Over the past 13 years, a wealth of data has accumulated on the dexamethasone intravitreal implant (Ozurdex; Allergan) from pivotal trials of over 2,500 patients1-3 across the 3 approved indications: DME, macular edema following RVO, and posterior segment uveitis. These trials have provided a wealth of data to assess patient outcomes. This article takes a deep dive into the data across the various trials, evaluating key learnings and outcomes as well as providing an update on the current thinking around the relationship between ocular hypertension, intraocular pressure (IOP) elevation, and glaucoma - a much-discussed side effect of steroid treatments.
Seenu M. Hariprasad, MD, is chief of the vitreoretinal service at the University of Chicago. Sophie J. Bakri, MD, is a retina specialist and professor of ophthalmology at Mayo Clinic in Rochester, Minnesota. Dr. Hariprasad is a consultant or on the speakers’ bureau for Alcon, Allergan, EyePoint, OD-OS, Clearside Biomedical, Sandoz/Novartis, Alimera Sciences, Leica, Spark Therapeutics, and Regeneron. Dr. Bakri has served as a consultant for Genentech and Allergan. Dr. Bakri has served as a consultant for Genentech and Allergan. Reach Dr. Hariprasad at email@example.com.
ELEVATED IOP AND GLAUCOMA
An elevated IOP does not automatically indicate that a patient has glaucoma, as elevated IOP is an independent risk factor for glaucoma and varies for individual patients.4 Therefore, not all patients with ocular hypertension have, or develop, glaucoma.
Two large, multicenter trials are well recognized and respected among ophthalmologists. The Baltimore Eye Survey, a population-based prevalence survey conducted in 5,308 black and white individuals at least 40 years of age, showed that even with an IOP of 30 mmHg, most patients did not have glaucoma.5 Detailed ocular exams were performed on all subjects.6
The Ocular Hypertension Treatment Study (OHTS), a randomized trial conducted at 22 clinical centers with 1,636 participants from 40 years to 80 years of age with no evidence of glaucomatous damage and an IOP between 24 mmHg and 32 mmHg, demonstrated that with an untreated IOP of 24 mmHg to 32 mmHg, significantly more patients (9.5%) developed glaucoma damage in the 5 years the study was conducted, compared with the 4.4% of patients who received treatment.6 The goal in the 817-patient treatment group, compared with 819 patients in the observation group, was to reduce the IOP by 20% or more and to reach an IOP of 24 mmHg or less. The primary outcome was the development of primary open-angle glaucoma (POAG) in one or both eyes.6 Interestingly, even without intervention, only 9.5% of patients with elevated IOP develop glaucoma over 5 years — a surprisingly low number.
For those still skeptical about the OHTS study, the American Academy of Ophthalmology (AAO) excludes IOP as part of the definition of glaucoma in its 2015 “Preferred Practice Pattern” guidelines.4 In these guidelines, the AAO defines POAG as “a chronic, progressive optic neuropathy in adults in which there is a characteristic acquired atrophy of the optic nerve and loss of retinal ganglion cells and their axons.”4 Although IOP was part of the POAG definition in the 2010 guidelines, it was removed from the definition in this latest iteration.7,8 Additionally, Medicare and CMS even have different ICD-10 codes for ocular hypertension and glaucoma,9 further making a case for the separation between the 2 conditions.
