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 Pathophysiology of diabetic retinopathy and diabetic macular edema  Pathophysiology of diabetic retinopathy and diabetic macular edema

Pathophysiology of diabetic retinopathy and diabetic macular edema - PowerPoint Presentation

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Pathophysiology of diabetic retinopathy and diabetic macular edema - PPT Presentation

Charles C Wykoff MD PhD FACS Physician Retina Consultants of Houston Blanton Eye Institute amp  Houston Methodist Hospital Houston USA Faculty Scope of the Problem 1st WHO Global Report 112 ID: 776561

ranibizumab dme protocol bevacizumab ranibizumab dme protocol bevacizumab laser diabetes vision year baseline years patients treatment aflibercept eyes website

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Slide1

Pathophysiology of diabetic retinopathy and diabetic macular edema

Charles C. Wykoff, MD, PhD, FACS

Physician, Retina Consultants of HoustonBlanton Eye Institute & Houston Methodist HospitalHouston, USA

Faculty

Slide2

Scope of the Problem

1st WHO Global Report: 1/12  8.5% have diabetesGlobally, DR is rising in prevalence 5th leading cause of blindnessIn developed countries, DR is the most common cause of vision loss and blindness among working-age peopleEyes are one of the earliest and most common organs affected

WHO. 2016 global report on diabetes.

Slide3

Among Patients With Diabetes, Who Gets DR?

If patients with diabetes live long enough, they will develop manifestations in the back of the eyeFor example, after 20 years of a diagnosis of diabetes, the following percentages will develop DR:100% of patients with T1DM80% of patients with T2DM

WHO. 2016 global report on diabetes.

Slide4

How Does Diabetes Impact the Eye?

There are 2 major manifestations in the eye:

Lens

Shifts in refraction based on blood sugar can occur

These can be transient and often improve as blood sugar improves

More lasting impact on lens is development of cataracts at an earlier stage than would typically develop without diabetes

Retina

Impact on retinal vasculature

Sensitive to blood sugar fluctuations, due to high density of small blood channels that run through the retina

Slide5

Capillary Damage: Manifestations in the Eye

Microscopic level

Pericyte loss

Capillary basement membrane thickening

Clinically, these 2 changes manifest as microaneurysms, the earliest manifestations of DR

on an exam

Slide6

Pathologic Changes Translate Into 2 Clinical Findings

Ischemia/capillary nonperfusion

A retina with insufficient blood flow cannot get adequate oxygen and nutrients it requires

Areas underperfused inside the retina begin to send off growth factors, including VEGF

VEGF is a major driver of DR

Breakdown of blood retinal barrier

Leads to extravasation of blood

Hemorrhage inside retina

Protein and lipid exudates

Serous fluid accumulation

Slide7

What Are the Clinical Manifestations of Changes That Cause Vision Loss?

DR has 2 major stages:

1.

NPDR

2.

PDR

Develops when new abnormal blood vessels grow from the retina through the internal limiting membrane into the vitreous cavity

New, weak blood vessels bleed/form scar tissue, resulting in

tractional

retinal detachments

Slide8

How Does DME Impact the Eye?

The most common cause of vision loss from diabetes is the development of DME

DME is present in approximately 10% of diabetics

DME has 3 categories:

Noncenter-involved fluid

Center-involved fluid with preserved central VA

Center-involved fluid with impaired central VA

Slide9

How Do We Slow Down the Process of Developing DME?

Ocular-specific treatments (laser modalities, pharmacologic agents)

Timely diagnosis and appropriate management results in effectively preventing blindness in approximately 90% of patients

Systemic CV risk factor control can slow the progression and development of DR

Slide10

Modifiable Risk Factors Associated With DR

Hyperglycemia

Hypertension

Hyperlipidemia

Smoking cessation

Weight loss and exercise

Slide11

Landmark Trials: DCCT and UKPDS

2 landmark randomized, multicenter trials of glycemic control involving > 5,500 T1DM or T2DM patients, respectively[a,b]These trials demonstrated that complications of diabetes could be dramatically reduced by improving blood sugar and blood pressure controlBlood sugar/blood pressure controlDecreases development of DRSlows progression of existing DR

a. DCCT Research Group.

N Eng J Med.

1993;329:977-986.

b. UKPDS Group.

Lancet.

1998;352:837-853.

Slide12

DCCT Trial Results: T1DM

DCCT Research Group. N Eng J Med. 1993;329:977-986.

