Subcutaneous Nadroparin Calcium in the Treatment of Recent Onset Retinal Vein Occlusion: A Pilot Study

Introduction

Retinal vein occlusion (RVO) is a major cause of visual loss.^1,2 This condition can involve the central trunk or branches of the retinal venous circulation (CRVO and BRVO, respectively), with reported 15-year cumulative incidences of 0.5% for CRVO and 1.8% for BRVO. ³

Different therapeutic strategies for RVO management have been assessed and reported with varying degrees of benefit, including systemic anticoagulation and immunosuppression, laser photocoagulation, intravitreal steroids and antivascular endothelial growth factor (anti-VEGF) agents, and pars plana vitrectomy.^4–6 Two evidence-based systematic reviews published in 2007 have emphasized that no systemic intervention has been demonstrated to favorably affect the natural history of CRVO and BRVO.^4,5 The recent public release of large phase-III trial results on the treatment of CRVO and BRVO with anti-VEGF agents (CRUISE, BRAVO, HORIZON, Copernicus, and Galileo)^7–12 and with implantable steroid depots (GENEVA)^13,14 is likely to redefine completely the unmet medical needs in RVO management.

Heparin has an established place in the prevention and treatment of vein thrombosis. Its anticoagulant activity is due to its high-affinity binding to a plasma co-factor, antithrombin. This binding induces a conformational change in the antithrombin molecule, which markedly accelerates the inhibition of thrombin and other serum proteases, including factors Xa, IXa, XIa, and XIIa. The main side effects of heparin are excessive bleeding and heparin-induced thrombocytopenia. Low-molecular-weight heparins (LMWHs), such as nadroparin, dalteparin, and parnaparin, share the same essential mechanism of action (binding to antithrombin) and show the following differences from unfractionated heparin: (1) higher anti-Xa activity; (2) bioavailability approaching 100%, leading to administration once daily; and (3) lesser interaction with heparin-binding proteins. Since LMWHs are at least as effective and safe as unfractionated heparin and have advantages in terms of pharmacokinetics and convenience of administration, they have replaced the latter in many indications. ¹⁵

Even though LMWHs are approved for use to treat venous thrombosis, there is a shortage of studies addressing their efficacy in the management of RVO.^16–20 Nadroparin calcium is routinely used subcutaneously at a dose of 200 I.U./kg/day in the treatment of deep vein thrombosis. ²¹ The purpose of this pilot study was to investigate whether or not systemic nadroparin calcium might be a potential candidate for the management of recent onset RVO (≤3 weeks' duration). Looking for signs of any biological effect that may be worth pursuing, we set up an open-label case–control study comparing RVO patients treated with subcutaneous nadroparin calcium with historic RVO controls treated with oral pentoxifylline, a xanthine-derived hemorheologic agent that decreases blood viscosity and platelet aggregation.^22,23

Methods

Twenty-four consecutive patients with recent onset RVO (≤3 weeks' duration) admitted to our institute between November 2007 and February 2009 were included in this study. The duration of visual symptoms, ocular medication, and ocular history was noted. A full ophthalmic evaluation of both eyes was carried out, including refraction by streak retinoscopy, best corrected visual acuity (BCVA), slit-lamp examination, applanation tonometry, fundus biomicroscopy, fluorescein angiography, and macular thickness measurement by Stratus OCT (Carl Zeiss Meditec). All refraction assessments and vision recording were performed using standard protocols that were similar for each patient. BCVA was always tested on the same Snellen chart.

Medical conditions, including diabetes mellitus, systemic hypertension, hypercholesterolemia, cardio- and cerebrovascular status (presence of angina, myocardial infarction, transient ischemic attacks, and stroke), decreased renal function, relevant drug history, and presence of blood dyscrasias, were also recorded. All patients underwent extensive medical evaluation, including blood pressure measurement, electrocardiogram, echocardiogram, Doppler imaging of the carotid artery, and blood tests, including a complete blood count, erythrocyte sedimentation rate, prothrombin time, partial thromboplastin time, fibrinogen, serum protein electrophoresis, fasting glucose, hepatic transaminases, total bilirubin, creatinine, cholesterol, homocysteine, folate, and vitamin B12. Exclusion criteria were duration of visual symptoms longer than 3 weeks, warfarin use, severe liver or kidney failure, platelet count <100,000 mm³, known active peptic gastric ulcer, and history of allergy to heparin or LMWHs.

