Evolving Treatment Paradigms in the Management of Diabetic Macular Edema

Highlights from a roundtable discussion held during the 2014 meeting of the American Society of Retina Specialists in San Diego.

MODERATOR
	Pravin U. Dugel, MD, is a managing partner at Retinal Consultants of Arizona, a founding member of Spectra Eye Institute and a clinical associate professor in the department of ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles.

PANELISTS
	Thomas Albini, MD, is a vitreoretinal surgeon who specializes in the treatment of uveitis. He is an associate professor of clinical ophthalmology at Bascom Palmer Eye Institute in Miami.
	Antonio Capone Jr., MD, is a vitreoretinal surgeon with Associated Retinal Consultants in Novi, Mich. and a clinical professor of biomedical sciences at Oakland University in Rochester, Mich.
	John W. Kitchens, MD, is a vitreoretinal surgeon with Retina Associates of Kentucky in Lexington.

Diabetes is a growing epidemic globally. The number of patients with this disease is expected to increase from 382 million in 2013 to 592 million in 2035,¹ an astonishing 55% increase. Diabetic macular edema (DME) currently is a leading cause of visual impairment in patients with diabetes.² This distinguished panel was assembled to discuss the role of dexamethasone intravitreal implant 0.7 mg (OZURDEX^®, Allergan) in the treatment algorithm for DME.

PRAVIN U. DUGEL, MD: What does the real-life landscape look like for patients with DME?

ANTONIO CAPONE JR., MD: DME is a consequence of diabetes, and it doesn’t occur in isolation. Patients who have DME are rife with other problems. Their systemic therapeutic burden is significant.²^,³

JOHN W. KITCHENS, MD: Agreed. Although we are retina specialists, we must take the whole patient into account and set expectations from the outset. Patients need to know what living with this chronic disease entails and that they will need to make a lifetime commitment to therapy.

DR. CAPONE: From my review related to DME, there seems to be a correlation that exists between visual outcomes and treating patients appropriately.⁴

A Multifactorial Disease

DR. DUGEL: Considering the pathophysiology of DME, we know it is a multifactorial disease What are your thoughts?

DR. KITCHENS: I believe inflammation is a contributing factor.

DR. DUGEL: If we agree that the goal is to suppress inflammation, then a steroid would be an appropriate treatment.⁵ We have several methods for delivering steroids. Can you describe these?

DR. CAPONE: In terms of injecting a bolus, we must administer large doses of a drug. We inject a large dose, hoping for a sustained effect over a prolonged period. With a sustained-release drug delivery device, a sustained delivery of drug on intraocular inflammation can be provided.⁶

DR. ALBINI: The biodegradable OZURDEX^® delivers a sustained level of drug that’s maintained in the eye until the implant is completely degraded.⁵

MEAD Study Findings

DR. DUGEL: Dr. Albini, what is your overall impression of the Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) study*?

DR. ALBINI: MEAD demonstrated good efficacy of OZURDEX^® (dexamethasone intravitreal implant) and provided enough data to convince me that the sustained-release dexamethasone intravitreal implant is a useful addition to my practice.

DR. CAPONE: There are several different factors in the design of the MEAD trial that had an overall effect on the 3-year results and that should be taken into consideration in 2015. This study was started in 2004, with that last patient entering the study in 2009. There was a true sham arm in the study, which means that patients in the sham group received no treatment, rather, a needleless injection.¹¹ Additionally, there was no rescue therapy in MEAD. Once patients in either the treatment group or the sham group were treated with an escape therapy, which included laser, triamcinolone acetonide injection, and later in the study’s timeline, anti-VEGF injection, they were exited from the study and their last observation of visual acuity was carried forward to be included in the final results.¹²

Efficacy.

DR. DUGEL: Dr. Albini, what were the overall efficacy results in MEAD?

