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ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 4  |  Page : 1252-1257

Systemic anticoagulant in management of central retinal vein occlusion


Department of Opthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission23-Jul-2020
Date of Decision06-Sep-2020
Date of Acceptance11-Sep-2020
Date of Web Publication24-Dec-2020

Correspondence Address:
Aya E El-Absawy
MBBCh, Shebin El Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_253_20

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  Abstract 


Background
Central retinal vein occlusion (CRVO) is one of the commonest retinal vascular diseases.
Objective
The aim was to compare between intravitreal injection of antivascular endothelial growth factors and combined intravitreal injection of antivasular endothelial growth factors with systemic anticoagulant drugs in treatment of CRVO.
Patients and methods
This study included 30 patients with CRVO who were divided into two groups. The first group was treated by intravitreal injection? of anti-Vascular endothelial growth factor (VEGF) (Ranibizumab) using three injections, 1 month apart. The second group was treated the same protocol of injection of the first group and systemic anticoagulant drugs, low-molecular-weight heparin. Optical coherence tomography was used to evaluate central macular thickness (CMT) at baseline and after treatment. Best-corrected visual acuity (BCVA) was documented before and after treatment.
Results
This study included 30 patients with CRVO. The first group treated by anti-VEGF (Ranibizumab) injection only improved in CMT from 702.9 ± 191.6 mm to 448.9 ± 178.0 mm (P = 0.001). BCVA also improved from 0.05 ± 0.01 to 0.11 ± 0.06 (P = 0.006). The second group treated by anti-VEGF (Ranibizumab) injection and systemic anticoagulant also improved in CMT from 814.4 ± 200.9 mm to 397.5 ± 166 mm (P = 0.001) and improved in BCVA from 0.06 ± 0.04 (range: 0.05–1.0) to 0.01 ± 0.11 (P = 0.002).
Conclusion
Systemic anticoagulant appears to be useful in the management of retinal vein occlusion regarding improvement in CMT and BCVA, but there is no difference regarding improvement between it and intravitreal injection of anti-VEGF (Ranibizumab).

Keywords: antivasular endothelial growth factors, central macular thickness, central retinal vein occlusi?on, low-molecular weight heparin


How to cite this article:
Elmazar HM, Ibrahim AM, Abd EL-Hafez MA, El-Absawy AE. Systemic anticoagulant in management of central retinal vein occlusion. Menoufia Med J 2020;33:1252-7

How to cite this URL:
Elmazar HM, Ibrahim AM, Abd EL-Hafez MA, El-Absawy AE. Systemic anticoagulant in management of central retinal vein occlusion. Menoufia Med J [serial online] 2020 [cited 2021 Apr 19];33:1252-7. Available from: http://www.mmj.eg.net/text.asp?2020/33/4/1252/304499




  Introduction Top


Central retinal vein occlusion (CRVO) is one of the commonest retinal vascular disorders and one of the most common causes of vision loss worldwide. Specifically, it is the second most common cause of blindness from retinal vascular disease after diabetic retinopathy[1]. CRVO has been recognized as an entity since 1855, but many aspects of the pathogenesis and management of this disorder remain uncertain. In the Canadian Journal of Ophthalmology in 2007, it was noted that 'research into CRVO is fraught with challenges, from accurate disease classification to its treatment; even the most prestigious trials have become controversial'[2].

Classical vascular risk factors such as high blood pressure, dyslipidemia, diabetes mellitus, and smoking represent the main etiopathogenic factors for CRVO[3].

RVO is classified according to where the occlusion is located. Occlusion of the central retinal vein at the level of the optic nerve is referred to as CRVO. Occlusion at the primary superior branch or primary inferior branch involving approximately half of the retina is referred to as hemiretinal vein[4].

Obstruction at any more distal branch of the retinal vein is referred to as branch retinal vein occlusion. The location of the occlusion influences the pathogenesis, clinical presentation, and management of RVO. CRVO is further divided into the categories of perfused (nonischemic) and nonperfused (ischemic), each of which has implications for prognosis and treatment[5].

Macular edema is a common complication and the primary cause of loss of vision in all forms of RVO [6–8].

