New questions being raised about treatment of retinal disease

Issue: February 2012

ByPaolo Lanzetta, MD

Paolo Lanzetta

In the last decade, the treatment armamentarium for the care of retinal vascular and neovascular diseases has dramatically evolved.

Anti-VEGF therapy is now considered a panacea for choroidal neovascularization secondary to age-related macular degeneration, macular edema secondary to diabetes and retinal vein occlusion. In addition, some reports have appeared on the use of anti-VEGF agents in the treatment of retinal neovascularization during proliferative conditions. As a result, other treatment choices, such as laser photocoagulation, have lost or are losing their position as first-line therapies. Similarly, fluorescein angiography as the mainstay in retinal diagnostics and monitoring tools is progressively being replaced by optical coherence tomography.

In this dynamic and complicated scenario, some important questions are being raised: What is the best drug available? What is the best regimen of treatment? What about post-marketing surveillance of pharmacotherapies? Is OCT the ideal tool to assist physicians in the re-treatment strategy? Is the cost of new ophthalmic pharmacotherapies a relevant issue?

Anti-VEGF treatment

VEGF is one of the key components of conditions linked to vascular hyperpermeability and proliferation. There are several other inflammatory cytokines and factors that may be targeted with the aim to reduce retinal edema and neovascular growth. Currently, anti-VEGFs and steroids have shown their superiority to photodynamic therapy, laser or observation. Lucentis (ranibizumab, Novartis/Genentech), Eylea (aflibercept, Bayer/Regeneron), Macugen (pegaptanib, Pfizer) and Ozurdex (dexamethasone intravitreal implant, Allergan) have been approved by the U.S. Food and Drug Administration or the European Medicines Agency for ocular use in different diseases. Other compounds targeting different steps in the pathogenic cascades are under evaluation and will hopefully increase the treatment possibilities, either as monotherapy or combination therapy.

Avastin (bevacizumab, Roche/Genentech) and to some extent triamcinolone acetonide are being widely used off label because of the low cost and some presumed evidence of efficacy. The use of off-label drugs raises important questions on the value of quality, safety and efficacy of human drugs. Modern medicine and regulatory standards are based on rigorous testing from the laboratory to the bedside. While the off-label use of drugs improves the treatment armamentarium in many conditions, it is also clear that there may be inadequate scientific evidence to support its effectiveness and overall safety. Policies and economics are part of the complex process of health management; however, they should not elude safety and efficacy assessment through adequately powered trials and improved surveillance systems. Suggesting that off-label drugs should be routinely used instead of on-label compounds in the absence of such strong evidence is not in the interest of patients’ health and might increase costs rather than save money in the long term. If on one hand anti-VEGFs have created the wonderful opportunity to offer something that really works for diseases in cases in which nothing could be done until recently, on the other hand, they have created an alarming situation for health care systems worldwide. If preserving vision is the issue at stake, ophthalmology becomes necessarily a field in which to invest considerable resources.

Some head-to-head studies are currently comparing or will start to compare the efficacy of different drugs in a variety of conditions such as AMD, diabetic macular edema and retinal vein occlusion. The CATT was a non-inferiority study comparing ranibizumab to bevacizumab in the treatment of wet AMD. The major efficacy results at 1 year showed that ranibizumab given on a monthly basis was not inferior to ranibizumab given in an individualized, as-needed regimen. This was quite unusual because all the preceding trials showed that the fixed monthly regimen provided the best visual outcomes as compared with other less stringent regimens such as as-needed and quarterly. Also, bevacizumab given monthly was non-inferior to ranibizumab given monthly. However, the comparison between as-needed bevacizumab and monthly ranibizumab or monthly bevacizumab were inconclusive. Ranibizumab did better at the end of follow-up in all the other parameters considered, such as leakage, change in retinal thickness and absence of fluid. Of note was that in the as-needed arms with both drugs, the number of injections was quite high as compared with real-life scenarios and other studies with as-needed regimens. In 1 year, patients in the bevacizumab arm received on average 7.7 injections and patients in the ranibizumab arm received on average 6.9 injections. Therefore, if bevacizumab is chosen as an alternative option to ranibizumab it should be given on a monthly basis. If an as needed regimen is preferred, at least eight injections in 1 year should be administered. Although the CATT was not powered to determine the safety of the two drugs, some safety signals should be considered. Second year outcomes of the study will bring relevant information.

In a recent study conducted at our clinic, 90 naïve eyes with CNV secondary to AMD treated with ranibizumab for 1 year were analyzed for deviations from the intended treatment protocol, number of injections received, visual acuity and retinal thickness outcomes. In this real-world setting, results were less favorable than reported in controlled clinical trials and protocol deviation was a frequent finding. Visual acuity could only be stabilized instead of improved, as usually reported with the use of anti-VEGFs within clinical trials. Patients received only 4.8 injections in 1 year. The conclusions are that current as-needed regimens with monthly follow-up may be difficult to achieve and patients may need a higher number of injections than usually given.

Therefore, alternative treatments and follow-up regimens more easily applicable in real-world clinical settings should be explored. The as-needed concept might be appealing. However, the criteria to tailor it to the individual patient’s response are still lacking, and re-treatment parameters and the interpretation of these parameters are still unclear. Spectral-domain OCT, which has now replaced time-domain OCT in the evaluation of patients with retinal conditions treated with anti-VEGFs, provides more information such as the volume of intraretinal and subretinal fluid including retinal pseudocysts, the integrity of the external limiting membrane and the inner segment/outer segment junction, which are still quite difficult to interpret and include into a re-treatment algorithm. It might make sense to consider treating patients on a fixed schedule with less stringent regimens, maybe every 2 months as suggested with aflibercept. As said, in the CATT, the average number of injections needed when rigorous as-needed re-treatment parameters are used is between seven and eight. Interestingly, a fixed schedule of injections at 2-month intervals leads to an equal number of injections but without the burden of monthly visits, OCTs, functional assessments and other imperfect variables that are subject to wrong interpretation.

Post marketing surveillance

Active post-marketing surveillance of adverse drug events is an essential part of the therapeutic process. However, monitoring drug use and safety is complicated and does not have a simple solution. Several steps should be considered, including improved collaboration between payers and insurers who approve and track usage as well as manufacturers, prioritizing higher-risk drugs in an improved drug surveillance system, better evaluation of new drugs, and greater surveillance powers for regulatory bodies. Post-marketing surveillance and risk-assessment programs are mandatory to identify adverse events that did not manifest during the drug approval process. However, monitoring safety of drugs used off label is even more complicated, and as a result, few reliable data on systemic safety may be available on the ocular use of bevacizumab.

Laser treatment

Finally, what about the role of laser in the treatment of retinal vascular and proliferative conditions in the era of pharmacotherapy? Many signals come from recent trials, mostly on diabetic macular edema, that suggest that, at least in the mid-term, anti-VEGFs are more efficacious than laser photocoagulation and that combining laser treatment to anti-VEGF use does not reduce the number of injections needed. In the meantime, the importance of laser is still well recognized in the treatment of retinal proliferative diseases. Newer, less invasive laser photocoagulators and laser treatment strategies may further expand the treatment armamentarium in the near future.

Paolo Lanzetta, MD, can be reached at University of Udine, Department of Ophthalmology, Piazzale S. Maria della Misericordia; 33100 Udine, Italy; +39-0432-559-905; fax: +39-0432-559-904; email: paolo.lanzetta@uniud.it.
Disclosure: Dr. Lanzetta is a consultant for Allergan, Bayer and Novartis.