Diabetic macular edema studies
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Transcript of Diabetic macular edema studies
DIABETIC MACULAR EDEMAREVIEW OF LITERATURE
Abubaker Ahmed MS 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 Retinopathy Study (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
Intravitreal Corticosteroids
Intravitreal Anti-VEGF
Combination therapy
Surgical management (PPV)
Intravitreal Corticosteroids
Corticosteroids interfere with the regulatory components of gene expression and inhibit the expression of proinflammatory genes as TNFα and other 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
Figueroa MS, Regueras A, Bertrand J, et al. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmol 2008;115(9):1447-1450.
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.
Intravitreal Anti-VEGF
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 RetinaStudy 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, et al. Primary intravitreal bevacizumab (Avastin) for diabetic macular edema: 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 Safety and Efficacy of Ranibizumab in Diabetic Macular Edema
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,” Diabetes Care, vol. 33, no. 11, pp. 2399–2405, 2010.
BOLT study
The 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, et al. A prospective randomized trial of intravitreal 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 ≥15 letters compared to the sham group
D. S. Boyer, J. Sy, A. C. Rundle et al., Ranibizumab for Vision Loss due to Diabetic Macular Edema—Results of two Phase III Randomized trials, American Diabetes Association 71st Scientific Sessions, San Diego, Calif, USA, 2011.
DRCR.net study 2011
Ranibizumab plus Prompt or Deferred Macular Laser Photocoagulation versus Triamcinolone plus Macular Laser Photocoagulation
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,” Ophthalmology, vol. 118, no. 4, pp. 609–614, 2011.
DRCR.net study 2011
Four 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.
RESTORE study
A randomized, double-masked, multicenter phase III study over 12 monthscompared 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,” Ophthalmology, vol. 118, no. 4, pp. 615–625, 2011.
RESTORE study
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.
RESTORE study
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.
Thank you