Evidence From Randamized Clinical Trials & Real Life Data, And Their Implications In Clinical Practice. (namd).

Transcription

1 Evidence From Randamized Clinical Trials & Real Life Data, And Their Implications In Clinical Practice. (namd). Mohamed Moghazy MD.,FRCSEd. Professor Of Ophthalmology. Ain-Shams University. Cairo, Egypt.

2 Definitions.

3 Response Good responders. Partial responders. Poor/Non responders.

4 Definitions Response Morphology Functional Good Absence of SRF, IRF, IRC or a reduction of CRT >75% of the baseline values Partial Reduction of CRT of between 25 and 75% of the baseline values, and/or persistence of SRF, IRF, IRC and or appearance of new IRC, IRF and SRF Poor Between 0 and <25% reduction in CRT and/or persistence of SRF, IRF, IRC and or appearance of new IRC, IRF and SRF Improvement in VA >5 letters from the baseline (ceiling effect in eyes with good starting VA defined as ETDRS 70 letters or above). Pay more attention to morphological features if VA is good esp >70) Change in VA of 1 5 letters from the baseline Change in VA of 0 4 letters Nonrespon se Unchanging or increasing CRT, SRF, IRF and/or PED compared with the baseline Change > 5 letters ie decline in VA from the baseline from 1 month after third initiation injection Defining response to anti-vegf therapies in neovascular AMD W M Amoaku,1,* U Chakravarthy,2 R Gale,3 M Gavin,4 F Ghanchi,5 J Gibson,6 S Harding,7 R L Johnston,8 S Kelly,9 A Lotery,10 S Mahmood,11 G Menon,12 S Sivaprasad,13 J Talks,14 A Tufail,15 and Y Yang16 eye 2015

5 Fading of a response Tachyphylaxis. Tolerance.

6 Fading of a response. Tachyphylaxis develops quickly and can be reverted by halting treatment temporarily. Tolerance develops slowly and can be partially overcome by increasing Eghoj MS, Sorensen TL (2012) Tachyphylaxis during treatment of exudative age-related macular degeneration with ranibizumab. Br J Ophthalmol 96:21 23 Binder S (2012) Loss of reactivity in intravitreal anti-vegftherapy: tachyphylaxis or tolerance? Br J Ophthalmic 96:1 2 Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29(6): Schaal S, Kaplan HJ, Tezel TH. Is there tachyphylaxis to intravitreal anti-vascular endothelial growth factor pharmacotherapy in age-related macular degeneration? Ophthalmology 2008;115(2): dosage or shortening the dosage interval

7 Possible explanations. The mechanisms are multifactorial Cellular: Upregulation of VEGF from local macrophages. Altered expression of surface receptors. Activation of alternate angiogenic signaling pathways. Metabolic Alterations in pharmacokinetics with changes in drug absorption, distribution, and metabolism. Humoral responses After intravitreal injection, a systemic immune reaction to anti-vegf molecules that have entered the patient s serum, as well as a local response secondary to a compromised blood-retinal barrier, may contribute to the formation of neutralizing antibodies.. Roa Vandekerckhove K. Aflibercept versus ranibizumab for treating persistent diabetic macular oedema. Int Ophthalmic 2015;35(4): De Falco S. The discovery of placenta growth factor and its biological activity. Exp Mol Med 2012;44(1):1 9Forooghian F, Cukras C, Meyerle CB, Chew EY, Wong WT. Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration. Retina 2009;29(6):

8 Patients respond individually to ranibizumab treatment Retrospective analysis of ranibizumab-treated patients with namd in ANCHOR, MARINA, PIER, and SAILOR trials (N=1,824) 100 Patients (%) Time to first gain of 15 letters (months) ANCHOR (n = 279) MARINA (n = 478) SAILOR cohort 1 treatment-naive (n = 946) PIER (n = 121) Of the patients who gained 15 letters during these studies, 15 29% achieved this by Month 3 1. Hariprasad SM, et al. J Ophthalmology 2012;2012:690641

