16.10.2012-AN OVERVIEW OF AMD AND IT'S TREATMENT.pptx

Age related macular degeneration

1. AN OVERVIEW OF AMD AND THE TREATMENT OF WET AND DRY AMD

2. introduction What is AMD? Age-related macular degeneration Degenerative disease of the central portion of the retina (macula)→ loss of central vision AMD is the leading cause of adult blindness & severe visual impairment 2 types of AMD: dry (atrophic) or wet ( neovascular or exudative )

3. CLINICAL PRESENTATION Early AMD is often asymptomatic Patients with dry AMD may complain of gradual loss of vision in 1 or both eyes. Wet AMD may present with acute visual distortion or loss of central vision as a result of subretinal hemorrhage or fluid accumulation.

4. CLINICAL PRESENTATION Distortion of straight lines is one of the earliest changes with wet AMD ( metamorphopsia ) Patients may also complain of a dark patch in their central vision ( scotoma )

5. RISK FACTORS Age: prevalence of AMD ↑ with age, starting after age 50 and becoming more pronounced over age 65. Smoking: smoking ↑ the risk of dry and wet AMD (relative risks ranging from 2 to 4). Smoking is also associated with increased risk of progression from early to advanced AMD and from geographic atrophy and bilateral involvement. Family history: there appears to be an increased risk in patients with a family history of AMD

6. RISK FACTORS Genetic factors: a common polymorphism of the complement factor H(CFH) gene predisposes to the development of AMD. Individuals with 1 allele with a histamine substitution for tyrosine in position 402 of the CFH gene on chromosome 1 appear to have 2.5-4.6X the risk of AMD, and individuals with both alleles affected appear to have 3.3-7.4X the risk. Cardiovascular disease: a history of stroke/ CHD (MI or angina) was associated with increased risk(RR=1.6) for AMD in a prospective 10yr study involving 2000 participants

7. RISK FACTORS Others: a variety of other potential factors have been suggested. Heavy alcohol usage (more than 3 drinks/day) is associated with an increased risk for early AMD. AMD appears to be more prevalent in whites than in blacks, with an intermediate prevalence in Hispanics and Chinese. Daily aspirin use was associated with increased risk in both dry and wet AMD.

8. DRY AMD Early lesions more common than later stage disease in dry AMD Dry AMD progesses to wet AMD in some patients. Findings in dry AMD include: Subretinal drusen deposits Focal or more widespread geographic atrophy of retinal pigment epithelium Pigment epithelial detachments Subretinal pigment epithelial clumping An area of pigmentary mottling beneath the retina

9. Small bright yellow drusen are visible Bright yellow drusen are coalescing, and a large area of atrophy is seen in the macular

10. WET AMD Characterized by growth of abnormal vessels into the subretinal space Abnormal blood vessels leak→leading to collections of subretinal fluid and/or blood beneath the retina More common than dry AMD among patients with advanced AMD Accounts for >80% cases with severe visual loss or blindness Areas of blood vessel leakage are present, with a large disciform scar Large area of subretinal hemorrhage

11. Dry AMD: vision loss slow & gradual Wet AMD: rapid loss of central vision

12. TREATMENT OF DRY AMD Dry AMD: progress slowly over many years Less threatening to vision than wet AMD No proven effective treatment for dry AMD Antioxidant vitamins and zinc: hypothesized to prevent celluar damage in the retina by limiting the effects of free radicals produced in the process of light absorption

13. TREATMENT OF DRY AMD AREDS (Age-related eye disease study) involving 3640 subjects were randomly assigned to one of 4 treatment groups: Antioxidants (vitamin C 500mg, vitamin E 400IU, beta-carotene 15mg) Zinc and copper (zinc oxide 80mg and cupric oxide 2mg) Antioxidants plus zinc Placebo

14. TREATMENT OF DRY AMD Results from the study after follow-up of 6.3yr: Patients with no AMD (category 1) or mild or borderline AMD (category 2) did not benefit from antioxidant and/or zinc supplementation Zinc plus antioxidants, compared with placebo, ↓risk for progression to advanced AMD/ loss of visual acuity in good eye in patients with moderate and advanced AMD (category 3 & 4) Zinc, alone was also associated with a lower risk of progression