Ranibizumab is a humanized antigen-binding fragment of a mouse monoclonal antibody to VEGF with several selective mutations to increase its binding affinity; ranibizumab binds to and inhibits all biologically active forms of VEGF A[9].

Optical coherence tomography (OCT) is useful in the assessment of macular edema and particularly in monitoring its course, especially with treatment of the ede?ma.

Typically, the OCT shows cystoid macular edema with or without subfoveal fluid. Epiretinal membrane or vitreomacular traction may also be evident.

In patients with recent-onset CRVO, OCT can detect areas of presumed ischemic edema in the plexiform layer owing to ischemia of intermediary neurons within the inner nuclear and inner plexiform layers[10].

In our study, we evaluated the effect of anti-VEGF (Ranibizumab) and systemic anticoagulant low-molecular weight heparin (LMWH) in treatment of CRVO regarding improvement in central macular thickness (CMT) and best-corrected visual acuity (BCVA). LMWH is safe and effective in inpatients and outpatients. LMWH improves vision and decreases ocular complications such as neovascularization.


  Patients and methods Top


This study evaluated 30 patients with CRVO from the retina outpatient clinic of Menoufia University Hospitals, from December 2018 to December 2019. A written informed consent was obtained from all patients to participate in the study and for publication of data. The study was approved by the Ethics Committee of Human Rights, Faculty of Medicine, Menoufia University. All procedures were performed under the tenets of the Helsinki Declaration. This is a randomized study, and patients of the two groups were randomized using a computer-generated random number table.

Patients were divided into two groups. The first group was treated with three successive intravitreal injections of antivascular endothelial growth factors one month apart; anti-VEGF (Ranibizumab) used was Lucentis (Novartis Pharma Stein AG, Stein, Switzerland). The second group was treated by combined three successive intravitreal injections of antivasular endothelial growth factors 1 month apart; anti-VEGF (Ranibizumab) used was Lucentis (Novartis Parma Stein AG), and systemic anticoagulant drugs. LMWH (Clexane) was used for seven days as subcutaneous injection, and patients completed treatment by oral rivaroxaban (Vaxato 10 mg) for three months. Follow-up of the patients was done clinically, and OCT scans were done using Heidelberg Spectral (Heidelberg Engineering, Heidelberg, Germany), which was used to evaluate macular thickness at baseline and after treatment.

The inclusion criteria for this study were recently diagnosed CRVO with secondary macular edema receiving anti-VEGF therapy. However, the exclusion criteria were any patient with history of ocular trauma; any ocular diseases such as diabetic macular edema, choroid neovascularization, and age-related macular degeneration; patients who received other treatment for retinal vein occlusion such as subtenon or intravitreal corticosteroids or laser photocoagulation; absolute contraindication to antithrombotic agents such as malignant hypertension; pregnancy; recent brain surgery; and severe active bleeding.

The two groups were compared according to improvement in visual acuity and CMT.

All patients' data were collected, such as age; sex; past medical history (hypertension and diabetes mellitus); BCVA based on spectacle correction; intraocular pressure using HAAG-STREIT AG, Swiss made Goldman application tonometer; anterior segment examination for cornea and iris (for iris neovascularization) done using slit lamp; gonioscopy done (angle neovascularization) using three-mirror Goldman gonioscopy lens; fundus examination for the retina, optic verve, and vitreous body done by slit lamp and auxiliary lens (volk + 90) after pupillary dilatation; and anti-VEGF (Ranibizumab) injection dates.

Surgical procedure

All injections were done with the same technique. Ranibizumab 0.5 mg/0.05 ml was administered by intravitreal injection in full sterile precautions in the operating room.

Before injection, topical anesthesia was applied. Povidone iodine 5% was applied to eyelids, lashes, and conjunctival surface, and a lid speculum was placed.

Ranibizumab injections were injected 3.5 mm in pseudophakic patients and 4.0 mm in phakic patients from limbus to the vitreous cavity. The site of the injection was compressed using a cotton swab to prevent reflux as the needle was removed. Postoperatively, antibiotic (ofloxacin) was applied topically for 7 days.