0

1

2

3

4

5

6

7

8

9

0

10

20

30

40

50

60

Patients, %

Study, y

P

< .001

Intensive

Conventional

375

220

79

52

342

202

78

49

0

1

2

3

4

5

6

7

8

9

0

10

20

30

40

50

60

Patients, %

Study, y

P

< .001

Intensive

Conventional

348

324

128

79

354

335

130

93

Sustained change in retinopathy in patients with T1DM

Primary prevention cohort

Secondary intervention cohort

Slide13

Even Small Changes Make a Big Impact

The DCCT[a] and UKPDS[b] trials have demonstrated over the last 20 to 30 years that even a small change in systemic CV risk factor control can make a big impact in preventing or slowing the development of DRUKPDS trial:[b] Absolute 1% change in HbA1c corresponds to approximately 50% decreased risk of DR progression

a. DCCT Research Group.

N Eng J Med.

1993;329:977-986.

b. UKPDS Group.

Lancet.

1998;352:837-853.

Slide14

Concluding Remarks

DR and DME are common causes of blindness and are increasing in prevalence around the world, including in South America and North America

The development of DR is a "when," not an "if" problem

DR causes vision loss through pathologic ischemia and breakdown of the blood retinal barrier causing DME and PDR

Optimal CV risk factor control slows the development and progression of all forms of DR over time

Slide15

The Socioeconomic

impact and Burden of DR and DME

Peter K. Kaiser, MDChaney Family Endowed Chair for Ophthalmology Research;Professor of OphthalmologyCole Eye InstituteCleveland, USA

Faculty

Slide16

Worldwide Epidemic: Diabetes and DR

Worldwide, there is an epidemic of diabetes and DR

In Latin America, diabetes is leading cause of blindness

Prevalence of diabetes is increasing due to sedentary lifestyles and obesity

Patients with poor glycemic control and blood pressure control are at a higher risk of developing DR

Slide17

DR: Burden of Disease

DR is leading cause of blindness in working-age patients

Economic burden

Patients cannot perform their job if they are unable to see

People are missing work days to receive care

Patients need to be diagnosed early in order to treat earlier to prevent this from happening

Slide18

The Importance of Screening

T2DM patients should be screened by an ophthalmologist for signs of DR

Patients could have DR even if they are not having vision problems

Earlier treatment leads to better visual outcomes

PCPs play an important role in the medical management of patients with diabetes

PCPs need to encourage/recommend eye exams for diabetic patients

Slide19

When DR Is Already Present

Annual eye exams are key

Must look at back of eye/retina with a dilated exam

Unfortunately, access to trained eye care professionals may be difficult, especially in Latin America

Patients must comply with annual eye exams

Slide20

Treatments for DR

Laser therapy: prevents loss of vision but does not improve VA

Gold-standard treatment: anti-VEGF agents

Improves VA

Improves DR

Slide21

Concluding Remarks

Patients should be seen at least once a year for ophthalmic exams

Patients should be treated immediately when signs of DR that are vision-threatening are seen

Maintaining good blood pressure, blood sugar levels, and lipid control are key to preventing DR

Slide22

IDENTIFYING PATIENTS AT RISK WITH DR

Faculty

Neil M. Bressler, MDChief, Retina DivisionThe Wilmer Eye Institute, Johns Hopkins HospitalThe James P. Gills Professor of OphthalmologyJohns Hopkins University School of MedicineBaltimore, USA

*Participation by Dr Neil Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.*

Slide23

Macula: Center of the Retina

Macula

Macula

Retina

Slide24

One of 2 Causes of Vision Loss in Diabetes: DME

Images courtesy of

Neil M. Bressler, MD

.

Slide25

As blood vessels in the retina are damaged from abnormal blood sugar levels, the retina may create abnormal growth factors that increase permeability of these vessels, which can lead to edema of the retina tissue, often in the macula

Growth Factors in DR

Damaged retina

Leaky blood

vessels

Blood

Slide26

Prevalence Estimates Among US Adults ≥ 40 Years With Self-Reported and Undiagnosed Diabetes

Varma R, et al. JAMA Ophthalmol. 2014;132:1334-1340.

PopulationDiabetes Diabetes without DR or DMEDR without DMEDMENHANES Sample Size1,03871327055% of U.S. Population Aged ≥40 Years With Diabetes (95% CI)10072.2 (68.7-75.7)24 (20.8-27.3)3.8 (2.7-4.9)No. of Adults in the U.S. Population Aged ≥40 Years with Diabetes 20.3 million (18.1-22.7 million)14.6 million (12.9-16.5 million)4.9 Million(4.1-5.8 million)839,000 (602,000-1,117,000)

Slide27

AAO website. DR - Latin America.