DR. ALBINI: At the month 39/final visit of the MEAD study, 19.5% (64/328) of all patients who were treated with OZURDEX^® had at least a 15-letter gain in BCVA and 13.7% (45/328) had a loss of 15 or more letters of BCVA from baseline. Among sham-treated patients, 10.7% (35/328) had at least a 15-letter gain in BCVA and 10.7% (35/328) had at least a 15-letter loss from baseline.¹² Among pseudophakic patients with DME treated with OZURDEX^®, 20% (16/82) had at least a 15-letter gain in BCVA, while 5% (4/82) had a loss of 15 or more letters of BCVA from baseline.⁵ Among sham-treated patients, 11% (11/99) had at least a 15-letter gain in BCVA and 7% (7/99) had at least a 15-letter loss from baseline. Among phakic patients with DME treated with OZURDEX^®, 20% (48/246) had at least a 15-letter gain in BCVA and 17% (41/246) had a loss of 15 or more letters of BCVA from baseline. Among sham-treated patients, 11% (24/229) had at least a 15-letter gain in BCVA and 12% (28/229) had at least a 15-letter loss from baseline.⁵

Intraocular Pressure.

DR. DUGEL: Dr. Capone, what is your overall impression of the safety data from MEAD?

DR. CAPONE: In MEAD, 28% of OZURDEX^® patients (91/324) had an IOP elevation ≥ 10 mm Hg from baseline at any visit versus 4% of sham patients (13/328) over 3 years.⁵ Mean IOP increases have been seen within each treatment cycle, but generally returned to baseline at the end of 6 months.

DR. DUGEL: We should also be aware of the distinction between increased IOP and glaucoma.

DR. CAPONE: That’s an important hair to split. Elevated IOP alone is not glaucoma. A glaucoma diagnosis can encompass elevated IOP accompanied by visual field changes and optic nerve head damage.¹³ Patients in MEAD who had IOP elevations were typically managed with topical IOP-lowering medications. One patient (0.3%) required incisional surgery for steroid-induced IOP increase. Forty-two percent of OZURDEX^® (dexamethasone intravitreal implant) patients (136/324) received IOP-lowering medications over 3 years (versus 10% of sham patients [32/328]).⁵

At the final study visit, 22.1% of OZURDEX^® patients (54/244) and 3.6% of sham patients (6/169) were using IOP-lowering medication.¹² The number of IOP medications that were required is important to note: from months 0-12, 20.1% of patients (n = 324) were given one IOP medication (5.8% (n = 328) sham), 8.6% received two medications (0.9% sham), and 5.6% received three or more medications (0.3% sham). At the final (year 3) visit of the MEAD study, 9.8% of OZURDEX^® patients were on one IOP-lowering medication (2.4% sham), 5.3% were on two medications (0.6% sham), and 7.0% were on three or more medications (0.6% sham).¹² So, in MEAD, IOP elevations were typically managed with topical IOP-lowering medication.

DR. KITCHENS: As per a subgroup analysis of patients who experienced IOP rises of equal or greater than 10 mm Hg over the course of the study, of the cumulative percentage of OZURDEX^® treated patients (91/324): 56% with the first injection cycle, 7% by the second injection, 86% by the third, 96% by the fourth, 99% by the fifth, 99% by the sixth, and 100% by the seventh injection cycle. In the sham group (13/328), 38% with the first sham injection cycle, 53% by the second, 84% by the third, 92% by the fourth, 92% by the fifth, 92% by the sixth and 100% by the seventh injection cycle.¹²

DR. DUGEL: Knowing what we know now, would you use OZURDEX^® to treat a patient whose pressure is treated with one antiglaucoma medication?

DR. CAPONE: Patients with glaucoma, who have cup-to-disc ratios of greater than 0.8 are contraindicated for OZURDEX^®,⁵ but if a patient has a healthy nerve, pressures in the teens, and is using a single IOP-lowering drug, and if dexamethasone is the appropriate therapy for that patient, I wouldn’t hesitate to use it. I would monitor pressures carefully and add a second IOP-lowering drug if necessary.

DR. KITCHENS: If a patient has a reasonably healthy optic nerve, a 0.7 cup-to-disc ratio and managed pressure, I wouldn’t hesitate to use OZURDEX^® if there aren't any contraindications.

DR. ALBINI: I would have no problem using OZURDEX^®, as long as the optic nerve and the visual fields look good.

Labeling Approved in September 2014

DR. DUGEL: The FDA approved OZURDEX^® to be used in the general DME patient population. Will this change the way you prescribe OZURDEX^® to your patients?

DR. CAPONE: The label allows me to use OZURDEX^® in patients with diabetic macular edema.

DR. KITCHENS: I’ve used OZURDEX^® routinely in non-infectious posterior segment uveitis and macular edema following BRVO/CRVO.

