Randomized Controlled Trial of Combined 5-Fluorouracil and Low-Molecular-Weight Heparin in the Management of Unselected Rhegmatogenous Retinal Detachments Undergoing Primary Vitrectomy

doi:10.1016/j.ophtha.2006.08.042

Ophthalmology

Volume 114, Issue 4, April 2007, Pages 698-704

https://doi.org/10.1016/j.ophtha.2006.08.042 Get rights and content

Objective

To determine the efficacy of a combination of 5-fluorouracil (5FU) and low-molecular-weight heparin (LMWH) in the treatment of unselected rhegmatogenous retinal detachment (RRD) undergoing primary vitrectomy.

Design

Double-masked, prospective, randomized, placebo-controlled clinical trial.

Participants

Six hundred forty-one patients presenting with primary RRD were recruited from 2 specialized vitreoretinal units—Moorfields Eye Hospital, London (n = 553) and St. Pauls Eye Unit, Liverpool (n = 88).

Intervention

All patients underwent primary vitrectomy and gas endotamponade. Adjuvant therapy in the treatment group consisted of 5 IU/ml LMWH and 200 μg/ml 5FU added to the perioperative infusion fluid.

Main Outcome Measures

The primary outcome measure was retinal reattachment after primary vitrectomy without any reoperations at 6 months. Secondary outcome measures recorded at 6 months were the occurrence and grade of proliferative vitreoretinopathy (PVR), best-corrected visual acuity in logarithm of the minimum angle of resolution, intraocular pressure (mmHg), corneal clarity, and complications.

Results

The overall primary success rate was 84.4%; in the treatment group, the primary success rate was 82.3% compared with 86.8% in the placebo group (P = 0.12). At 6 months, the final complete anatomical reattachment rate was 97.9% in both treatment and placebo groups. The number of patients who failed due to the development of PVR was not statistically significant, 23 in the treatment group (7.0%) and 14 in the placebo group (4.9%) (P = 0.309). There was no significant difference in the mean visual acuity at 6 months in the placebo group (0.48) versus the treatment group (0.53; P = 0.072). The visual acuity at 6 months of patients presenting with a macula-sparing retinal detachment was significantly worse in the treatment group (P = 0.0091). There was no significant difference between the 2 groups in patients who presented with a macula involving retinal detachment (P = 0.896).

Conclusions

Primary vitrectomy has a high anatomic and visual success rate for RRD. Adjuvant therapy with 5FU and LMWH does not improve the anatomic or visual success rate of unselected primary retinal detachments undergoing vitrectomy. After adjuvant therapy, a worse visual outcome was observed in patients presenting with macula-sparing retinal detachments. A combination of 5FU and LMWH should not be used routinely for primary RRD surgery.

Section snippets

Materials and Methods

Patients were recruited who had a rhegmatogenous retinal detachment to be managed by primary vitrectomy with intraocular gas tamponade, to include males over 16 years of age and postmenopausal women. The leading indications for primary vitrectomy surgery included retinal detachment with a posterior vitreous detachment owing to superior posterior, multiple, or tractional retinal breaks, pseudophakia, and/or an inadequate view of the fundus, for example, secondary to vitreous hemorrhage. Eyes

Results

Six hundred forty-one patients were recruited from 2 specialized vitreoretinal units—Moorfields Eye Hospital, London (n = 553) and St. Pauls Eye Unit, Liverpool (n = 88) between February 2001 and January 2005. Of the 641 patients who were recruited, 342 were randomly assigned to the treatment group and 299 to the placebo group. Figure 1 documents the progress of patients through the trial.

The baseline characteristics of the 2 groups were similar and are presented in Table 1. The mean age of

Discussion

The overall primary anatomic success rate of retinal detachment surgery in this study was 84.4%. At 6 months, the complete reattachment rate was 97.9% and the macular attachment rate was 99.7%. These results compare favorably with current published data1, 2, 5, 7, 21 and are consistent with that seen in specialist units.²¹ Recruitment of patients for this trial reflects the current management of retinal detachment in the 2 units involved: 70% to 80% of primary rhegmatogenous retinal detachments

