Trends in treatment of retinal vein occlusion

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A key development within the management of retinal disease has been the introduction of drug delivery directly into the posterior chamber of the eye. While there has been significant commentary on the use of agents such as Lucentis for wet macular generation, there is also a continuing focus on drug delivery for treatment of macular oedema as a result of other conditions, for example retinal vein occlusion.1 Such agents work by entering cells and blocking the production of vascular endothelial growth factor (VEGF) and prostaglandins, substances that are involved in inflammation and swelling.

Currently a range of products are competing for the market to manage macular oedema caused as a result of central or peripheral retinal vein occlusion. Intravitreal triamcinolone (IVT) is a widely used technique of steroid injection directly into the vitreous. The use of intravitreal bevacizumab (Avastin), however, is associated with evidence of reduced complications due to glaucoma.

Evidence: clinical studies

One early study of the use of intraviteral triamcinolone has been reported by Ip,2 which indicated a reduction in macular oedema based on measurement of mean foveal thickness in the period after initial treatment phase. A comparable study by Cekiç et al3 in 24 eyes confirmed the potential of intravitreal triamcinolone treatment to improve visual acuity and reduce macular oedema based on measurements of foveal thickness using OCT. Ocular hypertension was, however, observed in nine of 18 patients without a history of glaucoma. In addition, eight of 16 phakic eyes showed progression of cataract and two patients needed cataract extraction.

A recent review by Yilmaz et al4 of treatments for macular oedema using intravitreal triamcinolone indicated that intraocular pressure was significantly raised at three months and also at six months. In terms of visual acuity, there appeared to be significant improvement at three months but not at six months. This would suggest that the benefits of intravitreal triamcinolone do not persist long term without retreatments.

A major multicentre trial related to diabetic macular oedema5 of 693 subjects compared effects of treatment of retinal photocoagulation, 4mg triamcinolone and 1mg triamcinolone over a two-year period with retreatment provided for persistent or new oedema at four-month intervals. This indicated that grid photocoagulation was more effective and has fewer side effects than 1mg or 4mg doses of preservative free intravitreal triamcinolone. Intraocular pressure increased from baseline by 10mmHg or more at any visit in 4 per cent, 16 per cent, and 33 per cent of eyes in the three treatment groups, respectively. More significantly, cataract surgery was performed in 13 per cent, 23 per cent, and 51 per cent of eyes in the respective three treatment groups.

A recent study by Cekiç et al6 of intravitreal injection of triamcinolone (17 patients), bevacizumab (Avastin) (14 patients) or combination of triamcinolone-bevacizumab (21 patients) indicated similar therapeutic effects on macular oedema due to branch retinal vein occlusion at one month. Intravitreal injection of bevacizumab (Avastin) was found to yield better results of visual acuity than the others after six months. The study, however, did not monitor changes in intraocular pressure or record other side effects of treatments.

The SCORE CRVO study7 investigated the effect of intravitreal injection of triamcinolone (1mg and 4mg) and observation (no treatment) for central retinal vein occlusion. It was shown that improvement in vision was associated with intraviteral injection although a higher incidence of cataract was identified for the group receiving 4mg triamcinolone injections. The linked SCORE BRVO study8 for treatment of branch retinal vein occlusion undertook comparisons between intravitreal injection of triamcinolone (1mg and 4mg) and retinal photocoagulation. This showed that effectiveness of all three treatments was largely similar though with least side effects of increase in intraocular pressure and development of cataracts for laser photocoagulation. These SCORE studies confirm therefore the option of drugs such as intravitreal injection of triamcinolone for central retinal vein occlusion though laser photocoagulation remains the preferred treatment option for branch retinal vein occlusion.

Slow release drug technology

As part of the process of engineering new techniques for drug delivery, Allergan has developed the Ozurdex product which is a biodegradable implant containing the corticosteroid dexamethasone and which uses Novadur technology. Ozurdex is indicated for the treatment of adult patients with macular oedema following either branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). The action of Ozurdex is to block chemical pathways that lead to inflammation, leakage from the retinal blood vessels and oedema, and in so doing the drug can act to reverse associated vision loss. The drug was approved by the FDA in the US in June 2009 and in May 2010 by the European Medicines Agency.

The implant consists of a solid polymer matrix containing 0.7mg dexamethasone which biodegrades into lactic acid and glycolic acid. The implants are tiny rod-shaped units which are inserted by means of a patented applicator and which are delivered via a 22-gauge needle using a shelved injection technique. The implant is approximately 0.46mm in diameter and 6mm in length. Routine monitoring of intraocular pressure is, however, advised as part of the treatment with Ozurdex.

A recently published study by Haller et al9 reported the results of using Ozurdex in two multicentre, six-month, sham-controlled clinical trials of 1,267 patients with vision loss due to macular oedema associated with either branch or central retinal vein occlusion. It was found that patients showed significant visual improvement at 30 and 90 days compared with the sham group. There was, however, no comparison of Ozurdex treatment with retinal photocoagulation for branch retinal vein occlusion.

Discussion

The technique of sustained Ozurdex drug delivery points the way for drug delivery methods into the retina which reduce the frequency of individual injections and risks to the patient such as serious eye infection (endophthalmitis), eye inflammation, increased eye pressure, and retinal detachments and reducing the general burden of clinical management. This perhaps indicates the beginning of development of a new generation of directly implanted more complex drug delivery devices in the eye and which harness the rapidly expanding potential of nanotechnology. ?

References

1. Karia N Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol, 2010 30(4):809-16.
2. Ip MS, Gottlieb JL, Kahana A, Scott IU, Altaweel MM, Blodi BA, Gangnon RE, Puliafito CA. Intravitreal triamcinolone for the treatment of macular edema associated with central retinal vein occlusion. Arch Ophthalmol, 2004 122(8):1131-6.
3. Cekiç O, Chang S, Tseng JJ, Barile GR, Weissman H, Del Priore LV, Schiff WM, Weiss M, Klancnik JM Jr Intravitreal triamcinolone treatment for macular edema associated with central retinal vein occlusion and hemiretinal vein occlusion. Retina, 2005 25(7):846-50.
4. Yilmaz T, Weaver CD, Gallagher MJ, Cordero-Coma M, Cervantes-Castaneda RA, Klisovic D, Lavaque AJ, Larson RJ. Intravitreal triamcinolone acetonide injection for treatment of refractory diabetic macular edema: a systematic review. Ophthalmology, 2009116(5):902-11.
5. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology, 2008115(9):1447-9.
6. Cekiç O, Cakir M, Yazici AT, Alagöz N, Bozkurt E, Faruk Yilmaz O. A comparison of three different intravitreal treatment modalities of macular edema due to branch retinal vein occlusion. Curr Eye Res, 2010(10):925-9.
7. The SCORE Study Research Group. SCORE Study Report 5. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion. Arch Ophthalmol, 2009127:1101-1114.
8. The SCORE Study Research Group. SCORE Study Report 6. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular oedema secondary to branch retinal vein occlusion. Arch Ophthalmol, 2009127:1115-1128.
9. Haller JA, Bandello F, Belfort R Jr, Blumenkranz MS, Gillies M, Heier J, Loewenstein A, Yoon YH, Jacques ML, Jiao J, Li XY, Whitcup SM 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.

? Dr Douglas Clarkson is development and quality manager at the department of clinical physics and bio-engineering, Coventry and Warwickshire University Hospital Trust