DR in Latin America

DR is one of the leading causes of blindness in the work-productive population (16-64 years of age) in Latin America

Mexico is one of the countries with the highest prevalence of diabetes in the world, estimated at 11%

Approximately 10% of all diabetic patients have some degree of severe visual impairment

Less than 50% of diabetic patients in Latin America have access to an ophthalmologist

Slide28

Anti-Growth Factor to Treat DR

What if one injects anti-growth factors into the middle cavity of the eye? Would the edema go away and vision outcomes be better than laser treatment?

Slide29

Mean Change in VA (Letters)* at Follow-Up Visits

29

*

Values that were ±30 letters were assigned a value of 30.P values for difference in mean change in VA from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser < .001; ranibizumab + deferred laser < .001; and triamcinolone + prompt laser = .31.

DRCRnet website. Expanded follow-up for DME treatment.

Elman MJ, et al.

Ophthalmology

. 2011;118:609-614.

Slide30

Mean Change in VA Over 2-Year Treatment Interaction (

P

< .01) by Baseline VA Preplanned Subgroup

1-year treatment group comparison:*

Aflibercept vs bevacizumab

P < .001Aflibercept vs ranibizumab P = .0031Ranibizumab vs bevacizumab P = .21

2-year treatment group comparison:*Aflibercept vs bevacizumab P = .02Aflibercept vs ranibizumab P = .18 Ranibizumab vs bevacizumab P = .18

* P values adjusted for baseline VA and multiple comparisons

Aflibercept

Bevacizumab

Ranibizumab

DRCRnet website. Aflibercept, bevacizumab, or ranibizumab for DME.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide31

Brown MM, et al.

Ophthalmology. 2003;110:1076-1081.

How Does Vision Loss Compare With Other Health Problems?

* Based on VA in the better-seeing eye

Slide32

Identifying Characteristics of DME

Examine eye for lipid deposits, thickening, vision loss

However, patients can still have DME even with 20/20 vision and little or no lipid deposits

Therefore, special devices may be needed, such as optimal coherence tomography, to help identify DME

Slide33

Proliferative Diabetic Retinopathy

Left untreated, PDR often leads to loss of almost all vision in the eye from bleeding in the middle cavity of the eye and scar tissue detaching the retina off of the back wall of the eye

PDR can develop outside the center of the retina and therefore cannot be detected using a direct ophthalmoscope; more sophisticated imaging is needed

Slide34

Mean Change in VA AUC Analysis

AUC analysis: Preplanned secondary outcome

N = 203

N = 168

Mean VA Change (Letter Score)

0

16

32

52

68

84

104

Visit week

DRCRnet website. Aflibercept, bevacizumab, or ranibizumab for DME.

Gross JG, et al.

JAMA

. 2015;314:2137-2146.

Slide35

Awareness of Eye Diseases for US Adults ≥ 40 Years With Self-Reported Diabetes

Have you been told by a doctor that diabetes has affected your eyes or that you had retinopathy?

DRCRnet website. Protocol I follow-up. Bressler N, et al. JAMA Ophthalmol. 2014;132:168-173.

Slide36

Concluding Remarks

Vision is important!

A major complication of diabetes can be vision loss if DME or PDR is not detected BEFORE substantial vision loss has occurred

There are excellent treatments available, including anti-VEGF agents, if DME or PDR is identified before substantial vision loss occurs

Diabetes should be evaluated by someone who can detect DME or PDR

Direct ophthalmoscopy no longer

sufficient

Slide37

DIAGNOSIS AND SEVERITY SCALES OF DR AND DME

Baruch D. Kuppermann, MD, PhD

Professor of Ophthalmology and Biomedical EngineeringChief Retina Service; Vice Chair Clinical Research – OphthalmologyUniversity of California, IrvineIrvine, USA

Faculty

Slide38

Introduction

DR is a retinal vascular disorder that eventually affects almost all patients with long-standing diabetes

Most common cause of bilateral visual loss in

working-age group

Slide39

More Diabetic Patients = More Diabetic Eye Disease

20152040North America44.3 M60.5 MMSouth America29.6 M48.8 MMEurope59.8 MM71.1 MMMiddle East and North Africa35.4 MM72.1 MMAfrica14.2 MM34.2 MMWestern Pacific153.2 MM214.8 MMSoutheast Asia78.3 MM140.2 MMTotal 415 MM642 MM

Diabetes atlas website. Across the globe.