CMT was also recorded for all patients at baseline and after three-month follow-up, using OCT (Heidelberg Spectralis); the fast macula thickness map was used, which comprises three concentric circles centered at the fovea that divide the macula into three zones: the fovea (<1 mm diameter), the inner macula (1–3 mm), and the outer macula (3–6 mm). These zones were further divided into 9 ETDRS (Early Treatment Diabetic Retinopathy Study) regions.

Statistical analysis

Data were collected, tabulated, and statistically analyzed using an IBM personal computer with Statistical Package for the Social Sciences version 22 (SPSS Inc., Chicago, Illinois, USA), where the following statistics were applied:

  1. Descriptive statistics: in which quantitative data were presented in the form of mean, SD, and range, and qualitative data were presented in the form numbers and percentages.
  2. Analytical statistics: it was used to find out the possible association between studied factors and the targeted disease.


The used test of significance included the following:

Mann–Whitney test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variables.

Wilcoxon signed rank test (nonparametric test) is a test of significance used for comparison between two related groups not normally distributed having quantitative variables.

P value of greater than 0.05 was considered statistically non-significant, P value of less than 0.05 was considered statistically significant, and P value of less than 0.001 was considered statistically highly significant.


  Results Top


Results showed significant improvement in CMT before and after injection from 702.9 ± 191.6 mm (range: 347–951 mm) to 44809 ± 178 mm (range: 286–880 mm) (P = 0.001). [Table 1] shows that there was a highly significant difference between preinjection and postinjection cental macular thickness values in group 1, as it significantly decreased after injection; the percentage of decrease was 36.1% (P = 0.001) [Table 1].
Table 1: Comparison between pre- and post-treatment central macular thickness and visual acuity among studied groups (n=30)

Click here to view


Moreover, there was significant improvement in visual acuity in group 1 before and after injection, as BCVA improved from 0.05 ± 0.01 (range: 0.05–0.10) to 0.11 ± 0.06 (range: 0.05–0.20) (P = 0.006). It significantly increased, and the percentage of increase was 1.2% (P = 0.006) [Table 1].

Group 2, which was treated by combined systemic anticoagulant drugs and three successive intravitreal injection of anti-VEGF (Ranibizumab) 1 month apart, showed a significant improvement in CMT before and after injection from 814.4 ± 200.9 mm (range: 450–997 mm) to 397.5 ± 166.6 mm (range: 205–728 mm) (P = 0.001). CMT was significantly decreased after injection, and the percentage of decrease was 51.2% (P = 0.001) [Table 1].

Moreover, there was significant improvement in visual acuity in group 2 from 0.06 ± 0.04 (range: 0.05–1.0) to 0.01 ± 0.11 (range: 0.01–0.40) (P = 0.002). It significantly increased, and the percentage of increase was 66.7% (P = 0.002) [Table 1].

Comparison between the results of the two groups showed that pretreatment and post-treatment CMT values in the two groups showed no significant difference, as group 1 CMT improved from 702.9 ± 191.6 mm (range: 347–951 mm) to 448.9 ± 178.0 mm (range: 286–880 mm) and group 2 improved from 814.4 ± 200.9 mm (range: 450–997 mm) to 397.5 ± 166.6 mm (range: 205–728 mm) [Table 2].
Table 2: Comparison between studied groups regarding pretreatment and post-treatment central macular thickness and visual acuity (n=30)

Click here to view


Moreover, improvement in BCVA in group 1 from baseline value of 0.05 ± 0.01 (range: 0.05–0.10) to follow-up value of 0.11 ± 0.06 (range: 0.05–0.20) showed no significant difference from group 2, as it was improved in BCVA from 0.06 ± 0.04 (range: 0.05 ± 1.0) to 0.01 ± 0.11 (range: 0.01 ± 0.40) (P = 0.002) [Table 2].


  Discussion Top


Anti-VEGF improves vision and maintains BCVA among patients with macular edema secondary to CRVO. The median duration of CRVO in the study at baseline was 0 weeks, suggesting that the majority of patients received their first anti-VEGF injection within a week of RVO diagnosis. The aim of the treatment of CRVO is to achieve dry macula and good visual acuity[11],[12].

Our study in the treatment of CRVO demonstrated that intravitreal injection of anti-VEGF 0.5 mg (Ranibizumab) three successive times 1 month apart shows improvement in CMT and BCVA. Systemic anticoagulant, LMWH also shows improvement in CMT and BCVA. Patients in our study who were treated with LMWH did not show increased risk of vitreous hemorrhage.

