SUPPLEMENT TO NOVEMBER 2014 www.reviewofoptometry.com A Focus on Clinical Research This year, our experts review and summarize the landmark trials that most directly influenced the course of retinal disease management during the last three decades. Age-Related Macular Degeneration Genetic Retinal Disease Steven Ferrucci, OD, FAAO Charles M. Wormington, OD, PhD, FAAO Diabetic Eye Disease Retinal Venous Occlusion Carlo J. Pelino, OD, FAAO Julie Hutchinson McGinnis, OD, FAAO Joseph J. Pizzimenti, OD, FAAO Andrew S. Gurwood, OD, FAAO, Dipl. (Supplement Editor) NNNOOOVVVEEEMMMBBBEEERRR 222000111444 RRREEEVVIIEEEWWW OOOOFFFF OOPPTTOOMMEETTRRYYY 11 2014_cover_mh.indd 1 10/17/14 4:40 PM SYMPTOMATIC VITREOMACULAR ( ) ADHESION VMA SYMPTOMATIC VMA MAY LEAD TO VISUAL IMPAIRMENT FOR YOUR PATIENTS1-3 IDENTIFY Recognize metamorphopsia as a key sign of symptomatic VMA and utilize OCT scans to confi rm vitreomacular traction. REFER Because symptomatic VMA is a progressive condition that may lead to a loss of vision, your partnering retina specialist can determine if treatment is necessary.1-3 THE STEPS YOU TAKE TODAY MAY MAKE A DIFFERENCE FOR YOUR PATIENTS TOMORROW © 2014 ThromboGenics, Inc. All rights reserved. ThromboGenics, Inc., 101 Wood Avenue South, Suite 610, Iselin, NJ 08830 – USA. THROMBOGENICS and the THROMBOGENICS logo are trademarks or registered trademarks of ThromboGenics NV. 10/14 OCRVMA0220 References: 1. Sonmez K, Capone A, Trese M, et al. Vitreomacular traction syndrome: impact of anatomical confi guration on anatomical and visual outcomes. Retina. 2008;28:1207-1214. 2. Hikichi T, Yoshida A, Trempe CL. Course of vitreomacular traction syndrome. Am J Ophthalmol. 1995;119(1):55-56. 3. Stalmans P, Lescrauwaet B, Blot K. A retrospective cohort study in patients with diseases of the vitreomacular interface (ReCoVit). Poster presented at: The Association for Research in Vision and Ophthalmology (ARVO) 2014 Annual Meeting; May 4-8, 2014; Orlando, Florida. RP1114_Thrombogenics.indd 1 10/22/14 9:30 AM Age-Related Macular Degeneration By Steven Ferrucci, OD, FAAO OVER THE PAST decade or more, ately lost more many significant advances have vision than been made in the treatment of observation age-related macular degeneration eyes; however, (AMD). When I was a resident at 12-month from 1996 to 1997, we could offer follow-up, very little hope for our AMD treated eyes patients. All too often, we were demonstrated forced to look on idly as they better acuity suffered devastating vision loss. than obser- Now, with extensive research into vation eyes. the protective benefits of vitamin Thus, the long- On spectral-domain optical coherence tomography, we documented the presence of fluid associated with wet AMD. supplementation and the ability to term benefit treat neovascularization with anti- of improved visual acuity far out- of treated eyes lost fewer than VEGF therapy, we can offer our weighed the short-term vision loss 15 Snellen letters, compared to patients notably better quality of caused by laser treatment.1 38% of treated eyes.4 However, it life. Today, we can help preserve While MPS researchers noted should be noted that patients with existing visual function and, in that laser therapy certainly was not minimally classic lesions did not some cases, even partially restore the most ideal treatment modality, respond nearly as well to photody- lost vision. it was shown to be at least some- namic therapy.4 During the last 25 years, mul- what more effective at preserving Although intravitreal anti-VEGF tiple landmark trials on AMD visual acuity in wet AMD patients injection largely has supplanted diagnosis and management have than observation alone.1 photodynamic therapy, it remains been published. Many of these • TAP and VIP. Nearly a decade an important milestone in the his- studies are best known and iden- after MPS was published, the tory of AMD treatment. tified by clever acronyms (e.g., Treatment of Age-Related Macular • CAPT. One of the most com- AREDS). Here, we’ll review some Degeneration with Photodynamic prehensive studies that evaluated of the most important clinical data Therapy (TAP) and Verteporfin laser as a potential treatment documented in these major studies in Photodynamic Therapy (VIP) for AMD was the National Eye and will show how these findings studies evaluated the role of pho- Institute-funded Complications of can most effectively translate into todynamic therapy in patients with Age-Related Macular Degeneration improved patient care. CNV secondary to wet AMD.2,3 The Prevention Trial (CAPT).5 treatment used in these studies Published in 2006, this multi- Early Research consisted of an intravenous injec- centered study was designed to • MPS. One of the very first tion of verteporfin, a light-activated determine if low-intensity laser trials that evaluated potential drug. After infused verteporfin treatment of eyes with existing dru- treatments for choroidal neovascu- reaches the eye, it is activated by a sen would prevent long-term vision larization (CNV) was the Macular laser source, thereby