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

Ophthalmology. 2022 Oct;129(10):1129-1141. doi: 10.1016/j.ophtha.2022.05.024. Epub 2022 Jun 7.


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.

Keywords: Complication; Proliferative vitreoretinopathy; Prophylaxis; Retinal detachment; Vitrectomy.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dalteparin / therapeutic use
  • Double-Blind Method
  • Fluorouracil
  • Heparin / therapeutic use
  • Heparin, Low-Molecular-Weight / therapeutic use
  • Humans
  • Retinal Detachment* / surgery
  • Vitrectomy / adverse effects
  • Vitreoretinopathy, Proliferative* / drug therapy
  • Vitreoretinopathy, Proliferative* / etiology
  • Vitreoretinopathy, Proliferative* / prevention & control


  • Heparin, Low-Molecular-Weight
  • Heparin
  • Dalteparin
  • Fluorouracil