Patients were treated with the same anti-VEGF agent throughout the study. A similar study to ours by Jumper et al.[12] treated CRVO by monthly visits, and it revealed that intravitreal injections can be burdensome for patients. In this study, the mean number of anti-VEGF injections received by patients in the first, second, and third year was lower than if injections had been administered monthly throughout the year. The mean annual number of anti-VEGF injections could have been reduced in part because some patients stopped treatment owing to lack of efficacy or resolution of the macular edema. Longer inter-injection intervals after subsequent anti-VEGF injections could be explained in part by use of treat-and-extend or treat-as-needed treatment protocols[13]. Patients with CRVO received a median of six anti-VEGF injections in the first year of treatment and fewer injections in subsequent years, consistent with the results of this study[12]. Our patients in the study showed decrease in CMT after treatment in the first group. Patients started with CMT 702.9 ± 191.6 mm (range: 347–951 mm) improved to 448.9 ± 178.0 mm (range: 286–880 mm).

BCVA before injection of 0.05 ± 0.01 (range: 0.05–0.10) improved to 0.11 ± 0.06 (range: 0.05–0.20) (P = 0.006). Visual acuity gain was greater than or equal to 2. The early diagnosis and follow-up affect the results, and presence of retinal ischemia determines the improvement in visual acuity.

Visual and anatomic outcomes were suboptimal in a substantial number of patients in this study. After each of the first 16 injections, more than 40% of patients did not achieve 20/40 or better BCVA and more than 30% of patients did not achieve CRT less than or equal to 250 μm on TD-OCT or less than or equal to 300 μm on SD-OCT. Some patients who achieved 20/40 or better BCVA failed to meet the primary end point because CRT remained less than or equal to 250 μm on TD-OCT or less than or equal to 300 μm on SD-OCT, and conversely, some patients who achieved CRT more than 250 μm on TD-OCT or more than 300 μm on SD-OCT failed to meet the primary end point because their BCVA remained worse than 20/40. The percentage of patients who achieved CRT less than or equal to 250 μm on TD-OCT or less than or equal to 300 μm on SD-OCT was generally higher than the percentage of patients who achieved 20/40 or better BCVA, possibly because of ischemia, other complications of the RVO, or other ocular conditions that prevented visual acuity gains. The primary end point of combined visual and anatomic response was met by only one-third of patients after most injections. We believe that these results are unlikely to be explained solely by inadequate dosing frequency. In the BRAVO and CRUISE registration studies of ranibizumab for treatment of CRVO, 23% of patients had residual edema (center point thickness >250 μm on TD-OCT) after six monthly injections of ranibizumab 0.5 mg[14]. Therefore, some patients can be expected to respond suboptimally to anti-VEGF treatment even with monthly dosing. VEGF inhibitors are the standard treatment for RVO-associated macular edema because of their safety, as well as their efficacy in reducing macular edema and improving visual acuity in many patients. Our study has several limitations. First, follow-up of the patient and data collected was short at 3 months after anti-VEGF therapy. We do not know if these data are still the same after more follow-ups. So longer studies for 6 months or more could be helpful to determine validity of these data. Second, in our study, we used ranibizumab as anti-VEGF. Another anti-VEGF could produce different result.

Similar to our study, Lazo-Langner et al.[15] showed that use of LMWH results in improved visual acuity 6 months after symptoms onset and also in a 78% risk reduction of developing adverse ocular symptoms defined as any of the following: worsening of visual acuity, visual field, or fluorescein angiography or development of iris neovascularization, any neovascularization, or neovascular glaucoma. The use of LMWH in this particular setting is safe and might not be associated with an increased risk of vitreous hemorrhage. A similar study used parnaparin for 90 days. In the second group, we started treatment by combined three successive intravitreal injections of anti-VEGF one month apart and systemic anticoagulant drugs. In our study, we used subcutaneous injection of LMWH for 1 week and completed by oral rivaroxaban (Vaxato10 mg) for 3 months. Patients improved in CMT, and results showed that significant improvement in CMT before injection and after injection. Central macular thickness decreased from 814.4 ± 200.9 mm (range: 450–997 mm) to 397.5 ± 166.6 mm (range: 205–728 mm) (P = 0.001), and visual acuity improved [pre-BCVA 0.06 ± 0.04 (range: 0.05–1.0) to post-BCVA 0.01 ± 0.11 (range: 0.01–0.40)] (P = 0.002). Visual gain was greater than or equal to two lines. Early diagnoses and Follow-up affect the results, and the presence of retinal ischemia affect the visual acuity.

