Dexamethasone implant shows good safety, visual outcomes in MEAD study

October 1, 2014

Dexamethasone intravitreal implant 0.7 and 0.35 mg provided statistically and clinically significant improvement in best-corrected visual acuity and reduction in central subfield retinal thickness with an average of 4 to 5 injections over 3 years.

Take-home

Dexamethasone intravitreal implant 0.7 and 0.35 mg provided statistically and clinically significant improvement in best-corrected visual acuity and reduction in central subfield retinal thickness with an average of 4 to 5 injections over 3 years.

 

By Michelle Dalton, ELS; Reviewed by David S. Boyer, MD

Los Angeles-Inflammation is now considered a critical factor in diabetic retinopathy/diabetic macular edema (DME) pathogenesis,1 and steroids are well known for their ability to reduce edema quickly.

As such, the Macular Edema: Assessment of Implantable Dexamethasone in Diabetes (MEAD) study served as the foundation for the FDA approval of dexamethasone intravitreal implant 0.7 mg (Ozurdex, Allergan) for the treatment of DME.2

The MEAD study evaluated both the 0.7- and 0.35-mg versions in more than 1,000 patients over 3 years.

“The mean number of injections was around 4 in each group over the course of the study,” said David S. Boyer, MD, clinical professor of ophthalmology, Department of Ophthalmology, University of Southern California Keck School of Medicine, Los Angeles.

The dexamethasone intravitreal implantcan reduce the number of injections that patients need and the number of times they come into the office,” Dr. Boyer said. “We still have to be conscious of the fact they will need to come into the office for monitoring of their IOP.”

People who come from a long distance for the injection may be able to have their IOP checked by their general ophthalmologist and treated closer to home, if necessary. It is hoped that this will decrease the treatment burden to patients and to the people who bring them to the office, he noted.

In July 2014, the FDA approved the implant for the treatment of DME, but limited its use to pseudophakic patients or in phakic patients scheduled to undergo cataract surgery.

“It’s going to be most useful in patients who don’t get the response we would like to see with anti-vascular endothelial growth factor (VEGF) therapies,” Dr. Boyer said. Since some patients do not respond well to anti-VEGF therapies, “most would be helped with a corticosteroid, since that’s a totally different mechanism of action.”

 

Study details

In the MEAD study, 1,048 patients with DME, best-corrected visual acuity (BCVA) between 34 and 68 ETDRS letters, and central subfield retinal thickness (CRT) ≥300 mm by optical coherence tomography (OCT) were randomly assigned in a 1:1:1 ratio to treatment with dexamethasone implant 0.7 mg, dexamethasone implant 0.35 mg, or sham procedure.

Patients who met re-treatment eligibility criteria could be re-treated no more often than every 6 months.

The primary endpoint was achievement of ≥15-letter improvement in BCVA from baseline at study end in the intent-to-treat population with last-observation-carried-forward for missing values. Safety measures included adverse events (AEs) and IOP.

There were 22.2% of patients with ≥15-letter improvement in BCVA from baseline at study end in the 0.7-mg group, 18.4% in the 0.35-mg group and 12% in the sham group (p ≤ 0.018). Mean average reduction in central retinal thickness from baseline during the study was greater with dexamethasone implant 0.7 mg (–111.6 mm) and dexamethasone implant 0.35 mg (–107.9 mm) than sham (–41.9 mm) (p < 0.001, area-under-the-curve approach).

Rates of cataract-related AEs in phakic eyes were 67.9%, 64.1%, and 20.4% in the dexamethasone implant 0.7 mg, dexamethasone implant 0.35 mg, and sham groups, respectively. IOP increases were usually controlled with medication or no therapy.

 

Safety concerns

Phakic patients who receive multiple dexamethasone injections may lead to cataract development, Dr. Boyer noted. For young patients with a clear lens, he recommends staying with anti-VEGF therapy.

“I do feel one [dexamethasone] injection is well tolerated and will not lead to cataract formation, but multiple injections are likely to cause cataract,” he said.

In the MEAD study, phakic patients who developed cataract (about 59%) had vision improvements to better than baseline after the cataract was removed and similar to pseudophakic patients, about a 6- to 7-letter gain.

As for IOP spikes, “the profile was much safer than any other steroid that has been examined,” he said. “Compared with Iluvien, Triescence, or Kenalog, Ozurdex is much less likely to cause permanent pressure effects.”

In the MEAD study, only one patient (0.3%) needed filtration surgery to manage steroid-induced glaucoma. Differences in the pharmacologic and pharmacokinetic profiles of the various steroids may account for the differing profiles, and explain why those who received dexamethasone underwent significantly fewer incisional surgeries to treat IOP spikes.

“These are typically self-limiting curves,” Dr. Boyer said. “They peak at 8 weeks and then taper over the next 6 to 8 weeks.”

Dexamethasone itself is less liphophilic than triamcinolone acetonide or fluocinolone acetonide and does not accumulate to the same extent in the trabecular meshwork or lens, according to the study authors.

 

Co-management

Dr. Boyer recommends patients with diabetes undergoing evaluation for cataract surgery have a retinal consult to at least get an optical coherence tomography.

If there are no signs of diabetic retinopathy and no signs of thickening, cataract surgeons can continue as they normally would, he noted.

“If they do have any form of diabetic retinopathy, we know it will worsen after cataract surgery,” Dr. Boyer said.

Even patients with diabetes who undergo uncomplicated cataract surgery seem to have an increase in retinal thickness, regardless of current therapy.

“Having [dexamethasone] on board 2 to 3 weeks before probably will reduce chances of developing edema,” Dr. Boyer said.

 

References

1.     Tang J, Kern TS. Inflammation in diabetic retinopathy. Prog Retin Eye Res. 2011;30:343-358.

2.     Boyer DS, Yoon YH, Belfort Jr. R., Bandello F, et al. Three-year, randomized, sham-controlled, trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Jun 4. pii: S0161-6420(14)00378-9. doi: 10.1016/j.ophtha.2014.04.024. [Epub ahead of print]

 

David S. Boyer, MD

E: vitdoc@aol.com

This article was adapted from Dr. Boyer’s presentation at the 2014 meeting of the Association for Research in Vision and Ophthalmology. Dr. Boyer is a consultant or advisor to Allergan, Genentech, Novartis, Regeneron, and Roche.