A decade ago, no pharmacologic treatments for exudative age-related macular degeneration (AMD) were available. Since 2000, several such treatments have appeared and have been widely adopted by retinal specialists. Photodynamic therapy (PDT) with verteporfin (Visudyne, Novartis AG) was the first pharmacologic treatment for wet AMD to receive regulatory approval. Its approval was followed by two vascular endothelial growth factor (VEGF) inhibitors formulated for intravitreal injection: pegaptanib (Macugen, OSI/Eyetech) and ranibizumab (Lucentis, Genentech). In addition to these approved therapies, another anti-VEGF agent, bevacizumab (Avastin, Genentech) is now widely used off-label in a manner similar to ranibizumab.
In two prospective clinical trials, monthly administration of ranibizumab was shown to improve vision by 6.6 and 11.3 letters on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart at 12 months.1,2 In another trial, three monthly doses of ranibizumab followed by less frequent, quarterly injections produced less robust visual gains at 1 year.3
Although monthly injection of ranibizumab appears to be the most efficacious administration schedule, frequent visits to the retina specialist put heavy demands on elderly patients, increase traffic in the clinician's office, and present a risk of infection at every visit, as well as the theoretical risk of systemic VEGF inhibition. It would be desirable to have a longer-lasting treatment for neovascular AMD that is equal in efficacy to monthly ranibizumab.
To this end, interest has recently grown in combining verteporfin PDT with injection of a VEGF inhibitor in a single treatment session. Verteporfin PDT on a quarterly injection schedule was shown to be effective in improving visual outcomes in patients with choroidal neovascularization (CNV) in AMD.4 Because full-fluence PDT can cause a transient decrease in vision, a reduced-fluence treatment was evaluated and found to be equally effective and as safe as full-fluence in patients with minimally classic CNV in AMD.5
Recently, a number of investigators have evaluated various combinations of PDT and anti-VEGF agents.6-12 Combination therapies take advantage of the different mechanisms of action of the two treatments and the fact that they work on different aspects of CNV; PDT treats existing vasculature, while anti-VEGF agents inhibit new vessel growth. Because PDT causes inflammation, some of these investigators have also included intravitreal steroids as part of double or triple combination therapies.
SAME-DAY TRIPLE THERAPY
To the best of our knowledge, no one has previously reported results with a triple combination of reduced-fluence verteporfin PDT and intravitreal bevacizumab and dexamethasone, administered in the office in the same treatment session. We retrospectively evaluated results in 31 patients treated with this regimen and with at least 1 year follow-up.13
In this triple-therapy procedure, the patient first underwent reduced-fluence PDT, with the full 83 seconds of laser exposure but half the standard fluence: 300 mW/cm², for a total light dose of 25 J/cm². After PDT, the patient was prepared for intravitreal injection with application of topical anesthesia and povidone-iodine. Dexamethasone 200 µg (0.05 cc) and bevacizumab 1.25 mg (0.05 cc) were injected intravitreally with separate needles for each drug.
Snellen visual acuity was measured and converted to logMAR for calculation purposes. Central macular thickness (CMT) was measured with optical coherence tomography (OCT).
Patients were followed at 1- or 2-month intervals at the discretion of the physician. Criteria for retreatment were the appearance of subretinal fluid or intraretinal edema on OCT.
RESULTS AND CONCLUSIONS
Thirty-one patients with subfoveal CNV were treated with same-day, in-office triple therapy. Mean follow-up was 13.7 months. The mean greatest linear diameter of the CNV lesion at baseline, as measured on fluorescein angiography, was 3.9 mm.
Mean baseline visual acuity was 0.61 logMAR (20/80), and mean vision on final follow-up was 0.58 (20/60) (P=.69). Mean baseline CMT was 293 µm at baseline and 245 µm at final follow-up (P=.053).
A mean of 1.7 anti-VEGF injections and 0.2 triple-therapy retreatments were given in the first 6 months, and a mean 2.3 anti-VEGF injections and 0.3 triple-therapy retreatments were given through final follow-up.
No increases in intraocular pressure or occurrences of endophthalmitis were seen in the course of follow-up.
Our goal in designing this triple therapy regimen was to offer a procedure that can be performed in one session with a minimally invasive technique (requiring no vitrectomy or paracentesis). We used dexamethasone instead of triamcinolone because of its shorter residence time in the eye. We hoped to blunt the inflammation caused by PDT but avoid side effects of long-term steroid use such as ocular hypertension and cataract. Bevacizumab was used because ranibizumab was not approved at the time we started performing the procedure. Additionally, bevacizumab lasts longer in the eye,14,15 and its use reduces the cost of triple therapy compared with use of ranibizumab.
Same-day triple therapy in this retrospective study provided some promising outcomes: No adverse events were seen, mean visual acuity remained stable or improved, and CMT decreased, although the difference in CMT from baseline was not statistically significant at 1 year.
This was a "real-world" study, not a controlled clinical trial. While it is difficult to compare such different studies, the mean visual acuity improvement of two Snellen lines seen in this study was similar to the one to two lines of ETDRS vision improvement seen in the randomized trials of monthly ranibizumab monotherapy.1,2 This suggests that same-day triple therapy may be a promising approach to treatment of CNV in AMD, at least in the short term. Longer and larger trials are needed to assess the visual outcomes of triple therapy and to optimize the doses of steroid and anti-VEGF agent and the fluence of PDT. Triple therapy appears to be useful in the management of selected patients with neovascular AMD.
Sophie J. Bakri, MD, is an Assistant Professor of Ophthalmology in the Department of Vitreoretinal Diseases and Surgery at the Mayo Clinic in Rochester, MN. Dr. Bakri states that she has served on advisory boards for Genentech and Novartis. She may be reached at sbakri@hotmail.com.
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