Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy

TY - JOUR

T1 - Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy

T2 - Results from a Randomized Clinical Trial

AU - Schaub, Friederike

AU - Schiller, Petra

AU - Hoerster, Robert

AU - Kraus, Daria

AU - Holz, Frank G

AU - Guthoff, Rainer

AU - Agostini, Hansjürgen

AU - Spitzer, Martin S

AU - Wiedemann, Peter

AU - Lommatzsch, Albrecht

AU - Boden, Karl T

AU - Dimopoulos, Spyridon

AU - Bemme, Sebastian

AU - Tamm, Svenja

AU - Maier, Mathias

AU - Roider, Johann

AU - Enders, Philip

AU - Altay, Lebriz

AU - Fauser, Sascha

AU - Kirchhof, Bernd

AU - PRIVENT Study Group

N1 - Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

PY - 2022/10

Y1 - 2022/10

N2 - 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.

AB - 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.

KW - Dalteparin/therapeutic use

KW - Double-Blind Method

KW - Fluorouracil

KW - Heparin/therapeutic use

KW - Heparin, Low-Molecular-Weight/therapeutic use

KW - Humans

KW - Retinal Detachment/surgery

KW - Vitrectomy/adverse effects

KW - Vitreoretinopathy, Proliferative/drug therapy

U2 - 10.1016/j.ophtha.2022.05.024

DO - 10.1016/j.ophtha.2022.05.024

M3 - SCORING: Journal article

C2 - 35680097

VL - 129

SP - 1129

EP - 1141

JO - OPHTHALMOLOGY

JF - OPHTHALMOLOGY

SN - 0161-6420

IS - 10

ER -