treating the loss associated with wet AMD. Photocoagulation Study (MPS).1 CNV while reducing thermal dam- The CAPT researchers admin- It was published in 1991 and con- age to surrounding tissues. istered unilateral laser treatment sisted of a series of three separate The cumulative results of TAP to more than 1,000 AMD patients clinical tests designed to evaluate and VIP confirmed that patients with bilateral drusen formation. the role of laser photocoagulation with classic CNV lesions lost less After five years of follow-up, they in wet AMD patients. vision following treatment than determined that laser yielded no MPS results indicated that eyes untreated controls. (Classic lesions clinically significant benefit on with subfoveal CNV secondary to are those that tend to leak early visual acuity compared to untreat- AMD benefited more from laser and have well-defined borders, ed contralateral eyes. In fact, treatment than observation.1 Eyes compared to occult lesions.) At 20.5% of treated eyes and 20.5% receiving laser therapy immedi- the two-year TAP follow-up, 53% of observed eyes lost at least three NOVEMBER 2014 REVIEW OF OPTOMETRY 3 001_ro1114 RetinaGuide_mh.indd 3 10/17/14 4:48 PM Snellen lines from baseline acu- increased to 18%. Lastly, those ity measurements.5 Further, the patients with the lowest quintile cumulative rate of CNV forma- of dietary lutein and zeaxanthin tion was 13.3 % for both treated intake experienced the greatest and observed eyes.5 reduction in disease progres- sion when taking supplemental Vitamin Studies lutein and zeaxanthin.7 So, • AREDS. The original Age- based on these findings, it Related Eye Disease Study seems clear that it is beneficial (AREDS) was one of the first to replace beta carotene in the large-scale clinical trials that original AREDS formulation evaluated whether high-dose with 10mg lutein and 2mg zea- antioxidant supplementation xanthin. slowed or halted AMD progres- sion.6 The results showed that Anti-VEGF Trials the AREDS formulation—com- This patient with stage 3 (i.e., moderate) dry age-related • VISION. In December macular degeneration would be an ideal candidate for prised of 15mg beta carotene, supplementation with an AREDS 2-formulated vitamin. 2004, the anti-VEGF agent 500mg vitamin C, 400IU vita- Macugen (pegaptanib sodium, min E, 80mg zinc and 2mg cop- and indicated that the addition of Valeant) secured FDA approval per—lowered the risk of progres- lutein, zeaxanthin and omega-3 for the treatment of neovascular sion to advanced AMD by 25% fatty acids to the original AREDS AMD. The VEGF Inhibition Study in patients with intermediate or formulation did not further reduce in Ocular Neovascularization advanced macular degeneration.6 the risk of progression to advanced (VISION) showed that 70% of • AREDS 2. The second AREDS AMD.7 However, because beta car- patients who received a series of study evaluated whether the otene supplementation has been intravitreal Macugen injections addition of 10mg lutein, 2mg associated with an increased risk of lost fewer than 15 letters of acuity zeaxanthin and 1,000mg omega- lung cancer in former smokers, the vs. just 55% of controls.8 Macugen 3s offered greater protection researchers determined that lutein also reduced the risk of severe against AMD progression than with zeaxanthin are appropriate vision loss by more than 50%. the original AREDS formula carotenoid substitutes in the for- Further, 33% of treated patients alone.7 Additionally, the AREDS 2 mulation.7 maintained or gained acuity after researchers removed beta carotene The comparison of low-dose vs. two years of injections vs. just 23% from the original formula, as well high-dose zinc showed no evidence of untreated patients.8 as reduced the amount of zinc. of a statistically significant effect, VISION researchers recom- This multicenter trial was so a definitive clinical recommen- mended injection every six weeks conducted at 82 clinical sites in dation cannot be made.7 Also, for two years.8 Over that period, the US from 2006 to 2012, and daily lutein and zeaxanthin supple- Macugen appeared to be relatively included 4,203 participants aged mentation had no statistically sig- safe, with few adverse events (i.e., 50 to 85 years. The AREDS 2 par- nificant effect on cataract surgery mild anterior chamber reaction). ticipants consented to either take rates or opacity-related vision loss. More serious events, such as endo- the original AREDS formulation However, upon deeper analysis, phthalmitis, traumatic lens injury or a randomly assigned variation. it seems that lutein and zeaxanthin and retinal detachment were very The principal outcome measure- have a more positive effect than rare.8 However, following the ment was progression to advanced first noted. The researchers deter- introduction of both Lucentis AMD (i.e., either CNV or central mined that the addition of lutein (ranibizumab, Genentech/ geographic atrophy). Progression and zeaxanthin to the original Roche) and Avastin (bevacizumab, of lens opacity and/or necessity formula decreased the