Slide40

Classification of DR

Wu L, et al. Classification of diabetic retinopathy and diabetic macular edema. World J Diabetes 2013;4(6):290-4 Figure 1

Slide41

DR Disease Severity Scale

No apparent retinopathy

No abnormalities

Mild NPDR

Microaneurysms only

Moderate NPDR

More than just microaneurysms, but less than severe NPDR

Severe NPDR

Any of the following (4-2-1 rule) and no signs of proliferative retinopathy:

Severe intraretinal hemorrhages and microaneurysms in each of 4 quadrants

Definite venous beading in 2 or more quadrants

Moderate IRMA in 1 or more quadrants

Any of the following and no signs of proliferative retinopathy:

More than 20 intraretinal hemorrhages in

each of 4 quadrants

Definite venous beading in 2 or more quadrants

Prominent IRMA in 1 or more quadrants

PDR

One or both of the following:

NeovascularizationVitreous/preretinal hemorrhage

US definition

International definition

Disease Severity Level

Observable Upon Dilated Ophthalmoscopy

Wilkinson CP, et al.

Ophthalmology

. 2003;110:1677-1682.

Slide42

ETDRS. Ophthalmology. 1991;98:823-833.

The ETDRS DR Severity Scale

1

2

3

4

5

6

10, 12

DR absent

14, 15, 20

DR questionable

35

Mild NPDR

43

Moderate

NPDR

47

Moderately

Severe NPDR

53

Severe NPDR

7

8

9

10

11

12

60, 61

Mild PDR

65

Moderate PDR

71

High-risk

PDR

75

High-risk

PDR

81

Advanced

PDR

85

Advanced

PDR

Slide43

Clinically Significant Macular Edema

Image courtesy of

Baruch D. Kuppermann, MD, PhD

.

Slide44

SAVE: A Grading Protocol for Clinically Significant DME Based on OCT

Adapted by permission from BMJ Publishing Group Limited. [BJO, Bolz M, et al, 98, 1612-1617, copyright 2014.

CONTENT NO LONGER AVAILABLE

Slide45

Advanced Diabetic Eye Disease

Preretinal and vitreous hemorrhage Tractional retinal detachment Rubeosis iridis and neovascular glaucoma

Image courtesy of

Baruch D. Kuppermann, MD, PhD

.

Slide46

Management Recommendations for Patients With Diabetes

AAO, Preferred Practice Patterns: Diabetic Retinopathy, 2014, updated Jan 2016

Severity of Retinopathy

Normal or Minimal

NPDR

Mild NPDR

Moderate NPDR

Severe NPDR

Non

-High-Risk PDR

High-Risk PDR

Presence of ME

No

No

ME

CSME

No

ME

CSME

No

ME

CSME

No

ME

CSME

No

ME

CSME

Follow-up

(months)

12

12

4 to 6

1

12

3 to 6

1

4

2 to 4

1

4

2 to 4

1

4

4

1

PRP

laser

No

No

No

No

No

No

No

Sometimes

Sometimes

Sometimes

Sometimes

Sometimes

Sometimes

Recommended

Recommended

Recommended

Focal and/or grid laser

No

No

No

Sometimes

No

No

Sometimes

No

No

Sometimes

No

No

Sometimes

No

Sometimes

Sometimes

Intravitreal anti-VEGF therapy

No

No

No

Sometimes

No

No

Sometimes

No

No

Sometimes

No

No

Sometimes

Alternative

Usually

Usually

Slide47

Simplified Strategy for Low and Intermediate Resources

Guidelines for Diabetic Eye Care, International Council of Ophthalmology, January 2017

DR

Classification

No apparent DR, mild NPDR,

and no DMEMild NPDRModerate NPDRSevere NPDRPDR

Re-examination or next screening schedule

Re-examination in 1 to 2 years1 to 2 years6 to 12 months< 3 months< 1 month

Referral to ophthalmologist

Referral not requiredReferral not requiredReferral requiredReferral requiredReferral required

Classification

Noncentral involved DME

Central involved DME

Re-examination or next screening schedule

3 months1 month

Referral to ophthalmologist

Referral not required (recommended if laser resources available)Referral required

DME

Slide48

PAHO/WHO website. La diabetes muestra una tendencia ascendente en las Américas.

