Friederike Schaub1, Petra Schiller2, Robert Hoerster3, Daria Kraus4, Frank G Holz5, Rainer Guthoff6, Hansjürgen Agostini7, Martin S Spitzer8, Peter Wiedemann9, Albrecht Lommatzsch10, Karl T Boden11, Spyridon Dimopoulos12, Sebastian Bemme13, Svenja Tamm14, Mathias Maier15, Johann Roider16, Philip Enders17, Lebriz Altay17, Sascha Fauser18, Bernd Kirchhof17. 1. Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. Electronic address: friederike.schaub@uk-koeln.de. 2. Faculty of Medicine, Institute of Medical Statistics and Computational Biology, University of Cologne, Cologne, Germany. 3. MVZ Augenärztliches Diagnostik- und Therapiecentrum (ADTC) Mönchengladbach/Erkelenz GmbH, Erkelenz, Germany. 4. Clinical Trials Center Cologne, Cologne, Germany. 5. Department of Ophthalmology, University of Bonn, Bonn, Germany. 6. Department of Ophthalmology, Faculty of Medicine, University of Düsseldorf, Düsseldorf, Germany. 7. Eye Center, Albert-Ludwigs-University of Freiburg, Freiburg, Germany. 8. Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 9. Department of Ophthalmology, University of Leipzig, Leipzig, Germany. 10. Department of Ophthalmology, Franziskus Hospital, Münster, Germany. 11. Eye Clinic Sulzbach, Knappschaft Hospital Saar, Sulzbach, Germany. 12. Center of Ophthalmology, University Eye Hospital Tübingen, Tübingen, Germany. 13. Department of Ophthalmology, University Medical Center Göttingen, Göttingen, Germany. 14. Department of Ophthalmology, University of Regensburg, Regensburg, Germany. 15. Department of Ophthalmology, Technical University Munich (TUM), Munich, Germany. 16. Department of Ophthalmology, University of Kiel, Kiel, Germany. 17. Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. 18. F. Hofmann-La Roche AG, Basel, Switzerland.
Abstract
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.
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.