DIABETIC RETINOPATHY TRIALS

Dr. Karan Bhatia

DIABETIC RETINOPATHY STUDY (DRS)

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

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

DRS – STUDY PATTERN (3)• Eligibility criteria – presence of PDR

Each Patient’s eyes – randomizedImmediate

Photocoagulation

Scatter – Panretinal

Local – direct confluent treatment of new vessels

Focal – for macular edema

Follow up without treatment

Randomized

Argon Xenon

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

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

DRC – HIGH RISK CHARCTERISTICS (6)1. Presence of Vitreous/ pre-retinal haemorrhage2. Presence of new vessels3. NVD – New vessels on or within 1 DD of Optic disc4. Severe new vessels ( NVD >1/3 disk area or NVE >1/2 disk area)

EARLY TREATMENT DIABETIC RETINOPATHY STUDY (ETDRS)

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

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

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.

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

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.

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

DIABETES CONTROL AND COMPLICATIONS TRIAL (DCCT)

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

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

DCCT – STUDY PATTERN (3) Type 1 Insulin Dependent Diabetes Mellitus Age 13–39 years patients randomized to Conventional Treatment or Intensive Treatment Group

Inclusion CriteriaPrimary – prevention cohort

Secondary – intervention cohort

Type 1 DM 1-5 years 1-15 yearsDR grade No

retinopathyMild 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

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%

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

UNITED KINGDOM PROSPECTIVE DIABETES STUDY

(UKPDS)

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

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

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

DIABETIC RETINOPATHY VITRECTOMY STUDY

(DRVS)

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

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

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

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)

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.

DIABETIC RETINOPATHY CLINICAL RESEARCH NETWORK

(DRCR.NET)

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

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

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 DME

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

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

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

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

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

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

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)

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

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

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

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)

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

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

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).

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

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.

OTHER IMPORTANT CONCLUSIONS OF DRCR.NET1. Decline in Best Corrected ETDRS VA after dilatation in diabetic

subjects. Therefore, post dilatation ETDRS VA should not be used2. 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