All eligible patients were treated with 1 daily injection of subcutaneous nadroparin calcium (200 I.U./kg/day) for 6 weeks. In patients taking oral acetylsalicylic acid, clopidogrel, or ticlopidine, the antiplatelet medication was temporarily discontinued before starting the treatment with nadroparin calcium. Patients were re-examined after 3 and 6 months; BCVA and macular thickness were measured, and fluorescein angiography was performed. In case of signs of retinal ischemia, scatter laser photocoagulation was used. Focal laser treatment was given in BRVO eyes with chronic macular edema.

The occurrence of major and minor hemorrhage and/or allergic response to nadroparin calcium was recorded as an adverse event. A major hemorrhage was defined as the presence of intracranial, intra-articular, retroperitoneal, or vitreous bleeding; acute reduction in hemoglobin levels (≥2 g/dL); or transfusion of 2 or more units of blood in response to a specific identified bleeding episode. A minor hemorrhage was defined as bleeding not included in the definition of major hemorrhage.

Twenty-four patients with recent onset RVO treated with oral pentoxifylline [400 mg twice a day (b.i.d)] for 1 month, matched for age, gender, RVO type, eye involvement, and BCVA at presentation, randomly selected from the RVO register in the period 1996–2005, were used as controls. This hemorheologic agent was routinely used in almost all RVO patients seen at our institute during this time span. As in the study group, all the control subjects had undergone extensive ophthalmic and medical evaluation. BCVA and fluorescein angiography at baseline and at months 3 and 6 were analyzed and compared with those of the corresponding study case; data about laser treatment were also obtained. In the control group, data about macular thickness were not available.

The Mann–Whitney rank sum test, Student's t-test, Chi-square test, or Fisher exact text was used, when appropriate, to calculate differences between groups. P≤0.05 was considered to be statistically significant (StatGraphics ver. 5.0 for Windows; StatPoint, Inc.).

The Institutional ethics review board's approval was obtained, and the study was conducted in full accord with the tenets of the Declaration of Helsinki. Each participant received detailed information and provided informed consent before inclusion.

Results

Patients' and controls' systemic characteristics are reported in Table 1. Both groups consisted of 24 patients (11 men and 13 women) with similar systemic characteristics. Mean age was 64.2±8.4 years in the study group and was 64.5±8.7 years in the controls. Both groups had similar values of systolic and diastolic blood pressure, similar levels of plasma glucose and total cholesterol, and similar rates of systemic hypertension, diabetes, hypercholesterolemia, angina/myocardial infarction, transient ischemic attacks/stroke, and antiplatelet use.

Tables 2 and 3 show demographics and clinical settings of patients and controls. Involvement of the right eye was more frequent (67%). In both groups, 11 patients had BRVO, affecting one of the temporal branches, and 13 had CRVO. Median BCVA was 20/70 (range 20/1,000–20/20) at baseline, 20/40 (range 20/100–20/20) after 3 months, and 20/30 (range 20/200–20/20) after 6 months in the study group. Median BCVA was 20/70 (range 20/1,000–20/20) at baseline, 20/60 (range 20/320–20/25) after 3 months, and 20/60 (range 20/500–20/20) after 6 months in the control group. BCVA values showed a non-normal distribution; accordingly, a statistical analysis was performed using the Mann–Whitney rank sum test. Differences between groups were statistically significant at months 3 (P=0.025) and 6 (P=0.024); however, the statistical power of the analysis was below the threshold value of 0.8.

In the group treated with subcutaneous nadroparin calcium, vision improved from baseline in 19 (79%) patients, was stable in 1, and decreased in 4. In the group treated with oral pentoxifylline, BCVA improved from baseline in 12 (50%) patients, was stable in 2, and decreased in 10.

In the study group, the mean macular thickness detected by Stratus OCT was 510±207 μm at baseline, 384±198 μm after 3 months, and 313±170 μm after 6 months. OCT values showed a normal distribution; accordingly, a statistical analysis was performed using the Student's t-test. Differences between baseline and months 3 and 6 were statistically significant (P=0.004 and P<0.001; statistical power >0.8).

Median BCVA and the mean macular thickness in CRVO and BRVO cases are shown in Table 4. In both subgroups, the Student's t-test showed significant differences between OCT measurements at baseline and at month 6 (CRVO: P<0.001; BRVO: P=0.01). Even though CRVO cases showed more macular thinning and better vision improvement than BRVO cases, there were no statistically significant differences between the subgroups at the different time points (baseline, month 3, and month 6).