9 Pooled retrospective analysis of ranibizumab clinical trial data Ranibizumab Monthly PRN ANCHOR 1 and MARINA 2, HARBOR 3 and CATT 4 (Pooled RBZ 0.5 mg and 0.3 mg) HARBOR 3 and CATT 4 (RBZ 0.5 mg) Determine the proportion of early and slow 15 letter gainers Early gainers: 15 BCVA letter gain from baseline at Month 3 Slow gainers: 15 BCVA letter gain from baseline between Month 3-12 Compare early and slow 15 letter gainers with monthly versus PRN dosing BCVA, best-corrected visual acuity; PRN, pro re nata; RBZ, ranibizumab 1. Brown DM, et al. Ophthalmology 2009;116: Rosenfeld PJ, et al. N Engl J Med 2006;355: Busbee BG, et al. Ophthalmology 2013;120: Martin DF, et al. Ophthalmology 2012;119: Gale R et al. World Ophthalmology Congress, April 2-6, 2014, Tokyo,

10 Proportion of patients who gained 15 letters with monthly ranibizumab dosing 18-29% of patients were early gainers 15-16% of patients were slow gainers % of patients gaining 15 letters Early gainers Slow gainers MARINA ANCHOR HARBOR CATT namd: neovascular age-related macular degeneration; BCVA: best-corrected visual 1. acuity Gale R et al. World Ophthalmology Congress, April 2-6, 2014, Tokyo,

11 Proportion of patients who gained 15 letters with PRN ranibizumab dosing An additional 8-13% of patients achieved a 15 letter BCVA improvement at Month 12 compared with Month 3 % of patients gaining 15 letters % 8 CATT Early gainers Slow gainers 13% HARBOR 1. Gale R et al. World Ophthalmology Congress, April 2-6, 2014, Tokyo,

12 Early gainers have a lower mean VA at baseline compared with slow gainers. Early gainers Slow gainers 100 Mean number of ETDRS letters MARINA ANCHOR HARBOR n=87 n=77 n=82 n=41 n=266 n=135 *p <0.05 comparing early 15-letter responders versus delayed 15- letter responders in MARINA and ANCHOR; p= in HARBOR 1. Gale R et al. World Ophthalmology Congress, April 2-6, 2014, Tokyo, Japan

13 Patients respond individually to ranibizumab treatment: EXCITE study BCVA with quarterly ranibizumab dosing in the EXCITE study* Mandatory ranibizumab injections Intention-to-treat population *Data are pooled for patients receiving 0.3 mg or 0.5 mg ranibizumab BL, baseline 1. Eldem B et al. ARVO 2009; Poster D1107

14 Patients respond individually to ranibizumab treatment: PIER study 11.4% of patients achieved no gain in BCVA at Month 3 (N=184) Mean BCVA change from baseline (ETDRS letters ± SE) Month Maintained initial gain of >0 letters at Month 3 (n=16) Initial gain of >0 letters at Month 3 not maintained (n=24) No initial gain at Month 3 (n=21) 6 ranibizumab injections over 12 months 40% of initial gainers did not require monthly dosing SE, standard error 1. Regillo CD, et al. Am J Ophthalmol 2008;145:239-48; 2. Holz F, et al. Invest Ophthalmol Vis Sci 2010;51:405-12

15 When to switch treatment for namd? Good response Continue or consider tx change Continue or consider tx change Continue Continue More imaging Consider tx change More imaging Consider tx change Continue or consider tx change Continue Visual acuity Discontinue and review Discontinue and review More imaging Consider tx change unless poor visual potential Discontinue and review More imaging Consider tx change More imaging Consider tx change Continue unless poor visual potential Continue unless poor visual potential No response Morphology Good response Tx, treatment 1. Adapted from Amoaku WM, et al. Eye 2015;0:1-11

16 Studies On Switching In namd Methodologic issues in switching studies l Lack of control arms Most studies are single-arm, and are usually retrospec5ve evalua5ons l Lack of consensus for switching an6-vegf agents Reasons for switching differ between physicians and regions May not always involve clinical parameters l Lack of consensus for outcomes following switching l Unknown effect on VA outcomes Comparison with pa5ents who did not switch? What is the defini5on of resistance to an5-vegf agents? What is the defini5on of a clinically-relevant outcome?

