Case study: IVAN Impact Case Study
The IVAN trial was funded by the NIHR Health Technology Assessment (HTA) programme and supported by the NIHR Clinical Research Network's (CRN) Ophthalmology Specialty. Find out more about the NIHR support for ophthalmology research here.
The IVAN Trial: A randomised controlled trial comparing alternative treatments to inhibit vascular endothelial growth factor (VEGF) in neovascular age-related macular degeneration (nAMD)
- The study was funded by the NIHR Health Technology Assessment programme
- The IVAN trial recruited, randomised and treated 610 participants across 23 ophthalmic units in the NHS
- The final primary outcome was best corrected distance visual acuity at two years follow-up
- The study found no difference in treatment efficacy between the two drugs investigated
- The study found that continuous monthly treatment was more effective than discontinuous treatment
Background and Investigation
Macular degeneration comprises a group of diseases characterised by the gradual breakdown of the tissues in the central portion of the eye (the macula). Age-related macular degeneration (AMD) is the most common cause of blindness in the UK and is thought to affect one in ten people over 50 years of age. Neovascular AMD (nAMD), also referred to as ‘wet AMD’, is particularly severe and can cause blurry or distorted vision, or a central blind spot. The condition is due to the growth of leaky new blood vessels in the eye, caused by a protein called vascular endothelial growth factor (VEGF). Without treatment, two thirds of people with nAMD experience severe loss of sight within two years of diagnosis.
The standard treatment for nAMD is injection of VEGF-inhibitors. The IVAN Trial sought to answer two nAMD treatment questions. Firstly, the trial compared the efficacy of the existing treatment for nAMD, the expensive drug ranibizumab (Lucentis), with a cheaper alternative (bevacizumab - or Avastin). Secondly, it evaluated treatment frequency. Patients either received continuous monthly treatment for two years or received three monthly injections and were then monitored for two years, with treatment being repeated if there were any signs that the condition had worsened.
A total of 610 patients were recruited and were randomised into different treatment groups. They were given one of the two VEGF-inhibiting drugs and were treated either continuously (monthly) or discontinuously (three-monthly, with a review and treatment re-initiated if signs of disease activation were identified).
Outcomes and Findings
Two years after the study, patients attended follow-up appointments where their visual acuity was checked. The results showed that the two drugs had improved eyesight by a similar amount. It was also shown that monthly treatment improves eyesight slightly more than intermittent treatment, and appears to be safer.
Two years of treatment with Lucentis costs more than £18,500 per patient, while the same treatment with Avastin costs £3,000. The results of the IVAN trial clearly showed that Lucentis was not cost-effective compared with Avastin.
The team welcome the fact that the NHS will have the opportunity to extend the use of Avastin to routine clinical practice.
Professor Usha Chakravarthy, Chief Investigator
Value to the NHS
The IVAN trial is regarded by the NIHR as one of the most important trials of the last decade. It provided clear evidence that Avastin is a cheaper, effective alternative to Lucentis for the treatment of nAMD. In the UK, if Avastin were used as the treatment of choice, the NHS would be able to save millions of pounds each year.
The study findings have had an international impact, acting as the basis for recommendations made in the World Health Organisation’s (WHO) 2017 report ‘The selection and use of essential medicines’, and informed National Institute for Health and Care Excellence (NICE) clinical guidelines on the treatment of nAMD, concluding that Avastin was as safe and effective as Lucentis. NHS Clinical Commissioners and the Royal College of Ophthalmologists welcomed the fact that NICE had acknowledged the similar safety and effectiveness of all the anti-VEGF drugs.
In September 2018, the findings of the IVAN trial helped win a landmark court ruling between two drug companies and 12 Northern Clinical Commissioning Groups (CCGs) which focused on the CCG’s decision to offer the drug which is not currently licensed to treat nAMD.
The long-term information which the researchers have been able to collect with additional NIHR funding, combined with the original IVAN dataset, is immensely valuable both to doctors and commissioners in the UK but also beyond. Since the trial ended, the team have had several requests from academics and industry for the IVAN dataset and associated retinal images, even though imaging technology has advanced hugely since the study recorded its data.
There is now the potential to make considerable cost savings whilst empowering ophthalmologists to make clinical judgements with individual patients on the most appropriate choice of treatment.
A joint statement from NHS Clinical Commissioners and the Royal College of Ophthalmologists
Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation: 2-year findings of the IVAN randomised controlled trial. Lancet 2013; 382: 1258-67. doi: 10.1016/s0140-6736(13)61501-9.
Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Wordsworth S, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology 2012; 119(7): 1399-411. doi: 10.1016/j.ophtha.2012.04.015.
Dakin HA, Wordsworth S, Rogers CA, Abangma G, Raftery J, Harding SP, et al. Cost-effectiveness of ranibizumab and bevacizumab for age-related macular degeneration: 2-year findings from the IVAN randomised trial. BMJ Open 2014; 4: e005094. doi: 10.1136/bmjopen-2014-005094.
Chakravarthy U, Harding SP, Rogers CA, Downes S, Lotery AJ, Dakin HA, et al. A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN). Health Technology Assessment 2015; 19(78). doi: 10.3310/hta19780.
Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews 2014; (9): CD011230. doi: 10.1002/14651858.CD011230.pub2.
Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database of Systematic Reviews 2019; (3): CD005139. doi: 10.1002/14651858.CD005139.pub4.