incidence Genentech/Roche), Macugen of cataract surgery served as a sec- of disease progression by 10%. quickly lost its standing as the anti- ondary outcome. Further, if the beta carotene was VEGF agent of choice for the treat- Data from the primary analysis removed and replaced with lutein ment of wet AMD. was first published in May 2013, and zeaxanthin, the risk reduction • ANCHOR. In the summer 4 REVIEW OF OPTOMETRY NOVEMBER 2014 001_ro1114 RetinaGuide_mh.indd 4 10/17/14 4:48 PM of 2006, Lucentis received FDA treatments if there was a change Considering the favorable approval for the treatment of wet in optical coherence tomography results of systemic Avastin use, AMD. Early studies of Lucentis (OCT) appearence or a new hem- surgeons began administering showed an actual improvement in orrhage. intravitreal Avastin off-label for visual acuity following treatment— At 12 months, mean acuity in the treatment of wet AMD (see the first wet AMD study to do so.8,9 the treated group improved by “Avastin: The Off-Label Alternative,” In the Anti-VEGF Antibody nine letters, with an average cen- below). It should be noted that due for the Treatment of tral retinal thickness decrease of to the lack of a large, multicenter, Predominantly Classic Choroidal 178μm.3 Acuity improved by 15 controlled study, Avastin’s safety Neovascularization in AMD letters or more in 35% of patients, profile and administration sched- (ANCHOR) study, research- with an average of 5.6 injections ule is less substantiated than those ers evaluated 423 patients with over a 12-month period.11 of Lucentis. predominantly classic CNV. Following the publication of Many published reports—as well At 12-month follow-up, 94% these results, most retinal special- as clinical experience—indicate of patients who received serial ists have adopted an injection that it is a very effective agent for Lucentis injections remained schedule similar to that employed the treatment of wet AMD.12,13 stable, with a mean acuity loss of by PRONTO researchers—three Nonetheless, all patients must be fewer than 15 Snellen letters.8 consecutive monthly injections as informed that intravitreal Avastin Impressively, more than one- a loading dose, followed by indi- use for AMD is an off-label appli- third of the patients improved by vidual treatment based on clinical cation that’s not approved by the 15 or more letters from baseline.9 findings.11 FDA. Similarly to Lucentis, most ANCHOR researchers recom- • SANA. The Systemic Avastin retinal specialists advocate one mended intravitreal injection every for Neovascular Age-Related Avastin injection per month for four weeks for two years. Macular Degeneration (SANA) three months, then PRN retreat- • MARINA. The Minimally study was the first trial that ment based upon clinical, OCT or Classic/Occult Trial of the Anti- analyzed the clinical efficacy fluorescein angiography findings. VEGF Antibody Ranibizumab in of Avastin for the treatment of • CATT. In 2007, officials from the Treatment of Neovascular CNV.12 the National Eye Institute and Age-Related Macular Degeneration The researchers administered National Institutes of Health (MARINA) was the second study systemic (not intravitreal) Avastin announced that they would to evaluate anti-VEGF therapy on to nine wet AMD patients, and conduct a two-year study to occult lesions.10 Researchers docu- determined that the drug was well evaluate the relative safety and mented findings that were similar, tolerated and yielded improved efficacy of Avastin and Lucentis but slightly less impressive, than visual acuity, optical coherence in the Comparison of Age-Related those published in the ANCHOR tomography results and fluores- Macular Degeneration Treatment study.10 cein angiography outcomes in all Trials (CATT).13 The researchers • PRONTO. In 2007, one subjects.12 intended to determine if Avastin research group evaluated whether adjusting the dosing schedule Avastin: The Off-Label Alternative of Lucentis (one injection every Avastin (bevacizumab, Genentech/Roche) is a full-length, recombinant, humanized, monoclonal vas- four weeks) could affect treat- cular endothelial growth factor antibody. The drug is not FDA approved for the treatment of AMD, but ment results.11 In the two-year is available as a systemic medication for metastatic colorectal cancer and certain lung cancers. Prospective Optical Coherence Avastin is essentially the parent drug of Lucentis––but researchers initially believed that, due to its Tomography Imaging of Patients large molecular size, it would be unable to penetrate the retina. Therefore, it was genetically engi- with Neovascular Age-Related neered to be about one-third the size of the original molecule and was entered into clinical trials for the treatment of neovascular AMD. While waiting for Lucentis to secure approval, some retinal spe- Macular Degeneration Treated cialists began to evaluate Avastin’s role in the treatment of neovascular AMD, and discovered that it with Intraocular Lucentis could slow, stop or even reverse vision loss. (PRONTO) study, participants