The intravitreal dexamethasone implant (Ozurdex, Allergan) is approved by the US Food and Drug Administration (FDA) for the treatment of diabetic macular edema (DME).1macular edema associated with retinal vein occlusion (RVO),2and non-infectious posterior uveitis.3It delivers a potent corticosteroid through a biodegradable polymer that gradually dissolves in water and carbon dioxide while delivering the drug in a sustained, safe dose over several months.4
Corticosteroids have a broad spectrum of biological effects, including downregulation of inflammatory cytokines, endothelial adhesion molecules, and growth factors such as VEGF, conferring anti-inflammatory, antivascular permeability, and antiangiogenic effects, respectively, in this class of drugs.4These molecular mechanisms are dysregulated to varying degrees in many vitreoretinal disorders, making corticosteroids effective treatment options for a variety of disease states. However, not all corticosteroids are created equal and their different chemical structures result in different clinical properties.
SOLUBILITY IN WATER
Triamcinolone is minimally soluble in water and becomes a depot for steroid-releasing crystals, resulting in a long half-life.5On the other hand, dexamethasone has two additional hydroxyl groups on the acetonide functional group, making it significantly more hydrophilic compared to triamcinolone and fluocinolone.6Water solubility has two advantages: a shorter half-life, which makes it suitable as a sustained-release drug, allowing a controlled and constant release6; and less aggregation in ocular structures such as the trabecular meshwork,7which appears to result in lower rates of increased intraocular pressure (IOP).
By using intravitreal corticosteroids in our practice, we ensure that patients have a clear understanding of the risk of cataract progression and possible ocular hypertension. We found that patients are less concerned about their cataract and see cataract surgery as a treatment issueSeinstead ofSe. Most patients take eye drops for ocular hypertension, but glaucoma surgery is always an undesirable outcome. Among the various intravitreal steroid options, the intravitreal implant of dexamethasone has a favorable IOP profile.
In the MEAD study, 0.6% of patients with DME treated with the 700 µg dose of intravitreal dexamethasone implant required incisional glaucoma surgery.1For comparison, 33.8% of patients treated with the 0.59 mg fluocinolone acetonide implant (Retisert, Bausch + Lomb)84.8% two patients treated with 0.19 mg fluocinolone acetonide implant (Iluvien, Alimera Sciences),9and 1.2% were treated with 4.0 mg of intravitreal triamcinolone10,11in the corresponding large clinical trials evaluating these therapies in patients with DME, incisional glaucoma surgery was required.
As reflected in the results of the MEAD study, we found that the IOP elevation with the intravitreal dexamethasone implant is small and predictable. These increases peak 6 to 8 weeks after injection and then return to near baseline after 3 or 4 months.1In our practice, we have not experienced the so-called gradual progressive increase in IOP with repeated injections, as is sometimes seen with triamcinolone. IOP elevation with triamcinolone also appears to be less predictable in terms of time (a few days to many months).12and severity (between 70-80 mmHg).13-15In contrast, 89% of patients who developed ocular hypertension at any time during the MEAD study had it within the first three injections, and 99% of patients who developed ocular hypertension had it within the first four injections.16This means that if a patient does not experience an IOP spike on the third or fourth injection, it is unlikely that they will after future injections.
Clinical use of the intravitreal dexamethasone implant is widespread, and many studies have reported uses beyond FDA-approved indications. Its effectiveness has been demonstrated in macular edema after cataract surgery,17-19retinal detachment repair,19,20epiretinales Membranpeeling,19,21radiation maculopathy,22,23retinitis pigmentosa,24,25and in combination with anti-VEGF agents for neovascular age-related macular degeneration.26Pediatric applications have also been described.27,28
In our practice, we most commonly use intravitreal dexamethasone implantation in patients with DME and RVO who respond poorly to anti-VEGF agents. Literature supports the efficacy of intravitreal dexamethasone implant as a salvage treatment for recalcitrant DME29-31as well as branch and central RVO.31,32The controversial question is when to switch to the intravitreal dexamethasone implant - in other words, after how many ineffective anti-VEGF injections do you consider a patient to have a poor anti-VEGF response?
It has been shown that if the central retinal thickness does not decrease by at least 25% after the first anti-VEGF injection in patients with RVO, the patient is likely to have a poor response, regardless of the number of injections.33Similar findings have been reported in patients with DME (Shah AR, et al, unpublished data). We can therefore switch to the intravitreal dexamethasone implant relatively early, and these patients generally respond well (Figure).
There is controversy over faster clearance of anti-VEGF agents34,35and triancinolone36in eyes submitted to vitrectomy. The intravitreal dexamethasone implant, like other sustained-release devices, has theoretical advantages in vitrectomized eyes, as the secreted corticosteroid is immediately replaced by more drug elution.37Studies have demonstrated the efficacy of intravitreal implantation of dexamethasone in vitrectomized eyes with uveitic cystoid macular edema,38DME,39by RVO.40
Figure. The efficacy of intravitreal dexamethasone implant for DME with poor response to anti-VEGF agents is illustrated. The patient's eye had previously undergone a vitrectomy for non-healing vitreous hemorrhage (A). DME was treated with ranibizumab 0.3 mg (Lucentis, Genentech; A). A subtle response was seen 5 weeks after injection (B). The patient returned after 11 weeks with worsening intraretinal fluid (C). Aflibercept (Eylea, Regeneron) was administered. At 6 weeks, minimal response was seen and another injection of aflibercept was used (D). Eight weeks later, the edema worsened and the patient was transferred to the intravitreal dexamethasone implant (E). Edema showed acute resolution for the first time, evident 7 weeks after injection of the intravitreal dexamethasone implant (F). At the 8-week follow-up, slight intraretinal fluid was observed and aflibercept was administered (G). The edema worsened after 8 weeks and it was decided to resume treatment with an intravitreal implant of dexamethasone (H). The edema disappeared 8 weeks later (I). The patient remains with the intravitreal dexamethasone implant every 3 to 4 months as needed, demonstrating excellent edema control for over a year.
ADVANTAGE OF A DISADVANTAGE
The intravitreal dexamethasone implant and the two fluocinolone acetonide implants are all sustained release products but differ in their duration of action. Fluocinolone implants are designed to last 3 years. Significantly fewer injections are needed, but once the implant is in place, the eye faces a potential 3 years of steroid exposure and complications from IOP. On the other hand, based on our experience with refractory edema, the intravitreal implant of dexamethasone, although originally designed to last 6 months, usually provides clinically significant effects for 3 to 4 months. The downside of requiring more injections becomes an advantage when treating IOP problems as the effects of the steroids wear off sooner.
The intravitreal dexamethasone implant is a potent steroid delivery system that provides a controlled and predictable sustained release of a potent and safe steroid. It has played an important role in our practice's treatment paradigms for retinovascular disease and posterior uveitis.N
Yoshihiro Yonekawa, MD, is a second-year Fellow in Vitreoretinal Surgery at Associated Retinal Consultants/William Beaumont Hospital in Royal Oak, Michigan. He declares that there are no conflicts of interest. Dr Yonekawa can be reached at email@example.com.
Jeremy D. Wolfe, MD, is a partner at Associated Retinal Consultants, Royal Oak, Michigan, and an assistant professor of ophthalmology at the William Beaumont School of Medicine at Oakland University. He is a consultant for Allergan, Alimera and Genentech. dr Wolfe can be reached at firstname.lastname@example.org.
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