 1, with 17 patients completing 2 rounds and 6 patients completing 3 implant rounds. Reasons for dropout/withdrawal are listed in Table 3. After the first round, 13 patients
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2015 VOLUME 35 NUMBER 8
Table 2. Mean IOP at Initiation, 2 Months, and 6 Months of Follow-up Mean IOP
Group
No. of Implants
Overall
84
1 implant
61
2 implants
17
P value 1 versus 2 implants 3 implants
6
P value 1 versus 3 implants Nonglaucoma
71
Glau/OHT
13
P value Glau versus nonGlau CRVO
39
BRVO
45
P value CRVO versus BRVO
Initiation
P Initiation Versus 2 Months
2 Months
15.48 (±2.86) 15.34 (±2.82) 16.06 (±3.29) 0.118
18.02 (±6.20) 18.26 (±6.68) 17.18 (±4.77) 0.267
15.17 (±2.04) 0.881
18.00 (±5.18) 0.926
0.177
15.27 (±2.69) 16.62 (±3.57) 0.108
17.15 (±5.41) 22.77 (±8.17) 0.015
0.004
16.18 (±3.14) 14.87 (±2.46) 0.035
19.49 (±7.67) 16.76 (±4.26) 0.043
chose not to continue, although treatment was indicated and no adverse event had been experienced. These patients were not included in later calculations on the complication rate. Discussion This study consists of 84 IDI of 61 patients over 3 treatment rounds. Of these 84 implants, there was approximately a 50:50 ratio of CRVO and BRVO Table 3. Number of Patients Withdrawing After Each Treatment Round Reason for Withdrawal Resolution of MO Failure to respond/other treatment pursued IOP complications Patient choice not to continue treatment (although indicated) Excluded Total number
After 1st Implant
After 2nd Implant
11 (18%) 14 (23%)
2 (12%) 7 (41%)
5 (8%) 13 (21%)
0 0
1 (2%)* 44 (72%)
2 (12%)† 11 (65%)
*Neovascular glaucoma. †Macular argon laser during follow-up period.
0.0002 0.001 0.217
0.008
0.006 0.005
6 Months 16.11 (±3.87) 16.41 (±4.31) 15.65 (±2.32) 0.244
P Initiation Versus 6 Months
IOP .25 mmHg
IOP Rise .10 mmHg
0.079
10 (12%) 8 (10%)
0.0308
7 (11%)
7 (11%)
0.2935
2 (12%)
0 (0%)
0.974
0.147
1 (17%)
1 (17%)
0.713
0.713
14.50 (±2.35) 0.292
0.2829
15.74 (±3.43) 18.62 (±5.12) 0.032
0.21
6 (8%)
5 (7%)
0.087
4 (31%)
3 (23%)
0.011
0.018
0.064
7 (18%)
6 (15%)
0.402
3 (7%)
2 (4%)
0.057
0.041
17.39 (±4.92) 15.00 (±2.17) 0.005
cases, and 15.5% of total implants were in the Glau/ OHT subgroup. A number of cases underwent previous interventions, and this introduces a degree of confounding to this study (Table 1). The proportion of patients with previous interventions is less than that in comparable studies. The fact that patients were treatment naive on entry helps to minimize confounding. Previous laser and anti-VEGF therapies were on average 7.39 and 5.17 months before IDI therapy initiation, respectively. It would be expected that any effect on IOP would be minimal after this period. These previous therapies could of course continue to influence cataract development. In total, 3 (3.6%) cases previously had intravitreal triamcinolone therapy at an average of 21 months before IDI initiation. Intravitreal triamcinolone is more likely to cause IOP rises and cataract. After 21 months, the effect of intravitreal triamcinolone on IOP should be stable/minimized. Intraocular Pressure The greatest mean IOP rise in the overall group was observed at 2 months of (day 60) follow-up and was statistically significant (+2.54 mmHg). The mean IOP
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL
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Fig 2. A. Incidence of cataract surgery across implant groups. B. Time to cataract surgery event after first dexamethasone exposure. pts, patients.
