top amd stories: 2008

Top Ten AMDStories of 2008

Rick Trevino, OD

Evansville VA Clinic

http://richardtrevino.net

and early 2009

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10.

Top Ten AMD Stories

Topical TherapyBaseline Characteristics

10.9.

http://www.osnsupersite.com/view.aspx?rid=36107

Baseline Characteristics

AREDS: Progression Risk Factors

• Significant predictors of AMD progression Age Smoking AREDS-formula supplement treatment Severity of AMD at initial presentation



AREDS: Progression Risk Factors• Rate of advanced AMD at 10 years based on

presence of large drusen or pigmentary changes at initial exam: Absent: 1% Present: 72%

• Persons predisposed to progression have more severe AMD right from the start • Genetic predisposition?• Identify at-risk patients early



Patients with better initial vision need fewer Lucentis injections to get dry

• Retrospective study of 62 patients receiving Lucentis for wet AMD with 1yr follow-up

• Number of injections required to achieve full resolution of macular fluid with a single Lucentis injection related to baseline characteristics



Patients with better initial vision need fewer Lucentis injections to get dry

• One-injection group: 20/66 and 263 µm• Two-injection group: 20/76 and 279 µm• Three-injection group: 20/80 and 297 µm• Four-injection group: 20/93 and 410 µm

• Yet another reason to encourage patients with AMD to closely monitor their vision to detect the earliest symptoms of CNV.

http://www.ncbi.nlm.nih.gov/pubmed/18486222


CAPT: Early detection with close monitoring

• “Close monitoring of high-risk eyes… can lead to detection of CNV when it is more likely outside the fovea, relatively small, and without a large loss in visual acuity.” At the time of detection 69% had 20/40 or better VA Amsler grid, Preferential hyperacuity perimetry

• Much of the vision lost to CNV is lost prior to the initiation of treatment

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk Factors


Modifiable Risk Factors

Beaver Dam Eye Study: Smoking

• Smokers… had 47% increased risk of developing early AMD developed AMD at a younger age (69.2 years) than

former smokers (72.3 years) and those who had never smoked (74.4 years).

had increased risk of AMD progression over 15 years

• Exposure to second-hand smoke was not associated with AMD

The Bolton News, 3/24/2008


• EU political movement underway to place warnings on cigarette packets about the risk of blindness

• "We are seeking to convince the European Commission of the public health importance of the hazards of smoking on the eyes and for warnings along those lines to now appear on cigarette packets."



Atherosclerosis Risk in Communities Study: Obesity

• Decreasing abdominal obesity lowers AMD risk• Population-based study of over 12,500 persons• Middle-aged persons with a ≥3% reduction in

WHR were less likely to have AMD All participants: 29% lower risk Initially obese participants: 59% lower risk

• "Our findings suggest a role of weight loss in preventing the development of AMD."



Vigorous Exercise Decreases Risk of AMD

• Running has a significant protective effect on the development of AMD

• 40,000 runners followed for 7.7 years• The relative risk for AMD decreased 10% for

every kilometer per day that the person ran• Compared with persons who averaged <2 km/d:

Running 2-4 km/d had 19% lower risk Running 4 km/d had 42% to 54% lower risk


What’s

Good for the Heart

Is also

Good for the Eye!

Don’t smoke

Lose weight

Exercise regularly

Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMD

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Cataract and AMD

EUREYE: Sunlight increases risk of AMD in persons with low antioxidant levels

• Population-based study of 4700 people in 7 European countries

• High sunlight exposure and low serum antioxidant levels associated with 4-fold increased risk of wet AMD Sunlight not hazardous if antioxidant levels are

adequate Risk greatest with low levels of zeaxanthin, vitamin E,

and vitamin C


Cataract and AMD

Blue-blocker IOLs may impair vision• Color perception and contrast sensitivity may be

impaired by yellow IOLs• 48 eyes of 24 consecutive patients with age-

related cataract. Implanted a blue-light-filtering IOL in one eye and a UV-filtering IOL in their other eye Blue-light-filtering IOLs had worse contrast acuity and

lower foveal thresholds than the UV-filtering IOLs


Cataract and AMD

Blue-blocker IOLs may impair vision

• The negative consequences of blue-blocking IOLs may out weight theoretical advantages “The relationship between blue light and AMD is

speculative and not proven by available evidence.” Centers for Medicare and Medicaid Services

Blue-blocker IOLs may upset the circadian rhythm, causing insomnia, daytime sleepiness, depression, and poor concentration


Cataract and AMD

AREDS: CE does not increase the risk of AMD progression

• There is no clinically important increased risk of progression to advanced AMD after cataract surgery Contrary to the results of some older population-

based studies (Beaver Dam, Blue Mountain)