DR. ALBINI: The label for OZURDEX^® allows me to use OZURDEX^® in phakic patients with DME. Although I will use it only in those patients in whom cataract surgery is unproblematic, or who are not in immediate need of cataract surgery.

DR. DUGEL: I’d like to respond to this. The revised label is appropriate because it puts the disease into perspective. We’re using this product in patients who have visual acuity losses. Although there’s nothing that comes without consequences, the possible adverse reactions that are of major concern to me are increased IOP and an increased risk of cataract formation, among others, and are weighed against the possible visual acuity improvement.

In the case of increasing cataract risk, patients with diabetes have a higher incidence of cataracts when compared with patients without diabetes.¹⁴^,¹⁵ In my experience, in about 20% of that population we are risking the chance that any cataract would need to be removed sooner. Sixty-eight percent of phakic OZURDEX^® (dexamethasone intravitreal implant) patients (n = 243) experienced cataracts versus 21% of sham patients (n = 230). The occurrence of cataracts impacted visual acuity during the study.⁵

Based on the MEAD clinical trial, we anticipate when the pressure may rise.⁵^,¹² We know what to look for in our patients, which makes it easier to screen, treat, and monitor pressure increases. ■

*The FDA approval of OZURDEX^® for DME is based on the MEAD study. MEAD includes two multicenter 3-year sham-controlled, masked randomized clinical studies assessing the proportion of patients with 15 or more letters improvement in best-corrected visual acuity (BCVA) from baseline.

References

1. Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Prac. 2014;103(2):137-149.

2. Bhagat N, Grigorian RA, Tutela A, Zarbin MA. Diabetic macular edema: Pathogenesis and treatment. Surv Ophthalmol. 2009;54(1):1-32.

3. Wallick CJ, Hansen RN, Campbell J, et al. Increased health care utilization among patients with diabetic macular edema compared with diabetic patients without edema. Presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 4-8, 2014; Orlando, FL.

4. Campbell J, Cole AL, Almony A, et al. Real world vision outcomes in DME treated with anti-VEGF injections—An analysis of EMR data from a large health system. Presentation at: Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO); May 4-8, 2014; Orlando, FL.

5. OZURDEX^® Prescribing Information.

6. Hunter RS, Lobo AM. Dexamethasone intravitreal implant for the treatment of noninfectious uveitis. Clin Ophthalmol. 2011;5:1613-1621.

7. Jain A, Varshney N, Smith C. The evolving treatment options for diabetic macular edema. Int J Inflam. 2013;2013:689276.

8. Ehrlich R, Harris A, Ciulla TA, Kheradiya N, Winston DM, Wirostko B. Diabetic macular oedema: physical, physiological and molecular factors contribute to this pathological process. Acta Ophthalmol. 2010;88(3):279-291.

9. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica. 2010;224(suppl 1):8-15.

10. Zhang W, Liu H, Al-Shabrawey M, Caldwell RW, Caldwell RB. Inflammation and diabetic retinal microvascular complications. J Cardiovasc Dis Res. 2011;2(2):96-103.

11. 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; 121(10):1904-1914.

12. Data on file, Allergan, Inc.

13. National Eye Institute (NEI). Facts about glaucoma. National Eye Institute website. https://www.nei.nih.gov/health/glaucoma/glaucoma_facts. Accessed March 17, 2015.

14. Obrosova IG, Chung SS, Kador PF. Diabetic cataracts: mechanisms and management. Diabetes Metab Res Rev. 2010;26(3):172-180.

15. American Diabetes Association. Living with diabetes: complications. http://www.diabetes.org/living-with-diabetes/complications/eye-complications/. Accessed December 3, 2013.

Evolving Treatment Paradigms in the Management of DME

CASE #1

A 64-year-old male with an 8-year history of type 2 noninsulin-dependent diabetes mellitus was referred for retinal exam in 2008 after an outside LASIK evaluation noted moderate non-proliferative diabetic retinopathy OU. Prior poor glucose control resulted in severe chronic macular edema despite recent tight control and A1c of 6.7.

Over a period of 6 years, he was treated with various treatments but experienced only limited improvement in his macular edema. He was treated with OZURDEX^® (dexamethasone intravitreal implant) on 10/27/2014 with initial VA 20/60-2 and OCT as shown (Figure 1, Left). A follow-up visit on 12/10/2014 demonstrated improved VA to 20/40-2 and notable improvement on OCT (Figure 1, Right).