In the group treated with subcutaneous nadroparin calcium, laser photocoagulation was performed in 7 (2 CRVO and 5 BRVO) patients. Of these, 2 CRVO and 2 BRVO cases received scatter treatment, and 3 BRVO cases had focal treatment. In the group treated with oral pentoxifylline, laser photocoagulation was performed in 14 (5 CRVO, 9 BRVO) patients. Of these, 5 CRVO and 2 BRVO patients received scatter treatment, 1 BRVO patient had focal treatment, and 6 BRVO patients had combined scatter/grid laser photocoagulation. In both BRVO groups, focal treatment was always performed at the 6-month follow-up examination. Although the number of control subjects receiving laser treatment was twice as high as that of RVO cases, differences between groups fell short of statistical significance (P=0.08).

Treatment with subcutaneous nadroparin calcium was well tolerated, and no patient had systemic side effects. Redness and itching at the injection site was reported by 1 patient.

Discussion

This was a pilot study on the management of recent onset RVO, looking for signs of any biological effect that may be worth pursuing. We found that median BCVA after 6 months was significantly higher in patients treated with subcutaneous nadroparin calcium than in patients treated with oral pentoxifylline; however, the statistical power of the analysis was below the threshold value of 0.8. In the study group, the mean macular thickness was significantly reduced from 510±207 μm at baseline to 313±170 μm after 6 months. Further studies are necessary to establish whether these findings might have any practical importance.

CRVO is one of the most common causes of visual loss. Population-based studies have reported a CRVO prevalence of 0.1%–0.4% in ≥40-year-old individuals.^24,25 Many systemic and ocular risk factors have been reported, including hypertension, cardiovascular disease, diabetes, and open-angle glaucoma.^1,26 Although several different mechanisms, ranging from vasculitis to a hypercoagulable state, have been shown to cause CRVO, its pathogenesis is still uncertain. Visual morbidity and blindness in CRVO are primarily due to the development of persistent macular edema, macular ischemia, and neovascular glaucoma.

Various treatments for CRVO have been advocated over the last 2 decades.^4,27,28 These include medical therapy with anticoagulants, fibrinolytics, corticosteroids, acetazolamide, and isovolemic hemodilution. CRVO has been reported in patients receiving chronic, therapeutic levels of warfarin, implying that this medication may be ineffective as prophylaxis.^29,30 Similarly, other vascular agents, including streptokinase, ³¹ ticlopidine, ³² tissue plasminogen activator, ³³ and pentoxifylline, have been studied,^22,23 but they have shown a limited or no benefit. Panretinal photocoagulation has been reported to yield regression of neovascularization in >90% of cases and to reduce the risk of neovascular glaucoma to 1%. ³⁴ In an evidence-based systematic review published in 2007, Mohamed et al. ⁴ found limited level-I evidence for any intervention to improve vision in CRVO patients. Very recently, results from large phase-III clinical trials have shown that intravitreal injections of anti-VEGF agents (ranibizumab and aflibercept) and intravitreal dexamethasone implant provided rapid improvement of visual acuity and macular edema after CRVO, with low rates of ocular and nonocular adverse events.^8,10–14 The availability of such efficacious drugs is likely to substantially change the treatment recommendations for CRVO.

BRVO is the second most common retinal vascular disease, affecting men and women almost equally and occurring most frequently after the age of 60 years, with an incidence peak between the ages of 65 and 74.^2,3 The interruption of venous flow in BRVO almost invariably occurs at an arteriovenous crossing, where the surrounding glial tissue binds the artery and vein together. ³⁵ Arterial hypertension, atherosclerosis, a history of cardiovascular disease, and increased plasma lipoprotein have been identified as systemic risk factors for BRVO.^36,37 Visual loss in BRVO may be the result of the presence of macular edema, macular nonperfusion, retinal neovascularization, vitreous or intraretinal hemorrhages, tractional retinal detachment, or a combination of these.

Many treatments have been advocated for the management of BRVO, including peripheral scatter and macular grid laser photocoagulation, anticoagulants, steroids, hemodilution, and vitrectomy with or without adventitial sheathotomy.^5,38 As was found for CRVO, McIntosh and coworkers reported limited level-I evidence for any interventions for BRVO, apart from laser photocoagulation. ⁵ More recently, results from large multicenter studies have shown that treatment with intravitreal anti-VEGF agents (bevacizumab and ranibizumab) and with intravitreal dexamethasone depots may be effective in improving vision and macular edema following BRVO, with a favorable safety profile.^{7,9,11,13,14,39}