• AREDS is the only prospective study in which the severity of AMD was documented before and after cataract surgery in a large number of cases with more than 5 years of regular follow-up

Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic Therapy

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Photodynamic Therapy

PDT plus steroids: Two year results

• Prospective study of 84 patients with AMD randomized to receive PDT alone or PDT + steroids

• PDT combined with intravitreal steroid injection will initially improve vision in patients with wet AMD, but these improvements are lost over a 24-month follow-up period



PDT plus steroids: Two year results

• This study casts doubt over the long-term vision benefits of standard PDT

• “Safety enhanced” PDT protocols are being developed with the hope that outcomes can be improved Half-dose verteporfin Low fluence laser

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal Prostheses

Retinal Prostheses

General Concepts

• Generate phosphenes through direct electrical stimulation of retinal cells

• Requires healthy ganglion cells Not suitable for diseases such as glaucoma

• Two types of implants: Epiretinal implant: Stimulate ganglion cells Subretinal implant: Stimulate inner nuclear layer

Retinal Prostheses

Engineering Approaches

• Implanted Multielectrode Array (MEA) Implant stimulating electrodes Use transcutaneous telemetry to transfer data

and power to electrodes. Image capture and processing takes place

externally. Usually implanted epiretinally and stimulate

retinal ganglion cells directly.

Retinal Prostheses


• Microphotodiode array (MPDA) Implant optoelectronic devices that directly

convert light into electricity• “Artificial photoreceptors”

Usually implanted subretinally and stimulates inner nuclear layer cells

Takes advantage of existing image processing functions of the retina

Retinal Prostheses


• Biochemical prosthesis Virally re-engineer ganglion and/or bipolar

cells to become light sensitive. Early development, at least 5 years away from

commercialization

Retinal Prostheses

Subretinal Implant

Retinal Prostheses

Epiretinal Implant

Retinal Prosthesis

Commercial Development• Ongoing long-term implantation clinical trials:

Second Sight • Epiretinal MEA • Argus I: 16-electrode device • Argus II: 60-electrode device (improved spatial resolution)

Intelligent Medical Implants • Epiretinal MEA • Features an “adaptive retinal encoder” to assist with

adjustment of stimulation parameters for individual patients Epiret

• Epiretinal 25-electrode MEA

Retinal Prostheses

Commercial Development• Three companies aim to release

commercial devices before the end of 2010 Second Sight Intelligent Medical Implants Retina Implant

• Subretinal MPDA • Hybrid device incorporating both light amplification

and electrical stimulation functions

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal ProsthesesLutein


Lutein

LUNA: Supplementation leads to long-term increase in macular pigment

• 108 subjects with and without AMD taking Ocuvite with lutein for 6 months Contains 12mg lutein and 1mg zeaxanthin

• Only a slight decline occurs in macular pigment levels 9 months after subjects stopped taking supplement

Lutein

LUNA: Supplementation leads to long-term increase in macular pigment

• Baseline: 0.50 ODU• 3 mos after stopping: 0.59 ODU (peak)• 6 mos after stopping: 0.54 ODU• 9 mos after stopping: 0.57 ODU

• Lutein and zeaxanthin supplementation may be necessary to raise macular pigment density; but a normal healthy diet may contain enough carotenoids to maintain gains Long-term lutein supplementation may be

unnecessary


Lutein

Lutein not protective against early AMD

• Nurses' Health Study and The Health Professionals Follow-up Study A prospective study of dietary habits and health status

of 113,000 persons followed for 18 years

• Lutein intake not associated with early AMD risk• Nonsignificant and nonlinear association

between lutein intake and neovascular AMD risk


Lutein

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal ProsthesesLuteinAnti-VEGF Therapy

Anti-VEGF Therapy

Evolving anti-VEGF treatment protocols

• Despite excellent outcomes, monthly injections of anti-VEGF drugs are undesirable because: It is inconvenient and time-consuming Costly Risk of complications of injections

• A number of studies are investigating ways to decrease the number of injections without compromising clinical outcomes.

Anti-VEGF Therapy


• Combination Therapy Anti-VEGF + PDT Anti-VEGF + PDT + Steroid

• Injection Schedule PIER: Quarterly injections, worse outcomes PrONTO: PRN based on 5 criteria

• 5.6 injections over 12 mos with good outcomes

Treat and Extend: OCT and biomicroscopy

Anti-VEGF Therapy


• CATT: PRN based on signs of active CNV Lucentis vs. Avastin: Head-to-head “Relaxed” PrONTO retreatment criteria Rely primarily upon OCT and biomicroscopy Results available in 2011

• Published studies have not yet clearly established an anti-VEGF treatment standard What’s really needed are better anti-VEGF drugs

Anti-VEGF Therapy

VEGF Trap-Eye• New anti-VEGF drug to treat wet AMD

Higher affinity for VEGF than any currently available drug

Binds all sub-types of VEGF Risk to choriocapillaris from long-term total

VEGF blockade?• Phase 3 Clinical Trial: VIEW Study

Head-to-head with Lucentis Fixed vs variable dosing

Anti-VEGF Therapy

Is there a visual acuity benefit of late anti-VEGF therapy for wet AMD?

