What you should know about anti-VEGF intravitreal injections using Avastin, Lucentis and Eylea

Important facts about Bevacizumab (Avastin) and systemic risks associated with Avastin when administered by intravitreal injection

Avastin is an inhibitor of vascular endothelial growth factor (VEGF) and is approved for the treatment of some cancers. Avastin has been used off-label by the intravitreal route (injection in the vitreous cavity of the eye) at a dose of 1.25 mg to 2.5 mg (ie 150 times less than the systemic dose). When given systemically to patients with cancer, Avastin is associated with an increased risk of thromboembolic events (stroke and myocardial infarction).

There is no long-term solid data to confirm the systemic safety of Avastin when given by intravitreal injection. There are however several studies that have attempted to answer this question. The systemic safety of Avastin however, probably depends on the patient population being studied. For instance, patients receiving Avastin for eye conditions are healthier than cancer patients, and receive a significantly smaller dose, delivered only to the cavity of their eye. Furthermore the baseline risk of thromboembolic events varies with the age of the study population.

I should point out at this stage that Ranibizumab (Lucentis) is a similar drug to Avastin that is approved for age-related macular degeneration (ARMD), diabetic macular oedema (DMO) and retinal vein occlusion (RVO). The rates of systemic adverse events in randomised controlled trials of Ranibizumab (Lucentis) were similar to those of placebo.

Ophthalmologists believe that the risk of systemic complications following the intravitreal injection of Avastin for patients with eye conditions is very low. Prospective uncontrolled studies of Avastin showed no increased risk of systemic events.

An internet-based survey (Fung et al 2006) that relied on self-reporting of adverse events to assess the safety of Avastin involving 70 centres included hypertension (0.21%), deep venous thrombosis (0.01%), transient ischaemic attack (0.01%), stroke (0.07%), myocardial infarction (0), death (0.03%).  The observed rates do not show an increased rate beyond that expected in an elderly population. The study however has limitations as it is based on voluntary self-reporting of adverse events. One would expect some degree of under-reporting from such a survey.

In 2009, Roche UK issued a safety information of severe eye inflammation and sterile endophthalmitis following the use of off-label Avastin in Canada and there were later a small number of similar reports from the EU.

Curtis et al published an article in October 2010 on the risks of systemic adverse events associated with treatment for wet age-related macular degeneration.  The authors observed a reduced risk of death, myocardial infarction and stroke with Ranibizumab (Lucentis) compared to Bevacizumab (Avastin). A secondary analysis was done because of the possibility of selection bias as patients with higher socioeconomic status may have been more likely to receive Ranibizumab (Lucentis). In the secondary analysis, among patients whose physicians used either medication exclusively, the risks of death, myocardial infarction and stroke were not different.

The National Eye Institute sponsored trial comparing the efficacy of Ranibizumab (Lucentis) and Bevacizumab (Avastin) was published in 2011 (The CATT research group, New Engl J Med 2011). Given the baseline risks of thromboembolic events in the ARMD population, the sample size needed to detect a 50% relative increase in risk (from 2% to 3%) would be an order of magnitude larger than the trial protocol dictates. The CATT trial therefore was not adequately powered to assess relative safety of the 2 therapies.

Ranibizumab (Lucentis) vs. Bevacizumab (Avastin); The CATT Research group; one-year results (New Engl J Med 2011):

The trial compared both treatments and included 4 treatment arms: Bevacizumab (Avastin) as required and monthly, Ranibizumab (Lucentis) as required and monthly

• Bevacizumab was equivalent to Ranibizumab when both drugs were given monthly and when the drugs were given as needed
• Ranibizumab as needed was equivalent to Ranibizumab monthly
• Ranibizumab as needed was equivalent to bevacizumab monthly
• There was a significant increase in ≥1 serious systemic event in the bevacizumab group in comparison with the ranibizumab group (p=0.04).

The authors concluded the following: “At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Differences in rates of serious adverse events require further study”.

The CATT Research group; 2-year results (Ophthalmology 2012):

The 2-year data from the CATT research group were published recently. The results at 2 years showed that the 2 drugs have equivalent effects on visual acuity when the dosing regimen was the same (ie with both monthly and as need treatments). However, visual acuity with monthly injections was slightly better than with as needed injections regardless of the drug used. Overall, monthly treatment resulted in about half a line of vision better than as needed treatment. There was also slightly less vision gain with as needed compared to monthly injections. Therefore patients seeking the small extra advantage of monthly injections may need to be mindful of the additional burden, risks, and costs of monthly treatments, bearing in mind that the as needed treatment group required 10 fewer injections than the monthly treatment group over the course of 2 years.

Safety data showed similar rates of death, myocardial infarction and stroke between drugs. The proportion of patients with serious adverse events (SAEs) were slightly higher in the Bevacizumab (Avastin) group (39.9% vs 31.7%). SAEs were distributed across many conditions, most of which were not associated with Bevacizumab (the greatest imbalance was in gastrointestinal disorders). The risk of SAEs was not higher with monthly compared to as needed injections.