15. TREATMENT OF DRY AMD Given the findings, treatment with antioxidant vitamins A,C & beta-carotene, plus zinc is suggested in nonsmoker patients with extensive intermediate size drusen , at least 1 large druse , or noncentral geographic atrophy in one or both eyes For smokers, treatment with the AREDS formula without beta-carotene is advised, due to the increased risk of lung cancer with beta-carotene in smokers No beta-carotene

16. TREATMENT OF WET AMD Pharmacology: choroidal neovascularization is controlled by a dynamic balance between membrane-bound and diffusible substances with properties that either promote or inhibit blood vessel development. Animal and human studies strongly suggest that VEGF is responsible for iris and retinal neovscularization associated with ischemic retinopathies VEGF-inhibitors & inhibitor-like drugs: Vascular endothelial growth factor is a potent mitogen and vascular permeability factor that plays a pivotal role in neovascularization

17. VEGF-INHIBITORS Bevacizumab 1.25mg ( Avastin ) Recombinant, humanized monoclonal antibody which binds to and neutralizes VEGF, preventing its association with endothelial receptors Not FDA approved in the treatment for wet AMD However, it is still used by our doctors Much cheaper,($195)due to 1 vial being reconstituted into multiple syringes

18. VEGF-INHIBITORS Ranibizumab ( Lucentis 10mg/ml): Recombinant humanized monoclonal antibody with specificity for VEGF An antibody fragment of bevacizumab with some modifications to amino acid sequence that ↑ binding to VEGF Dosing: 0.5mg (0.05ml) intravitreal inj once a month for at least 3/4 consecutive months (frequency may be ↓once every 3mth if monthly inj not feasible) Cost of 1 Lucentis inj is $1528.40

19. COMPARISON BETWEEN AVASTIN & LUCENTIS CATT (Comparison of AMD Treatment Trial) trial in US compares bevacizumab and ranibizumab (2 yr prospective, multi-center, randomized trial) *Funded by National Eye Institute (NEI)* 1 st year results from the trial were published in May 2011, which shows that bevacizumab and ranibizumab are equally effective 2 nd year results were just published this year in May: 30% higher risk in overall serious systemic adverse effects with bevacizumab ( Avastin ) compared to Lucentis (p=0.004)

20. COMPARISON BETWEEN AVASTIN & LUCENTIS Study also shows that arteriothrombotic events, systemic hemorrhage, congestive heart failure, venous thrombotic events, hypertension and vascular death were more frequent in bevacizumab treated patients (p=0.07) In addition, as in year one, there were significantly more gastrointestinal disorders in patients treated with intravitreal bevacizumab compared to Lucentis (p=0.005).

21. COMPARISON BETWEEN AVASTIN & LUCENTIS In addition, there have been reports of severe eye inflammation, some resulting in blindness, following unlicensed intravitreal bevacizumab use across the US and UK. Previously published retrospective studies that compared the safety of avastin and lucentis also showed that in patients treated with avastin , there is a 11% increased risk of death, 57% increased risk of hemorrhagic stroke and the risk of ocular inflammation was 80% higher.

22. OTHER VEGF-INHIBITORS Pegaptanib ( Macugen ): 1 st VEGF-inhibitor to be approved by the FDA for treatment for wet AMD. Benefit in the treatment is similar to that seen with photodynamic therapy. Aflibercept (not licensed in Spore): protein that competes for binding of VEGF, has similar effect to VEGF inhibitors. In trials comparing aflibercept and lucentis , aflibercept was shown to be similarly effective in improving visual acuity at 1yr compared to intravitreal lucentis .

23. OTHER TREATMENT OF WET AMD Photodynamic therapy: involves intravenous injection of the photosensitizing dye verteporfin ( Visudyne ) just prior to treatment with a photo-activating laser applied through the eye with a specific contact lens. Activated dye forms reactive free radicals →damage the vascular endothelium→ thrombosis of the neovascular tissue that retains dye more avidly than normal vessels. However, these vessels often reopen.