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Clinical therapeutics for proliferative vitreoretinopathy in retinal detachment
2024, Survey of Ophthalmology
Proliferative vitreoretinopathy (PVR) is an abnormal and prolonged healing response to retinal injury (retinal detachment, post retinal detachment surgery) characterised by: pre/subretinal membrane formation; retinal gliosis and retinal shortening, retinal pigment epithelium cell proliferation; and increased glial (mainly Mu¨ller cells), fibroblast and inflammatory cell (macrophage, lymphocyte) activity, leading to tractional retinal holes/breaks and multiple costly eye operations suffered by patients. PVR can cause retinal re-detachment following primary surgical intervention for rhegmatogenous retinal detachment. Vitrectomy and scleral buckling surgery are the main approaches for treating PVR complications of retinal detachment. Patients require many operations to remove the scar tissue but vision results are suboptimal, and do not meet patient expectations. Over the past 40 years, this has been one of the greatest challenges for vitreoretinal surgeons and patients. Despite previous large clinical trials of multiple candidate drug therapeutics, no proven adjunctive treatment currently exists to either prevent, reduce, or treat PVR formation in retinal detachment. Both cellular proliferation and the intraocular inflammatory response are realistic targets for adjunctive treatments in PVR. The cellular components of PVR periretinal membranes (retinal pigment epithelial, glial, inflammatory and fibroblastic cells) proliferate and are thus targets for antiproliferative agents. In recent years, several new therapeutics have been tested, and we present an updated review of the clinical therapeutics for PVR in retinal detachment.
Association of Cutaneous Keloids, Hypertrophic Scarring, and Fibrosis with Risk of Postoperative Proliferative Vitreoretinopathy
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To assess an association between cutaneous keloids, hypertrophic scarring, and fibrosis (KHF) and risk of postoperative proliferative vitreoretinopathy (PVR) after rhegmatogenous retinal detachment (RRD) repair.
Retrospective, population-based cohort study.
Patients aged ≥ 18 years who underwent initial retinal detachment (RD) repair with pars plana vitrectomy with or without scleral buckle (SB) (Current Procedural Terminology [CPT] 67108), pneumatic retinopexy (67110), and primary SB (67107) from January 1, 2003, to March 1, 2023.
A de-identified electronic health record database through TriNetX, a global health research network, was used to analyze patients. Patients were queried for International Classification of Diseases, 10^th Revision (ICD-10) codes L91.0 (hypertrophic scar) and L90.5 (scar conditions and fibrosis of skin). Frequency of subsequent diagnosis of PVR (H35.2) and CPT codes for secondary surgery including complex RD repair (67113) were determined. Patients with proliferative diabetic retinopathy (PDR) (ICD-10 H10.35/H11.35) were excluded. Descriptive statistics (Z-test) and propensity score matching (PSM) were used to match for age, sex, and race.
Prevalence of H35.2 and CPT 67113 within 180 days after RRD repair in the KHF cohort versus the non-KHF cohort.
Among patients with CPT 67108, 1061 in each cohort (KHF and non-KHF) were analyzed after PSM. The mean (standard deviation) age was 60.7 (15.2) years. Within 180 days, 10.1% of patients in the KHF cohort and 3.4% in the non-KHF cohort had a diagnosis of PVR (H35.2) (P < 0.001, odds ratio [OR], 3.2; 95% confidence interval [CI], 2.13–4.71). A total of 8.3% of patients in the KHF cohort and 5.4% of patients in the non-KHF cohort underwent complex RD repair (CPT 67113) (P = 0.008; OR, 3.2; 95% CI, 1.13–2.25). When including all RD repair types (CPT 67108, 67110, 67107), the rate of PVR diagnosis was still significantly greater in the KHF cohort than in the non-KHF cohort (9.0% vs 4.2%, P < 0.01; OR, 2.28; 95% CI, 1.64–3.16).
A dermatologic history of KHF may be a risk factor for PVR after RD repair.
Proprietary or commercial disclosure may be found after the references.
Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial
2022, Ophthalmology
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.
Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis.
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.
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.
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.
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.
Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.
Controlled release of triamcinolone from an episcleral micro film delivery system for open-globe eye injuries and proliferative vitreoretinopathy
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Citation Excerpt :
At present, there is no effective drug formulation or device available to manage the prevention of PVR in open globe trauma [33]. Several high-profile therapeutics in sustained release system have been experimentally evaluated in animal models with some success [26,30,34], however, the results from clinical trials without a delivery system have been dismal [35–37]. We hypothesize that the poor results from clinical studies may be attributed to a lack of a controlled release [26,38].
Open globe trauma is the major cause for single eye blindness that stem from subsequent proliferative vitreoretinopathy (PVR). Though biomaterials and tissue engineering have significantly advanced drug delivery and management of human diseases, currently there is no effective drug formulation or device to pharmacologically mitigate PVR formation after open-globe eye trauma. This highlighted the challenge we are facing to bring the technology from bench to bedside. The current study reported an engineered episcleral drug film using biodegradable material, Poly(L-lactide)-co-poly(ɛ-caprolactone), and triamcinolone acetonide (TA) as a model drug. The film can be conveniently sized into any shape to fit the configuration of the eye globe trauma and easily installed onto the ruptured sclera during primary trauma repair surgery. The film allows therapeutic TA to slow release for at least 6 months without toxicity and demonstrated a significant benefit to reduce the odds of developing severe PVR by 5.7 times when compared with a no-drug film control on a rabbit trauma PVR model. Our results suggested this micro episcleral drug film as promising drug delivery carrier for the targeted treatment of various unwanted retinal proliferation diseases.
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View all citing articles on Scopus

: Manuscript no. 2006-163.

: Financial support: Royal Blind Asylum/Royal College of Surgeons, Edinburgh, United Kingdom, and Special Trustees of Moorfields Eye Hospital.

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Original ArticleRandomized Controlled Trial of Combined 5-Fluorouracil and Low-Molecular-Weight Heparin in the Management of Unselected Rhegmatogenous Retinal Detachments Undergoing Primary Vitrectomy

Objective

Design

Participants

Intervention

Main Outcome Measures

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Results of primary retinal reattachment surgery: a prospective audit

Eye

Primary vitrectomy without scleral buckling for rhegmatogenous retinal detachment

Graefes Arch Clin Exp Ophthalmol

Cryopexy in primary rhegmatogenous retinal detachment: a risk factor for postoperative proliferative vitreoretinopathy?

Graefes Arch Clin Exp Ophthalmol

Preoperative vitreous hemorrhage associated with rhegmatogenous retinal detachment: a risk factor for postoperative proliferative vitreoretinopathy?

Graefes Arch Clin Exp Ophthalmol

Pars plana vitrectomy for the treatment of rhegmatogenous retinal detachment uncomplicated by advanced proliferative vitreoretinopathy

Br J Ophthalmol

Clinical risk factors for proliferative vitreoretinopathy after retinal detachment surgery

Retina

Original Article
Randomized Controlled Trial of Combined 5-Fluorouracil and Low-Molecular-Weight Heparin in the Management of Unselected Rhegmatogenous Retinal Detachments Undergoing Primary Vitrectomy