HOW LONG SHOULD WE TREAT PATIENTS WITH ANTI-VEGF THERAPY FOR WET AMD ONCE THE LESION IS DRY?

By Thomas Friberg, MD

Although our knowledge of the pathogenesis of wet age-related macular degeneration (AMD) has improved, we still know relatively little about what exactly triggers new blood vessel formation. We assume that most of the vascular endothelial growth factor (VEGF) that induces choroidal neovascularization is produced locally and we must rely on indirect measures of new vessel activity such as optical coherence tomography (OCT) alterations and leakage on fluorescein angiography (FA) to guide us. However, eyes with little retinal thickening can still demonstrate leakage (activity) on FA, and the patient’s visual acuity is often not reflected by the OCT findings.  

In treating wet AMD, we are strongly influenced by the results of our clinical trials but we are not bound directly to them.  For instance, in the pivotal Genentech MARINA and ANCHOR trials, patients were treated with Lucentis (Ranibizumab) on a monthly basis and showed visual improvement after a year in about 30 to 35% of patients.  Similarly, the pioneering VISION trial also demonstrated efficacy for Macugen (pegaptanib sodium) in preventing visual loss.  With both drugs, there was reasonably strong evidence that continued treatment is superior to intermittent treatment with respect to visual outcome.  However, the economic cost of treatment is high, as is the treatment burden for the patient and the physician.  Hence, we are quite interested in reducing the frequency of intraocular injections. 

At present, we use FA, OCT measurements, and visual acuity to help us make our treatment decisions, particularly after several rounds of injections.  A change in these parameters as seen over time is more useful than a single result.  For instance, in the context of decreasing visual acuity, or for that matter an increasing visual acuity, many physicians would not stop therapy until a steady state was reached almost independent of the OCT or FA result.  Retreatment decisions are based most often on OCT thickness and FA in conjunction with the clinical exam.  In the face of a lesion that is growing in diameter or that is associated with increasing subretinal fluid or retinal thickening, most specialists would continue to treat. 

If no incremental changes in these parameters are present after several months of treatment, many retinal specialists try to reduce the frequency of treatment.  From my point of view, when I am considering a cessation of treatment after following a specific treatment regimen, I am likely to treat with at least one more injection after clinical stability is reached.  After that, I monitor the patient relatively carefully, and have the patient come back in four to six weeks to reassess the situation. Typically, I obtain either an OCT or an FA to follow my treated patients at each visit (both are obtained at the initial visit).  If I am considering a treatment hiatus at a follow-up visit, I am inclined to order both an OCT and a FA before making that decision.  If no additional loss of vision or increase in lesion activity develops, I might defer treatment longer.  One could also use general guidelines for retreatment such as a retinal thickness increasing by 100 microns or more, or a visual acuity reduction of three to four letters or more.  While such an approach may seem generally practical, there are several implicit dangers; specifically, if a patient misses a visit, vision might decrease between treatments and not be recoverable.  Hence, one’s practice must be very diligent about missed patient visits. The patient also must be told to come in immediately if their vision deteriorates.

In a sense, initiation of treatment for wet AMD is a more simple decision than the continuation of treatment decision.  One could draw a parallel with uveitis where patients are treated with high-dose steroids or other anti-inflammatory medications and then weaned off, if possible.  However, when diminishing the dosing regime, patients are followed quite carefully to avoid any flare-up or visual loss.  Similarly with wet AMD, monitoring a patient for changing parameters and treating accordingly is, to many, a reasonable alternative strategy compared to one or two years of multiple continued injections done independent of any monitoring. Arguably, treating automatically “according to protocol” for years makes follow up monitoring with OCT and FA superfluous, as the test results are not influencing treatment decisions.

One could also consider an induction-maintenance type approach where once the exudative lesion has been induced to a more inactive state, the patient is shifted to a drug that has greater durability and/or a better safety profile over the long term.  While several studies are investigating this approach, including (OSI)/EyeTech’s LEVEL trial, it remains uncertain at this time whether the desired result (sustained and stable visual improvement with a reduced treatment burden) will be attained with this strategy.  What does seem certain is that years from now, longer acting, more robust anti-VEGF agents combined with better delivery systems will replace today’s need for so many repeated injections.