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
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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
Slide2Scope 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.
Slide3Among 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.
Slide4How 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
Slide5Capillary 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
Slide6Pathologic 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
Slide7What 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
Slide8How 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
Slide9How 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
Slide10Modifiable Risk Factors Associated With DR
Hyperglycemia
Hypertension
Hyperlipidemia
Smoking cessation
Weight loss and exercise
Slide11Landmark 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.
Slide12DCCT 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
Slide13Even 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.
Slide14Concluding 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
Slide15The 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
Slide16Worldwide 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
Slide17DR: 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
Slide18The 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
Slide19When 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
Slide20Treatments for DR
Laser therapy: prevents loss of vision but does not improve VA
Gold-standard treatment: anti-VEGF agents
Improves VA
Improves DR
Slide21Concluding 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
Slide22IDENTIFYING 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.*
Slide23Macula: Center of the Retina
Macula
Macula
Retina
Slide24One of 2 Causes of Vision Loss in Diabetes: DME
Images courtesy of
Neil M. Bressler, MD
.
Slide25As 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
Slide26Prevalence 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)
Slide27AAO 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
Slide28Anti-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?
Slide29Mean 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.
Slide30Mean 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.
Slide31Brown 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
Slide32Identifying 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
Slide33Proliferative 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
Slide34Mean 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.
Slide35Awareness 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.
Slide36Concluding 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
Slide37DIAGNOSIS 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
Slide38Introduction
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
Slide39More 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.
Slide40Classification of DR
Wu L, et al. Classification of diabetic retinopathy and diabetic macular edema. World J Diabetes 2013;4(6):290-4 Figure 1
Slide41DR 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.
Slide42ETDRS. 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
Slide43Clinically Significant Macular Edema
Image courtesy of
Baruch D. Kuppermann, MD, PhD
.
Slide44SAVE: 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
Slide45Advanced Diabetic Eye Disease
Preretinal and vitreous hemorrhage Tractional retinal detachment Rubeosis iridis and neovascular glaucoma
Image courtesy of
Baruch D. Kuppermann, MD, PhD
.
Slide46Management 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
Slide47Simplified 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
Slide48PAHO/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%
Slide49Challenges 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.
Slide50Concluding 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
Slide52Anti-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
Slide53Who 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.
Slide54Mean 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.
Slide55Preservation 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.
Slide56Mean 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.
Slide57Mean 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.
Slide58Mean 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.
Slide59Mean 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.
Slide60Prespecified 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.
Slide61Prespecified 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.
Slide62Summary 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
Slide63PDR 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)
Slide64AUC 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.
Slide65Summary 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
Slide66Anti-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!
Slide67treatment 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
Slide68DRCR 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
Slide69Protocol 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.
Slide70Bressler 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
Slide71Protocol 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
Slide72Focal/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.
Slide73Lessons 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
Slide74DRCR 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.
Slide75Mean 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.
Slide76Mean 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.
Slide77Protocol 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
Slide78DME 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.
Slide79Mean 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.
Slide80Mean 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.
Slide81DRCR 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.
Slide82N = 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.
Slide83Concluding 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