DIABETIC MACULAR EDEMA REVIEW OF LITERATUREAbubaker AhmedMS Ophth
Introduction DME: retinal thickening within 2DD from the center of the macula. CSME : retinal thickening 500 microns from fovea , hard exudates within 500 microns from fovea with retinal thickening, or at least 1 DD of thickening any part of which within 1 DD of fovea
Pathophysiology DME is the result of breakdown of the inner blood retinal barrier leading to incompetence of the vessels and fluid leakage Retinal edema results once this fluid leakage overwhelms the capacity of the retinal pigment epithelial pump to remove it.
Pathophysiology contd Focal retinal ischemia due to retinal arteriolar closure Macular ischemia resulting from closure of retinal capillaries and arterioles may stimulate VEGF which exacerbating CME.
Treatment of DME The Early Treatment Diabetic Retinopathy Study (ETDRS) in 1985 set the guidelines for treatment of DME : Glycemic control, optimal BP control and macular focal/grid photocoagulation reducing the risk of moderate vision loss by 50%
The Early Treatment in Diabetic RetinopathyStudy (ETDRS) The ETDRS was a large-scale, multicenter, randomized clinical trial sponsored by the National Eye Institute in 1979 designed to investigate whether early treatment of macular edema by focal argon laser photocoagulation could prevent moderate visual loss
ETDRS Eyes with macular edema in the setting of mild to moderate non proliferative diabetic retinopathy with a visual acuity of 20/40 or worse were divided into two treatment groups: immediate versus delayed focal laser photocoagulation.
ETDRS conclusion Based on three years of follow-up data, the ETDRS concluded : Immediate focal photocoagulation halved the rate of moderate visual loss. Treatment of center involving CSME resulted in a 67% decrease in the rate of visual loss Treatment of center-sparing CSME resulted in only an approximate 45% decrease in the rate of visual loss.
Drawback However, as was reported by the ETDRS, only 17% of eyes with baseline vision of worse than 20/40 experienced modest visual improvement, and a certain proportion of patients did not respond to focal laser therapy at all
Other treatment modalities I vitre a l Co rtic o s te ro id s ntra I vitre a l A ntra nti-VEG F Co m bina tio n the ra p y Surg ic a l m a na g e m e nt (PPV)
I vitre a l Co rtic o s te ro id sntra Corticosteroids interfere with the regulatory components of gene expression and inhibit the expression of proinflammatory genes as TNF α a nd o the r cytokines Inhibit the phospholipase A2 pathway, and reduce leucocyte chemotaxis Corticosteroids inhibit the expression of VEGF and VEGF gene
DRCR.net study 2008 Diabetic Retinopathy Clinical Research Network A multi-center, large scale, randomized clinical trial included 840 eyes and evaluated 1mg and 4mg doses of preservative-free triamcinolone compared with focal/grid photocoagulation for DME
DRCR.net study At four months, the 4mg triamcinolone group had better visual acuity but by one year there were no significant differences. At 3 years, mean visual acuity was better in the laser group than in the two triamcinolone groups (recently published ) Elevation of IOP and the need for cataract surgery were higher in the 4mg triamcinolone group.
I vitre a l Antra nti-VEG F VEGF has been linked to leakage of retinal vessels and hence to the formation of retinal edema , this was the rationale for testing anti- VEGF drugs for the treatment of DME. Ranibizumab(or Lucentis) and bevacizumab (or Avastin) are sister molecules of humanized murine monoclonal antibodies with affinity for binding VEGF isoforms.
PACORES study The Pan-American Collaborative Retina Study Group Retrospective interventional multicenter study evaluated the retinal thickness and visual acuity data of 80 consecutive patients (139 eyes) receiving intravitreal Avastin of 1.25 or 2.5mg with a minimum followup of 24 months Arevalo JF, e t a l. Prim a ry intra vitre a l be va c iz um a b (A a s tin) fo r d ia be tic m a c ula r v e d e m a : results from the Pan-American Collaborative Retina Study Group at 6-month follow-up. Ophthalmology 2007;114(4):743-750.
PACORES study Results showed that at 24 months 44.6% eyes remained stable, 51.8% improved 2 or more lines, and 3.6 % decreased 2 or more lines. Patients who received on average 5.8 injections of single or double dose Avastin demonstrated a maintained partial resolution of macular edema
RESOLVE Study The Sa fe ty a nd Effic a c y o f Ra nibiz um a b in Dia be tic M c ula r Ed e m a a A multicenter, randomized, and double masked evaluated the efficacy and safety of intravitreal ranibizumab (0.3 or 0.5mg) compared with sham treatment in 151eyes with DME over 12 months
RESOLVE Study Results showed a significant and continuous improvement in BCVA and central retinal thickness for ranibizumab versus sham. P. Massin, F. Bandello, J. G. Garweg et al., “Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study): a 12-month, randomized, controlled, double-masked, multicenter phase II study,” Dia be te s Ca re , vo l. 3 3 , no . 1 1 , p p . 2399–2405, 2010.