17 Studies On Switching In namd There are no consistent criteria for resistance to an/-vegf agents Persistent IRF or SRF No further defini.on A0er 5 or 6 months of monthly treatment Requiring monthly treatment Requiring treatment at 6 weekly intervals Requiring treatment at 8 weekly intervals Recurrent IRF or SRF Minimum of 2 recurrences a0er the eyes have been completely dry Recurrence requiring 3 monthly injec.ons (loading doses) within the last year Other criteria Appearance of subre.nal hemorrhage Ac.ve namd Ins.tu.onal policy decision Total of 46 studies iden.fied; Colla.on of available studies study designs may vary IRF, intra-re.nal fluid; SRF, sub-re.nal fluid; VEGF, vascular endothelial growth factor

18 Studies On Switching In namd Number of Studies about switch to/from or back to Ranibizumab 46 studies from Ranibizumab to Aflibercept Ranibizumab 1 study from Aflibercept to Ranibizumab Aflibercept 3 studies From Ranibizumab to Aflibercept then switch back to Ranibizumab

19 Studies On Switching In namd To further the understanding of the long-term outcomes of switching to aflibercept, published studies with sufficient follow-up/pa;ent numbers were analyzed 46 studies iden;fied To facilitate evalua;on of long-term outcomes No adequately powered, controlled studies regarding switching agents 27 studies excluded due to follow-up dura;on of <12 months 19 studies To minimize the risk of data bias 11 studies excluded due to pa;ent popula;on size <50 8 studies Colla%on of available studies study designs may vary

20 Studies On Switching In namd Summary of the analyzed studies

21 Switching To Aflibercept RetrospecFve review Arcinue et al 2015 Previous treatment Ranibizumab (median 5 injecfons) or bevacizumab (median 13 injecfons) q4w unfl dry bonus injecfons Maximum refnal thickness (µm) Anatomical outcomes Baseline (n = 63) Q4w, every 4 weeks q8w, every 8 weeks P < Median difference at 12 months was -107 µm 6 months (n = 63) Reason for switching MulFple recurrences ( 2 recurrences aser the eyes have been completely dry) or persistence of exudafon for at least 5 months on monthly therapy months (n = 63) VA (logmar) FuncKonal outcomes Baseline (n = 63) Treatment switched to Aflibercept q8w; in cases of persistent fluid, q4w Mean difference at 12 months was logmar (-2 lefers; P = ) 6 months (n = 63) 12 months (n = 63) Arcinue CA, et al. Am J Ophthalmol 2015;159:

22 Switching To Aflibercept Retrospec)ve trial Barthelmes et al 2016 Previous treatment Ranibizumab treat and extend or PRN (average of 39.8 months) Reason for switching Reason not reported Treatment switched to Aflibercept treat and extend or PRN (average 6.6 injec)ons at 12 months) Anatomical outcomes Fluid-free macula was achieved by 84 (22%) pa6ents VA (leaers) Func6onal outcomes P = 0.17 No difference in VA at 12 months 0 Baseline (n = 384) 12 months (n = 384) Barthelmes D, et al. Br J Ophthalmol 2016; [Epub ahead of print].

23 Switching To Aflibercept Retrospec8ve review He et al 2015 Previous treatment 17.5 ± 10.1 injec8ons of ranibizumab or bevacizumab over 23.4 ± 13.8 months Reason for switching Reason for switching not reported Treatment switched to Aflibercept (mean 7.5 injec8ons at 12 months) Central subfield thickness (µm) Anatomical outcomes Baseline (n = 90) P = Mean difference at 12 months was µm 12 months (n = 70) VA (le[ers) FuncIonal outcomes Baseline (n = 142) P = Mean difference at 12 months was -2.5 lecers 12 months (n = 140) He L, et al. Ophthalmic Surg Lasers Imaging Re8na. 2015;46:542-9.

24 Switching To Aflibercept Retrospec?ve review Major et al 2015 Previous treatment 24.8 injec?ons of ranibizumab or bevacizumab Reason for switching Reason for switching not reported Treatment switched to Aflibercept administered according to the discre?on of the trea?ng physician PED thickness (µm) Anatomical outcomes Baseline (n = 60) P < Mean difference at 12 months was -53 µm 12 months (n = 60) VA (lesers) Func:onal outcomes Baseline (n = 60) P = 0.27 Mean difference at 12 months was 0.5 leeers 12 months (n = 60) Major JC, et al. Can J Ophthalmol. 2015;50:373-7.