Even after the approval of Lucentis, many eye care providers have preferred to treat their wet received three consecutive month- AMD patients with compounded intravitreal Avastin because of its significantly smaller price tag. ly injections of Lucentis as a load- Specifically, CATT researchers determined that treating patients with Lucentis PRN cost $13,800 per year vs. just $385 per year for PRN Avastin.13 ing dose, followed by additional NOVEMBER 2014 REVIEW OF OPTOMETRY 5 001_ro1114 RetinaGuide_mh.indd 5 10/17/14 4:48 PM and Lucentis were clinically genetics of AMD, intravitreal equivalent for the treatment injections of new drugs and of wet AMD. novel sustained-release deliv- CATT researchers ran- ery mechanisms for current domly assigned more than agents. ■ 1,200 patients to receive Dr. Ferrucci is chief of optom- Avastin or Lucentis, either etry and residency director at on a monthly or PRN the Sepulveda VA Ambulatory basis.13 The results indicated Care Center and Nursing Home that patients who received in North Hills, Calif. He’s also monthly Avastin injections a professor at the Southern gained 8.0 letters vs. 8.5 let- California College of Optometry at ters in those who received Marshall B. Ketchum University monthly Lucentis.13 in Fullerton, Calif. Further, patients who received PRN Avastin injec- 1. Macular Photocoagulation Study Group: Laser tions gained 5.9 letters vs. This patient presented with wet AMD. We referred him to a retinal photocoagulation of subfoveal neovascular lesions specialist to initiate anti-VEGF therapy. in age-related macular degeneration. Results 6.8 letters in those who of a randomized trial. Arch Ophthalmol. 1991 received PRN Lucentis.13 Other rel- Essentially, VIEW 1 and 2 indi- Sep;109(9):1220-31. 2. Treatment of age-related macular degeneration with photody- evant findings included slightly bet- cated that bimonthly Eylea admin- namic therapy (TAP) Study Group. Photodynamic therapy of subfo- veal choroidal neovascularization in age-related macular degenera- ter anatomic results with Lucentis, istration was clinically equivalent tion with verteporfin: one-year results of 2 randomized clinical such as a greater mean decrease in to monthly injections of Lucentis.14 trials--TAP report. Arch Ophthalmol. 1999 Oct;117(10):1329-45. 3. Treatment of age-related macular degeneration with photody- central retinal thickness, as well as More specifically, approximately namic therapy (TAP) Study Group. Verteporfin therapy of subfoveal a higher rate of serious systemic 95% of Eylea patients exhibited choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with adverse events following Avastin stable vision during a 52-week evalu- occult with no classic choroidal neovascularization--verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001 administration (24.1% vs. 19.0% for ation period vs. 94% for Lucentis May;131(5):541-60. Lucentis).13 patients. Further, mean change in 4. Bressler NM; Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic In short, however, the CATT best-corrected acuity documented Therapy of Subfoveal Choroidal Neovascularization in Age Related researchers determined that Avastin in all Eylea treatment groups was Macular Degeneration with Verteporfin: Two Year Results––TAP report number 2. Arch Ophthalmol. 2001 Feb;119(2):198-207. and Lucentis demonstrated clini- within 0.5 letters of that document- 5. Complications of Age-Related Macular Degeneration Prevention Trial Research Group. Laser treatment in patients with bilateral cally equivalent effects on visual ed in all Lucentis treatment groups. large drusen: the complications of age-related macular degenera- acuity when administered in accor- Ocular and systemic adverse events tionprevention trial. Ophthalmology. 2006 Nov;113(11):1974-86. 6. Age-Related Eye Disease Study Research Group. A randomized, dance with the same dosing sched- were similar in all treatment groups, placebo-controlled, clinical trial of high-dose supplementation ule. Thus, due to the substantial as well. with vitamins C and E, betacarotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch cost savings with similar results, the Based on these findings, Eylea Ophthalmol. 2001 Oct;119(10):1417-36. 7. Age-Related Eye Disease Study 2 Research Group. Lutein majority of clinicians have accepted secured FDA approval for wet AMD + zeaxanthin and omega-3 fatty acids for age-related macular Avastin as the primary treatment in November 2011, and is indicated degeneration: the Age-Related Eye DiseaseStudy 2 (AREDS 2) ran- domized clinical trial. JAMA. 2013 May 15;309(19):2005-15. for wet AMD patients, with Lucentis for bimonthly dosing. 8. Gragoudas ES, Adamis AP, Cuningham ET Jr, et al. Pegaptanib reserved for those who do not for neovascular age-related macular degeneration. N Engl J Med. 2004 Dec 30;351(27):2805-16. respond favorably to Avastin. The data collected from these 9. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N • VIEW 1 and 2. Eylea (afliber- studies have helped delay or pre- Engl J Med. 2006 Oct 5;355(14):1432-44. cept, Regeneron) is the latest FDA- vent devastating vision loss in hun- 10. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. approved agent for the treatment dreds of thousands of wet AMD 2006 Oct 5;355(14):1419-31. 11. Fung AE, Rosenfeld PJ, Dubovy SR, et al. An optical coher- of neovascular AMD. Two similarly patients. While the trials mentioned ence tomography-guided, variable dosing regimen with intravitreal designed, Phase III studies—VEGF were among the most groundbreak- ranibizumab (Lucentis) for neovascular age-related macular degen- eration. Am J Ophthalmol. 2007 Apr;143(4):566-83. Trap-eye: Investigation of Efficacy ing, many others also were instru- 12. Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic beva- and Safety in Wet AMD 1 and 2 mental in the evolution of AMD cizumab (Avastin) therapy for noeovascular age-related macular degeneration. Ophthalmology. 2005 Jun;112(6):1035-47. (VIEW 1 and 2)—compared monthly treatment. 13. The CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. and bimonthly dosing of intravitreal This journey will continue, how- 2011 May 19;364(20):1897-908. aflibercept with monthly Lucentis ever, with many new studies evalu- 14. Heier JS, Brown DM, Chong V. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. for wet AMD.14 ating such considerations as the 2012 Dec;119(12):2537-48. 6 REVIEW OF OPTOMETRY NOVEMBER 2014 001_ro1114 RetinaGuide_mh.indd 6 10/17/14 4:49 PM Diabetic Eye Disease By Carlo J. Pelino, OD, FAAO, and Joseph J. Pizzimenti, OD, FAAO DIABETIC RETINOPATHY (DR)is the years.1-3 Additionally, the ETDRS cosylated hemoglobin evaluation leading cause of blindness among researchers also determined that decreased the risk of retinopathy adults living in the western world. the stage of NPDR at the time of development and progression.4 Proliferative DR (PDR) is charac- initial diagnosis should largely dic- terized by new vessel formation in tate the patient’s follow-up and/or PDR Treatment the retina and at the level of the treatment schedule. Cases of PDR usually involve optic disc that results from hypox- • DCCT. Improved systemic panretinal laser photocoagulation ia, microangiopathy and capillary control is essential for proper (PRP) surgery to seal leaking ves- occlusion. In addition to PDR, NPDR management. The Diabetes sels and prevent neovasculariza- associated diabetic macular edema Control and Complications Trial tion. Fluorescein angiography can (DME) and tractional retinal (DCCT) research group showed be used to visualize the perfusion detachment may result in severe that intensive glycemic control status of the retina and identify vision loss. involving multiple, daily blood whether macular edema coexists. As the number of people living sugar measurements; nutritional This is important because focal with type 2 diabetes mellitus (DM) counseling; and medical evalua- laser treatment is used to clear increases in proportion with high- tions every three months with gly- macular edema before photocoag- er overall levels of obesity, eye care providers will diagnose and man- Understanding DR: Research on its Pathogenesis age more cases of DR and DME than ever before. This article will Most individuals with diabetes develop some degree of retinopathy.21,22 DR results from biochemical pro- review how research from more cesses that damage vessels, alter retinal blood flow and degrade the retina’s nutritional supply. As the than a dozen landmark clinical tri- highly vascular tissue becomes undernourished and ischemic, its neuronal and vascular elements break als helped shape the way in which down and cause vascular distortions, leakage, intraretinal bleeding and fluid accumulation. DR inhibits we currently treat the most visually retinal capillary function first, then it affects larger vessels.5,23,24 devastating forms of diabetic eye The exact cause of microvascular complications associated with DM is unknown.5,23 Supportive capil- disease. lary pericyte loss is an early histologic finding associated with DR. It induces leakage and precipitates capillary endothelial cell dysfunction.5,23 Researchers believe that excess glucose contained within the NPDR Treatment retinal capillary leads to the production of potentially harmful biochemicals, such as vascular endothelial Evidence of nonproliferative growth factor (VEGF), protein kinase C (PKC) and advanced glycation end-products (AGEs), which alter diabetic retinopathy (NPDR) is of capillary pericyte integrity.5,25 tremendous significance to eye The production of reactive oxygen species (ROS) likely is the unifying mechanism behind the patho- care providers, because it clini- logical pathways triggered by hyperglycemia.26 AGEs appear to play a central role in this process. cally signifies that retinal changes Hyperglycemia promotes microvascular damage via an influx of glucose and other sugars through the are occurring secondary to inad- polyol pathway, increased intracellular AGE formation, and interaction between AGEs and their receptors equate glucose control. If NPDR is (termed RAGEs). This, in