BOLT studyThe most meaningful study concerning Bevacizumab for DME Compare the efficacy of anti-VEGF therapy to focal laser photocoagulation in 80 patients with CSME . A prospective, randomized phase III clinical trial Michaelidis K, Kaines A, Hamilton RD, e t a l. Ap ro s p e c tive ra nd o m iz e d tria l o f intra v itre a l bevacizumab or laser therapy in the management of diabetic macular edema (BOLT) study) 12-month data: report 2. Ophthalmology 2010;117:1078-1086.
BOLT study Bevacizumab injections given every 6 weeks or laser treatment performed every 4 months. Injected eyes received 3-9 injections, whereas the focal laser eyes received 1-4 treatments in the 12-month study period.
BOLT study Patients in the bevacizumab group were 5.1 times as likely to gain at least 10 letters. BOLT 2012 : long term effect of Bevacizumab is maintained at 24 months The BOLT study suggested that intravitreal bevacizumab therapy should be considered as a first choice in the management of center- involving DME.
RIDE study Double-blinded, sham-controlled randomized studies with a followup of 36 months. Patients received monthly injections of 0.3 mg ranibizumab, 0.5 mg ranibizumab, or sham. As twice as many patients in the ranibizumab groups gained ≥1 5 le tte rs c o m p a re d to the s ha m g ro up D. S. Boyer, J. Sy, A. C. Rundle et al., Ra nibiz um a b fo r Vis io n Lo s s d ue to Dia be tic M c ula r Ed e m a — Re s ults o f two Pha s e IIRa nd o m iz e d tria ls , A e ric a n Dia be te s a I m A s o c ia tio n 7 1 st Scientific Sessions, San Diego, Calif, USA, 2011. s
DRCR.net study 2011 Ra nibiz um a b p lus Pro m p t o r De fe rre d M c ula r a La s e r Pho to c o a g ula tio n ve rs us Tria m c ino lo ne p lus M c ula r La s e r Pho to c o a g ula tio n a Multicenter, randomized clinical trial which included 854 eyes of 691 patients M. J. Elman, N. M. Bressler, H. Qin et al., “Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema,” O p htha lm o lo g y , vo l. 1 1 8 , no . 4, p p . 6 0 9 – 6 1 4, 2 0 1 1 .
DRCR.net study 2011Four treatment groups: Prompt laser with sham injection, 0.5 mg of ranibizumab with prompt laser 0.5mg of ranibizumab with laser deferred for at least 24 weeks 4mg of triamcinolone with prompt laser.
DRCR.net study 2011 At one year, the two groups treated with ranibizumab had a significant change in mean VA from the baseline. The triamcinolone and laser alone groups did not show a significant change in VA. a subgroup analysis of pseudophakic eyes in the triamcinolone group showed similar results as for those in the ranibizumab groups.
RESTO RE s tud y A randomized, double-masked, multicenter phase III study over 12 months compared ranibizumab + sham laser and ranibizumab + laser with laser + sham injection for DM in 345 patients P. Mitchell, F. Bandello, U. Schmidt-Erfurth et al., “The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema,” O p htha lm o lo g y , v o l. 1 1 8 , no . 4, p p . 6 1 5 – 6 2 5 , 2 0 1 1 .
RESTO RE s tud y Ranibizumab or sham injections were given monthly for three months and then PRN; laser or sham laser was given at baseline and then PRN after an interval of at least three months.
RESTO RE s tud y In the ranibizumab and ranibizumab + laser groups a rapid improvement of VA was observed after one month which continued up to three months and was sustained until month 12 Likewise, the percentage of patients reaching VA ≥ 20/40 was greater in the two ranibizumab groups Ranibizumab monotherapy and combination with laser treatment are superior to laser treatment alone for DME.
Pars plana vitrectomy Many studies suggest that removal of the vitreomacular traction or the vitreous itself with vitrectomy may, in some patients be followed by resolution of macular edema Patients with refractory CSME and a taut posterior hyaloid face who have not responded to macular laser treatment may benefit from a vitrectomy
Where are we today? Ranibizumab monotherapy and ranibizumab in combination with laser are more effective than macular laser photocoagulation monotherapy. Bevacizumab, superiority has been shown for combination with macular laser photocoagulation to each of them alone. Combination therapy of IVTA plus macular laser is more effective than either monotherapy and may be comparable to anti- VEGF plus laser in pseudophakic patients.
Though intravitreal corticosteroids and anti- VEGF drugs have different ways of action there was no adjunctive effect found with combination therapy. Further investigation of additional treatment options is needed in order to optimize therapy.
Future Therapies VEGF Trap-Eye is a soluble VEGF receptor fusion protein that binds all forms of VEGF-A and related placental growth factor (PGF). When administered as a single 4 mg intravitreal injection in a phase 1 study, a marked decrease in central retinal thickness and mean macular volume was noted.
Future Therapies The phase III FAME (fluocinolone acetonide in diabetic macular edema) trial is evaluating the Medidur fluocinolone-based injectable implant. The phase III trial of Posurdex biodegradable implant (sustained delivery formulation of dexamethasone) for the treatment of diabetic macular edema is underway.