25 Switching To Aflibercept RetrospecFve review Narayan et al 2015 Previous treatment Ranibizumab according to a treat-andextend treatment regimen following 3 monthly loading doses Reason for switching Treatment resistance eyes requiring 4- or 6-weekly treatment intervals a\er 12 months based on CNV acfvity Treatment switched to Aflibercept at the same frequency as previously and extended in absence of fluid to 6 or 8 weeks Anatomical outcomes Func9onal outcomes P = 0.09 Fluid-free macula was achieved by 16 (20%) pa9ents IRF resolved in 14 (17.5%) of pa9ents and submacular fluid in 1 (1.3%) pa9ent VA (logmar) Mean difference of ( 0.5 leaers) at 12 months CNV, choroidal neovascularizafon 0 Baseline (n = 80) 16 months (n = 80) Narayan DS and Muecke J. Indian J Ophthalmol. 2015;63:832-6.

26 Switching To Aflibercept review CRT (µm) Pinheiro-Costa et al 2015 Previous treatment Mean of 21.2 of ranibizumab or bevacizumab Anatomical outcomes P < Mean difference at 14.7 months was -79 µm Reason for switching Persistent exuda@on ayer 3 monthly injec@ons or recurrent exuda@on OR Due to ins@tu@onal policy decision VA (leoers) Func=onal outcomes Treatment switched to Aflibercept (mean 8.5 injec@ons at 12 months) P = Mean difference of -2.1 legers at 14.7 months 0 Baseline (n = 85) 14.7 months (n = 85) 0 Baseline (n = 85) 14.7 months (n = 85) Pinheiro-Costa J, et al. Ophthalmologica 2015;233:

27 Switching To Aflibercept RetrospecBve review Messenger et al 2015 Previous treatment Mean of 21.4 injecbons of ranibizumab or bevacizumab Reason for switching Reason for switching not reported Treatment switched to Aflibercept (mean 7.2 injecbons at 12 months) Central macular thickness (µm) Anatomical outcomes Baseline (n = 109) P = Mean difference at 12 months was -26 µm 12 months (n = 109) VA (logmar) Func9onal outcomes Baseline (n = 109) P = 0.89 There was no mean difference at 12 months 12 months (n = 109) Messenger WB, et al. Br J Ophthalmol. 2014;98:

28 Messages from these studies What do these studies tell us?

29 Effect On CMT. Following the switch to aflibercept, the studies showed wide varia7ons in re7nal thickness changes from baseline to end of study 180 He 2015 (n = 70) Messenger 2014 (n = 109) Major 2015 (n = 60) Pinheiro-Costa 2015 (n = 85) Arcinue 2015 (n = 63) Sarao 2015 (n = 92) 130 Change in CRT (µm) Anatomical outcomes were not reported by Barthelems et al. or Narayan et al. Arcinue CA, et al. Am J Ophthalmol 2015;159:429-36; He L, et al. Ophthalmic Surg Lasers Imaging ReWna. 2015;46:542-9; Major JC, et al. Can J Ophthalmol. 2015;50:373-7; Messenger WB, et al. Br J Ophthalmol. 2014;98:1205-7; Pinheiro-Costa J, et al. Ophthalmologica 2015;233:155-61; Sarao V, et al. ReWna [Epub ahead of print].

30 Correlation Between CMT and VA. No correla)on between CRT reduc)on and VA improvement highlights a disconnect between visual and anatomical outcomes 180 He 2015 (n = 70) Messenger 2014 (n = 109) Major 2015 (n = 60) Pinheiro-Costa 2015 (n = 85) Arcinue 2015 (n = 63) Sarao 2015 (n = 92) 130 Change in CRT (µm) Change in VA Anatomical outcomes were not reported by Barthelems et al. or Narayan et al. Arcinue CA, et al. Am J Ophthalmol 2015;159:429-36; He L, et al. Ophthalmic Surg Lasers Imaging ReWna. 2015;46:542-9; Major JC, et al. Can J Ophthalmol. 2015;50:373-7; Messenger WB, et al. Br J Ophthalmol. 2014;98:1205-7; Pinheiro-Costa J, et al. Ophthalmologica 2015;233:155-61; Sarao V, et al. ReWna [Epub ahead of print].

