The outcome after ranibizumab therapy in the MARINA and ANCHOR Phase III trials was achieved using an intensive dosing schedule of monthly injections into the vitreous cavity of the eye. A small study (PIER) of a less intensive dosing schedule (monthly injections for 3 months followed by injections every three months) failed to replicate these visual acuity results, although another small study (PrONTO) suggested benefit from a more individualised approach to injection frequency and follow-up.
Bevacizumab is the parent molecule from which ranibizumab was derived, and is substantially cheaper (although unlicensed in this setting). The IVAN study was developed to test whether or not visual results obtained with bevacizumab in the treatment of neovascular age-related macular degeneration (AMD) were as good as those obtained with ranibizumab. It was also designed to investigate whether a strategy of withdrawing anti-VEGF treatment after 3 months and only retreating if certain criteria were met could maintain the visual outcomes seen with continuous monthly dosing.
The study included patients aged ≥50 years with a best corrected distance visual acuity (BCVA) ≥ 25 letters measured on an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart. Randomised treatment was with ranibizumab (0.5mg) or bevacizumab (1.25mg), and was either continuous (monthly treatment) or discontinuous treatment (monthly for three months, followed by retreatment with a further cycle of three doses only if prespecified clinical and OCT criteria for active disease were met). In all cases patients were reviewed on a monthly basis.
The primary end point was mean BCVA after 2 years of follow-up; this did not differ significantly either by drug or by regimen. The comparison by drug was however inconclusive, as bevacizumab was neither inferior (as the 95% CI of the difference included zero) nor non-inferior (as the 95% CI included the 3.5-letter non-inferiority margin) to ranibizumab. The economic evaluation found that ranibizumab was not cost-effective (cost of £3.5M per quality-adjusted life year [QALY] gained compared with bevacizumab); it remains uncertain whether or not continuous bevacizumab is cost-effective compared with discontinuous bevacizumab (£30,220 per QALY).
The authors conclude that ranibizumab and bevacizumab have similar visual acuity outcomes, although bevacizumab provides much better value for money. They comment that the lack of change in UK practice as a result of this study is ‘disappointing’; despite investment in the IVAN trial, the UK has one of the lowest uses of bevacizumab for ophthalmic conditions among comparable developed countries.
NICE issued guidance (TA155; 2008) recommending the use of ranibizumab for the treatment of wet AMD under certain circumstances – please see the link below for further information.