24. OTHER TREATMENT OF WET AMD As an example, 33% of 108 eyes in one study showed evidence of recurrent choriodal neovascularization at 18mth following a course of photodynamic therapy. Re-treatment with photodynamic therapy is safe. Prior to anti-VEGF treatments, photodynamic therapy was primarily indicated in patients with a subfoveal neovascular membrane. An analysis of 2 randomized trials (609pat) and a subsequent systematic review of 3 trials (1022pat) found that compared with placebo, photodynamic therapy was associated with a lower rate of vision loss at 1yr & vision remained stable over 3yr of follow-up.

25. VEGF- INHIBITORS WITH ADJUVANT THERAPY 2 techniques that cause vascular occlusion to the target tissue have been investigated for role as an adjuvant treatment to be used in combination with VEGF-inhibitors. In a randomized trial, combined lucentis with Visudyne photodynamic therapy was more effective than photodynamic therapy alone. Combination of photodynamic therapy with bevacizumab has been effective in case series, with randomized trials underway.

26. VEGF- INHIBITORS WITH ADJUVANT THERAPY Another adjuvant therapy is using TTT ( transpupillary thermotherapy) TTT delivers radiation near the infrared spectrum through the pupil to the target tissue. At low doses, the surrounding neurosensory retina is not damaged. In a randomized trial with a sham procedure as control, 100 patients were assigned to receive quarterly low dose TTT or sham TTT for 2 yr. Patients in the TTT group required fewer treatments with Lucentis compared to those in the sham group. However, there was no difference in corrected visual acuity or lesion area between groups.

27. OTHER TREATMENT OF WET AMD Thermal laser photocoagulation: uses relatively high intensity of thermal laser energy to coagulate the abnormal choriodal neovascular membrane. Adverse consequence of this treatment is focal damage to the overlying retina with the formation of a permanent blind spot. Thus, if used, treatment should be limited to lesions outside of the central macula. Surgery: 2 types of surgery have been tried for AMD, submacular surgery and macular translocation surgery

28. OTHER TREATMENT OF WET AMD Submacular surgery: involves the removal of abnormal subretinal neovscularization and large sumacular hemorrhages,if present. Macular translocation surgery is experimental and invloves moving the macular to a less dieseased area of the retina in patients with subfoveal choriodal neovascularization . Surgical risks are substantial, with high rates of retinal detachment, thus limiting its use.

29. OTHER TREATMENT OF WET AMD Radiation therapy: external beam radiation therapy has been studied in patients with AMD. A meta-analysis of randomized, controlled trials concluded that there was no consistent evidence of benefit. Glucocorticoids : An uncontrolled trial of intravitreal injections with triamcinolone acetonide (25mg) found short-term improvements in vision in two-thirds of treated eyes. Triamcinolone has also been injected into the posterior sub- Tenon’s space for ARMD and other conditions. The risks associated with this technique appear to be minimal.

30. OTHER TREATMENT OF WET AMD Zinc and antioxidant vitamins: AREDS study mentioned previously found a statistically significant benefit of antioxidants (vitamins C and E and beta-carotene) plus zinc supplemention on progresssion of early AMD in 1 eye in patients with wet AMD or vision loss due to AMD in the other eye. As mentioned before, beta-carotene has been linked to an increased risk of lung cancer and possibly increased risk of coronary heart disease. Thus, smokers are advised to take AREDS formula, without the beta-carotene.

31. PREVENTION OF AMD Diet Diet that includes fruits, vegetables, fish and nuts have been associated with a lowered risk of AMD Nutritional and vitamin supplement Antioxidant vitamins and zinc may have a beneficial effect in certain groups of patients, however their role in prevention is unclear Physical activity: associated with a lower risk of developing AMD Smoking: ↑risk of developing wet and dry AMD

32. FUTURE TREATMENT Several investigational clinical trials are underway to evaluate treatment options for dry AMD. Potential new treatments include: topical antioxidant eye drops, implantation of encapsulated human NTC cells, and fetal cell transplantation. Ongoing trials for patients with neovascular AMD include evaluation of the angiogenesis inhibitor pazopanib given as topical eye drops, subconjuntival injection of an antiproliferative polyamine analog (CGC-11047). A topical kinase inhibitor with multiple growth factor targets, including VEGF, suppressed choriodal neovascularization in a mouse model.