Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

Prophylactic intravitreal 5-fluorouracil and heparin to prevent proliferative vitreoretinopathy in high-risk patients with retinal detachment: study protocol for a randomized controlled trial.

BACKGROUND: Proliferative vitreoretinopathy (PVR) is the major cause for postoperative failure after vitreo-retinal surgery for primary rhegmatogenous retinal detachment (RRD). Adjunct pharmaceutical therapy was found to be ineffective once PVR is established. Preliminary data suggest that prevention of PVR yields better functional outcome. So far, there is no standard therapy to prevent PVR. METHODS/DESIGN: This is a randomized, double-blind, controlled, multicenter, interventional trial with one interim analysis. High-risk patients for PVR with primary RRD will be allocated equally to the following treatment arms: (a) verum: intraoperative adjuvant application of 5-fluorouracil (5-FU) and low-molecular-weight heparin (LMWH) via intraocular infusion during routine pars plana vitrectomy (PPV) and (b) placebo: routinely used intraocular infusion with balanced salt solution during routine PPV. PVR risk is assessed by non-invasive aqueous flare measurement by using laser flare photometry. The primary endpoint of the trial is the occurrence of PVR grade CP (C: full-thickness retinal folds or subretinal strands in clock hours; P: located posterior to equator) 1 or higher within 12 weeks after treatment. Secondary endpoints include PVR grade CA (A: located anterior to equator), best corrected visual acuity, number and extent of surgical procedures to achieve retinal re-attachment, and occurrence of drug-related adverse events within 12 weeks. It is assumed, on the basis of previously published results, that the incidence of PVR grade CP 1 is 35% in the control group and that a reduction by one third would be clinically relevant. Given the sequential design and adjustment for a dropout rate of 5%, a total sample size of 560 patients (280 per group) was calculated to ensure a power of 80% for the confirmatory analysis. DISCUSSION: The present trial uses intraoperative intravitreal 5-FU and LMWH as a prophylactic therapy in high-risk patients with primary RRD, aiming to reduce the incidence of PVR in the group that receives the trial drug. Using laser flare photometry to identify high-risk patients for PVR, this trial will test the effectiveness of a simple treatment to prevent PVR. TRIAL REGISTRATION: EudraCT no.: 2015-004731-12, registered October 21, 2015; ClinicalTrials.gov Identifier: NCT02834559 , registered July 12, 2016. Protocol version: Version 02. Date: September 18, 2016.

[Prevention of proliferative vitreoretinopathy using 5-FU heparin: clinical tolerance and efficacy]. / Evaluation clinique de 5FU-héparine dans la prévention de la prolifération vitréorétinienne.

PURPOSE: To study the safety and efficacy of adjuvant combination therapy using 5-fluorouracil and heparin for prevention of proliferative vitreoretinopathy (PVR) during vitrectomy for retinal detachment surgery. METHODS: Two consecutive groups of 30 eyes with a rhegmatogenous retinal detachment (grade C1 or more) were prospectively compared. In the study group, 5-FU and heparin were administrated in the intraoperative infusion. Clinical safety and the efficacy were regularly studied over 1 year. RESULTS: In the 5-FU heparin therapy group, keratitis was more frequently observed the 1st day after surgery (p = 0.005), but not after 1 week (p = 0.54). However, conjunctival hyperemia was more severe after 1 and 7 days (p = 0.04). In both groups, no differences were found concerning intraocular pressure, postoperative hemorrhage or inflammatory reaction (flare) of the anterior chamber and the aspect of the eyelids (p > or = 0.14). The number of reoperations resulting from PVR, after 1 month and 1 year, was not significantly different between the two groups (p > or = 0.3). The reattachment rate and visual acuity (BSCVA) were not statistically different after 1 year (p > or = 0.12). CONCLUSION: Adjuvant combination therapy using 5-FU and heparin seems to be safe. However, its efficacy needs to be demonstrated by larger studies including eyes presenting a lower grade of PVR (grade B).

[Progressing myopia in children: does it need treatment or not?].