YES Avastin therapy can improve vision in patients with

long-standing low vision secondary to wet AMDhttp://www.ncbi.nlm.nih.gov/pubmed/18664935

NO Vision did not significantly improve in patients that

had advanced lesions that were fibrotic or had been previously treated by other means http://www.ncbi.nlm.nih.gov/pubmed/18937801

Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal ProsthesesLuteinAnti-VEGF TherapyGenetics

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Genetics

Overview of AMD genetics• Family History - first degree relatives:

Increased risk of developing AMD (odds ratio: 2.4) Increased risk of late AMD (odds ratio: 4.2) Affected at younger age

• Complement factor H (CFH) and LOC387715 Two major AMD risk genes Associated with both wet and dry AMD

• Other AMD-associated genes May increase or decrease AMD risk Complement factor B, Complement component 2, etc

Genetics

Overview of AMD genetics

• Compliment factor H gene (CFH) CFH inhibits the alternative complement pathway Y402H polymorphism

• Specific mutation associated with AMD• Impairs inhibition of inflammation?

Implicated in all stages of AMD (early and late) and both major subtypes (dry and wet)

• LOC387715 gene (ARMS2) Function unknown A69S polymorphism


Genetics

TTTC

CC

GG

GT

TT

0

10

20

30

40

50

60A

MD

OD

DS

RA

TIO

(%

)

CFH

ARMS2


Genetics

AREDS: CFH genotype predicts benefit of vitamin/mineral supplement

• Persons with the high-risk CFH genotype (CC) have a smaller treatment response to the AREDS supplement than persons with the low-risk CFH genotype (TT)


Genetics

- Low risk

- Low risk


Genetics

CFH gene determines benefit of AREDS supplement on AMD progression

• Genetic testing could identify those most likely to benefit from treatment Avoid side effects in those unlikely to benefit from

supplement (genitourinary trouble, anemia)

• AREDS researchers do not advocate routine genetic testing at this time because: Some benefit is derived by all individuals No alternative intervention is currently available

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal ProsthesesLuteinAnti-VEGF TherapyGeneticsFish Oil


Fish Oil

Meta-analysis: consumption of omega-3 fatty acids cuts risk of AMD

• Literature review finds that consumption of foods rich in omega-3 fatty acids and fish intake twice or more per week may prevent AMD

• Only examined papers that investigated use of fish oil in the primary prevention of AMD Primary prevention: No sign of AMD at start of study 9 papers met inclusion criteria. None were RCTs

Pooled odds ratios for AMD, comparing the highest with the lowest dietary intake categories.

A: Omega-3 fatty acid intake and late AMD 38% reduction in risk.

B: Fish intake and early AMD 24% reduction in risk. If only prospective studies are pooled, there is a 37% reduction in risk.

C: Fish intake and late AMD 33% reduction in risk.

The diamond’s vertical axis indicates the pooled odds ratios, while its horizontal axis spans the 95% confidence intervals (CIs) from pooled analyses. * Indicates acase-control study; †, cross-sectional study; error bar, 95% CIs; squares,point estimates of each study.

Fish Oil

Meta-analysis: consumption of omega-3 fatty acids cuts risk of AMD

• This study found highly statistically significant pooled estimates that omega-3 fatty acids and fish are associated with a reduced risk of both early and late AMD

• “Routine recommendation of omega-3 fatty acid and fish intake for AMD prevention is not warranted until additional information from prospective studies and RCTs emerges.”


Fish Oil

AREDS: Fish oil consumption cuts risk of progression of both wet and dry AMD

• Fish oil decreases the risk of progression to advanced stages of both wet and dry AMD by 30% over 12 years

• Secondary prevention: All AREDS participants had AMD at start of study.

Fish Oil

AREDS: Fish oil consumption cuts risk of progression of both wet and dry AMD

• AREDS vitamin/mineral supplement Effective for a narrow range of AMD patients Potential for undesirable side effects Contraindicated for smokers

• Fish oil No serious adverse effects (mild anticoagulant) Appears to be effective in both primary and secondary

prevention of the disease

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Top Ten AMD Stories

Topical TherapyBaseline CharacteristicsModifiable Risk FactorsCataract and AMDPhotodynamic TherapyRetinal ProsthesesLuteinAnti-VEGF TherapyGeneticsFish Oil

top amd stories: 2008

Health & Medicine

risk of amd progression

early amd

amd stories

development of amd

wet amd

lower risk

increased risk

relative risk