I. Conceptos generales
3. Aplicación en la escuela y en las edades infantiles y juveniles
Introduction
The onset of neovascularisation in age-related macular degeneration (AMD) is accompanied by central distortion and blurring which, when left untreated, intensifies into a dense central scotoma.1These visually disabling effects of neovascular age-related macular degeneration (nAMD) are monitored by measuring distance visual acuity (VA), which is a surrogate for central visual function; a drop of≥15 letters in the number of letters read on a logMAR [log(minimum angle of resolution)] letter chart (equivalent to the loss of three lines of letters) is considered to be a visually significant event.2Until 2005, all treatments that were considered beneficial in the management of nAMD merely limited VA loss relative to untreated control subjects or natural history.3,4Thus, at that time successful treatment was defined in terms of slowing down the rate of VA loss. The most effective treatment for nAMD was verteporfin (Visudyne, Novartis) photodynamic therapy (PDT) which resulted in a reduction of the proportion of patients who suffered a 15-letter loss [three lines on the Early Treatment of Diabetic Retinopathy Study (ETDRS) VA chart] from 69% to 54%.3,5The most impressive change that occurred around this time was the introduction of ranibizumab (Lucentis®, Novartis). Ranibizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF), which is a potent mitogen and inducer of permeability in blood vessels.6Two pivotal ANCHOR (ANti-vascular endothelial growth factor antibody for the treatment of predominantly Classic CHORoidal neovascularization in age-related macular degeneration) and MARINA (Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular Age-related macular
degeneration) clinical trials that established the superiority of ranibizumab as a treatment for nAMD reported their findings.7,8At 12 and 24 months,>90% of eyes treated with ranibizumab (0.5 mg) avoided the loss of three lines of VA compared with<64% of eyes treated with PDT (the comparator in the ANCHOR trial) or 62% of eyes treated with sham injections (the comparator in the MARINA trial). Even more importantly, eyes treated with ranibizumab showed on average anincreasein acuity of between 5 and 10 letters read on an ETDRS vision chart with some 30% achieving 70 letters (Snellen equivalent of 6/12), a level of vision which is compatible with visually demanding tasks such as fluent reading and driving. These results exceeded all expectations, as trials of other therapeutic agents, including the VEGF inhibitor pegaptanib (Macugen, Pfizer),3,4had shown on average areductionin acuity in treated eyes of between two and three lines over 24 months.
Although the outcome after ranibizumab therapy was clearly impressive, this was achieved using an intensive dosing schedule of monthly injections of the drug into the vitreous cavity of the eye. The method of administration is an invasive procedure with the attendant risks of infection and iatrogenic eye trauma. In addition, the requirement for monthly attendance over many years poses serious challenges for elderly patients. Furthermore, such intensive treatment regimens also create difficulties in terms of resource implications for health service providers. A small study [PIER: a study of rhuFAB V2 (ranibizumab) in subjects with subfoveal choroidal neovascularization secondary to age-related macular degeneration], which used a less intensive dosing schedule of three 4-weekly injections of ranibizumab 0.5 mg followed by retreatment at fixed 3-monthly intervals, did not yield equivalent VA results as those observed in the MARINA and ANCHOR trials.9Although mean VA improved in the PIER study in the first 3 months in a manner similar to that seen in ANCHOR and MARINA, it gradually decreased thereafter, dropping back by 12 months to the mean observed at baseline. By contrast, PrONTO [Prospective Optical Coherence Tomography (OCT) Imaging of Patients with Neovascular Age-Related Macular Degeneration Treated with intraOcular Ranibizumab], another small clinical trial of some 40 patients, suggested that a reduction in treatment frequency could be achieved through rigorous tailoring of treatment to morphological
parameters without compromising VA outcomes.9,10Taken together, these findings implied that there was a variable need for retreatment among patients, and that a reduction in treatment frequency or alteration
of dosing interval would require continuous monitoring and tailoring of therapy. The study design of the ANCHOR and MARINA and other smaller randomised controlled trials (RCTs) that investigated effectiveness of ranibizumab also did not permit conclusions to be drawn about the total duration of treatment required.
Although the role of ranibizumab in the management of nAMD was being investigated, another drug [bevacizumab (Avastin®, Roche)] was identified by a number of small uncontrolled case series as having equivalent visual benefits.11Remarkable improvements in acuity and morphological findings following intravitreal injection of bevacizumab were reported by investigators from countries across the world,12,13 primarily because it was available and the cost was more affordable. Bevacizumab (a pan-VEGF
monoclonal antibody, as is pegaptanib) is the parent molecule from which ranibizumab was derived and the same manufacturer holds the patents and licences for both drugs. Bevacizumab was licensed for use in colorectal cancer, and the therapeutic dose for systemic administration for this condition is approximately 1000 times greater than that required for intraocular use. Thus clinicians were able to offer a cheap alternative to ranibizumab through unlicensed use of bevacizumab. The IVAN (Inhibit VEGF in Age-related choroidal Neovascularisation) trial was developed to test whether or not visual results obtained with bevacizumab were as good as those obtained with ranibizumab.