STEROID-INDUCED IOP ELEVATION
Elevated IOP is primarily due to increased outflow resistance.10 It may be facilitated by upregulation of glucocorticoid receptors on trabecular meshwork cells, altering the rate of protein synthesis and inhibiting degradation of the extracellular matrix.10,11 Some of the risk factors for steroid-induced IOP elevations include certain aspects in a patient’s history, such as POAG patients and first-degree relatives of POAG patients12,13 and a history of steroid-related IOP increases.12,14 Factors apparent in the physical examination include higher baseline IOP, high myopia, and angle recession.11,15
When do we not use steroids to treat diseases? The dexamethasone intravitreal implant is contraindicated in glaucoma patients with a cup-to-disc ratio >0.8.16
IOP ACROSS VARIOUS INDICATIONS
Table 1 summarizes the occurrence of IOP elevations that occurred specifically with the dexamethasone intravitreal implant in clinical trials of patients with DME, macular edema following RVO, or noninfectious posterior segment uveitis. The percentage of patients with IOP elevations 10 mmHg or greater was similar in patients with DME and macular edema following RVO (approximately 27% to 28%) and around under 10% in patients with noninfectious posterior segment uveitis.17
|Indication||Study||Percentage of eyes with ≥10 mmHg IOP increase from baseline||Percentage of eyes with IOP ≥35 mmHg||Peak mean IOP timing||Return to baseline|
|Diabetic macular edema||MEADc||28.1% (91/324)17,a||4.0% (13/328)17,a||6.2% (20/324)17,a||0.9% (3/328)17,a||1.5 or 3 months after injection18||180 days after injection18|
|Macular edema following retinal vein occlusion||GENEVAd||26.6% (112/421)17,a||1.4% (6/423)17,a||5.9% (25/421)1,a||0% (0/423)17,a||60 days after injection1||180 days after injection1|
|Noninfectious posterior-segment uveitis||HURONe||9.6% (7/73) at week 81||0% (0/71) at week 817||7.9% (6/76)1,b||1.3% (1/75)17,b||42 days after injection17||182 days after injection17|
|a, at any visit; b, overall; c, pooled results from 2 multicenter, masked, randomized, sham-controlled, 3-year studies;1 d, pooled results from 2 multicenter, randomized, masked, sham-controlled, 6-month studies;3 e, multicenter, masked, randomized, 26-week study.2|
In most cases, elevated IOP levels returned to baseline within 180 days after injection.17,18 Across the indications, most patients with elevated IOP were managed with topical drops, but about 1% of patients required surgery for elevated IOP.16,17
DEXAMETHASONE IMPLANT IOP IN DME
In the MEAD pooled study results from 2 multicenter, masked, randomized, sham-controlled, 3-year studies of 347 dexamethasone intravitreal implant patients and 350 sham patients, there were few reports of open-angle glaucoma or other type of glaucoma, and generally these cases were of elevated IOP rather than actual glaucoma. None of the 6 patients (1.7%) in the dexamethasone intravitreal implant group with a report of glaucoma or open-angle glaucoma had a meaningful change in the cup-to-disc ratio or a documented change in the visual field.18
Intravitreal triamcinolone (Kenalog, Bristol-Myers Squibb; Triesence, Alcon) is used off-label to treat macular edema due to DME, RVO, and uveitis. The Diabetic Retinopathy Clinical Research Network (DRCR) evaluated this in patients with DME,19 and the SCORE trial evaluated this in patients with RVO. In the DRCR trial, IOP increased by more than 10 mmHg at any visit over the 3-year period in 4% of eyes in the laser group, 18% of eyes in the 1-mg triamcinolone group, and 33% of eyes in the 4-mg triamcinolone group.
In the SCORE trial, the numbers were similar - an IOP increase of more than 10 mmHg occurred at any visit between baseline and 3 years in 4% eyes in the laser group, 18% of eyes in the 1-mg triamcinolone group, and 33% of eyes in the 4-mg triamcinolone group.20 Although we lack head-to-head trial data on the dexamethasone implant vs intravitreal triamcinolone, it appears that the IOP data are more favorable with the dexamethasone implant.
HOW IS OCULAR HYPERTENSION DIFFERENT FROM STEROID-INDUCED IOP ELEVATION?
Ocular hypertension equates to long-term IOP elevation that likely lasts for years and gradually increases, and there is also an apparent resistance of the optic nerve to damage.21 With the dexamethasone intravitreal implant, there is short-term IOP elevation regardless of indication for injection. In DME pivotal trials, mean IOP generally returned to baseline between treatment cycles.1,16 In RVO pivotal trials, after the treatment cycle at day 180, 1.2% of patients had IOP elevations ≥10 mmHg from baseline.3,sup1 In the uveitis pivotal trials, after the treatment cycle at week 26, 1.4% of patients had IOP elevations ≥10 mmHg from baseline.17
When deciding whether a glaucoma patient needs treatment, risk and benefit must be assessed. Specialists should consider how high the IOP is, what target IOP is appropriate to maintain visual field, and whether the patient is at high risk for developing glaucoma damage.22 The goals of managing patients with elevated IOP are to monitor or lower IOP through treatment if an eye is likely to progress to POAG or to develop progressive optic disc, retinal nerve fiber layer, or visual damage.22
IOP can be medically managed with drops (given the desired IOP-lowering magnitude,4 PGAs can be effective, but there is concern for underlying uveitis or macular edema exacerbation4,23), lasers (laser trabeculoplasty4), or surgery (filtration surgery and tube shunts).4 In the dexamethasone intravitreal implant clinical trials, IOP was generally managed with topical medications or observation.15,16,24 Between 17% and 23% of patients treated with the dexamethasone intravitreal implant across clinical trials in DME, macular edema following RVO, and noninfectious posterior segment uveitis were receiving IOP medication at the final study visit,8 and only around 1% of patients required incisional surgery for elevated IOP.1,3,16
Analysis of dexamethasone implant US Food and Drug Administration registration trials shows that elevated IOP does not indicate that a patient has glaucoma.5 Across indications, treatment with the dexamethasone intravitreal implant has demonstrated clinical efficacy in DME, macular edema following RVO, and noninfectious posterior segment uveitis without the need for monthly injections.16 In general, short-term IOP elevations1,3,16,17 are manageable when they occur.8 RP
- Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-1914.