Case presented by Ryan Whitted, MD, currently an ophthalmology resident at Vanderbilt University. He is in his first year of fellowship in Lexington, KY.

CASE #2

This is a 65-year-old woman who had DME in the right eye that was still significant after previous treatment. The visual acuity in the right eye was 20/80.

She was treated with OZURDEX^® (dexamethasone intravitreal implant) and responded nicely. Four weeks post OZURDEX^® BCVA was 20/80; 11 weeks post OZURDEX^® BCVA was 20/60. After 20 weeks, the visual acuity had decreased to 20/80 and edema recurred.

The patient received a second OZURDEX^® treatment. Twelve weeks post second OZURDEX^® BCVA was 20/40. Visual acuity decreased after 18 weeks to 20/200, and edema recurred.

The patient received a third OZURDEX^® treatment; 9 weeks later, she developed a cataract, which was removed. Her BCVA at the 9-week visit was 20/100. Seventeen weeks after the third OZURDEX^® (4 weeks post cataract extraction) her BCVA was 20/200.

Eleven weeks after her fourth OZURDEX^®, her BCVA was 20/50. Her visual acuity decreased around 4.5 months to 20/80. Edema also recurred.

Six weeks after the patient’s fifth OZURDEX^® injection, visual acuity had improved to 20/40. The CMT was measured at 200 microns. At 19 weeks post-injection, her BCVA decreased to 20/100 and CMT increased.

The patient was injected with a sixth OZURDEX^® implant. Eight weeks after the sixth injection, the patient’s BCVA was 20/40.

Thirty-three weeks following the sixth OZURDEX^® treatment, again, the visual acuity decreased to 20/160, and macular thickness increased.

The patient responded well to a seventh injection of OZURDEX^®, with an improvement in VA to 20/100 at the 5-week visit. Her CMT was measured at 179 microns.

Case presented by Anat Lowenstein, MD, MHA, Professor of Ophthalmology and Deputee dean of the medical school at the Sackler Faculty of Medicine, Tel Aviv University.

Indications and Usage

Retinal Vein Occlusion

OZURDEX^® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).

Posterior Segment Uveitis

OZURDEX^® is indicated for the treatment of noninfectious uveitis affecting the posterior segment of the eye.

Diabetic Macular Edema

OZURDEX^® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of diabetic macular edema.

Dosage and Administration

FOR OPHTHALMIC INTRAVITREAL INJECTION. The intravitreal injection procedure should be carried out under controlled aseptic conditions. Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.

IMPORTANT SAFETY INFORMATION

Contraindications

Ocular or Periocular Infections: OZURDEX^® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.

Glaucoma: OZURDEX^® (dexamethasone intravitreal implant) is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8.

Torn or Ruptured Posterior Lens Capsule: OZURDEX^® is contraindicated in patients whose posterior lens capsule is torn or ruptured because of the risk of migration into the anterior chamber. Laser posterior capsulotomy in pseudophakic patients is not a contraindication for OZURDEX^® use.

Hypersensitivity: OZURDEX^® is contraindicated in patients with known hypersensitivity to any components of this product.

Warnings and Precautions

Intravitreal Injection-related Effects: Intravitreal injections, including those with OZURDEX^®, have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection.

Steroid-related Effects: Use of corticosteroids including OZURDEX^® may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection.

Adverse Reactions

Retinal Vein Occlusion and Posterior Segment Uveitis

Adverse reactions reported by greater than 2% of patients in the first 6 months following injection of OZURDEX^® (dexamethasone intravitreal implant) for retinal vein occlusion and posterior segment uveitis include: intraocular pressure increased (25%), conjunctival hemorrhage (22%), eye pain (8%), conjunctival hyperemia (7%), ocular hypertension (5%), cataract (5%), vitreous detachment (2%), and headache (4%).

Increased IOP with OZURDEX^® peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX^® required surgical procedures for management of elevated IOP.

