Anti-VEGF Pharmacotherapy as an Alternative to Panretinal Laser Photocoagulation for Proliferative Diabetic Retinopathy.

From 1976 to 1981, the results of the Diabetic Retinopathy Study identified that panretinal laser photocoagulation (PRP) for high-risk proliferative diabetic retinopathy (PDR) reduced the rate of severe visual acuity loss by more than 50% compared with the natural history of the disease.1,2 The Diabetic Retinopathy Study identified 4 key risk features of PDR (retinal neovascularization [NV]; NVwithin 1 disc diameter of the optic disc [NVD]; severe NV [NVD >1⁄4 to 1⁄3 disc diameters orNVelsewhere >1⁄2disc diameter]; andpreretinal or vitreous hemorrhage) and indicated that the presence of 3 or more risk factors constituted high-risk characteristics for developing severe vision loss.3 The results of the Diabetic Retinopathy Study have served as the basis for the accepted standard of care in the management of PDR for decades. In this issue of JAMA, the investigators from the Diabetic RetinopathyClinicalResearchNetwork (DRCR.net)present the results of a clinical trial comparing PRP and intravitreous ranibizumab among patients with PDR.4 This noninferiority study included 305 adults with PDR, including 89 participantswhohadbotheyesenrolled, for a total of 394studyeyes. Patients in the ranibizumab group (n = 191 eyes) received intravitreous ranibizumab (0.5mg) (andPRP if treatment failed) and received ranibizumab as needed for diabetic macular edema, whereas patients in the PRP group (n = 203 eyes) received PRP and ranibizumab as needed for diabetic macular edema.At 2 years, themean improvement in visual acuity letter score was 2.8 in the ranibizumab group vs 0.2 in the PRP group (difference, 2.2; 95% CI, −0.5 to 5.0), meeting the prespecified 5-letter criterion for noninferiority. Theauthorsconcludethat“amongeyeswithPDR,treatment with ranibizumabresulted invisual acuity thatwasnoninferior to (notworse than)PRPat2years.Although longer-termfollowup isneeded, ranibizumabmaybeareasonable treatmentalternative at least through 2 years for patientswith PDR.” This study represents a fundamental alternative therapeutic option that is now available to clinicians for the management of PDR. Some important clinical decisionsneed tobe considered in themanagement of patientswithhigh-risk PDR (ie, presenceof PDR that theophthalmologist intends tomanage with patients with PRP alone and when PRP can be deferred for at least 4 weeks). First andmost important, the findingswerebasedona rigorous study design and result in an expanded treatment option forpracticingophthalmologists. By combining theknown standards of care with the new alternative strategies, clinicians nowhave evidence for an effective pharmacotherapeuticoption in theshort-termmanagementofpatientswithhighrisk PDR. The noninferiority design supports the use of an intravitreal anti–vascular endothelial growth factor (VEGF) agent such as ranibizumabas an alternative to immediate PRP for initial management of patients with high-risk PDR. Practicing ophthalmologists who care for patients with high-risk PDR should be aware of these important issues. In the context of awell-conducted randomizedclinical trial, consistent and reliable follow-upof studyparticipants usually occurs. However, the reality is that the practice and care of patientswithdiabetic eyedisease in thecommunity isnot always ideal. Regular follow-up is a critical element in the management of patients treated with intravitreal anti-VEGF therapy. In the community, poor follow-up could prove disastrous for visual outcomes amongpatientswho are nonadherent to recommended follow-up assessments and monitoring. For instance, if patients who are less adherent to recommended follow-up receive 1, 2, or 3 intravitreal anti-VEGF injections for high-risk PDR notice an improvement in visual acuity but fail to follow up for continued care, they may develop recurrent high-risk retinopathy andpotentially incur vision loss.On the other hand, high-risk patientswith PDRwhohave completed PRPand fail to return for carewould likelyhaveabetter chance of sustaining an effective, long-term treatment and thusmay reduce the long-term riskof severe vision loss. Clinicianswith decades of experience observing and managing the longtermcomplicationsofPDRunderstand thatmostpatientswith adequate PRP have stable retinopathy for many years.5,6 The visual acuity data presented in the study by the DRCR.net investigators indicated that ranibizumab resulted in noninferioroutcomescomparedwithPRPtreatmentat2years. Although the secondary visual acuity outcome based on the areaunder the curve favored theanti-VEGF therapygroup, the long-term implications remain uncertain and the results are likely more due to anti-VEGF effects on diabetic macular edema. Approximately half of the eyes in the PRP groupwere eligible for anti-VEGF therapy fordiabeticmacular edema.The authors correctly acknowledge that “the protocol essentially tested ranibizumab for PDR vs PRP plus ranibizumab when needed for diabetic macular edema treatment.” The authors reported a higher rate of vitrectomy in the PRPgroup (15%)vs the anti-VEGFgroup (4%).Anearlier study Related article page 2137 Opinion