Considerations for Latin America

PAHO/WHO estimates that 62.8 million people have diabetes in the Americas (2011)

For 2030, that number is expected to be 91.1 million

In Latin America, the prevalence of DM is 25 million and will be 40 million in 2030

In North America and Caribbean non-Hispanic countries, the prevalence is 38 million and will be 51 million by 2030

The higher prevalence of DM type 2 among adults in the Americas is found in non-Hispanic Caribbean countries, followed by the populations who live on both sides of the American-Mexican border

In Mexico, Central America, South America, and Hispanic-Caribbean, the prevalence is found to be between 8% and 10%

Slide49

Challenges in Latin America

Challenges in Latin America according to ALAD:

Increasing

rate

of DM

High rate of underdiagnosed DM

Treatment effectiveness is inadequate

Due to different factors including patient factors, health system access, appropriate care according the health system level, etc.

Slide50

Concluding Remarks

The management of these patients is a challenge for all health systems, including both the very wealthy and the impoverished

PCPs serve as a gateway to screening, evaluating, and referring patients

PCPs and

ophthalmologists need to work together to fight the battle against blindness associated with diabetes

Slide51

*Participation by Dr Susan B. Bressler in this activity does not constitute or imply endorsement by the Johns Hopkins University, the Johns Hopkins Hospital, or the Johns Hopkins Health System.*

Faculty

Characteristics of anti-vegf therapies for the

treatment of DR

Susan B. Bressler, MD

The Julia G.

Levy

PhD

Professor of

Ophthalmology

Johns

Hopkins University

Baltimore, USA

Slide52

Anti-VEGF Agents

a. EYLEA® SmPC 2016; b. EYLEA® PI 2014; c. EMA website. Lucentis® EPAR; d. Avastin® PI 2016; e. Avery RL, et al. Br J Ophthalmol. 2014;98:1636-1641.

Image courtesy of Bayer HealthCare

Anti-VEGF

Structure

Size (kDa)

Target(s)

Systemic

Half-LifeFc PortionAflibercept[a,b]Recombinant fusion protein97 to 115VEGF-A and PlGF5 to 6 daysYesRanibizumab[c]Antibody fragment48VEGF-AApprox. 2 hoursNoBevacizumab[d,e]Recombinant humanized monoclonal antibody149VEGF-A20 daysYes

VEGF

VEGF

VEGF

VEGF

VEGF

Aflibercept

Bevacizumab

Ranibizumab

Affinity

maturation

Two ranibizumab

molecules can bind each VEGF dimer

Slide53

Who Benefits From Anti-VEGF Treatment for DME

T1DM or T2DMVision impairment from DME: 20/32 to 20/320Center of macula is thickened (across spectrum of severity)Any associated level of DR

s/p aflibercept x 6

20/50

20/25

Images courtesy of Susan B. Bressler, MD.

Slide54

Mean Change in VA (Letters)* at Follow-Up Visits: Protocol I of DRCR.net

54

*

Values that were ± 30 letters were assigned a value of 30

P values for difference in mean change in VA from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser < .001; ranibizumab + deferred laser < .001; and triamcinolone + prompt laser = .31.

YES!

Anti-VEGF therapy is FIRST-LINE

therapy for DME

3injections

≤ 6injections

≤ 12injections

DRCRnet website. Protocol I.

Elman MJ, et al.

Ophthalmology

. 2011;118:609-614.

Slide55

Preservation of Vision: 5-Year Outcome

75% maintain ≥ 20/40

Retention of Reading and Driving Vision

Initial VA 20/50

Protocol I of DRCR.net

0

52

104

156

208

260

0

10

20

30

40

50

60

70

80

90

100

Eyes 20/40 or Better, %

Visit Week

Prompt

Deferred

52 weeks N = prompt: 165/deferred: 173

104 weeks N = prompt: 156/deferred: 161

156 weeks N = prompt: 144/deferred: 147

208 weeks N = prompt: 127/deferred: 122

260 weeks N = prompt: 124/deferred: 111

Bressler SB, et al.

Am J Ophthalmol

. 2016;164:57-68.

DRCRnet website. Protocol I follow-up.