Diabetic Macular Edema

Ocular adverse reactions reported by greater than or equal to 1% of patients in the two combined 3-year clinical trials following injection of OZURDEX^® for diabetic macular edema include: cataract (68%), conjunctival hemorrhage (23%), visual acuity reduced (9%), conjunctivitis (6%), vitreous floaters (5%), conjunctival edema (5%), dry eye (5%), vitreous detachment (4%), vitreous opacities (3%), retinal aneurysm (3%), foreign body sensation (2%), corneal erosion (2%), keratitis (2%), anterior chamber inflammation (2%), retinal tear (2%), eyelid ptosis (2%). Non-ocular adverse reactions reported by greater than or equal to 5% of patients include: hypertension (13%) and bronchitis (5%).

Increased Intraocular Pressure: IOP elevation greater than or equal to 10 mm Hg from baseline at any visit was seen in 28% of OZURDEX^® (dexamethasone intravitreal implant) patients versus 4% of sham patients. 42% of the patients who received OZURDEX^® were subsequently treated with IOP-lowering medications during the study versus 10% of sham patients.

The increase in mean IOP was seen with each treatment cycle, and the mean IOP generally returned to baseline between treatment cycles (at the end of the 6-month period).

Cataracts and Cataract Surgery: The incidence of cataract development in patients who had a phakic study eye was higher in the OZURDEX^® group (68%) compared with Sham (21%). The median time of cataract being reported as an adverse event was approximately 15 months in the OZURDEX^® group and 12 months in the Sham group. Among these patients, 61% of OZURDEX^® subjects versus 8% of sham-controlled subjects underwent cataract surgery, generally between Month 18 and Month 39 (Median Month 21 for OZURDEX^® group and 20 for Sham) of the studies.

Indications and Usage

Retinal Vein Occlusion

Posterior Segment Uveitis

OZURDEX^® is indicated for the treatment of noninfectious uveitis affecting the posterior segment of the eye.

Diabetic Macular Edema

OZURDEX^® (dexamethasone intravitreal implant) is a corticosteroid indicated for the treatment of diabetic macular edema.

Dosage and Administration

IMPORTANT SAFETY INFORMATION

Contraindications

Glaucoma: OZURDEX^® is contraindicated in patients with glaucoma, who have cup to disc ratios of greater than 0.8.

Hypersensitivity: OZURDEX^® is contraindicated in patients with known hypersensitivity to any components of this product.

Warnings and Precautions

Intravitreal Injection-related Effects: Intravitreal injections, including those with OZURDEX,^® have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored regularly following the injection.

Steroid-related Effects: Use of corticosteroids including OZURDEX^® (dexamethasone intravitreal implant) may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex because of the potential for reactivation of the viral infection.

Adverse Reactions

Retinal Vein Occlusion and Posterior Segment Uveitis

Adverse reactions reported by greater than 2% of patients in the first 6 months following injection of OZURDEX^® for retinal vein occlusion and posterior segment uveitis include: intraocular pressure increased (25%), conjunctival hemorrhage (22%), eye pain (8%), conjunctival hyperemia (7%), ocular hypertension (5%), cataract (5%), vitreous detachment (2%), and headache (4%).

Diabetic Macular Edema

Ocular adverse reactions reported by greater than or equal to 1% of patients in the two combined 3-year clinical trials following injection of OZURDEX^® (dexamethasone intravitreal implant) for diabetic macular edema include: cataract (68%), conjunctival hemorrhage (23%), visual acuity reduced (9%), conjunctivitis (6%), vitreous floaters (5%), conjunctival edema (5%), dry eye (5%), vitreous detachment (4%), vitreous opacities (3%), retinal aneurysm (3%), foreign body sensation (2%), corneal erosion (2%), keratitis (2%), anterior chamber inflammation (2%), retinal tear (2%), eyelid ptosis (2%). Non-ocular adverse reactions reported by greater than or equal to 5% of patients include: hypertension (13%) and bronchitis (5%).

Increased Intraocular Pressure: IOP elevation greater than or equal to 10 mm Hg from baseline at any visit was seen in 28% of OZURDEX^® patients versus 4% of sham patients. 42% of the patients who received OZURDEX^® were subsequently treated with IOP-lowering medications during the study versus 10% of sham patients.

The increase in mean IOP was seen with each treatment cycle, and the mean IOP generally returned to baseline between treatment cycles (at the end of the 6-month period).

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Evolving Treatment Paradigms in the Management of Diabetic Macular Edema

Evolving Treatment Paradigms in the Management of Diabetic Macular Edema