Comparison between the two groups showed that both groups improved in CMT, and in BCVA. Comparison between the two groups' results showed that regarding pretreatment and post-treatment in CMT, there was no significant difference between the two groups. The first group CMT improved from 702.9 ± 191.6 mm (range: 347–951 mm) to 448.9 ± 178.0 mm (range: 286–880 mm). The second group improved from 814.4 ± 200.9 mm (range: 450–997 mm) to 397.5 ± 166.6 mm (range: 205–728 mm). The table shows that there was no significant difference between studied groups regarding pretreatment and post-treatment CMT.

Moreover, there was improvement in BCVA in group 1 from pre 0.05 ± 0.01 (range: 0.05–0.10) to 0.11 ± 0.06 (range: 0.05–0.20). Second group also improved in BCVA from pre-BCVA 0.06±0.04 (range: 0.05–1.0) to post-BCVA 0.01 ± 0.11 (range: 0.01–0.40). The table shows that there was no significant difference between group 1 (injection group) and group 2 regarding pretreatment and post-treatment visual acuity (P > 0.05).

LMWH seems to improve the venous outflow from the retina and reduce the macular edema and the number of intravitreal injections required. We believe that the next steps in the treatment of vein occlusions will be to reduce the amount of injections and find a new strategy to treat patients who become resistant to conventional treatments. Even considering therapy with anti-VEGF and cortisone as essential for the treatment of macular edema in RVOs, LMWH could represent a new option for patients who show resistance to the conventional treatments and a candidate for secondary prevention[16].


  Conclusion Top


Systemic anticoagulant appears to be useful in the management of retinal vein occlusion regarding improvement in CMT and BCVA but there is no difference regarding improvement between it and intravitreal injection of anti-VEGF (Ranibizumab).

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Rogers S, Mcintosh RL, Cheung N, Lim L, Wang JJ, Mitchell P. The prevelance of retinal vein occlusion pooled data from population studies from the United States, Europe, Asia, Australia. Opthalmogy 2010; 117:117-313.  Back to cited text no. 4
    
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Hayreh SS, Podhajsky PA, Zimmerman MB. Central and hemicentral retinal vein occlusion: role of anti-platelet aggregation agents and anticoagulants. Ophthalmology 201?1; 118:1603–1611.  Back to cited text no. 8
    
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Steinbrook R. The price of sight–ranibizumab, bevacizumab, and the treatment of macular degeneration. N Engl J Med 200?6; 355:1409–1412.  Back to cited text no. 9
    
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Casselholm de Salles M, Lindberg C, Epstein D. Neovascular glaucoma in patients with central retinal vein occlusion: a real-life study in the anti-VEGF era. Acta Ophthalmol (Copenh?) 2020; 16:20-22.  Back to cited text no. 11
    
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Wecker T, Ehlken C, Bühler A, Lange C, Agostini H, Böhringer D, et al. Five-year visual acuity outcomes and injection patterns in patients with pro-re-nata treatments for AMD, DME, RVO and myopic CNV. Br J Ophthalmol 20?17; 101:353-359.  Back to cited text no. 13
    
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Bhisitkul RB, Campochiaro PA, Shapiro H, Rubio RG. Predictive value in retinal vein occlusions of early vs late or incomplete ranibizumab response defined by optical coherence tomography. Ophthalmology 201?3; 120:1057–1063.  Back to cited text no. 14
    
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Lazo-Langner A, Hawel J, Ageno W, Kovacs MJ. Low molecular weight heparin for the treatment of retinal vein occlusion: asystemic review and meta-analysis of randomized trials. Haematologica 20?10; 95:1587-1593.  Back to cited text no. 15
    
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