Anti-VEGF drug ranibizumab now indicated for treatment of macular oedema secondary to retinal vein occlusion

Macular oedema secondary to retinal vein occlusion (RVO) is a sight-threatening condition for which limited treatment options exist.1 Recent trials of the anti-vascular endothelial growth factor (VEGF) ranibizumab (Lucentis) have shown significant visual acuity benefit for patients with central or branch RVO-associated macular oedema.1,2

This has led to the approval of ranibizumab for the treatment of RVO-associated macular oedema in Australia³and other countries.¹ Although questions remain regarding the long-term effects of treatment and the applicability of trial results to specific clinical populations,² ranibizumab is an exciting new treatment option for patients whose sight is threatened by RVO- associated macular oedema.¹

Macular oedema

Macular oedema is a sight-threatening condition which arises due to the breakdown of the blood–retinal barrier and the associated increase in vascular permeability. It may arise as a complication of diabetic retinopathy, or occlusion of the central retinal vein or its branches.⁴ With increased vascular permeability, fluid may leak into the macula from the peri-foveal capillaries, causing macula oedema, which is commonly associated impaired visual acuity and blindness.⁵

Vision loss is a common and debilitating outcome in diabetic and RVO macular oedema,^1,8 and to date treatments have had limited efficacy in preventing vision loss.^1,9 Blindness is a much feared complication of the disease.⁸ Vision loss in one or both eyes is also highly debilitating, impairing reading ability and leaving many individuals dependent on others to complete tasks of daily living such as cooking meals.¹⁰

Most cases of macular oedema are underpinned by diabetic retinopathy¹ and diabetic macular oedema is highly prevalent amongst diabetics; 5% develop macular oedema within 5 years of diagnosis¹¹ and computer simulation models show some 42% will develop the condition in their lifetime.¹² RVO is second only to diabetes as a cause of macular oedema and an estimated 1–2% of the population aged > 40 years are affected by RVO-associated macular oedema.¹

The retinal vein and macular oedema

The central retinal vein and its branches are the only blood vessels which remove blood from the retina. Damage to, or occlusion of, these vessels is associated with a high risk of retinal damage or disorder, including macular oedema.¹

RVO occurs as a result of arteriosclerosis affecting the retinal vessels and, similar to systemic arteriosclerosis, cardiovascular risk factors play a key role in the pathogenesis of the disorder. Hardening of the retinal arterial walls induces narrowing of retinal veins and, in turn, thrombosis which occludes the retinal vein and causes elevated pressure in veins and capillaries. This exerts pressure on the retinal artery and slows blood flow to the retina, causing hypoxia. It may also result in haemorrhage from the veins or capillary damage, and ultimately increased interstitial pressure.¹

Exudation of serous fluid resulting from occlusion causes macular oedema, which may be permanent or temporary. In severe instances oedema induces degenerative changes to the macula, including macular holes and epiretinal membranes. Haemorrhages may then occur in the vicinity of the occluded vein and, in severe cases, can cause atrophy of the retinal pigment epithelium. Ischaemic changes to the retina may also occur, and result in the loss of capillaries. This may in turn cause further complications including neovascularisation and associated vitreous haemorrhage or retinal detachment.¹

VEGF-A is a cytokine² which plays a key role in angiogenic processes.¹ Hypoxia stimulates the production of VEGF-A within affected cells. VEGF-A then circulates extracellularly and binds to receptors on endothelial cells. Vascular permeability increases and endothelial cells proliferate as a result. Reduced retinal blood flow due to RVO causes hypoxia and stimulates VEGF production in retinal cells. Concentrations of VEGF are particularly high in the vitreous fluid of individuals affected by the condition.¹

For more information about the structure and function of the eye, see The Eye and Vision.

Types of retinal vein occlusion induced macular oedema

There are two distinct forms of RVO associated with macular oedema: RVO affecting the central retinal vein (CRVO); or occlusion affecting one or more of its branches (BRVO). The clinical presentation, natural course and clinical management of these subtypes are distinct. BRVO typically presents with mild deterioration of visual acuity. Laser coagulation of areas of capillary leakage may be of benefit to BRVO patients with visual acuity of > 20/40; however, a significant proportion of patients in this group fail to improve with laser treatment.¹

CRVO typically presents with more severe visual loss¹ for which there is no established treatment.² In cases of non-ischaemic disease, spontaneous resolution of oedema occurs in about 30% of patients. If the condition persists, in the absence of ischaemia, neovascularisation is uncommon. Ischaemic CRVO macular oedema is associated with considerably poorer visual prognosis.¹ Visual improvement is unlikely and the risk of neovascularisation high. Laser surgery to occlude leaking vessels does not significantly improve visual outcomes for patients with CRVO, and while limited efficacy has been reported for intravitreal steroid injections, application of this treatment is limited.¹ Until the recent approval of ranibizumab for this indication,³ there was no established treatment for macular oedema secondary to CRVO.² and limited treatment options for patients with BRVO.¹

Ranibizumab

Ranibizumab is a chimeric, monoclonal recombinant immunoglobulin fragment, consisting of murine and human components. The human component has no binding function but reduces antigenicity of the drug. The murine component binds to receptors for VEGF-A and its subtypes.¹ In doing so it prevents VEGF-A binding.² The drug was developed to overcome the limitations of full length murine monoclonal antibodies, (e.g. bevacizumab) which preclinical studies suggests were too large to penetrate the retina.¹

