Steroids for CNV/AMD: Injecting some caution into the discussion

ByAndrew P. Schachat, MD

Although many treatment options are available for patients with age-related macular degeneration, none works as well as ophthalmologists would like; most stabilize vision, but improvements in visual acuity are uncommon and minimal. The supplements used in the Age-Related Eye Disease Study, comprised of vitamins C and E, beta carotene, zinc and copper, reduced the risk of developing advanced AMD in one-quarter to one-third of patients in the study when used prophylactically.¹ In the search for better treatments, physicians are turning to intravitreal triamcinolone, but this off-label use for AMD treatment is a mix of unmet need and uncertain evidence.

Lack of evidence-based argument for treatment with steroids

Evidence-based medicine is the integration of the best research evidence with clinical expertise and consideration of patient values; essentially, taking valid study results and applying them to the individual patient in the office. Most studies on the use of intravitreal steroids for the treatment of AMD are characterized by short follow-up, retrospective study design and a lack of concurrent controls or good comparison groups. Level one evidence, or evidence from at least one properly conducted, well-designed, randomized controlled trial with a reasonable sample size and duration of follow-up or a meta-analysis of randomized controlled trials, in support of using intravitreal triamcinolone does not exist.

Rationale vs. actual efficacy and safety issues

Evidence suggests that steroids have strong anti-permeability and antiangiogenic effects, induce antiangiogenic activity and inhibit vascular endothelial growth factor (VEGF)-induced activities.^2,3

Jeffrey Edelman, PhD, and colleagues conducted a study to examine the effects of triamcinolone acetonide and dexamethasone in a rabbit model.²When administered systemically for 3 days, dexamethasone completely blocked VEGF-induced blood-retinal and blood-aqueous barrier breakdown, according to the study. Additionally, a 2-mg intravitreal dose of triamcinolone acetonide demonstrated complete blockage of VEGF-induced retinal and iris leakage for 45 days.

In another study, H. Logan Brooks, Jr, MD, and colleagues found that triamcinolone significantly reduced VEGF and chemokine stromal-derived factor 1, a stimulator of VEGF expression.³ In addition, diffuse macular edema was eliminated and active neovascularization regressed.

Infection is more common in patients treated with intravitreal triamcinolone than with other treatments.
– Andrew P. Schachat, MD

Despite this rationale, a number of safety issues exist. Infection is more common in patients treated with intravitreal triamcinolone than with other treatments.⁴ In addition, case series typically reveal that about 40% of triamcinolone-treated patients develop cataract and 30% develop glaucoma, with 1% requiring filtering surgery.

In addition to these safety concerns, there is a lack of data proving long-term efficacy. In one study of 187 patients, 115 of whom were treated with 25 mg triamcinolone acetonide, visual acuity increased in triamcinolone-treated patients and decreased in the control group at 1 and 3 months.⁵ Visual acuity increased by two or more lines in 37.4% of the triamcinolone-treated patients.⁵ However, in another study of 205 patients, visual acuity measurements taken at 1 month, 2 months and 3 months post-injection were not significantly different from baseline, and measurements taken at 6 months, 9 months and 12 months post-injection were significantly lower than baseline,⁶ indicating no long-term efficacy.

In a randomized, controlled study of a single dose of intravitreal triamcinolone, no effect on the risk of the loss of visual acuity was shown during the first year posttreatment, despite a significant antiangiogenic effect at 3 months.⁷

Because AMD is a chronic disease, the early benefits seen with steroids cannot be sustained without chronic steroid treatment.

Intravitreal triamcinolone and photodynamic therapy

Intravitreal triamcinolone administered early in the course of photodynamic therapy may achieve better patient outcomes by suppressing VEGF chronically, according to new data. The initial reports by Richard Spaide, MD, indicated improved visual acuity at 6 months and 1 year, but the study was conducted without a control group.^8,9

Because AMD is a chronic disease, the early benefits seen with steroids cannot be sustained without chronic steroid treatment.
– Andrew P. Schachat, MD

In a prospective case series of 184 patients treated with 25 mg intravitreal triamcinolone administered 16 hours post-PDT, a mean increase of 1.2 lines of visual acuity was noted with a mean number of treatments of 1.2 or 1.3.¹⁰ PDT alone would typically require three treatments. However, a number of adverse events were also reported: 25% of these patients required treatment for high IOP, 1% required filtering surgery for the treatment of glaucoma and a significant number had cataract progression. In addition, it is unclear whether the improvement in visual acuity was associated with the removal of cataracts. The study had a short follow-up and no control group.¹⁰

Although a synergistic effect between PDT and intravitreal triamcinolone may exist,¹¹ further evidence and randomized, controlled studies are needed to determine efficacy.

Conclusion

Monotherapy with intravitreal triamcinolone has not been proven efficacious in controlling CNV in patients with AMD, and any antiangiogenic effects do not appear to last beyond a few months. Safety concerns are numerous with intravitreal triamcinolone. Although intravitreal triamcinolone used in conjunction with PDT shows promise in uncontrolled studies, further evidence is needed before ophthalmologists can safely consider it as treatment for patients with CNV associated with AMD.

References
Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. Arch Ophthalmol. 2001;119:1417-1436.
Edelman JL, Lutz D, Castro MR. Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown. Exp Eye Res. 2005;80(2):248-258.
Brooks HL Jr., Caballero S Jr., Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Opthalmol. 2004;122(12):1801-1807.
Ozkiris A, Erkilic K. Complications of intravitreal injection of triamcinolone acetonide. Can J Ophthalmol. 2005;40(1):63-68.
Jonas JB, Degenring RF, Kreissig I, et al. Exudative age-related macular degeneration treated by intravitreal triamcinolone acetonide. A prospective comparative nonrandomized study. Eye. 2005;19:163-170.
Jonas JB, Spandau UH, Kamppeter BA, Harder B. Follow-up after intravitreal triamcinolone acetonide for exudative age-related macular degeneration. Eye[Epub ahead of print]. 2006; January 13, 2006. Available at: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract
&list_uids=16410809&query_hl=22&itool=pubmed_docsum. Last accessed February 28, 2006.

Gillies MC, Simpson JM, Luo W, et al. A randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: One-year results. Arch Ophthalmol. 2003;121:667-673.
Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2003;110:1517-1525.
Spaide RF, Sorenson J, Mranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2005;112:301-304.
Augustin AJ, Schmidt-Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone in all types of choroidal neovascularization due to age-related macular degeneration. Ophthalmology. 2006;113(1):14-22.
Kaiser PK. Verteporfin therapy in combination with triamcinolone: Published studies investigating a potential synergistic effect. Curr Med Res Opin. 2005;21(5):705-713.