Slide56

Mean Change in VA Over 2 Years: Full Cohort

* P values adjusted for baseline VA and multiple comparisons

104-Week Treatment Group Comparison:*

Aflibercept vs bevacizumab P = .024Aflibercept vs ranibizumab P = .47 Ranibizumab vs bevacizumab P = .11

+13.3

+11.2

+9.7

+10.0

+12.3

+12.8

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide57

Mean Change in VA Over 2 Years: Baseline VA 20/32 to 20/40

* P values adjusted for baseline VA and multiple comparisons

104-Week Treatment Group Comparison:*

Aflibercept vs bevacizumab P = .51Aflibercept vs ranibizumab P = .51 Ranibizumab vs bevacizumab P = .31

~50% of cohort

+8.0

+8.3

+7.5

+6.8

+8.6

+7.8

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide58

Mean Change in VA Over 2 Years: Baseline VA 20/50 or Worse

[52 week: A vs B P < .001; A vs R P = .003; R vs B P = .21]* P values adjusted for baseline VA and multiple comparisons

104-Week Treatment Group Comparison:*

Aflibercept vs bevacizumab P = .020Aflibercept vs ranibizumab P = .18 Ranibizumab vs bevacizumab P = .18

~50% of cohort

+18.9

+14.2

+11.8

+13.3

+16.1

+18.3

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide59

Mean Change in OCT CST Over 2

Years: Full Cohort

2-Year Treatment Group Comparison:*Aflibercept vs bevacizumab P < .001Aflibercept vs ranibizumab P = .080Ranibizumab vs bevacizumab P = .001

*P values adjusted for baseline VA, OCT CST, and multiple comparisons

Mean Improvement in OCT CSF Thickness From Baseline (µm)

-169

-147

-101

-126

-149

-171

DRCRnet website. Protocol T

.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide60

Prespecified Ocular Adverse Events Through 2 Years (Study Eyes)

% of Eyes With at Least 1 EventNo. of InjectionsEndophthalmitis*Inflammation†Retinal Detachment/TearVitreous HemorrhageInjection-Related CataractIOP Elevation‡Aflibercept(N = 224)29980317117Bevacizumab(N = 218) 3115< 1118< 112Ranibizumab(N = 218)30660215016Global P valueN/A0.660.691.00.370.380.31

*Nonstudy eyes: endophthalmitis in < 1% in aflibercept and ranibizumab groups; 0 in bevacizumab group.†Includes anterior chamber cell/flare, choroiditis, episcleritis, iritis, vitreous cells.‡Includes intraocular pressure increase ≥ 10 mm Hg from baseline at any visit, intraocular pressure ≥ 30 mm Hg at any visit, initiation of intraocular pressure-lowering medications not in use at baseline, or glaucoma surgery.

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide61

Prespecified APTC Adverse Events Through 2 Years

*Pairwise comparisons (adjusted for multiple comparisons): aflibercept-bevacizumab: P = .34, aflibercept-ranibizumab: P = .047, bevacizumab-ranibizumab: P = .20. Global P value adjusting for gender, age at baseline, HbA1c at baseline, diabetes type, diabetes duration at baseline, insulin use, prior coronary artery disease, prior MI, prior stroke, prior transient ischemic attack, prior hypertension, smoking status: P = .089.

% of Eyes With at Least 1 Event[a]Nonfatal MI, %Nonfatal Stroke, %Vascular Death, %Any APTC Event, %Aflibercept(N = 224)3< 115Bevacizumab(N = 218) 1348Ranibizumab(N = 218)35412Global P Value.047*

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide62

Summary of Anti-VEGF Therapy for DME

Vision gains are commonly seen with all 3 drugs through 2 years,

despite

Reduced number of injections and lasers in year 2

When initial VA loss is mild

, on average there is little difference in vision outcomes between drugs

At worse levels of initial VA

,

aflibercept

is more effective at improving VA vs bevacizumab, but not

ranibizumab

.

AUC analysis through 2 years

shows superiority of

aflibercept

to either bevacizumab or

ranibizumab

Slide63

PDR Treatment

PRP has been the treatment for PDR over the last 4 decadesSubstantially reduces risk of severe vision loss, but…Inherently destructivePeripheral VF lossNight-vision lossExacerbation of pre-existing DMENot perfect: 5% severe vision loss despite PRP (worse than 5/200 at 2 consecutive visits) Anti-VEGF, when given for DME, decreases risk of DR worsening (progression) and increases chance of improved retinopathy level (regression)

Slide64

AUC analysis: Preplanned secondary outcome

PRP vs Anti-VEGF Mean Change in VA: Protocol S of DRCR.net

N = 203

N = 168

Mean VA Change (Letter Score)

0

16

32

52

68

84

104

Visit Week

DRCRnet website. PRP vs intravitreous ranibizumab for PDR.