turn, causes intracellular signaling and subsequent cell function disruption. unmanaged in patients with poor At the extracellular level, soluble RAGEs in plasma are implicated in diffuse micro- and macrovascular systemic control, the likelihood of damage. Through the actions of ROS, AGE accumulation leads to vessel thickening, hypertension, progression to PDR increases sig- endothelial dysfunction and loss of pericytes. AGEs also reduce platelet survival and increase aggrega- nificantly. tion, fostering a pro-coagulant state, causing ischemia and the development of growth factors. These • ETDRS. The Early Treatment processes result in angiogenesis and neovascularization. Thus, the roles of AGEs may help explain the Diabetic Retinopathy Study clinical link between micro- and macrovascular disease and diabetes.26 (ETDRS) showed that patients with Capillary out-pouchings, called microaneurysms, frequently are the earliest clinically detectable signs mild NPDR have a 5% risk of pro- of DR. Over time, poor circulatory perfusion weakens the capillary walls, resulting in bulging, leaking or gressing to PDR within one year scarring. Subsequently, affected individuals experience tissue ischemia and angiogenic growth factor following diagnosis, and 15% risk upregulation and release. These processes foster new blood vessel formation (neovascularization) and of progressing to high-risk PDR increased vascular permeability, which cause retinal edema.23,27,28 (neovascularization of the disc or When leakage from the perifoveal vessels affects the area centralis (fovea), patients develop diabetic neovascularization elsewhere with macular edema (DME)––one of the most common causes of central vision loss and decreased quality of vitreous hemorrhage) within five life in American adults.29,30 NOVEMBER 2014 REVIEW OF OPTOMETRY 7 001_ro1114 RetinaGuide_mh.indd 7 10/17/14 4:49 PM ulation is indicated in patients with concomitant macular edema and PDR.5 In PDR, weaker blood ves- sels can rupture, scar, compromise healthy retinal tissue function and induce tractional retinal detach- ment. • DRS. The Diabetic Retinopathy Study (DRS) indicated that pan- retinal laser photocoagulation reduced the incidence of severe vision loss (i.e., 5/200 or worse) in 60% of PDR patients.6 PRP treatment is not without its con- sequences, however. The retinal tissue scarring inherent in thermal laser photocoagulation may cause reduced contrast sensitivity, poor dark adaptation and visual field loss. Intravitreal injections of anti- VEGF agents (e.g., pegaptanib, Intensive control of blood sugar, blood pressure and serum lipids may prevent or reduce complications of diabetic retinopathy, as seen in this patient. bevacizumab, ranibizumab and aflibercept), have proven to be plicated retinal detachment and it’s essential to treat CSME as soon effective as first-line or adjunctive severe neovascular proliferation as possible to prevent irreversible proliferative diabetic retinopathy that’s non-responsive to laser. functional vision loss. treatments.7 The Diabetic Retinopathy • Wisconsin study. Early • DRVS. As PDR develops, it Vitrectomy Study (DRVS) results results from the 1984 Wisconsin scaffolds across a thickened poste- showed that early vitrectomy was Epidemiologic Study of Diabetic rior vitreous cortex. Consequent beneficial in restoring and pre- Retinopathy suggested that laser posterior vitreous cortex shrink- serving vision in patients with photocoagulation might slow the age leads to the development of PDR who presented either with or progression of DME.9 Focal or preretinal hemorrhages, vitreous without associated vitreous hemor- grid laser photocoagulation yields hemorrhages and tractional reti- rhage.8 coagulation necrosis—the arrest nal detachments. In some cases of vessel leakage by heat-induced of PDR, three-port pars plana Conventional Laser for DME closure. The strategy for treating vitrectomy surgery is performed. The most common cause of macular edema with laser depends Indications for vitrectomy include functional visual loss (worse than on both the type and extent of a vitreous hemorrhage that blocks 20/40) in patients with DR is vessel leakage. Even today, some the view of the retina, dense DME—specifically, clinically signifi- clinicians still regard laser photo- premacular hemorrhage, com- cant macular edema (CSME).9 So, coagulation as the “gold standard” treatment for diabetic macular Glucose Control and DR edema. If the edema is due to leakage The Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes from specific microaneurysms, Study (UKPDS) showed that intensive control of blood sugar, blood pressure and serum lipids may pre- the offending vessels are treated vent DR or reduce complications associated with DR, including DME.4,31 DCCT researchers clearly docu- directly with focal laser photocoag- mented that tight control of blood sugar and a glycosylated hemoglobin [HbA1c] of less than 7% was ulation. In cases where the foci of associated with a lower incidence of DR. Additionally, both studies indicated that