The DRCR Retina Network reported the results of Protocol V at the ARVO meeting in Vancouver recently and clinicians are wondering how to incorporate the findings into their own clinical practice.1 The study aimed to examine the right treatment regimen for patients with center involved diabetic macular edema and good vision.
Take for example this case: This patient is a 55-year-old diabetic with moderate non-proliferative disease and center involved diabetic macular edema. The vision is 20/25 best corrected with a central subfield thickness of 585 microns in the right eye and 507 microns in the left eye.
Protocol V addressed this question by randomizing 702 participants with center-involved DME and visual acuity of 20/25 or better to initial management with Eylea (aflibercept, Regeneron) (n = 226), laser photocoagulation (n = 240) or observation (n = 236). In the aflibercept group, injections were administered as needed. In the laser photocoagulation group, patients were treated at baseline with re-treatment at 13 weeks if indicated. In the observation group, no treatment was given at baseline. Patients in the laser and observation were allowed to be switched to aflibercept if a decrease of two or more lines at any visit or one line at two consecutive visits was reported. The study results demonstrated at 2 years, the rates of visual acuity loss of five or more letters did not differ significantly between groups, and the average visual acuity was 20/20, as it was at baseline, with all three management strategies. 26% of the patients in the laser group required anti-VEGF and 36% in the observational arm required rescue anti-VEGF treatment. The number of injections in these groups were almost similar to the original aflibercept group indicating these patients on average received more frequent treatments. The study concludes: “Observation without treatment unless visual acuity worsens may be a reasonable strategy for these eyes.” So should we really observe patients like in the case above until they deteriorate? Let’s explore the issues:
- Issue 1 – A significant number of patients needed rescue. Therefore, we can certainly wait for those to lose vision before initiating therapy but we know what many diabetic patients fail to follow up. In a recent study, patients with DME in the U.S. had 1.591- times increased odds of cancelling or no- showing to their appointments than patients with wet AMD (P < .0001).2 Their combined cancellation and no show rate was 24%. So we have to weigh treating today or instead hoping that the patient follows up when vision loss occur.
- Issue 2 – We really don’t know from the results how patients with DME in the focal laser arm and observational arms fared following anti-VEGF treatment. The study combined the results for the rescued group with the non-rescued group and found no difference in final vision but a detailed subgroup analysis is likely forthcoming.
- Issue 3 – This does not apply to treated patients. So if you have initiated therapy and the patient’s vision improves to 20/25, this study doesn’t validate observing these patients for vision decline for re-initiating therapy. The phase 3 studies of aflibercept and ranibizumab validated that continual therapy helps to maintain vision gains.
- Issue 4 – We are not addressing diabetic retinopathy in the interim. Protocol V enrolled patient’s mainly with mild and moderate disease and therefore they will not progress significantly over the two year study period. However, for patients with severe NPDR, anti-VEGF can decrease retinopathy by 2 steps in 70-80% of patients depending on the study viewed. Thus was the case in the patient above who maintained the same vision with a two-step improvement.
Protocol V provides early guidance on initiating therapy in patients with anti-VEGF therapy and good vision. The issues above take into the context the complexities of applying a clinical trial into routine clinical practice.
- Baker CW, Glassman AR, Beaulieu WT, et al. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. Published online April 29, 2019. doi:10.1001/jama.2019.5790
- Jansen, M.E., Krambeer, C.J., Kermany, D.S., Waters, J.N., Tie, W., Bahadorani, S., Singer, J., Comstock, J.M., Wannamaker, K.W. and Singer, M.A., 2018. Appointment compliance in patients with diabetic macular edema and exudative macular degeneration. Ophthalmic Surgery, Lasers and Imaging Retina, 49(3), pp.186-190.