Gross JG, et al.

JAMA

. 2015;314:2137-2146.

Slide65

Summary of Anti-VEGF Therapy for PDR

Ranibizumab injections for PDR:

No worse than (not inferior to) PRP for VA at 2 years

Superior vision over the course of 2 years (AUC)

Reduces the incidence of DME

Less peripheral and central VF loss

Fewer vitrectomies

No major safety differences from PRP identified, except

1 case of endophthalmitis

Slide66

Anti-VEGF Therapy for DME or PDR

While capable of fantastic outcomes, requires the following:

Commitment to frequent office visits

Availability of frequent retinal imaging

Availability and affordability of the drugs

Presents challenges for delivery of care that may vary from country to country… but a good problem to have!

Slide67

treatment of dR and dME using anti-VEGF agents

John A. Wells, III, MD

Founder, Palmetto Retina CenterChairman, Department of OphthalmologyPalmetto Health/USC Medical GroupColumbia, USA

Faculty

Slide68

DRCR Protocols Changed DME Treatment

Protocol I: Center-involved DME

Ranibizumab 0.5 mg with prompt laser

Ranibizumab 0.5 mg with deferred laser for 6 months

Triamcinolone 4 mg with prompt laser

Prompt laser with sham injection

Protocol T: Center-involved DME

Aflibercept 2 mg vs ranibizumab 0.3 mg vs bevacizumab 1.25 mg

Protocol S: PDR with center-involved DME

Ranibizumab 0.5 mg vs PRP + ranibizumab 0.5 mg

Slide69

Protocol I: Mean Change in Visual Acuity Through 2 Years

*

Values that were ± 30 letters were assigned a value of 30P values for difference in mean change in VA from sham + prompt laser at the 52-week visit: ranibizumab + prompt laser < .001; ranibizumab + deferred laser < .001; and triamcinolone + prompt laser = .31.

Protocol I: Mean Change in VA Through 2 Years

DRCRnet website. Protocol I.

Elman MJ, et al.

Ophthalmology

. 2011;118:609-614.

Slide70

Bressler SB, et al. Am J Ophthalmol. 2016;164:57-68.DRCRnet website. Protocol I follow-up.

Mean Change in VA at Follow-Up Visits: 5 Years

0

52

104

156

208

260

0

1

2

3

4

5

6

7

8

9

10

11

12

Mean Change in Visual Activity

From Baseline (Letter Score)

Visit Week

Prompt

Deferred

52 weeks N = prompt: 165/deferred: 173

104 weeks N = prompt: 156/deferred: 161

156 weeks N = prompt: 144/deferred: 147

208 weeks N = prompt: 127/deferred: 122

260 weeks N = prompt: 124/deferred: 111

Slide71

Protocol I: Injections Prior to 5 Year*

*Only eyes that completed 5-year visit

Median # of Injections in Year 1Median # of Injections in Year 2Median # of Injections in Year 3Median # of Injections in Year 4Median # of Injections in Year 5Median # of InjectionsPrior to 5-Year Visit % of Eyes That Received ≥ 1 Injection in Year 4% of Eyes That Received ≥ 1 Injection in Year 5Ranibizumab+ prompt laser (N = 124)82100134638Ranibizumab + deferred laser (N = 111)93210175548

Bressler SB, et al. Am J Ophthalmol. 2016;164:57-68.DRCRnet website. Protocol I follow-up.

*only eyes that completed 5 year visit

Slide72

Focal/Grid Laser Prior to 5 Years*

* Only eyes that completed 5-year visit

% of Eyes That Did NOT Receive Laser Treatments Prior to the 5-Year VisitMedian # of Laser Treatments Prior to the 5-Year VisitRanibizumab+ prompt laser (N = 124)03Ranibizumab + deferred laser (N = 111)560

Bressler SB, et al.

Am J Ophthalmol

. 2016;164:57-68.

DRCRnet website. Protocol I follow-up.