Other relevant findings from this trial indicate that Ranibizumab treated eyes were more likely to have complete resolution of fluid than Bevacizumab treated eyes. There were more eyes in the monthly treated eyes with no fluid compared to the as needed treated eyes at 2 years.  However the Ranibizumab monthly treated eyes also had the highest incidence of geographic atrophy (GA was more common in both monthly treated eyes than as needed treated eyes). This may be an important finding when considering monthly vs. as needed treatment.

The authors of this trial concluded “The choice of drugs and dosing regimen must balance the comparable effects on vision, the possibility of true differences in adverse events, and the 40-fold difference in cost per dose between Ranibizumab and Bevacizumab”.

In summary, the take home messages are the following:

• Lucentis is licensed for wet ARMD, DMO and RVO
• Avastin is not licensed for intraocular use
• Avastin is a commonly used drug in the United States and Europe for wet ARMD, despite the absence of large scale randomised trials to support its use (Brechner et al. Am J Ophthalmol 2011)
• Ocular side effects of intravitreal injections are similar with both Avastin and Lucentis
• The Royal College of Ophthalmologists does not currently support the routine use of Avastin for ARMD over other anti-VEGF agents which are licensed for this indication
• There is insufficient data on the safety of intravitreal Avastin, but the small differences in safety between Avastin and Lucentis will continue to fuel more discussions

What about Eylea (Aflibercept) for macular degeneration?

Aflibercept (Eylea; Regeneron/Bayer), also called VEGF-trap is a double decoy receptor (VEGFR1 and VEGFR2) fused to the Fc region of human IgG1. It is the most recent member of the anti-VEGF agents, and was developed to have a more potent and prolonged effect. Two important phase III trials of Aflibercept in wet AMD were recently conducted (VIEW1 and VIEW2). Both trials tested the 0.5 MG and 2 MG doses and randomised the 2 MG dose to monthly and 2 monthly treatment regimens compared to monthly Ranibizumab 0.5 MG. During the second year of treatment, both trials changed the treatment regimen to a PRN ie “as required” regimen.

At one year, 95% of patients maintained vision (lost less than 3 lines of vision) when using the 2 MG dose (monthly or 2 monthly). Patients receiving 2 MG Aflibercept monthly gained more letters than Ranibizumab monthly in VIEW1 (10.9 vs. 8.1 letters) but not in VIEW2 (7.6 vs. 9.4 letters) but changes in macular thickness were not different. Racial and ethnic differences between the patients enrolled in the 2 trials may explain the observed differences. Patients receiving 2 monthly Aflibercept showed fluctuations in macular thickness but no corresponding fluctuations in visual acuity. In both trials, the 2 MG Aflibercept dose given every 2 months delivered a comparable gain in visual acuity to monthly ranibizumab. The average number of injections in the 2 monthly Aflibercept group was 11.2 injections over the 2 year period, and 4.7 during the second year (compared to 16.5 and 4.7 for the Ranibizumab group).

The side effect profile of Aflibercept is very similar to that of Ranibizumab. Strokes and myocardial infarction occurred with similar frequencies (Aflibercept 0.7% and 2.6%; Ranibizumab 1.6% and 2.6% respectively).

In summary, Aflibercept offers an attractive alternative to other anti-VEGF agents because of similar efficacy with a longer duration of action.  The above data cannot be extrapolated to non-AMD diseases such as diabetic macular oedema or retinal vein occlusion. Aflibercept (Eylea) is also licenced for Central Retinal Vein Occlusion (CRVO) and expected to have final approval from NICE for DMO in 2015.

PATIENT RESPONSIBILITIES

I will urgently contact my ophthalmologist if any of the following signs of infection or other complications develop:  pain, blurry or decreased vision, sensitivity to light, redness of the eye (compared to immediately after the injection), or discharge from the eye.  I have been instructed NOT to rub my eyes or swim for three days after each injection. Although the likelihood of serious complications affecting other organs of my body is low, I will urgently contact my General Practitioner or go to the hospital casualty if I experience abdominal pain, chest pain, severe headache, slurred speech, or weakness on one side of the body.

Known risks of intravitreal eye injections in general

Your condition may not get better or may become worse.  Serious complications of an intravitreal injection are rare but any or all of the listed complications may cause decreased vision and/or have a possibility of causing vision loss.  Additional procedures may be needed to treat these complications.  During the follow up visits, you will be checked for possible side effects and the results will be discussed with you.

Possible complications and side effects of the intravitreal injection procedure include but are not limited to eye infection (endophthalmitis), retinal detachment, cataract formation (clouding of the lens of the eye), glaucoma (increased pressure in the eye), hypotony (reduced pressure in the eye), damage to the retina or cornea (structures of the eye), and intraocular bleeding.

Patients receiving an intravitreal injection may experience less severe side effects related to the pre-injection preparation procedure. These side effects may include eye pain, subconjunctival hemorrhage (bloodshot eye), vitreous floaters, swelling of the cornea, inflammation of the eye, and visual disturbances. You will receive eye drops with instructions on when to use them to reduce the possibility of an infection.

Prepared by Mr. H.J. Zambarakji
Consultant Ophthalmic surgeon