A summary of important Diabetic Retinopathy Trials

1. DIABETIC RETINOPATHY
TRIALS
Dr. Karan
Bhatia

2. DIABETIC RETINOPATHY STUDY
(DRS)

3. DRS – INTRODUCTION (1)
• laser photocoagulation – introduced in 1959
• Inadequate evidence of actual value of laser photocoagulation
• DRS started in 1971

4. DRS (2) - PURPOSE
• To determine whether laser photocoagulation helps to prevent
severe visual loss from PDR
• To determine whether a difference exists in the efficacy and safety of
argon versus xenon photocoagulation for PDR

5. DRS – STUDY PATTERN (3)
• Eligibility criteria – presence of
PDR
Each Patient’s
eyes –
randomized
Immediate
Photocoagulation
Scatter – Panretinal
Local – direct confluent treatment
of new vessels
Focal – for macular edema
Follow up without
treatment
Randomized
Argon Xenon

6. DRS – RESULTS (4)
• Photocoagulation (both argon & xenon) reduced risk of visual loss by
50 % or more compared with no treatment
• Study identified a stage of retinopathy – High Risk PDR, where
benefits of photocoagulation definitely outweighed risks
• Severe vision loss (5 year rate) reduced from 50% without treatment
to 20% with treatment
• No benefit for eyes with severe NPDR/ PDR without HRC

7. DRS – CONCLUSION (5)
• Both argon & xenon laser photocoagulation inhibited progression of
retinopathy
• PDR with HRC – prompt treatment with PRP
• Less severe retinopathy – findings do not provide a choice b/w
prompt treatment or deferral

8. DRC – HIGH RISK CHARCTERISTICS
(6)
1. Presence of Vitreous/ pre-retinal haemorrhage
2. Presence of new vessels
3. NVD – New vessels on or within 1 DD of Optic disc
4. Severe new vessels ( NVD >1/3 disk area or NVE >1/2 disk area)

9. EARLY TREATMENT DIABETIC
RETINOPATHY STUDY (ETDRS)

10. ETDRS – INTRODUCTION (1)
• DRS – did NOT
• Address the question of timing or extent of PRP in DR
• Clarify role of Laser photocoagulation in NPDR and early PDR
• ETDRS – multicentre, randomized clinical trial, designed to evaluate
argon laser photocoagulation and aspirin treatment in management
of NPDR or early PDR
• 3711 patients recruited, minimum of 4 years follow up
• Recruitment began in December 1979 and was completed in July
1985

11. ETDRS – PURPOSE (2)
•To evaluate the effectiveness of argon laser photocoagulation and in
delaying or preventing progression of early DR to more severe stages
of visual loss and blindness
•To help determine the best time to initiate PRP in DR
•To determine if photocoagulation is effective in management of DME
•To evaluate the effectiveness of aspirin treatment in altering the
course

12. ETDRS – STUDY PATTERN (3)
Patient eyes
randomized
One eye
Immediate
photocoagulation
Other eye
Deferral of
photocoagulation
(careful Follow up)
(until high risk PDR
developed)
DME
Immediate
photocoagulation
Focal leaks -
Focal
Diffuse leaks -
Grid
Deferred
Patients
Aspirin Placebo
Term
‘Clinically significant macular
edema’
coined
to designate this level of
severity
• Eligibility criteria – presence of mild to very severe NPDR and/or non high risk PDR with
or without macular edema in both eyes.

13. ETDRS - RESULTS (4)
•High-risk PDR –
• Both early scatter and deferral were followed by low rates of severe visual loss (5 year rates in
deferral subgroups were 2-10%; in early photocoagulation groups these rates were 2-6%).
• Statistically significant reduction in severe visual loss for eyes with early treatment, especially for
those patients with Type 2 DM. However, the reduction was small and the risk was low in the
deferral group.
•Macular Edema –
• ‘Less severe retinopathy’ – focal with delayed scatter, initiated only when more severe retinopathy
developed
• ‘More severe retinopathy’ – immediate focal + mild scatter
• Worst outcome strategy – immediate full-scatter photocoagulation & focal deferred
• Focal photocoagulation reduced the risk of moderate vision loss by 50% or more and increased the
chance of a small improvement in visual acuity, especially in eyes where the centre of macula was
involved or threatened
• Thickening involved or threated centre of macula – clear benefit of focal laser
• Visual prognosis worse for eyes with worse baseline vision, although magnitude of treatment benefit
increased as baseline VA decreased
• Fluorescein leakage – not a sufficient indication for laser treatment in absence of CSME. Observe at 4
monthly intervals

14. ETDRS - RESULTS (5)
•Visual fields – Significant visual loss occurred in immediate full scatter
subgroup
•Accommodative amplitude – Full scatter photocoagulation produced
transient reduction in accommodative amplitude
•Vitrectomy –
• Overall vitrectomy rate 5.6%
• Patients undergoing vitrectomy – white, type 1 DM, younger at onset of DM, more likely
to have proteinuria, higher HBA1c and severe NPDR or worse at baseline
• Visual outcome – not altered by treatment assigned to immediate or deferred
photocoagulation or by pre-operative presence of RD
•Aspirin – use did not affect the progression of retinopathy to the high-risk
proliferative stage but aspirin also did not increase the risk of vitreous
hemorrhage, did not affect vision, and was associated with a decreased risk
of cardiovascular disease.

15. ETDRS – CONCLUSION (5)
•Severe NPDR/ Early PDR – consider scatter treatment, especially for
Type 2 DM
•High Risk PDR – scatter treatment, without delay
•Mild to moderate NPDR with CSME – focal photocoagulation
•Severe NPDR/ PDR with CSME – focal photocoagulation
•Aspirin –
• no clinically important beneficial effect on progression of retinopathy in mild to
severe NPDR or early PDR
• No ocular contraindications to it for CVS or other medical indications

16. DIABETES CONTROL AND
COMPLICATIONS TRIAL (DCCT)

17. DCCT (1)
• Examined whether intensive treatment with the goal of maintaining
blood glucose concentrations close to normal range could decrease
the frequency and severity of complications of DM
• Multicentre study done from 1983 to 1993
• Done in USA
• Funded by National Institute of Diabetes and Digestive and Kidney
Diseases
• 1441 patients with Type 1 DM

18. DCCT – PURPOSE (2)
• To assess the effect of tight glycaemic control on complications of
diabetes (nephropathy, neuropathy and diabetic retinopathy) for
persons with Type 1 DM

19. DCCT – STUDY PATTERN (3)
Type 1 Insulin Dependent Diabetes
Mellitus Age 13–39 years patients
randomized to Conventional
Treatment or Intensive Treatment
Group
Inclusion Criteria
Primary –
prevention
cohort
Secondary –
intervention
cohort
Type 1 DM 1-5 years 1-15 years
DR grade No
retinopathy
Mild to
moderate
NPDR
Urinary
albumin
excretion
(mg/24
hours)
<40 <200
Exclusion Criteria
• Hypertension
• Hypercholesterolemia
• Severe diabetic complications or
medical conditions
1 or 2 daily
insulin
injections
External insulin pump or >3
daily insulin injections,
guided by frequent blood
glucose monitoring

20. DCCT – RESULTS (4)
Primary Prevention Cohort Secondary Intervention Cohort
Intensive
therapy
Reduced risk of development
of DR by 76% in comparison
to other group
Slowed progression of DR by
54%
Reduced development of PDR or
severe NPDR by 47%
Intensive therapy reduced occurrence of
• Microalbuminuria by 39%
• Albuminuria by 54%
• Clinical nephropathy by 60%

21. DCCT – CONCLUSION (5)
Intensive therapy effectively delays onset and slows progression of
microvascular complications of diabetes – DR, nephropathy and
neuropathy in patients with Type 1 DM

22. UNITED KINGDOM PROSPECTIVE
DIABETES STUDY (UKPDS)

23. UKPDS (1)
• Done to determine whether improved blood glucose control in Type
2 diabetics would prevent complications of DM
• Multicentre, randomized controlled trial
• 5102 people with newly diagnosed Type 2 DM
• UK
• 1977 – 1991

24. UKPDS (2)
Purpose
 To determine whether the risk of CVS and microvascular complications in type 2
DM can be reduced by intensive control of Blood glucose
 In patients with high BP, to determine whether the risk of complications can be
reduced by tight control of BP
 To determine if any specific measurement for type 2 DM confers any particular
benefit
Study Pattern
 Inclusion criteria – newly diagnosed type 2 DM
 Outcome measure – follow up of patients to major fatal and non-fatal clinical end
points

25. UKPDS (3)
Result
• For every percentage point decrease in HbA1C (e.g.9% to 8%), there was a 35%
reduction in the risk of microvascular complications of disease
• More intensive blood pressure control resulted in a 37% reduction in microvascular
complications of DM
Conclusion
• Complications of DM can be reduced by improving blood glucose and/or BP,
greatest effect being on microvascular complications

26. DIABETIC RETINOPATHY VITRECTOMY
STUDY
(DRVS)

27. DRVS (1)
• Done with view that it was important to determine whether early
vitrectomy had a better visual outcome or instead produced a rate of
serious complications higher than the rate associated with
conventional management in patients vitreous haemorrhage
• October 1976 – June 1983

28. DRVS – PURPOSE (2)
• To compare two therapies, early vitrectomy and conventional
management for recent severe vitreous haemorrhage secondary to DR
•To compare early vitrectomy and conventional management in eyes
that have good vision but a poor prognosis, because they are
threatened with haemorrhage or retinal detachment from very severe
PDR
•To study natural history of severe PDR
Conventional management – included vitrectomy if haemorrhage failed
to clear during a waiting period of 6 – 12 months or if retinal
detachment involving the centre of macula developed at any time

29. DRVS– STUDY PATTERN (3)
Inclusion criteria –
• At least 1 eye with severe VH & VA <5/200
• Extensive active neo-vascular or fibro-vascular proliferations & VA > 10/200
Outcome measure
• Primary outcome – VA
• ‘Good vision’ – VA >10/20
• ‘Poor vison’ – VA <5/200

30. DRVS – CONCLUSION (4)
•Recent severe VH causing significant reduction of vision  Early
vitrectomy (especially in Type 1 diabetics and if VA is poor in fellow
eye)
•Severe, active neo-vascular proliferation & moderate/ no VH – Early
vitrectomy (especially in those with both fibrous proliferations and at
least moderately severe vessels, in which extensive scatter
photocoagulation has been carried out or precluded by VH)

31. DRVS (5)
•Results of DRVS – obtained before development of modern vitrectomy
instrumentation, techniques and endo-laser photocoagulation. With
these techniques, results are more favourable
•Nowadays in general – Recommended timing of vitrectomy for severe
diabetic VH is before 3 months for Type 1 diabetics and 6 months for
Type 2 patients.

32. DIABETIC RETINOPATHY CLINICAL
RESEARCH NETWORK (DRCR.NET)

33. DRCR.NET
A collaborative network dedicated to facilitating multicentre clinical
research of DR, DME and associated conditions
Formed in September 2002
Funded by National Eye Institute

34. PROTOCOL A: PILOT STUDY OF
LASER PHOTOCOAGULATION FOR
DME
Purpose
• To compare 2 laser photocoagulation
techniques for treatment of DME : modified
ETDRS (mETDRS) technique and mild macular
grid (MMG) technique
Methods
• Patients randomized into 2 treatment groups
• MMG burns –
lighter, more diffuse in nature & distributed throughout
macula in both areas of thickened and unthickened
retina
Microaneursysms - NOT directly photocoagulated
• mETDRS direct/ grid photocoagulation –
treats only thickened retina, areas of retinal non-
perfusion & leaking microaneursyms
Modification to ETDRS protocol – burns are less intense
(gray) and smaller (50 µ)
• VA, fundus photographs, OCT – taken at 3, 5,
8, 12 months
• Main outcome measure – change in OCT
measures at 12 months
Results
• From baseline to 12 months  CMT (central
subfield thickening) decreased by an average
of 88µ in mETDRS group & 49µ in MMG group
• At 12 months  mean change in VA was 0
letters in mETDRS group & 2 letters worse in
MMG group
Conclusion
• At 12 months of treatment, MMG less effective
than mETDRS at reducing retinal thickening.
• However, VA same b/w 2 groups
Application to Clinical Practice
• mETDRS photocoagulation should continue as
standard approach for treating DME

35. PROTOCOL B: RANDOMIZED TRIAL
COMPARING IVTA AND LASER
PHOTOCOAGULATION FOR DME
Purpose
• To evaluate of efficacy and
safety of 1 mg and 4 mg
dose of IVTA in comparison
with focal/ grid
photocoagulation (LP) for
DME
Methods
• Eyes randomized into 3
groups – LP, 1 mg IVTA & 4
mg IVTA
• Retreatment given for
persistent or new edema – 4
months intervals
• Outcome measures – ETDRS
VA, OCT – macular thickness
and safety at 3 years
Results
• 4 months  mean VA better in 4 mg IVTA group than other
2 groups
• 1 year  no significant differences among groups
• OCT results – same as VA results
• IOP increase and cataract surgery being performed  4 mg
IVTA > 1mg IVTA > LP
Conclusion
• Over 2- 3 years  LP more effective, lesser side effects
• Most eyes receiving 4 mg IVTA  likely to require cataract
surgery
• 4 mg IVTA – did reduce progression of DR, but its use not
warranted
Application to Clinical Practice
• Focal/ grid photocoagulation – benchmark for treatment of

36. PROTOCOL C: TEMPORAL
VARIATION IN OCT
MEASUREMENTS OF DME
Clinical impact of diurnal variation of macular edema is likely to be
small and not significant

37. PROTOCOL D: EVALUATION OF
VITRECTOMY FOR DME
Vitrectomy performed for eyes with at least moderate vision loss and
VMT usually result in a reduction in macular thickening
VA results are less consistent with some eyes improving and some
eyes worsening

38. PROTOCOL E: RANDOMIZED TRIAL OF
PERIBULBAR TRIAMCINOLONE
ACETONIDE (TA) WITH AND WITHOUT
FOCAL PHOTOCOAGULATION FOR MILD
DME – PILOT STUDY
Unlikely that significant clinical benefit exists for TA in cases of DME
with good VA

39. PROTOCOL F: OBSERVATIONAL
STUDY OF DEVELOPMENT OF DME
FOLLOWING SCATTER LP
PRP for DR can be safely administered in a single sitting in patients
with relatively good VA and no or mild pre-existing center involved
DME

40. PROTOCOL G: SUBCLINICAL
MACULAR EDEMA
Patients with subclinical DME should be monitored more closely for
progression

41. PROTOCOL H: PHASE 2 RANDOMIZED
CLINICAL TRIAD OF INTRAVITREAL
BEVACIZUMAB (IVB) FOR DME
Results demonstrated that IVB can reduce DME in some eyes, but
study was not designed to determine whether treatment was
beneficial