returned to near baseline by 6 months where the mean IOP rise was not significant (+0.63 mmHg). This pattern of IOP change correlates with findings from the GENEVA studies, which demonstrated a maximal dexamethasone effect at day 60, returning to near baseline by 180 days.2,4 Proportionally, the number of implants causing IOP rises is similar to that reported in comparable studies listed in Table 1, with the exception of the SHASTA study.16 All IOP complications (11%) were managed medically but for 1 case (1.2%), which required surgical intervention (deep sclerectomy) after failure of maximal medical management. This figure for surgical intervention is comparable with other studies of IDI in retinal vein occlusion at approximately 1% or less (again excluding the SHASTA study).3,15 The SHASTA study (n = 289) quotes IOP rises in approximately 30% of cases and a surgical management requirement of IOP in 3.1%.16 It should be noted that SHASTA had a large Glau/OHT group (31.5%) relative to comparable publications (Table 1). During the first implant round, an IOP rise of +2.92 mmHg at 2 months and +1.07 mmHg at 6 months were statistically significant. The second and third implant rounds demonstrated a rise at 2 months that were not significant and no mean IOP rise at 6 months. Table 4. Cataract Surgery Incidence Over Three Treatment Rounds Cataract Surgery Required After IDI No. Patients Exposure 1 implant 38 5 2 implants 11 5 P of 1 versus 2 implants = 0.019 3 implants 5 3 P of 1 versus 2 implants = 0.011 Overall 54 13
%
Average Time to Cataract Surgery After IDI Exposure
13.2 374.20 (±92.87) 45 298.20 (±129.85) 60
514.00 (±16.52)
24.1 377.23 (±125.79)
The smaller (insignificant) mean IOP rise in the second and third implant groups may be attributable to the dropout of patients of greater steroid sensitivity after one treatment round. After 1 IDI round, 5 patients (8%) dropped out because of IOP complications compared with none after 2 implant rounds (Table 3). After exclusion of those patients with IOP complications, no statistically significant rise was present in the second or third treatment rounds. Therefore, if intravitreal dexamethasone is initially tolerated in treatment-naive patients, it seems that repeated treatment does not lead to further/progressive IOP complications. A reduced IOP complication rate has been noted elsewhere after the first IDI implant round.13 This may demonstrate clinical selection of patients not experiencing IOP adverse events into the later IDI treatment rounds. The mean IOP was investigated in two further subgroups. In the Glau/OHT versus non-Glau/OHT subgroups, no significant difference between the mean IOP was present at initiation. This suggests a wellcontrolled Glau/OHT subgroup on entry. At 2 months of follow-up, a significantly greater mean IOP rise in the Glau/OHT subgroup was seen. At 6 months, a significant difference in the mean IOP rise remained where the Glau/OHT subgroup was +2.00 mmHg from baseline compared with the non-Glau/OHT subgroup at +0.47 mmHG. Glaucoma is a recognized risk factor for steroid-induced OHT.8,17 A comparison with the SHASTA study (which had a relatively larger Glau/ OHT population) seems to corroborate this relationship (Table 1). In the CRVO subgroup, the mean IOP recorded at initiation was significantly greater compared with the BRVO subgroup. The mean IOP rise from baseline was also significantly greater at 2 months and at 6 months in the CRVO subgroup relative to the BRVO subgroup. This is not surprising as increased IOP is associated with CRVO.18,19 Glaucoma or OHT may be the primary event in CRVO, and there is increased risk
1654 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
of developing neovascular glaucoma in cases of CRVO versus BRVO.19–21 It is also worth noting that the surgically managed case in this study was from the CRVO subgroup as was the one excluded case of neovascular glaucoma. Cataract Cataract development is a well-documented consequence of intravitreal steroid treatment.9,22,23 The overall incidence of cataract surgery after IDI in this study was 24.1%. This value is similar to those reported in the published literature on intravitreal triamcinolone but higher than many similar IDI publications (Table 1).14,16,21 After 12 months (2 treatment cycles), GENEVA reported a positive correlation between IDI and cataract progression, which was proportional to the number of IDI treatments.6 An increase in the incidence of cataract surgery was observed with the second and third implant groups relative to the 1 implant group. This is a significant finding but is confounded to some extent by an increased follow-up duration in the later groups (i.e., 1 implant cycle = 6 months vs. 3 implant cycles = 18 months). Previously, it has been suggested that cataract surgery is an event expected much later than 12 months.12 However, time to cataract surgery after the first IDI exposure in this study was an average of 377 days. No other adverse events were identified, which suggests that the insertion technique is safe and did not lead to complications and that the local effect of dexamethasone causes the recorded complications (i.e., IOP rise and cataract formation).
Conclusion This study confirms previous findings for IDI treatment regarding its safety profile. Rise in IOP was greatest at 2 months, and surgical management of IOP was required in 1.2% of cases. After the exclusion of 5 patients (8%) who were sensitive to intravitreal steroid, no significant rise in the mean IOP rise was demonstrated in the subsequent IDI treatment rounds (i.e., second or third exposures). Intravitreal dexamethasone implant offers the benefits of longer action and reduced clinical load when compared with anti-VEGF alternatives. For patients with no IOP complications after the first IDI exposure, further implants remain a safe treatment option over multiple treatment rounds. Alternative intravitreal agents should be considered if patients experience IOP complications after one exposure to IDI.
