Adopting the Results of Everest II Into Practice: A Clearer View From a Higher Level Study.

Polypoidal choroidal vasculopathy (PCV), an oddity shown at fluorescein conferences 35 years ago, is now recognized as a common cause of neovascular maculopathy among thoseolder than50years.1 Its prevalencehasnot increased, but new imaging techniques have revealed its features and ophthalmicconsciousnesshasbeen raised.Randomizedclinical trials that compare treatments, rather than case series, are now feasible. Whether PCV is a form of neovascular age-related macular degeneration (nAMD)or adistinct entity is controversial,1,2 but theprevailingnotion is thatPCVisasubtypeofnAMD.Both affect older people and lack systemic associations, yet PCV shows amale predominance that is not present in nAMD,3 the natural history of PCV seems better than that of NAMD with less subretinal fibrovascular proliferation, and PCV responds to photodynamic therapy better than nAMD. In PCV, drusen are absent or sparse in the fellow eye, but these are typically present in nAMD. Polypoidal choroidal vasculopathy constitutesupto55%ofcasesofnAMDinAsianpeople,4 14%inwhite people,5 and anunknownpercentage in people of African ancestry, although it is probably high.1 In this issueof JAMAOphthalmology, Kohandcolleagues6 reported the 12-month results of the EVEREST II randomized clinical trial that compared combined intravitreal ranibizumab (IVR) and PDT with IVR monotherapy among Asian people. The combined therapeutic approach was associated with greater improvement in best-corrected visual acuity (BCVA), more polyp closure, and fewer injections than IVR monotherapy. Using PDT did not increase hemorrhagic complications,7 nor were there other increased adverse effects in the combined arm. Combined IVR+PDT, as performed by the investigators, was better than IVR monotherapy forPCVamongAsianpeople.Moreover, becauseof the pivotal rolesof indocyaninegreenangiography (ICGA)andPDT in the study, the clinical importance of these procedures has been enhanced. Clarification of 3 aspects of the retreatment regimen would help clinicians to adopt the results into practice. Retreatment occurred after the mandatory 3 monthly injections if BCVA dropped relative to the previous visit or if there was any evidence of disease activity on spectral-domain optical coherence tomography (SD-OCT). Conventional interpretation would suggest that a threshold for BCVA of change of 5 letters would be used, and that was what was used in EVEREST, but what was actually used in the EVEREST II? For the SD-OCT criterion, conventional interpretation would be that any intraretinal or subretinal fluid implied activity and a need to retreat; was that the criterion used in the clinical trial? Also, because in PCVmany SD-OCT changes involve the subretinal pigment epithelial features, did these enter into the criteria for retreatment? Thediagnosis of PCV is tricky and requires ICGA.Thedefinition is early focalhyperfluorescenceon ICGAplus 1of the following: nodular polypsona stereoscopic viewing, ahypofluorescent halo around a nodule, a branching vascular network, pulsatile nodule on dynamic ICGA, an orange subretinal nodule on color fundusphotography results, or subretinal hemorrhage thatwas4discdiameters ormore.8TheEVEREST II protocolprojecteda screen fail rateof 20%,but theactual ratewas 34%. It would be helpful to knowwhat led to the screen fails. If it was because investigators diagnosed PCV but the reading center disagreed, that would signal how difficult the diagnosis can be and emphasize scrutiny of ICGA for polyps and branching vascular networks and SD-OCT for tall, peaked, and notched pigment epithelial detachments and the double layer sign. The results of EVEREST II suggest that all Asian people older than50yearswithaserosanguinousmaculopathyshould have ICGA to help determine if PCV is the cause. If the definition is met, combined IVR+PDT as described in Koh et al6 offers better outcomes than serial IVR monotherapy. If typical nAMDwithout these features is found instead, serial intravitreal antivascular endothelial growth factor therapy without PDT is assumed, but not known, to be a better option. What about serosanguinous maculopathy in older patients from other racial/ethnic groups? The results of EVEREST II cannot be generalized to these patients without additional research, but there is reason to suspect that they might also apply to these racial/ethnic groups. Thus, baseline ICGA in all cases of serosanguinous maculopathies to look for PCV is rational, and if PCV is present, combined therapy in these subgroups is worth considering. To apply the results of EVEREST II, ICGA also needs to be done during follow-up if the BCVA drops compared with the previous visit or if the optical coherence tomography results showdiseaseactivityand ithasbeenmore than3months since the last PDT. In the aftermath of EVEREST II, the use of ICGA and PDT by retina specialists may increase. What about combined therapy inwhich aflibercept or bevacizumab are substituted for ranibizumab?EVEREST II does not address this issue, andclinicianswill need touse their own judgment if IVRisunavailableoreconomically impractical.Further comparative effectiveness studies of these combined approaches will need to be done. What should the clinician do who lacks ICGA or PDT and is confrontedwithanAsianpatientwithactivePCV?Serial IVR produces good results, if not as good as combined IVR+PDT. If PDT is available but not ICGA, it may be tempting to apply Related article page 1206 Research Original Investigation RanibizumabWith orWithout Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy