1、The Diabetic Retinopathy Clinical Research Network,Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema Michael Elman, MDSupported through a cooperative agreement from the National Eye Institute and the National Institute
2、 of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services EY14231, EY14229, EY018817,1,Background: Protocol B IVT vs Laser,2,Intravitreal triamcinolone was evaluated previously as a “monotherapy” treatment for DME in a randomized trial con
3、ducted by DRCR.net ():Results suggested that IVT without laser was not superior to focal/grid photocoagulation Focal/grid photocoagulation in eyes with center-involved DME produces gradual visual acuity improvement of 2 lines in about 30% of eyes after 2 years, although approximately 20% of laser tr
4、eated eyes worsen by 2 lines,3,Laser-Ranibizumab-Triamcinolone Randomized Clinical Trial for DME:,Study ObjectiveEvaluate efficacy and safety of:0.5-mg intravitreal ranibizumab plus prompt laser (within 1 week); or 0.5-mg intravitreal ranibizumab plus deferred laser (24 weeks); or4-mg intravitreal t
5、riamcinolone plus prompt (within 1 week) laser, in comparison with sham plus prompt laser for treatment of diabetic macular edema.,4,Study Design,Primary outcome: Change in visual acuity from baseline to 1 year (intent to treat analysis),Randomized, multi-center clinical trial,At least one eye meeti
6、ng all of the following criteria: Electronic-ETDRS best corrected visual acuity letter score of 78 to 24 (20/32 to 20/320) Definite retinal thickening due to diabetic macular edema involving the center of the macula on clinical examination Central subfield (Stratus OCT) 250 m,Visit/Treatment Schedul
7、e: Year 1 the “4:2:7” Guide,5,Sham+Prompt Laser,Ranibizumab +Prompt LaserRanibizumab +Deferred Laser,Triamcinolone +Prompt Laser,Visits were every 4 weeks regardless of whether the eye status was successful, improved, or failed. *Success: Visual acuity letter score 84 (20/20) or OCT CSF 10% or visua
8、l acuity letter score improved by 5.,Follow-up Visits at and After 52 Week Visit if Ranibizumab Injection Given,6,Ranibizumab +Deferred or Prompt Laser,Drug,52,56,Four wks after any ranibizumab injection, the study eye is evaluated for possible additional ranibizumab injection using retreatment crit
9、eria as in year 1: If not a success*, but improvement since last injection, retreatment required; otherwise, retreatment is up to investigator.,60,64,68104,*Success: Visual acuity letter score 84 (20/20) or OCT CSF 10% or visual acuity letter score improved by 5.,Drug,Drug,Drug,Drug,Drug,Visit,Visit
10、*,Visit*,Visit*,Visit*,Visit*,Follow-up Visits at and After 52 Week Visit if Ranibizumab Not Given (4 to 8 to 16 Weeks),7,Ranibizumab +deferred or Prompt Laser,No Drug,52,56,If a ranibizumab injection is not given at the current and previous 2 visits (e.g. week 60 above), the next follow-up visit is
11、 in 8 weeks.If at the next 8 week interval visit the injection is deferred again, the next follow-up visit is in 16 weeks; visits continue every 16 weeks unless a ranibizumab injection is given, at which point the visit schedule goes back to 4 week intervals.,No Drug,60,64,68.84,No Drug,No Drug,No D
12、rug,Visit,Visit,Visit,Skip Visit,Visit,Skip 16 wks,Visit,Study Enrollment and Completion,8,Ranibizumab +Prompt Laser N = 187,Ranibizumab +Deferred Laser N = 188,Sham +Prompt Laser N = 293,Triamcinolone +Prompt Laser N = 186,Eyes Randomized: N = 854 (691 Participants),1 Year Visit (Primary Outcome) C
13、ompletion: 94%*,2 Year Visit Completion: 87%*,* Includes deaths * Includes deaths and excludes pending and dropped who are not yet in window,9,Baseline Characteristics,10,Injections/Sham Prior to 1 Year,*Excludes 56 eyes among 163 participants with 2 study eyes unmasked at baseline when assigned ran
14、ibizumab + deferred laser. % of visits reported; 12% of eyes in the triamcinolone group compared with 3% and 4% in the ranibizumab groups,11,Additional Information On Injections/Sham to 2 Yrs,* Failure is defined as: VA 10 or more worse than baseline, OCT CSF 250 microns, DME present on clinical exa
15、m that is the cause of the visual loss, complete laser given AND 13w since last laser treatment with no improvement since the last laser treatment,Out of 26 maximum,Out of 26 maximum,12,Laser Treatments Prior to 1 Year,* 3 eyes deviated from the protocol and received laser prior to 24 weeks (2 were
16、given laser at the 1 week safety visit and 1 at the 20 week visit).,Out of 4 maximum,Out of 4 maximum,Out of 2 maximum,Out of 4 maximum,Visual Acuity,13,Mean Change in Visual Acuity (Letters)* at Follow-up Visits,14,* Values that were 30 letters were assigned a value of 30 P-values for difference in
17、 mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser 0.001; ranibizumab+deferred laser 0.001; and triamcinolone+prompt laser=0.31.,Change in Visual Acuity (LOCF) at 1 Year*,15,*Visits occurring between 308 and 420 days from randomization were included a
18、s 1-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1-year target date were used. For other eyes with out any 1-year data (19 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 10 eyes in the ranibizumab+deferred laser
19、group, and 10 eyes in the triamcinolone+prompt laser group) the last observation carried forward (LOCF) method was used to impute data for the primary analysis. *Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity,Change in Visual Acuity at 2 Years*,16,*Vi
20、sits occurring between 616 and 840 days from randomization were included as 2-year visits *Analysis of covariance adjusted for correlation between 2 study eyes and baseline visual acuity,10 Letter Improvement in Visual Acuity at Follow-up Visits,17,P values for the difference in proportion of 10 let
21、ter improvement in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser 0.001; ranibizumab+deferred laser 0.001; triamcinolone+prompt laser = 0.16,Visit Week,10 Letter Worsening in Visual Acuity at Follow-up Visits,18,Visit Week,P values for the difference in proportio
22、n of 10 letter worsening in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser 0.001; ranibizumab+deferred laser =0.001; triamcinolone+prompt laser = 0.75,Visual Acuity Subgroup Analyses,19,20,Subgroup Analyses,No obvious clinically important difference in results at
23、 1-year primary outcome visit for any of the following subgroups: Prior treatment for DME Baseline visual acuity Baseline OCT-measured central subfield thickening Baseline level of diabetic retinopathy on photos Description of edema by ophthalmologist as predominantly focal or predominantly diffuseI
24、n the subset of pseudophakic eyes at baseline (n = 273), visual acuity improvement in the triamcinolone+prompt laser group appeared comparable to the ranibizumab groups,Change in Visual Acuity at 1 Year Stratified by Pseudophakic at Baseline,21,Retinal Thickening,22,Mean Change in Central Subfield T
25、hickening at Follow-up Visits,23,Visit Week,P values are for the difference in mean change in OCT CSF retinal thickness from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser 0.001, ranibizumab+deferred laser 0.001, and triamcinolone+prompt laser 0.001.,Change in Retinal Thickening at
26、 1 Year*,24,*Visits occurring between 308 and 420 days from randomization were included as 1 year visits. When more than 1 visit occurred in this window, data from the visit closest to the 1 year target date were used. *Analysis of covariance adjusted for baseline OCT retinal thickness and visual ac
27、uity and correlation between 2 study eyes a Missing data for 22 eyes in the sham+prompt laser group, 16 eyes in the ranibizumab+prompt laser group, 13 in the ranibizumab+deferred Laser, and 13 eyes in the triamcinolone+prompt laser group (includes missing and ungradeable data 3 in sham+prompt laser,
28、 2 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser,Change in Retinal Thickening at 2 Years*,25,*Visits occurring between 616 and 840 days from randomization were included as 2-year visits. When more than 1 visit occurred in this window, data from the visit closest to the 2-year tar
29、get date were used. * Analysis of covariance adjusted for baseline OCT retinal thickness and visual acuity and correlation between 2 study eyes Excluding pending- Missing data for 2 eyes in the sham+prompt laser group, 2 eyes in the ranibizumab+prompt laser group, 2 in the ranibizumab +deferred lase
30、r, and 6 eyes in the triamcinolone+prompt laser group; Ungradeable data for 1 in the ranibizumab+prompt laser, 1 in ranibizumab+deferred laser and 2 in triamcinolone+prompt laser,Both groups still have central DME in about 45% at 2 yr,Retinopathy (hidden pearl within the trial),26,27,Step Changes of