31 Injection Frequency. But what about the effect of a q8w regimen on injec6on frequency?

32 Injection Frequency. In studies with 12-months post-switch follow up, there is limited evidence to suggest that dosing or monitoring frequency can be reduced a?er switching The relaave injecaon frequency in the 12 months or 6 months prior to the switch was rarely reported Switching to aflibercept also someames incurred a new loading-dose regimen, which may have affected VA gains due to the higher intensity of treatment

33 Loading Dose..Again?! When aflibercept loading doses have not been used following a switch from ranibizumab, no significant VA gains have been observed No LD LD VA (ETDRS) Barthelmes 2016 Baseline VA Narayan 2015 Grewal 2014 VA gain from baseline axer switching to aflibercept Arcinue 2015 Aghdam 2016 Singh 2015 Chang 2015 StaGsGcally significant VA gain from baseline axer switching to aflibercept Mantel 2015 He ReGna 2015 He 2015 VA loss from baseline axer switching to aflibercept Hall 2014 Homer 2015 Kanesa-Thasan A 2015 Due to limited published evidence, this analysis does not exclude studies involving < 50 pagents

34 What If?! Is there any evidence to suggest that con2nuing on ranibizumab produces comparable outcomes to switching to aflibercept?

35 Switch VS no Switch. Switch vs no switch Mantel et al 2016 Extension of a prospec4ve study The ini,al 2-year study evaluated observe-and-plan ranibizumab treatment regimen in namd (n = 115). Following comple,on, pa,ents who s,ll needed monthly retreatment based on OCT criteria were eligible for the extension study Primary objec4ve Study design Pa4ents on ranibizumab treatment (n = 21) Switched to aflibercept treatment (n = 10) Con4nued on ranibizumab treatment (n = 11) Comparison of switch to aflibercept therapy versus con,nuing ranibizumab treatment in namd requiring monthly ranibizumab treatment Switch Mantel I, et al. Re,na 2016;36:53-8.

36 Switch VS no Switch. Switch vs no switch Mantel et al months a+er switch Mean change in BCVA from switch (lefers) Ranibizumab to aflibercept Afliberept to ranibizumab p = 0.07 namd requiring monthly retreatment with ranibizumab responded in a similar way to both ranibizumab and aflibercept treatment There were no stahshcal differences in VA outcomes or injechon frequency between the two treatment groups at 12 months Ranibizumab à aflibercept ConHnue on ranibizumab Mantel I, et al. ReHna 2016;36:53-8.

37 Switch VS no Switch. Switch vs switch Milnes et al 2016 Observa6onal study RetrospecSve cohort study using electronic medical records from US resna pracsces Study design Pa6ents on ranibizumab treatment (n = 255) Switched to aflibercept treatment (n = 255) Primary objec6ve Non-inferiority of BCVA change from baseline to Month 12 for eyes switched from ranibizumab to aflibercept versus aflibercept to ranibizumab Pa6ents on aflibercept treatment (n = 80) Switch Switched to ranibizumab treatment (n = 80) Milnes F, et al. Poster n D0168 presented at ARVO, May 1 5, 2016, SeaBle, Washington, USA.

38 Switch VS no Switch. Switch vs switch Milnes et al months a1er switch Mean change in BCVA from switch (lekers) Ranibizumab to aflibercept 0.21 Afliberept to ranibizumab Least squares mean es8mate (SD): 0.93 (1.89); p = 0.62 No sta=s=cally significant or clinically relevant difference was observed between ranibizumab and aflibercept in mean BCVA change 12 months post-switch (non-inferiority achieved) This was observed irrespec=ve of baseline VA (< or 69 lekers) Ranibizumab à aflibercept Aflibercept à ranibizumab Milnes F, et al. Poster n D0168 presented at the Annual Mee=ng of the Associa=on for Research in Vision and Ophthalmology (ARVO), May 1 5, 2016, SeaKle, Washington, USA.

39 Switching Back. Switch Back Nudleman et al 2016 Retrospec7ve interven7onal case series Method Eyes with neovascular AMD, previously well controlled with monthly injecgons of ranibizumab, which then developed worsening of subregnal fluid aser being switched to aflibercept were included. Well controlled* Pa7ents on monthly Ranibizumab (n = 17) Switched to aflibercept treatment (n = 17) Objec7ve A series of pagents whose eyes with neovascular AMD were well controlled for a minimum of 12 months with intravitreal ranibizumab therapy and were switched to intravitreal aflibercept in an effort to extend treatment intervals. Switch *Defined as having no idengfiable subregnal or intraregnal fluid on opgcal coherence tomography Nudleman et al. Clinical Ophthalmology 2016: June 2016.