- Lowder C, Belfort R Jr, Lightman S, et al; Ozurdex HURON Study Group. Dexamethasone intravitreal implant for noninfectious intermediate or posterior uveitis. Arch Ophthalmol. 2011 May;129(5):545-553.
- Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010;117(6):1134-1146.
- Prum BE Jr, Rosenberg LF, Gedde SJ, et al. Primary open-angle glaucoma Preferred Practice Pattern guidelines. Ophthalmology. 2016;123(1):P41-P111.
- Sommer A, Tielsch JM, Katz J, et al. Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans. The Baltimore Eye Survey. Arch Ophthalmol. 1991;109(8):1090-1095.
- Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701-713.
- American Academy of Ophthalmology Glaucoma Panel. Preferred Practice Pattern Guidelines. Primary Open-Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2010.
- American Academy of Ophthalmology Glaucoma Panel. Preferred Practice Pattern Guidelines. Primary Open-Angle Glaucoma. San Francisco, CA: American Academy of Ophthalmology; 2015.
- Glaucoma H40-. ICD10Data.com website. http://www.icd10data.com/ICD10CM/Codes/H00-H59/H40-H42/H40- . Accessed May 7, 2018.
- Zhang X, Clark AF, Yorio T. FK506-binding protein 51 regulates nuclear transport of the glucocorticoid receptor beta and glucocorticoid responsiveness. Invest Ophthalmol Vis Sci. 2008;49(3):1037-1047.
- Kiddee W, Trope GE, Sheng L, et al. Intraocular pressure monitoring post intravitreal steroids: a systematic review. Surv Ophthalmol. 2013;58(4):291-310.
- Becker B, Hahn KA. Topical corticosteroids and heredity in primary open-angle glaucoma. Am J Ophthalmol. 1964;54:543-551.
- Davies TG. Tonographic survey of the close relatives of patients with chronic simple glaucoma. Br J Ophthalmol. 1968;52(1):32-39.
- Gaston H, Absolon MJ, Thurtle OA, Sattar MA. Steroid responsiveness in connective tissue diseases. Br J Ophthalmol. 1983;67(7):487-490.
- Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res. 2012;47(2):66-80.
- Allergan. Ozurdex prescribing information. https://www.allergan.com/assets/pdf/ozurdex_pi
- Data on file, Allergan.
- Maturi RK, Pollack A, Uy HS, et al; OZURDEX MEAD Study Group. Intraocular pressure in patients with diabetic macular edema treated with dexamethasone intravitreal implant in the 3-year MEAD study. Retina. 2016;36(6):1143-1152.
- Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, Aiello LP, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 2009;127(3):245-251.
- Aref AA, Scott IU, Oden NL, Ip MS, Blodi BA, VanVeldhuisen PC; SCORE Study Investigator Group. Incidence, risk factors, and timing of elevated intraocular pressure after intravitreal triamcinolone acetonide injection for macular edema secondary to retinal vein occlusion: SCORE Study Report 15. JAMA Ophthalmol. 2015;133(9):1022-1029.
- Chang-Godinich A. Ocular hypertension. Medscape. http://emedicine.medscape.com/article/1207470-overview#a5 . Updated December 29, 2017. Accessed April 25, 2018.
- Prum BE Jr, Lim MC, Mansberger SL, et al. Primary open-angle glaucoma suspect Preferred Practice Pattern guidelines. Ophthalmology. 2016;123(1):P112-P151.
- Healy P, Ritch R, Lerner F. Medical treatments of other types of open-angle glaucoma. In: Weinreb RN, Liebmann J, eds. Medical Treatment of Glaucoma. Amsterdam: Kugler Publications; 2010.
- Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results. Ophthalmology. 2011;118(12):2453-2460.