31、 Improvement/Worsening in Diabetic Retinopathy by Baseline Severity,*Photos were missing or ungradeable for 61 eyes in the sham+prompt laser group, 72 eyes in the ranibizumab groups, and 33 eyes in the triamcinolone+prompt laser group,Retinopathy Progression During 1 Year of Follow-up,28,Safety,29,3
32、0,Major Ocular Adverse Events During 2-Years of Follow-up,30,*One case unrelated to study drug injection (following cataract extraction) in the sham+prompt laser group; 1 case related to study drug injection and 1 case unrelated to injection (following cataract surgery) in the ranibizumab+prompt las
33、er group; 2 cases related to study drug injection in the ranibizumab+deferred laser group. The 3 cases related to study drug injection in the ranibizumab groups are 0.08% of ranibizumab study drug injections given. One case unrelated to the study drug injection (vitreous opacity with hypopyon) and o
34、ne case related to study drug injection in the triamcinolone group. Includes 2 central retinal vein occlusions and 4 branch retinal vein occlusions. Includes 1 traction retinal detachment with proliferative diabetic retinopathy and prior panretinal photocoagulation at baseline.,31,Elevated Intraocul
35、ar Pressure/Glaucoma During 2-Years of Follow-up,31,*Excludes eyes with IOP lowering medications at baseline *Includes 2 filter and 2 cilliary body destruction,32,Cataract Surgery During 2-Years of Follow-up,32,Number of Deaths,33,*Study participants with 2 study eyes are counted in their injection
36、group.,34,Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists Collaboration through 2-Years,34,* N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per even
37、t. One participant had a non-fatal myocardial infarction and a non-fatal stroke (only counted once in the any cardiovascular event row) Four of the vascular deaths in the sham group, 1 of the vascular deaths in the ranibizumab group, and 1 of the vascular deaths in the triamcinolone group were from
38、an unknown cause,Discussion,35,36,Intravitreal Ranibizumab Summary,Intravitreal ranibizumab with prompt or deferred (24 weeks) focal/grid laser had superior VA and OCT outcomes compared with focal/grid laser treatment alone. 50% of eyes had substantial improvement (10 letters) while 30% gained 15 le
39、tters Substantial visual acuity loss (10 letters) was uncommon Results were similar whether focal/grid laser was given starting with the first injection or it was deferred 24 weeks So what is your Standard Care for Center Involved DME?,36,37,Intravitreal Ranibizumab Summary,If ranibizumab is to be g
40、iven as it was in this study, the data indicate a need to follow eyes continuously undergoing this treatment Additional ranibizumab and/or laser were needed in most eyes through 2 years, even if success criteria were met early in the course of treatment. So how are you following patients and determi
41、ning when to re-treat?,37,38,Intravitreal Ranibizumab Treatment Protocol,Results are based on rigorous adherence to a detailed retreatment protocol on a web-based real-time data entry system that provided feedback to the treating physician regarding the treatment to be prescribed at each follow-up v
42、isit.The underlying rationale of the treatment algorithm is to place 4 mandatory injections and then continue treatment, as needed, until stabilization or lack of further improvement is noted.,39,Intravitreal Ranibizumab Treatment Protocol,Once a retreatment is withheld, the algorithm is designed to
43、 identify when there is a need to re-initiate treatment. The goal was to avoid substantial vision loss while also avoiding a regimen which requires monthly treatments regardless of the clinical course.The impact of different retreatment approaches or use of other anti-VEGF drugs (such as bevacizumab
44、) in clinical practice cannot be determined from this study.,39,40,Intravitreal Triamcinolone Summary,Intravitreal triamcinolone combined with focal/grid laser did not result in superior VA outcomes compared with laser alone, despite greater reduction in retinal thickening at 1 year (but not 2 years
45、) compared with laser alone.In an analysis limited to pseudophakic eyes, the triamcinolone groups outcome for VA appeared to be of similar magnitude to that of the 2 ranibizumab groups, but is associated with an increased risk of intraocular pressure elevation.So what will your first line management recommendation be for pseudophakic patients?,40,
