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A New Technique to Save Patients' Sight

Op-Med is a collection of original articles contributed by Doximity members.

**Editor's Note:** Dr. Sean Adrean recently published a new treatment protocol for wet macular degeneration in _Ophthalmology Retina_. He talked to Doximity about how his protocol differs from existing treatment regimens, takeaways from his findings, and the inspiration behind the study.

Age-related macular degeneration is the leading cause of blindness in adults over 65 in the United States. There are two types of macular degeneration: 1. Dry or degenerative, composed of drusen and/or retinal pigment epithelial abnormalities including geographic atrophy 2. Wet or exudative, which occurs when new blood vessels grow from the choroid underneath the retina, leading to photoreceptor damage and visual loss from bleeding and swelling. The current standard of care for wet macular degeneration is treatment with anti-VEGF injections into the vitreous to prevent the growth of new blood vessels. When these treatments emerged in September 2005, patients experienced tremendous gains in vision. In spite of this, I noticed that after we treated these patients for an extended period of time (average 3 years) and the wet macular degeneration was stopped, quite a few patients came back with a recurrence of the wet AMD. In early 2016, I saw my second patient in the same morning who had a recurrence of their neovascular age-related macular degeneration (nAMD) or "wet macular degeneration" about 6-8 months after stopping treatment. I had seen another patient earlier in the week with a recurrence as well, and I started wondering, *"Just what was the recurrence rate after I stopped therapy?*" Perhaps more importantly, I feared my patients were losing vision permanently as a result of this treatment approach. As I was publishing my findings in response to these questions, I discovered that my treatment regimen differed from my fellow retinal colleagues. Most of my colleagues treat for 10-12 weeks, then continue injections indefinitely, which is known as a Treat-And-Extend (TAE) regimen. Since my coauthors and I stopped therapy at that time, we termed our protocol Treat-Extend-Stop (TES), detailed below. This protocol has the advantage of requiring fewer injections overall. #### A Conversation with Doximity: **1. How is wet macular degeneration diagnosed? What are next steps for a patient and PCP?** The symptoms of wet macular degeneration are blurred and distorted central vision. Patients have a loss of central details and have difficulty reading and recognizing faces, and usually straight lines are curved or bent. The central area of vision may even be black or darkened. Wet macular degeneration is diagnosed by examination; there are likely signs of dry macular degeneration, including drusen and RPE abnormalities, as well as the presence of fluid, exudate and/or blood in the central macula. Optical coherence tomography (OCT) as well as fluorescein angiography (FA) aid and help confirm the diagnosis.   Once a patient or PCP notices central visual loss, if the patient is over age 60, they should be referred to an ophthalmologist or retina specialist (that's my specialty), especially if they have a family history or other risk factors like smoking or hypertension. (I would recommend that any patients that have blurred and distorted central vision should be referred to an ophthalmologist, but this is particularly important if over age 60.) This would be in contradistinction to patients with generalized blurriness. Glasses may solve this; if glasses don't help and/or if they are in the 60+ range, it may be cataracts. **2. How is wet macular degeneration treated by ophthalmologists?** There are three main treatment strategies. The first is fixed interval dosing, which is a mainstay of randomized clinical trials. Patients receive monthly, bi-monthly or quarterly intravitreal injections of anti-VEGF medicine to treat the choroidal neovascular membrane (CNVM). This is a highly effective method but requires many visits over the years, and patients and doctors may experience "injection fatigue." Another popular method is treating patients on a pro-re-nata (PRN) basis, typically after patients are treated with three monthly loading doses of an anti-VEGF agent. Treatments are continued until there is no fluid or exudate in the retina; this is termed a "dry" macula, which is typically corroborated by spectral domain optical coherence tomography (SD-OCT). Treatments are then stopped and only re-initiated when intraretinal and subretinal fluid reaccumulate from the CNVM. The third and most common method is the TAE regimen. Patients are typically given 3 injections on a monthly basis, and injections are likewise continued on an approximate monthly regimen until the macula is "dry." Instead of holding the injection, as done in the PRN method, the time interval between injections is increased by 1 to 2-week intervals, treating with intravitreal injections at each visit. If at any time, there is an increase in exudation or retinal fluid, then the time injection interval would be reduced by at least 2 weeks or more depending on the time interval. If the patient did not appear to be responding, then the anti-VEGF agent could be changed. **3. What are the key differences between these treatment strategies? Are there differences in outcome?