Slide73

Lessons From Protocol I

Ranibizumab superior to steroids or laser for center-involved DME

Triamcinolone effective in pseudophakic eyes, but glaucoma risk limits its use

Deferral of laser for 6 months may result in better

2- and 5-year VA outcomes, especially in eyes with 20/50 or worse baseline vision

Treatment burden declines over 5 years

Slide74

DRCR Protocol T: 2-Year Results

In eyes with baseline vision 20/32 to 20/40, mean VA gain +8 letters with all 3 agentsIn eyes with baseline vision 20/50 or worse, mean VA gain with aflibercept +18 letters equivalent to ranibizumab +16 letters, but superior to bevacizumab +13 lettersAUC analysis favored aflibercept over 2 years in worse baseline VA eyesIn worse baseline vision eyes, 3-line gainers greater with aflibercept at 1 year but equivalent at 2-year endpoint

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide75

Mean Change in VA Over 2 Years: Baseline VA 20/32 to 20/40

* P values adjusted for baseline VA and multiple comparisons

104-Week Treatment Group Comparison:*

Aflibercept vs bevacizumab P = .51Aflibercept vs ranibizumab P = .51 Ranibizumab vs bevacizumab P = .31

~50% of cohort

+8.0

+8.3

+7.5

+6.8

+8.6

+7.8

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide76

Mean Change in VA Over 2 Years: Baseline VA 20/50 or Worse

[52 week:

A vs B P < .001; A vs R P = .003; R vs B P = .21]* P values adjusted for baseline VA and multiple comparisons

104-Week Treatment Group Comparison:*Aflibercept vs bevacizumab P = .020Aflibercept vs ranibizumab P = .18 Ranibizumab vs bevacizumab P = .18

~50% of cohort

+18.9

+14.2

+11.8

+13.3

+16.1

+18.3

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide77

Protocol T: 2-Year Results

Treatment burden is essentially equal with all

3 agents: 15 to 16 injections through 2 years (9-10 in year 1, 5-6 in year 2)

Laser treatment given more often to bevacizumab-treated eyes because these eyes have less reduction in CST on OCT

Bevacizumab reduces OCT CST about 40% to 50% less than ranibizumab and aflibercept

Slide78

DME Treatment: Anti-VEGF(Completers of the Given Visit Only)

NOTE: 98% of protocol-required reinjections were given over 2 years * Seven study eyes received 1 injection and 2 eyes received 2 injections of 0.5 mg of ranibizumab prior to the FDA approving a 0.3-mg dosage of ranibizumab for DME treatment and protocol revision to use 0.3-mg dose† Pairwise comparisons (adjusted for multiple comparisons): A-B: P = .045; A-R: P = .19; B-R: P = .22.

# of Injections: Median (25th, 75th percentile)Year 1Year 2Over 2 YearsAflibercept9 (8, 11)5 (2, 7)15 (11, 17)Bevacizumab10 (8, 12)6 (2, 9)16 (12, 20)Ranibizumab*10 (8, 11) 6 (2, 9)15 (11, 19) Global P value.045†.32.32

DRCRnet website. Protocol I follow-up.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide79

Mean Change in OCT CST Over 2 Years:

Baseline VA 20/32 to 20/40

* P values adjusted for baseline VA, OCT CST, and multiple comparisons

2-Year Treatment Group Comparison:*Aflibercept vs bevacizumab P < .001Aflibercept vs ranibizumab P = .26Ranibizumab vs bevacizumab P < .001

-129

-119

-67

-68

-125

-133

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide80

Mean Change in VA Over Time by Baseline VA and OCT

N = 32

N = 30

N = 43

DRCRnet website. Protocol T.

Wells JA, et al.

Ophthalmology

. 2016;123:1251-1359.

Slide81

DRCR Protocol S: PDR With Coexisting Central DME

Protocol S showed eyes with PDR and DME gained more vision if treated with Ranibizumab alone than eyes treated with ranibizumab + PRPAdditional benefit of less VF loss from deferring PRPStrongly consider anti-VEGF therapy with deferral of PRP as first-line treatment of these eyes

Gross JG, et al.

JAMA

. 2015;314:2137-2146.

Slide82

N = 42

N = 33

N = 46

N = 37

Mean Change in VA Stratified by Baseline DME

N = 147

N = 126

N = 155

N = 130

DRCRnet website. Aflibercept, bevacizumab, or ranibizumab for DME.

Gross JG, et al.

JAMA

. 2015;314:2137-2146.

Slide83

Concluding Remarks

Anti-VEGF therapy is now the mainstay of treatment of DME

DRCR protocols have clarified many issues:

Laser should be deferred fo

r 6 months

Aflibercept is more effective over the course of 2 years in eyes with baseline VA 20/50 or worse

All 3 agents are equally effective in eyes with baseline VA 20/32 to 20/40

Bevacizumab reduces OCT edema less effectively

Eyes with PDR and DME did better with ranibizumab alone vs ranibizumab + PRP

Treatment burden declines over time