Intravitreal injection: balancing the risks

Abstract

Intravitreal triamcinolone (iVTA) had gathered pace in the management of retinal diseases. By simply searching with the string ‘intravitreal triamcinolone’ in PubMed, it returns over 400 publications, with over 300 in the past 2 years. Despite the large number of publications, there are still very limited data on long-term efficacy (over 12 months). Furthermore, if one considers sham-controlled prospective randomised clinical trials (RCT) only, the efficacy is in doubt. One of the original RCT in using iVTA in neovascular age-related macular degeneration (AMD) showed a negative result. Similar results were obtained in a more recent study on central retinal vein occlusion over 4 months. The difference between vision changes was significant only at 1 month. There was no meaningful difference in the occurrence of neovascularisation of the iris between the two groups. The only RCT with positive results is on diabetic macular oedema over 6 months from Jonas et al. The control group was only 12 eyes and laser treatment was not offered. When laser treatment was offered, there were no differences. Furthermore, when macular grid laser was performed 3 weeks after iVTA, visual outcome was better than iVTA alone especially at 6 months. However, the complications of using iVTA are numerous; intraocular pressure rise and cataract are common occurrences. In a retrospective analysis in Southampton, the ocular morbidity is high as well as the case report of ocular perforation and inadvertent administration of intralenticular injection. One would probably consider in the face of the lack of evidence that is unacceptably high. Nevertheless, the introduction of this off-label treatment has not received any political problems in the UK. It is apparent to us that as triamcinolone is widely available in the NHS hospital formulary, is relatively inexpensive and hence can be used without going through any funding request nor special committees. It has become widely available. Nonetheless, failure to communicate to patients that iVTA treatment is off-label, might have medicolegal implication. So are we seeing the same with the introduction of off-label used of Avastin? Several editorials in the UK, including in this journal as well as the British Journal of Ophthalmology, have discussed the issues. As a recap, Avastin and Lucentis have presented with us an unprecedented dilemma. Lucentis is licensed in the US in June 2006 and is likely to be licensed in Europe, including the UK, in the first quarter of 2007. The clinical trial results of Lucentis were nothing short of amazing, with over 95% of patients attaining stabilisation and up to 40% with significant visual improvement. However, Lucentis is considered expensive. In the USA, Lucentis is priced at USD$1950 per single use vial, given either monthly or of injections every 3 months after a three dose loading phase given every month. This reduced dosing regimen led to less impressive results than regular monthly dosing (PIER study, unpublished data). Avastin is derived from the same murine antibody as Lucentis, has similar binding sites, but is a significantly larger molecule with potentially less effective retinal penetration. The affinity to those binding sites are of the order of 16-fold less. Nonetheless, in animal models, Avastin stays in the eye longer, although the half-life of Avastin when administered intravitreously in humans, is yet to be determined, and when given systemically in man for colorectal cancer, the half-life of Avastin has been reported at 21 days, significantly greater than 2 h with Lucentis. Hence, longer eye exposure of Avastin and increased systemic exposure compared to Lucentis might balance out the lower VEGF-binding affinity and the slower retinal penetration. On the basis of small-scale animal studies, Avastin may be safe leading to extensive but short-term, uncontrolled, widespread use in Laser and Retinal Research Unit, King’s College Hospital, Denmark Hill, London SE5 9RS, UK