Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: Two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization-verteporfin in photodynamic therapy report 2

PURPOSE: To determine if photodynamic therapy with verteporfin (Visudyne; N ovartis AG, Bulach, Switzerland), termed verteporfin therapy, can safely re duce the risk of vision loss compared with a placebo (with sham treatment) in patients with subfoveal choroidal neovascularization caused by age-relat ed macular degeneration who were identified with a lesion composed of occul t with no classic choroidal neovascularization, or with presumed early onse t classic choroidal neovascularization with good visual acuity letter score , METHODS: This was a double-masked, placebo controlled (sham treatment), ran domized, multicenter clinical trial involving 28 ophthalmology practices in Europe and North America. The study population was patients with age relat ed macular degeneration, with subfoveal choroidal neovascularization lesion s measuring no greater than 5400 mum in greatest linear dimension with eith er 1) occult with no classic choroidal neovascularization, best-corrected v isual acuity score of at least 50 (Snellen equivalent approximately 20/100) , and evidence of hemorrhage or recent disease progression; or 2) evidence of classic choroidal neovascularization with a best-corrected visual acuity score of at least 70 (better than a Snellen equivalent of approximately 20 /40); assigned randomly (2:1) to verteporfin therapy or placebo therapy. Ve rteporfin (6 mg per square meter of body surface area) or placebo (5% dextr ose in water) was administered by means of intravenous infusion of 30 mi ov er 10 minutes. Fifteen minutes after the start of the infusion, a laser lig ht at 689 nm delivered 50 J/cm(2) by application of an intensity of 600 mW/ cm(2) over 83 seconds using a spot size with a diameter 1000 mum larger tha n the greatest linear dimension of the choroidal neovascularization lesion on the retina. At follow-up examinations every 3 months, retreatment with t he same regimen was applied if angiography showed fluorescein leakage. The main outcome measure was at least moderate vision loss, that is, a loss of at least 15 letters (approximately 3 lines), adhering to an intent-to treat analysis with the last observation carried forward to impute for missing d ata. RESULTS: Two hundred ten (93%) and 193 (86%) of the 225 patients in the ver teporfin group compared with 104 (91%) and 99 (87%) of the 114 patients in the placebo group completed the month 12 and 24 examinations, respectively. On average, verteporfin-treated patients received five treatments over the 24 months of follow-up. The primary outcome was similar for the verteporfi n-treated and the placebo-treated eyes through the month 12 examination, al though a number of secondary visual and angiographic outcomes significantly favored the verteporfin-treated group. Between the month 12 and 24 examina tions, the treatment benefit grew so that by the month 24 examination, the vertepor-fin-treated eyes were less likely to have moderate or severe visio n loss. Of the 225 verteporfin-treated patients, 121 (54%) compared with 76 (67%) of 114 placebo-treated patients lost at least 15 letters (P =.023). Likewise, 61 of the verteporfin-treated patients (30%) compared with 54 of the placebo-treated patients (47%) lost at least 30 letters (P = .001). Sta tistically significant results favoring verteporfin therapy at the month 24 examination were consistent between the total population and the subgroup of patients with a baseline lesion composition identified as occult choroid al neovascularization with no classic choroidal neovascularization, This su bgroup included 166 of the 225 verteporfin-treated patients (74%) and 92 of the 114 placebo-treated patients (81%). In these patients, 91 of the verte porfin-treated group (55%) compared with 63 of the placebo-treated group (6 8%) lost at least 15 letters (P =.032), whereas 48 of the verteporfin-treat ed group (29%) and 43 of the placebo-treated group (47%) lost at least 30 l etters (P =.004). Other secondary outcomes, including visual acuity letter score worse than 34 (approximate Snellen equivalent of 20/200 or worse), me an change in visual acuity letter score, development of classic choroidal n eovascularization, progression of classic choroidal neovascularization and size of lesion, favored the verteporfin-treated group at both the month 12 and month 24 examination for both the entire study group and the subgroup o f cases with occult with no classic choroidal neovascularization at baselin e. Subgroup analyses of lesions composed of occult with no classic choroida l neovascularization at baseline suggested that the treatment benefit was g reater for patients with either smaller lesions (4 disc areas or less) or l ower levels of visual acuity (letter score less than 65, an approximate Sne llen equivalent of 20/50(-1) or worse) at baseline. Prospectively planned m ultivariable analyses confirmed that these two baseline variables affected the magnitude of treatment benefit. Of the 123 verteporfin-treated patients and 64 placebo-heated patients with either visual acuity score Less than 6 5 or lesion size 4 disc areas or less at baseline, 60 (49%) and 48 (75%) lo st at least 15 letters (P < .001), respectively, and 26 (21%) and 31 (48%) lost at least 30 letters (P <.001), respectively, at the month 24 examinati on. Conversely, treatment may not be beneficial for patients with both larg er lesions and good visual acuity (both greater than 4 disc areas and lette r score 65 or greater, an approximate Snellen equivalent of 20/50 or better ). With respect to safety for the entire study group, 10 of 225 verteportin -treated patients (4. 4%) and none of the placebo-treated patients had a severe decrease of visio n (at least 20 letters compared with the visual acuity just before the trea tment) within 7 days after treatment, judged to be the result of the develo pment of subretinal pigment epithelial blood, marked subretinal fluid assoc iated with choroidal hypofluorescence, or no obvious cause. Five of these 1 0 patients had recovery of vision to less than a 20-letter loss compared wi th the pretreatment vision score at 3 months after this event. Photosensiti vity reactions occurred in only one patient in each group. CONCLUSIONS: In this trial of patients with agerelated macular degeneration and subfoveal choroidal neovascularisation lesions composed of occult with no classic choroidal neovascularization, verteporfin therapy significantly reduced the risk of moderate and severe visual acuity loss. Subgroup analy ses suggest that a greater benefit was achieved in patients presenting with either smaller lesions (4 disc areas or less) or lower levels of visual ac uity (letter score less than 65, an approximate Snellen equivalent of 20/50 (-1) or less). The Verteporfin In Photodynamic Therapy Study Group recommen ds that this therapy should be considered for the treatment of patients wit h age-related macular degeneration with subfoveal lesions composed of occul t with no classic choroidal neovascularization who are presumed to have rec ent disease progression. Patients to be treated should be aware of a small (4%) risk of acute, severe vision decrease.<(c)> 2001 by Elsevier Science I nc. All rights reserved.).