Diabetic macular edema studies

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DIABETIC MACULAR EDEMA REVIEW OF LITERATURE Abubaker Ahmed MS Ophth

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Review of literature

Transcript of Diabetic macular edema studies

Page 1: Diabetic macular edema studies

DIABETIC MACULAR EDEMAREVIEW OF LITERATURE

Abubaker Ahmed MS Ophth

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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

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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.

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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.

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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%

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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

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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.

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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.

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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

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Other treatment modalities

Intravitreal Corticosteroids

Intravitreal Anti-VEGF

Combination therapy

Surgical management (PPV)

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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

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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.

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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.

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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.

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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.

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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

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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

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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

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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.

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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.

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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.

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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.

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Thank you