that improved glucose leakage are nonspecific, however, control significantly reduced the incidence of severe vitreal hemorrhage and proliferative retinopathy, as grid laser treatment is indicated. well as limited the extent of renal disease and failure. In this procedure, medium-inten- sity burns (100μm to 200μm) are 8 REVIEW OF OPTOMETRY NOVEMBER 2014 001_ro1114 RetinaGuide_mh.indd 8 10/17/14 4:49 PM placed one burn-diameter apart, The Right Combination covering the affected area. Focal laser treatment is intended to close In 2010, the Diabetic Retinopathy Clinical Research Network (DRCR.net) conducted a randomized con- the leaking microaneurysms, while trolled trial to assess whether intravitreal injection of ranibizumab combined with prompt or deferred grid laser is used to treat more dif- laser, or intravitreal triamcinolone acetonide combined with prompt laser, would yield better visual out- fuse edema.3,9 comes than focal/grid photocoagulation in DME patients.35 The goal of laser treatment for This Phase III study clearly showed that intravitreal ranibizumab, with either prompt or deferred laser, DME is not to improve vision, but provided better anatomic and functional outcomes after two years of treatment than laser alone. to slow or prevent central visual loss secondary to chronic edema and resultant tissue damage.3 It edema patients with an OCT- the first major trial to show that is worth noting that a secondary measured central subfield thick- intravitreal anti-VEGF injections ETDRS report published in 1991 ness of greater than or equal to could be used to treat DME.14 indicated that focal or grid laser 250μm and an entering visual Specifically, the READ-1 research- photocoagulation reduced the risk acuity measurement of 20/40 to ers documented a 12.3-letter of moderate visual loss due to clin- 20/320 were most appropriate can- increase in chronic DME patients ically significant macular edema by didates for ranibizumab treatment. who received five 0.5mg ranibi- 50%.10 • RESOLVE. Similarly to RISE zumab injections over a seven- and RIDE, 151 patients enrolled month period. Pharmacologic Treatments for DME in the Safety and Efficacy of Three years later, READ-2 Although laser therapy may slow Ranibizumab in Diabetic Macular evaluated 126 patients who were DME progression, it does not often Edema (RESOLVE) study were ran- randomized to receive 0.5mg of yield visual gain. Thus, intravitreal domized to receive either 0.3mg or ranibizumab, focal/grid laser injections of anti-VEGF agents or 0.5mg of intravitreal ranibizumab coagulation or a combination of steroids currently are used either monotherapy, or a sham injec- alone or in concert with laser treat- tion.13 However, laser photocoagu- Micropulse Laser Technology ment. lation was offered to patients who • RISE and RIDE. Pharma- exhibited persistent disease activity The anatomical and visual benefits of laser pho- cologic agents with VEGF- after three months of dosing. tocoagulation are effective over the long term; inhibiting properties have been Patients initially received three however, the procedure often causes adjacent shown to treat CSME effectively.11 consecutive monthly injections, retinal tissue damage. Fortunately, micropulse In 2012, intravitreal ranibizumab then were retreated PRN for the laser technology (MPLT) has been shown to be became the first medication to next nine months. At one-year fol- as effective as conventional argon laser for DME, secure FDA clearance for the treat- low-up, patients in the 0.3mg treat- without yielding intraretinal damage during or ment of DME. This approval was ment group experienced a mean after treatment.32,33 With MPLT, the temperature based on the results of the RISE increase in best-corrected visual increases in the target tissue remain sublethal, and RIDE studies—two identically acuity of 11.8 ETDRS letters; sub- widely limiting visible lesions and scar forma- designed, parallel, double-blind, jects in the 0.5mg treatment group tion. placebo-controlled, three-year clini- gained 8.8 letters; and those in the One study indicated that MPLT appeared to cal trials.12 sham group lost 1.4 letters. be as effective as modified-ETDRS laser pho- In RISE and RIDE, 759 patients Additionally, the researchers tocoagulation for the treatment of DME, while were randomized to receive recommended that DME patients causing far less damage to the retinal pigment monthly injections of 0.3mg ranibi- with a central retinal thickness of epithelium.34 In comparison to conventional zumab or 0.5mg ranibizumab, or a greater than or equal to 300μm laser, however, MPLT does have a few disad- sham injection. The results showed and an entering visual acuity vantages, including: that subjects who received 0.3mg measurement of 20/40 to 20/320 • It takes twice as long to yield the ranibizumab experienced signifi- should be referred for intravitreal therapeutic effect. cant, early and sustained improve- ranibizumab therapy.13 • The laser burns cannot be visualized ments in vision.12 • READ-1 and 2. The Rani- clinically, making