By virtue of their ability to inhibit all classes of VEGF, both ranibizumab and bevacizumab have the potential to induce serious ocular and systemic side effects. VEGF is known to have an important growth-promoting role in the retina14and is also thought to maintain the fenestrated phenotype of the choroidal vasculature.15Therefore, there is concern that pan inhibition of VEGF over long periods of time can cause atrophic changes in neural, retinal pigment epithelial (RPE) and vascular cells and tissues, with serious consequences for visual function.
Although no such adverse effects have been detected in clinical trials using VEGF inhibition
strategies,4,7–10,16the data available from trials relate to relatively short periods of follow-up, with few patients having been followed beyond 2 years. Repeated intraocular penetration for drug delivery carries a risk of endophthalmitis, traumatic cataract or retinal detachment. However, as shown by the VISION (pegaptanib for neovascular age-related macular degeneration) clinical trials, adherence to protocols that emphasise sterility and administration of the drug by experienced personnel reduces these risks to acceptable levels.4
Systemic side effects remain a concern as the pooled findings from ANCHOR and MARINA trials revealed a slight excess of thromboembolic events in the highest dose of ranibizumab groups and a small increase in non-ocular haemorrhages in the treatment groups.7–9In addition, circulating antibodies to ranibizumab were discernible in serum samples in a significant proportion of patients who received ocular administration of the drug.7,8As bevacizumab had not been tested in a controlled trial environment, there was no orderly collection of information on its potential to cause systemic drug toxicity. Therefore, the IVAN trial also proposed the collection of serum samples from participants immediately prior to the Trial, and at the first post-injection visit, for the assay of VEGF, the levels of VEGF inhibitors themselves and to detect circulating antibodies to the inhibitors.
The IVAN trial also offered the opportunity for the creation of an accompanying biobank of serum and deoxyribonucleic acid (DNA). The recent advances in pharmacogenomics have revealed that genetic variation modifies the therapeutic response to drugs in a number of disease conditions.17Thus, there is increasing enthusiasm for linking DNA biobanks to RCTs in which participants are extremely well
phenotyped. Trials using VEGF inhibition strategies in cancer have shown that both survival and toxicity are influenced by genetic variation.18It is plausible that similar mechanisms may influence visual outcomes following therapeutic VEGF inhibition in choroidal neovascularisation (CNV). The IVAN trial therefore proposed the construction of a DNA biobank to test pharmacogenetic associations between treatment responsiveness and key genetic polymorphisms.
Summary of existing evidence
There was no systematic review of VEGF inhibitors in the treatment of nAMD due to AMD in 2007 when the IVAN trial was conceived. Neither was there a head-to-head comparison of the two main inhibitors of VEGF that were available at that time. There were no data on the minimum treatment frequency/duration that is required to maintain the maximal visual benefit achieved with either of the drugs studied in IVAN, and no trial had compared continuing monthly treatment with early cessation of VEGF inhibition with treatment being restarted if signs of lesion reactivation were detected. Therefore, the research questions that the IVAN study set out to address had not been investigated directly previously.
Importance of the health problem to the NHS
Epidemiological studies have shown that there are some 25,000 incident cases of nAMD each year in the UK.1RCTs had demonstrated the substantial benefit of ranibizumab for nAMD. Bevacizumab is considerably cheaper than ranibizumab. The drug costs alone for monthly administration of ranibizumab were estimated to be about £11,000 per patient per year and the cost of assessments and treatment delivery about £2500 per year, with a potential annual cost to the UK NHS of up to £300M per year. The cost-effectiveness of VEGF inhibitor treatment is influenced greatly by the difference in drug cost, with ranibizumab being 20 times the price of bevacizumab. The costs of administering treatment are also high and there were no recommendations about the likely duration of treatment required.
The absence of robust information about the safety of bevacizumab, and uncertainty about treatment frequency for either drug, formed the basis for the alternative treatments in the IVAN trial.4Accumulating evidence that susceptibility to nAMD is influenced by the carriage of specific polymorphisms in a number of genes which encode proteins involved in immune mediation and regulation,19–21and the fact that antibodies to the VEGF inhibitors had been found to develop over time, provided a strong rationale for the establishment of a DNA and serum biobanks in the IVAN trial. While the IVAN trial was being designed, The Comparison of Age-related macular degeneration Treatments Trials (CATT)22,23was developed in parallel in the USA. With the acquiescence of the funding organisations of the two trials, agreement was reached to share information about the design and conduct of the trials, such as protocols and methods for the collection of adverse events (AEs). This exchange of information allowed CATT22and IVAN investigators to design the trials to facilitate future meta-analyses of the outcomes of the two trials.