42. PROTOCOL I: LASER-RANIBIZUMAB-
TRIAMCINOLONE STUDY FOR DME
PURPOSE
 To evaluate intravitreal 0.5 mg Ranibizumab or 4 mg
Triamcinolone combined with focal/grid laser
compared with focal/grid laser alone for treatment of
DME
METHODS
 Multicentre, randomized clinical trial enrolled a total
of 854 eyes of 691 participants with VA of 20/321 to
20/320 and DME involving the fovea
 Retreatment followed an algorithm facilitated by a web
based design
 Main outcome measures – BCVA and safety at 1 year
RESULTS
 1 year mean change in VA from baseline – significantly
greater in ranibizumab + prompt laser group and
ranibizumab + deferred laser group, but not in
Triamcinolone + laser group compared with sham +
prompt laser group. 2 year VA similar to 1 year
outcomes
 Reduction in mean CMT in triamcinolone + prompt
laser group similar to both ranibizumab groups and
greater than in sham + prompt laser group
 3 eyes (0.8%) had injection-related endophthalmitis in
Ranibizumab groups
 Elevated IOP and cataract surgery – more frequent in
Trimacinolone + prompt laser group
CONCLUSION
 Intravitreal ranibizumab with prompt or deferred laser
– more effective at 2 years compared with prompt
laser alone for treatment of DME involving central
macula
 Pseudophakic eyes – IVTA + prompt laser – more
effective than laser alone, but frequently with the risk
of IOP elevation.
APPLICATION TO CLINICAL PRACTICE
 Ranibizumab should be considered for patients with
DME including vision impairment with DME involving
centre of macula
Eyes - Randomized
Sham injection +
prompt laser (n=293)
0.5 mg Ranibizumab
+ prompt laser
(n=187)
0.5 mg Ranibizumab
+ deferred laser (>24
weeks) (n =188)
4 mg Triamcinolone +
prompt laser (n=186)

43. PROTOCOL J: LASER-
RANIBIZUMAB-TRIAMCINOLONE
STUDY FOR DME + PRP
Risk of short term exacerbation of macular edema and associated VA
loss following prompt PRP in eyes also receiving focal/grid laser for
DME – can be reduced by IVTA or Ranibizumab

44. PROTOCOL K: THE COURSE OF
RESPONSE OF FOCAL
PHOTOCOAGULATION FOR DME
PURPOSE
 To determine whether eyes with centre involved DME, treated with LP , in which there is a reduction in CMT measured
with OCT after 16 weeks
METHODS
 Prospective, multicentre, observational single group LP study of 122 eyes with centre involved DME (OCT CMT>250µ)
 At 16 weeks, continuing every 8 weeks - eyes assessed for retreatment
 Additional laser deferred – if VA score improved >5 letter or OCT CMT decreased >10% compared with visit 16 weeks
prior
RESULTS
 115 eyes completed 16 week visit
 AT 16 weeks  47% (54) had decreased CMT by >10% compared with baseline
 Of these, 48% (26) had CMT>250µ at 16 weeks, and were evaluable at 32 weeks
 11 of 26 eyes – further decrease in CMT >10% from 16 to 32 weeks without further treatment
CONCLUSION
 16 weeks following LP for DME, in eyes with definite reduction, but not resolution, of central edema, 23-63% will
continue to improve without additional treatment
APPLICATION TO CLINICAL PRACTICE
 Eyes undergoing focal/ grid laser, especially eyes with greater macular thickening may continue to have improvement in
VA and macular thickness even after 16 weeks

45. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME –
BACKGROUND (1)•Diabetic macular edema (DME) affects ~750,000 people in USA
•Intravitreous anti-vascular endothelial growth factor (anti-VEGF) injections of either aflibercept
(EYLEA), bevacizumab (Avastin), or ranibizumab (Lucentis) are effective in treating DME
•Relative efficacy and safety of these agents within a head-to-head study were unknown prior to
the results of this trial
•Aflibercept and ranibizumab are FDA approved for DME treatment
•Bevacizumab is not FDA approved for intraocular use
• used “off-label” for DME treatment
• repackaged into aliquots ~1/500 of systemic dose in cancer treatments
•Medicare allowable charges
• Aflibercept (2.0 mg): $1961
• Bevacizumab (repackaged 1.25mg): $67
• Ranibizumab (0.3 mg): $1189

46. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME –
PURPOSE(2)Primary Objective – For eyes with centre involved DME with
decreased VA, compare one year efficacy and safety of –
1. Intravitreal aflibercept (EYILEA)
2. Intravitreal Bevacizumab (AVASTIN)
3. Intravitreal Ranibizumab (LUCENTIS)

47. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME – STUDY
DESIGN (3)
47
Participants meeting all of the following criteria:
• At least 18 years old
• Type 1 or type 2 diabetes
Study eye meeting all of the following criteria:
• ~Snellen equivalent visual acuity 20/32 or worse and 20/320 or
better
• Central-involved DME on clinical exam
• Central subfield (CSF) thickness ≥ protocol-defined gender and
optical coherence tomography (OCT) machine-specific
thresholds
• No history of an anti-VEGF treatment for DME in the past 12
months or any other DME treatment in the past 4 months
Randomized, multi-center clinical trial (N = 89 Sites)
Primary Outcome: Change in visual acuity at one year adjusted for
baseline visual acuity using the intent-to-treat principle
Eyes
Randomized
( n=660)
Aflibercept 2.0mg
Bevacizumab 1.25mg
Ranibizumab 0.3mg

48. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME (4)
TREATMENT SCHEDULE
 Repeat injections at every 4 week visit if eye improved or worsened
 Otherwise  defer injections if either
 Visual acuity 20/20 or better and OCT CST “normal” or,
 At or after 24 weeks, visual acuity and OCT stable after 2 consecutive injections
 Resume injection if VA or OCT worsened
Improved/ worsened defined as –
 ≥ 5 letter change (~1 Snellen line) from last injection, or,
 ≥ 10% CST change on OCT from last injection
 Focal/grid laser – initiated at or after 24 weeks only if persistent DME not improving
after at least 2 injections

49. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME – RESULTS
(5)All three anti-VEGF agents, on average, produced substantial visual acuity
improvement by 1 month, sustained through 1 year.
On average, greater improvement occurred with aflibercept, but relative
effect varied by initial visual acuity.
 Mild initial vision loss (20/32-20/40, 50% of study eyes): little difference in mean visual acuity at
1 year
 Worse initial vision loss: aflibercept had an advantage over the other agents
Bevacizumab had a lesser effect on reducing macular edema than the other two
agents, regardless of starting acuity.
Few eyes in any group had substantial visual acuity loss.
Median number of injections: 9 to 10 in all three groups.
Fewer eyes in the aflibercept group received focal/grid laser for DME after 24
weeks, presumably because a greater % of eyes in the aflibercept group had
resolution of central DME (which drives decision to apply laser).

50. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME – RESULTS
(6)Serious adverse event, death, and hospitalization rates appeared similar
among treatment groups.
Significant differences in frequencies of major cardiovascular events were
not identified
 However, post-hoc analysis combining MedDRA system organ classes of cardiac and
vascular resulted in more participants in the ranibizumab group reporting these adverse
events.
 This is inconsistent with prior studies and may be due to chance.
Endophthalmitis was rare: 0.02% of injections.
No differences in intraocular inflammation.
Bevacizumab:
 Note: a central pharmacy repackaged into single use vials
• Testing was completed for sterility, purity, and potency, a standard that may not be available in a clinical practice
setting
Results may not apply to eyes with persistent or recurrent DME already receiving anti-VEGF

51. DRCR.NET - COMPARATIVE
EFFECTIVENESS STUDY OF
AFLIBERCEPT, BEVACIZUMAB, OR
RANIBIZUMAB FOR DME –
CONCLUSION (7)•All three anti-VEGF agents are effective treatments for DME
causing vision impairment.
•When initial visual acuity loss is mild, on average there is little
difference in visual acuity at 1-year.
•At worse levels of initial visual acuity aflibercept is more
effective at improving vision.

52. OTHER IMPORTANT CONCLUSIONS
OF DRCR.NET
1. Decline in Best Corrected ETDRS VA after dilatation in diabetic
subjects. Therefore, post dilatation ETDRS VA should not be used
2. Modest co-relation of OCT measured centre point thickness with
VA, modest correlation of changes in retinal thickening and VA
following focal laser treatment for DME.
3. CMT (central subfield mean thickness) is preferred OCT
measurement.
4. Low of endophthalmitis (for intravitreal injections) can be achieved
using topical povidone iodine, use of a sterile lid speculum and
topic anaesthetic, but does not require topical antibiotics
5. Transformation of OCT retinal thickness data to logOCT may assist
in assessment of clinically meaningful changes in retinal thickness