2015 VOLUME 35 NUMBER 8
The CRVO and Glau/OHT subgroups experienced greater IOP complications compared with the general study population prompting consideration of alternatives treatments (i.e., anti-VEGF agents) in such cases. Cataract development remains an unavoidable consequence of intravitreal steroid treatment, and the incidence of cataract surgery did significantly increase with multiple IDI exposures. Key words: intavitreal implant, dexamethasone, adverse effects, macular edema, retinal vein occlusion. References 1. Yau J, Lee P, Wong T, Best J. Retinal vein occlusion: an approach to diagnosis, systemic risk factors and management. Intern Med J 2008;38:904–910. 2. Glanville J, Patterson J, McCool R, et al. Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review. BMC Ophthalmol 2014;14:7. 3. Shyangdan D, Cummins E, Lois N, Royle P. Evidence review: dexamethasone implants (Ozurdex) for macular oedema after retinal vein occlusion. Single technology appraisal (STA) AbHTAG. 2010. Available at: http://www.nice.org.uk/ nicemedia/live/13037/52883/52883.pdf. Accessed July 2014. 4. Haller JA, Bandello F, Belfort R Jr., et al. Randomized, shamcontrolled Trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117:1134–1146.e3. 5. National Institute for Health and Care Excellence. Dexamethasone Intravitreal Implant for the Treatment of Macular Oedema Secondary to Retinal Vein Occlusion. [TA229]. London, England: National Institute for Health and Care Excellence; 2011. Available at: http://www.nice.org.uk/ nicemedia/live/13541/55590/55590.pdf. Accessed July 2014. 6. Haller JA, Bandello F, Belfort R Jr., et al. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion twelve-month study results. Ophthalmology 2011;118:2453–2460. 7. McLean JM, Woods AC. Clinical and experimental observation on the use of ACTH and cortisone in ocular inflammatory disease. Trans Am Ophthalmol Soc 1950;48:293–294. 8. Jones R, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol 2006;17:163–167. 9. James ER. The etiology of steroid cataract. J Ocul Pharmacol Ther 2007;23:403–420. 10. Jonas JB, Kreissig I, Degenring RF. Cataract surgery after intravitreal injection of triamcinolone acetonide. Eye (Lond) 2004;18:361–364. 11. Pommier S, Meyer F. RE-MI-DO Study: results of a multicenter study of dexamethasone implantation in eyes with macular oedema in retinal vein occlusion. Acta Ophthalmol 2012;90:1755–3768. 12. Moisseiev E, Goldstein M, Waisbourd M, et al. Long-term evaluation of patients treated with dexamethasone intravitreal implant for macular edema due to retinal vein occlusion. Eye (Lond) 2013;27:65–71. 13. Joshi L, Yaganti S, Gemenetzi M, et al. Dexamethasone implants in retinal vein occlusion: 12-month clinical effectiveness using repeat injections as-needed. Br J Ophthalmol 2013;97: 1040–1044.
COMPLICATIONS OF DEX IMPANT IN RVO OVER 3 ROUNDS REID ET AL 14. Querques L, Querques G, Lattanzio R, et al. Repeated intravitreal dexamethasone implant (Ozurdex) for retinal vein occlusion. Ophthalmologica 2013;229:21–25. 15. Coscas G, Augustin A, Bandello F, et al. Retreatment with ozurdex for macular edema secondary to retinal vein occlusion. Eur J Ophthalmol 2014;24:1–9. 16. Capone A Jr., Singer MA, Dodwell DG, et al. Efficacy and safety of two or more dexamethasone intravitreal implant injections for treatment of macular edema related to retinal vein occlusion (Shasta Study). Retina 2014;34:342–351. 17. Smithen LM, Ober MD, Maranan L, Spaide RF. Intravitreal triamcinolone acetonide and intraocular pressure. Am J Ophthalmol 2004;138:740–743. 18. Frucht J, Shapiro A, Merin S. Intraocular pressure in retinal vein occlusion. Br J Ophthalmol 1984;68:26–28.
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19. Lindblom B. Open angle glaucoma and non-central retinal vein occlusion—the chicken or the egg? Acta Ophthalmol Scand 1998;76:329–333. 20. Hayreh SS, Zimmerman MB, Beri M, et al. Intraocular pressure abnormalities associated with central and hemicentral retinal vein occlusion. Ophthalmology 2004;111: 133–141. 21. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005;24: 493–519. 22. Jonas JB. Intravitreal triamcinolone acetonide: a change in a paradigm. Ophthalmic Res 2006;38:218–245. 23. Petersen A, Carlsson T, Karlsson J-O, et al. Effects of dexamethasone on human lens epithelial cells in culture. Mol Vis 2008;14:1344–1352.