** This is a great question. In July [I published another paper]( looking at long term outcomes in these patients, and I thought that after that article was published in Doximity, I would follow it up with my next publication looking at that very outcome. In brief, the PRN methodology has quite poor long-term visual outcomes.  Fixed dosing and treat-and-extend have much better and very similar long-term outcomes. Treat-and-extend has far fewer injections and office visits. **4. How was your treatment regimen different from that of your colleagues?** Specifically, I would also increase the time interval between injections successively by 1-2 weeks, as long as the macula remained "dry," until 12 weeks were reached. The patient would then be treated 12 weeks later and be instructed to return in another 12 weeks. I would perform a fluorescein angiogram (FA), and an OCT, to assess the state of the CNVM. The patient would receive another intravitreal injection. If the macula was still fluid free and the FA didn't have leakage, the patient would return 12 weeks later and if there still was no fluid, then I would hold the injection. At this time, I would consider the patient's wet macular degeneration to be in remission and I would carefully monitor them. I would bring the patient back in 4 weeks to re-examine them, and if there was no fluid, I would successively extend the time interval by 2 weeks until 12 weeks were reached; then the patients were monitored quarterly. If at any time there was new exudate or subretinal fluid or hemorrhage seen, then the treatments would be re-initiated using the same protocol. **5. What were the findings of your study?** To answer my question about recurrence rates of wet macular degeneration after patients stopped therapy, my colleagues and I looked at 385 eyes of 321 patients and found that we stopped treatment in 143 eyes. We then found out that 42 of those eyes had a recurrence, or **recurrence rate of 29.5%.** That answered my first question about recurrence rate. We were also concerned that if we stopped therapy, maybe our patients were losing vision, so we looked at the visual outcomes in this study cohort. The patients started with an average visual acuity of 20/70 before treatment. After an average of 22 injections (or approximately 3 years of continuous treatment with extension), the visual acuity improved to 20/50, an approximate gain of +7.5 ETDRS letters or about a 2-line increase in vision, (p <0.01). At the time of recurrence, the vision dropped to 20/60 (p=0.003). Once we restarted treatment using the TES protocol, the visual acuity returned to 20/50. To my relief, **we found there was no difference between vision at the time of treatment cessation and after the recurrence, once the treatment resumed** (p=0.34). The average time between treatment cessation and recurrence of the CNV was 14 months. Overall, we have been very encouraged by these results and have continued this treatment regimen for the benefit of our patients with nAMD. **6. What is the actionable takeaway from your study for fellow retina specialists?** Patients with wet AMD don't need to be treated indefinitely.  In fact, many patients (37.1%) in this study were able to stop treatment and be closely monitored.  They didn't have a decline in vision and the disease of wet AMD was put into remission.  29% of those patients had a recurrence of the wet AMD and if there was a recurrence, the vision initially would drop, but that vision could be recovered and not lost once treatments were resumed. **7. What is the takeaway for patients and PCPs? What can they do to ensure successful outcomes?** For patients and PCPs, wet macular degeneration has an amazing treatment.  Prior to the anti-VEGF era, the outcomes were pretty dismal.  The previous treatment was called photodynamic therapy, where a cold laser was used to activate a chemical called verteporfin to cause closure of new blood vessels.  Approximately 60% of patients did not have a 3-line loss of vision after one year, while the rest did. With anti-VEGF therapy, 95% of patients did not have a 3-line loss of vision, over 1/3 of patients actually had a gain of 3 lines of vision, and the average visual improvement after one year usually averaged between 1-2 lines of visual gain.  Still, we are much better at preventing visual loss rather than gaining vision back, so the earlier patients are diagnosed, the better the outcomes for preserved vision.  If wet macular degeneration is even suspected, an earlier referral can save a patient's sight.  Quick in-office visual screening exams in the PCP's office for patients over 60, with special care to test each eye separately by completely covering one eye, is crucial. Since the brain compensates for unilateral vision loss, oftentimes patients don't notice when one eye has lost central vision. **Adrean SD**, Chaili S, Pirouz A, Grant S. Recurrence Rate of Choroidal Neovascularization in Neovascular Age-Related Macular Degeneration Managed by a Treat-Extend-Stop Protocol. Ophthalmology Retina 2018; 2(3)224-229.

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