The purpose of the case study was to evaluate the remote consequences of a complex of laser and repeated surgical sclerorestorative procedures made in progressing myopia and its complications. Three hundred and forty-six children, aged 8-10, with rapidly progressing uncomplicated myopia of 4.25 to 9.5 D were shared between 2 groups. Two hundred and forty patients of the experimental group were made sclerorestorative procedures and transscleral low-energy laser stimulation of the ciliary muscle by means of infrared laser MACDEL-09. No such treatment was applied to patients of the control group. When indicated, preventive laser coagulation of the retina was made in both groups. The dynamic 10-year follow-up over the status of refraction and eye bottom showed that the complex scheme of repeated sclerorestorative procedures and low-energy laser treatment combined with preventive peripheral laser coagulation of the retina cut the rate of progressing myopia and prevented peripheral vitreoretinal dystrophy and retinal detachment in children and teenagers with progressing myopia.

Case selection in macular relocation surgery for age related macular degeneration.

BACKGROUND: To date there has been no randomised controlled trial demonstrating the safety and efficacy of macular relocation surgery (MRS) for age related macular degeneration (AMD). Vision can be improved in some patients and made worse in others despite successful surgery or because of complications. PURPOSE: To determine which patients would benefit from MRS. METHODS: Twenty nine patients with exudative AMD took part in a prospective, non-comparative, interventional study. Macular relocation surgery involved phacoemulsification, vitrectomy, 360 degrees retinotomy, excision of choroidal neovascular membrane, and macular relocation using an infusion of 5-fluorouracil and low molecular weight heparin as adjuvant to prevent proliferative vitreoretinopathy. Patients underwent protocol refraction preoperatively and six-monthly postoperatively by designated optometrists. Preoperative fundus fluorescein angiograms were read by masked observers and the lesions were classified according to a set protocol. The main outcome measures were visual improvement, final vision of better than 20/400, reading speed, critical print size. Logistic and multiple stepwise linear regressions were used to identify independent factors which predicted the main outcomes. RESULTS: Preoperative visual acuity (20/120 or worse) and lesion type (predominantly classic or submacular haemorrhage) were significantly associated with visual improvement (coefficient of regression B = 26.8, p<0.001 and B = 14.9 with p = 0.045 respectively). There were no significant independent factors which predicted a final distance logMAR visual acuity of 1.3 (20/400) or any arbitrary definition of blindness. CONCLUSIONS: The study showed that it was possible to select cases that were more likely to experience an improvement in vision following MRS.

Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy : Results from a randomized, double-blind, controlled clinical trial.

PURPOSE: To assess the safety and efficacy of adjuvant combination therapy using 5-fluorouracil (5-FU) and low molecular weight heparin (LMWH) for prevention of proliferative vitreoretinopathy (PVR) after vitrectomy and retinal reattachment surgery. DESIGN: Prospective randomized, double-masked, placebo controlled trial. PARTICIPANTS: One hundred seventy-four high-risk patients were randomized to receive either 5-FU and LMWH therapy or placebo. Patients were selected from all patients undergoing primary vitrectomy for rhegmatogenous retinal detachment. METHOD: Results of standard surgery with 5-FU and LMWH therapy or placebo were compared at the 6-month follow-up. MAIN OUTCOME MEASURES: Development of postoperative PVR, retinal reattachment at 6 months after surgery, single operation reattachment rate, number of reoperations, and best-corrected visual acuity. RESULTS: There were 87 patients in the 5-FU and LMWH therapy group and 87 in the placebo group. The incidence of postoperative PVR was significantly lower (P = 0.02) in the 5-FU and LMWH therapy compared with the placebo group. In 26.4% (23/87) of the placebo group and in 12.6% (11/87) of the 5-FU and LMWH group, postoperative PVR developed. In the 5-FU and LMWH group, the number of patients undergoing more than one operation was 19.5% (17/87) and the number of reoperations resulting from PVR was 52.9% (9/17). In the placebo group, the number of patients undergoing more than one operation was 25.3% (22/87) and the number of reoperations resulting from PVR was 72.7% (16/22). The difference in visual acuity was not statistically different in the two treatment groups, although those patients in whom postoperative PVR developed tended to have poorer vision (P < 0.0001). There were no differences in complication rates between the two groups. CONCLUSIONS: There is a significant reduction in the incidence of postoperative PVR in patients receiving the 5-FU and LMWH therapy and in the reoperation rate resulting from PVR. This trial shows that incidence of PVR can be reduced with inexpensive and simple pharmacologic treatment with 5-FU and LMWH and should be used routinely in the treatment of patients at risk of developing PVR.