Ranibizumab was approved for the treatment of age-related macular degeneration in 2006.¹ In Australia the drug has been used for the treatment of diabetic macular oedema and was recently approved for the treatment of macular oedema occurring secondary to central or branch RVO.³

Evidence for ranibizumab in the treatment of CVO-associated macular oedema

Several studies provide rigorous evidence of the effectiveness of ranibizumab in the treatment of RVO-associated macular oedema.¹

Central retinal vein occlusion

Results of a trial assessing the efficacy of ranibizumab in the treatment of CRVO-associated macular oedema, reviewed by the Cochrane collaboration in 2010,² showed doses of either 0.3 mg or 0.5 mg of ranibizumab improved best-corrected visual acuity significantly compared to sham injections.⁶Patients randomised to receive 0.3 mg doses recorded a 12.7 letter visual acuity gain after 6 months treatment, while those receiving the higher dose (0.5 mg) experienced a 14.9 letter improvement in visual acuity. Patients allocated to receive placebo injections did not experience visual acuity improvements.⁶

Visual improvements occurred rapidly in the treatment groups, which experienced improvements of, on average, nine letters of visual acuity within a week of the initial dose. Almost half of the 0.3 mg and 0.5 mg groups (46% and 48% respectively) experienced improvements of 15 letters or more with 6 months of treatment,⁶ and treated patients were > 2.5 times more likely to achieve this outcome compared to placebo patients.² Improvements in the treated groups were seen within a week of administration of the initial loading dose and were significantly greater than those recorded for the placebo group. Improvements were significantly greater at each of the monthly check points. Both treatment groups also experienced significantly greater reductions in foveal thickness compared to the placebo group at all time points in the trial. Incidence of ocular and systemic adverse events was low, similar to safety with the administration of anti-VEGFs for other ocular conditions.²

Branch retinal vein occlusion

A small trial in which patients were randomised to receive either 0.3 mg or 0.5 mg of ranibizumab, which included 20 BRVO and 20 CRVO macular oedema patients, also reported benefit with this treatment after 2 years follow up. The average visual acuity improvement was 17.8 letters and 59% of treated patients gained at least three lines of visual acuity. Central retinal thickness (assessed with optical coherence tomography) reduced by almost half (481.5 µm to 245.8 µm).¹

A larger multi-centre randomised controlled trial (RCT) involving 397 patients with BRVO-associated macular oedema also reported positive results.¹Following 6 months of ranibizumab treatment, patients receiving a 0.3 mg dose of ranibizumab improved visual acuity by 16.6 letters and those receiving a 0.5 mg dose improved by 18.3 letters, compared to a 7.3 letter improvement in the sham injection group. More than half of treated patients (55.2% and 61.1% respectively for the 0.3 mg and 0.5 mg groups) improved visual acuity by ≥ 15 letters, compared to 28.8% of patients in the placebo group. The need for rescue laser treatment was significantly lower in the treatment groups compared to the sham injection group. Adverse events occurred at a similar rate to that in other trials of ranibizumab for the treatment of ocular conditions.⁷

There’s more work to do yet

Rigorous evidence of the effects of ranibizumab in the treatment of RVO-associated macular oedema have used small samples and have been of a short duration, which means some questions regarding the drug remain unanswered.² Smaller RCTs suggest that short-term visual acuity improvements are not sustained in the long term. For example, one RCT involving 10 subjects reported that benefits were limited following 9-month or quarterly re-treatment, despite good responses to the initial loading dose. 40% of patients experienced visual acuity improvements of > 15 letters in response to the loading dose, although after 9 months this had reduced to 30%, at which time there was an average visual acuity improvement of just one letter.¹

Implications for clinical practice and patients

The applicability of the evidence to clinical practice is unknown. Patients with ischaemic CRVO macular oedema, who have particularly poor prognosis, have been excluded from clinical trials conducted to date, so the results do not apply to this subgroup. Patients with comorbidities were necessarily excluded, as were those with better visual acuity (> 20/40). So while the short-term benefits of ranibizumab for the defined patient group are well supported, more work remains to elucidate the potential of this treatment in a broader context. Further RCT data are expected to be available soon which will hopefully answer questions such as whether the timing of treatment initiation is important and how many treatments are required to achieve stable visual improvements, amongst others.²

For those with non-ischaemic RVO-associated macular oedema, ranibizumab offers significant benefits over other treatment options, which have limited efficacy. Trial results suggest that frequent treatment (as often as monthly in the case of CRVO), long-term monitoring and aggressive retreatment of oedema when it occurs, is required to optimise the effectiveness of ranibizumab therapy.² Despite this, ranibizumab offers a treatment option today for sufferers of RVO-associated macular oedema who previously had very limited options.¹ Furthermore, ongoing clinical trials² hold great promise for expanding the utility of this treatment and improving treatment for patients whose sight is threatened by RVO-associated macular oedema.¹

References

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Braithwaite T, Nanji AA, Greenburg PB. Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. Cochrane Database Syst Rev. 2010;(10):CD007325. [Abstract | Full text]
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Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: Six-month primary end point results of a phase III study. Ophthalmol. 2010;117(6):1102-12. [Abstract]
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