treatment and Further, the researchers recom- bizumab for Edema of the Macula retreatment more challenging. mended that diabetic macular in Diabetes study 1 (READ-1), was NOVEMBER 2014 REVIEW OF OPTOMETRY 9 001_ro1114 RetinaGuide_mh.indd 9 10/17/14 4:49 PM The Optometrist’s Role in DR Management fusion protein that exhibits activity against VEGF and placental growth • Prevention. This includes patient education about the fundamental importance of proper nutrition factor (PLGF). It received FDA and healthy lifestyle. approval for the treatment of DME • Evaluation. Perform a comprehensive ophthalmic workup and annual dilated fundus examination. in July 2014. • Early Detection. Achieved via regular monitoring of ocular complications. The DME and VEGF Trap-Eye • Comanagement. Provide a timely referral to an endocrinologist, certified diabetes educator, Investigation of Clinical Impact podiatrist, dentist or retinal specialist, when appropriate. (DA VINCI) study showed that • Rehabilitation. Arrange low vision care for patients who experience significant vision loss. aflibercept produced a statistically significant and clinically relevant improvement in visual acuity when ranibizumab and laser therapy. to 12, injections were administered compared to macular laser photo- At six-month follow-up, patients as needed. coagulation in DME patients.18 in the ranibizumab monotherapy The mean improvement in best- • MEAD. Before the increased group gained seven ETDRS letters; corrected visual acuity from base- use of anti-VEGF therapy, intra- subjects in the combination treat- line was 6.1 ETDRS letters in the vitreal triamcinolone acetonide ment group gained 3.8 letters; and ranibizumab monotherapy group, was frequently used to treat DME. those in the laser monotherapy 5.9 letters in the combined therapy However, due in part to the group actually lost 0.4 letters.2,15 group and 0.8 letters in the laser agent’s capacity to induce cataract • RESTORE. In the Rani- monotherapy group.16 formation and increase intraocular bizumab Monotherapy or • BOLT. Bevacizumab (Avastin, pressure, its use has declined dur- Combined with Laser Versus Genentech/Roche) is a systemic ing the last few years. Additionaly, Laser Monotherapy for Diabetic anti-VEGF agent that exhibits one large trial reported that, for Macular Edema (RESTORE) study, chemical similarities to ranibizum- most patients, intravitreal triam- 345 patients were randomized to ab. Because compounded bevaci- cinolone acetonide yielded gener- receive 0.5mg ranibizumab plus zumab is markedly less expensive ally poorer visual outcomes than sham laser, 0.5mg ranibizumab than ranibizumab, retinal special- photocoagulation.19 plus active laser or sham injections ists often use it as an off-label DME In June 2014, Allergan’s with active laser.16 A treatment treatment. Ozurdex (dexamethasone intra- initiation phase included three The intravitreal Bevacizumab or vitreal insert) received FDA consecutive monthly intravitreal Laser Therapy in the Management approval for the treatment of injections of either ranibizumab or of Diabetic Macular Edema DME in pseudophakic patients a placebo. Then, from months four (BOLT) study was a prospective, or those scheduled for cataract single-center, randomized, two- surgery. The insert’s approval was Vitrectomy: No Sense of Humor year trial of 80 CSME patients.17 based on results of the Macular All enrolled subjects received at Edema: Assessment of Implantable Vitrectomy surgery could potentially aid in the least one previous macular laser Dexamethasone in Diabetes resolution of diabetic macular edema. The ratio- treatment. (MEAD) trial. nale for vitrectomy was established following The BOLT researchers com- This study evaluated 1,048 DME the publication of several epidemiologic stud- pared the clinical efficacy of patients in two multicenter, three- ies.36 Researchers observed that the incidence monthly intravitreal bevacizumab year, sham-controlled, masked, of complete posterior vitreous detachment injections with four monthly modi- randomized clinical trials.20 MEAD was lower in patients with DME than in those fied macular laser treatments. At researchers randomized patients to without. This suggested that a partially attached two-year follow-up, patients in the receive an 0.7mg dexamethasone vitreous is a risk factor for DME. bevacizumab group gained 8.6 implant, and 0.35mg implant or a Today, it is believed that vitrectomy removes ETDRS letters, while those in the sham implant. At three-year follow- the tractional forces at the retinal surface in laser therapy group lost 0.5 let- up, all patients in both treatment DME patients, as well as decreases oxygen con- ters.17 groups experienced an improve- sumption in the vitreous and reduces hypoxia in • DA VINCI. Aflibercept (Eylea, ment in best-corrected visual acu- the retina.36 Regeneron [previously known as ity. While the implant exhibited a VEGF Trap-eye]) is a recombinant good safety profile, approximately 10 REVIEW OF OPTOMETRY NOVEMBER 2014 001_ro1114 RetinaGuide_mh.indd 10 10/17/14 4:49 PM