Although LMWHs are approved for use to prevent and treat venous thromboembolic disease, the paucity of reports addressing their efficacy in the management of RVO is rather surprising.^19,20 In one study, nadroparin calcium (7,500 I.U.) injected subcutaneously twice daily for 10 days and once daily for 18 days was found to improve vision in about 50% of 30 RVO patients. ¹⁶ In another study, subcutaneous dalteparin (100 I.U./kg b.i.d. for 10 days and then once a day [q.d.] for another 10 days) was reported to be superior to aspirin (100 mg/day for 6 months) in terms of improving visual acuity and preventing iris neovascularization in CRVO patients. ¹⁷ Recently, in a multicenter, randomized, double-blind, controlled trial, subcutaneous parnaparin (6,400 I.U. b.i.d. for 7 days followed by 6,400 I.U. q.d. for a total of 3 months) has been shown to be more effective than aspirin (100 mg/day for 3 months) in preventing functional worsening in patients with RVO. ¹⁸ In a recent systematic review and meta-analysis of randomized trials evaluating the effect of LMWHs in RVO patients, Lazo-Langner and colleagues have reported that treatment with LMWHs seems to be associated with visual improvement and reduced rates of adverse ocular outcomes, such as visual-field or fluorescein angiography worsening, retinal or iris neovascularization, and neovascular glaucoma. ²⁰ On the basis of their findings, these authors suggested that LMWHs might be useful in the management of recent onset RVO (particularly in CRVO and less clearly in BRVO), but called for more research before definitive recommendations can be made. ²⁰

In the present study, we compared RVO patients treated with subcutaneous nadroparin calcium with historic RVO controls treated with oral pentoxifylline. This xanthine derivative has been used to increase the perfusion of occluded vessels in systemic vascular disorders since the 1970s^22,40; furthermore, it has also been reported to improve retinal blood flow in RVO ²³ and cistoid macular edema, but not vision, in CRVO. ⁴¹

Our results show that subcutaneous nadroparin calcium given at the same dose (200 I.U./kg/day) for deep vein thrombosis treatment was better than oral pentoxifylline in improving vision in patients with recent onset RVO. Overall, nadroparin calcium was well tolerated, and the sooner the treatment was started, the better the result.

In the study group, there was a significant reduction in the central macular thickness over time. Likewise, when cases were categorized by the type of vein occlusion, both CRVO and BRVO cases showed statistically significant changes in OCT measurements from baseline to month 6. However, it is important to stress that a decrease in the central macular thickness may also be observed during the natural history of the disease process. ²⁷ Thus, it cannot be concluded from the current data whether nadroparin calcium had an additional effect on macular edema improvement.

The administration of subcutaneous nadroparin calcium reduced the need for laser treatment by 50% when compared with controls receiving oral pentoxifylline; however, differences between groups fell short of statistical significance (P=0.08). Although we used age-, gender-, and otherwise-matched controls, there is a limited possibility that the results may be somewhat biased by a different severity degree of the RVO at baseline.

CRVO and BRVO are 2 different clinical entities with different pathogenesis, natural history, visual prognosis, and risks of macular edema and neovascularization. Nevertheless, they share a common underlying pathogenic mechanism: thrombus formation. This is the main reason that, in our study, CRVO and BRVO patients were grouped together. Furthermore, this was also done to obtain a higher number of cases. The pooling of CRVO and BRVO cases may be questionable, because analysis of these entities should ideally be done independently; however, this approach has previously been used in similar surveys.^{16–18,22,29}

The most important limitation of the present study is that it is not a randomized, prospective investigation in which the patients were randomly distributed between a study group and a control group. Indeed, the control group, even if matched for age, gender, RVO type, eye involvement, and BCVA at presentation, was selected retrospectively. Furthermore, the study and control groups were accrued during different time periods, which may be another confounder. Other limitations of the study are the relatively small sample size and the relatively short follow-up period.

In conclusion, the results of this pilot study suggest that subcutaneous nadroparin calcium might have a beneficial effect on patients with recent onset RVO. However, a prospective, randomized, large-scale study is necessary to confirm whether or not this LMWH may be advocated as a valid and safe therapeutic option for the management of the early stages of this disorder. Even in times where new efficacious drugs, such as intravitreal anti-VEGF agents and implantable steroid depots, are available for the management of RVO, it is important to note that not all patients are suitable for intravitreal injections and that anti-VEGF agents do nothing to treat the thrombus and have the potential to promote new thrombus formation. ⁴² In this general context, systemic LMWHs may surely be of interest as potential candidates for future treatment trials.