40 Switching Back. Switch Back Nudleman et al 2016 CMT (µm) Anatomical outcomes Before Switch (n = 17) P < month aler switch (n = 17) Switch Back All eyes developed increased subre>nal fluid when switched from ranibizumab to aflibercept. Pa>ents were switched back to ranibizumab and had subsequent rapid resolu>on of subre>nal fluid. Conclusion Switching from intravitreal ranibizumab to aflibercept in eyes with well-controlled neovascular AMD may result in worsening in a subset of pa>ents and resolves when therapy is switched back to ranibizumab. Nudleman et al. Clinical Ophthalmology 2016: June 2016.

41 Switching Back. Switch Back Despreaux et al 2015 Retrospec8ve Study Study design This retrospec>ve double-center study included 45 pa>ents with namd who were previously treated with ranibizumab, then aflibercept, and then ranibizumab again. Primary objec8ve Pa8ents on ranibizumab treatment (n = 45 ) Pa8ents switched to aflibercept treatment (n = 45 ) Pa8ents Switched back to ranibizumab treatment (n = 45 ) Change in best-corrected visual acuity (BCVA) measured on the Early Treatment Diabe>c Re>nopathy Study ETDRS chart before (T0) and ader (T1) the switch, and 3 months ader the switchback (T2). Secondary outcomes included changes in central foveal thickness (CFT) measured at T0, T1, and T2. Switch Switch Back Despreaux et al. June Clin Exp Ophthalmol (2016) 254:

42 Switching Back. CRT (µm) Switch Back Anatomical outcomes Despreaux et al T0 (n = 45) P = T0 : Before the switch. T1 : ARer the switch. T2 : 3 months arer the switchback. P = T1 (n = 45) P = T2 (n = 45) VA (lecers) Func>onal outcomes (27.7 %) gained five lefers or more ager switchback. T0 (n = 45) P = P = P = T1 (n = 45) T2 (n = 45) Conclusion A short-term benefit of switchback from one anv-vegf agent to another was observed in pavents with namd who had shown no benefit from the inival switch. Despreaux et al. June Clin Exp Ophthalmol (2016) 254:

43 Switching Back. Switch Back Slean et al Retrospec8ve Case Series Study design Evaluates pa<ents who were switched from bevacizumab or ranibizumab to aflibercept and then back again because of recurrent fluid Outcomes Pa8ents on ranibizumab/ bevacizumab treatment (n = 19) Pa8ents switched to aflibercept treatment (n = 19) Pa8ents Switched back to ranibizumab/ bevacizumab treatment (n = 19) Outcome variables included best available visual acuity (VA) converted to logmar (logarithm of minimum angle of resolu<on), central macular thickness (CMT). Switch Switch Back Slean et al. Interna<onal Journal of Re<na and Vitreous (2016) 2:2 DOI /s

44 Switching Back. Switch Back Slean et al Func;onal outcomes Median VA showed liale apparent change (Not significant) CRT (µm) Anatomical outcomes OCT 1 (n = 19) P = P = P = OCT 2 (n = 19) 296 OCT 3 (n = 19) 283 OCT 4 (n = 19) OCT 1 represents the last OCT on bevacizumab or ranibizumab prior to transidon to aflibercept. OCT 2 represents the first OCT a]er switching to aflibercept. OCT 3 indicates the last OCT on aflibercept before transidon back to bevacizumab or ranibizumab. OCT 4 represents the first OCT a]er switching back to bevacizumab or ranibizumab Anatomical Outcomes The total volume of subre;nal fluid, intrare;nal fluid, and pigment epithelial detachments also decreased on transidon from bevacizumab or ranibizumab (2.56 mm 3 ) to aflibercept (2.44 mm 3 ; p = 0.080), then worsened over the course of aflibercept treatment (3.18 mm 3 ; p = 0.019), and improved again on transidon back to bevacizumab or ranibizumab (2.11 mm 3 ; p = 0.016). Conclusion While aflibercept appears inidally effecdve, some padents develop recurrent fluid with aflibercept that improves with transidon back to bevacizumab or ranibizumab. RotaDng and-vegf agents may be beneficial with recurrent neovascular acdvity. Slean et al. InternaDonal Journal of ReDna and Vitreous (2016) 2:2 DOI /s

45 Final Thoughts There are no many options when it comes to treating namd. Shifting between Anti-VEGF molecules is sometimes mandatory due to several aspects of the namd treatment algorithm. Switching may work for sometime, in some patients. When to switch is the most important aspect of switching and not what to switch to. Long term follow up is necessary to establish the benefit of switching.

46 Final Thoughts In the absence of adequately powered prospective clinical trials, it is unknown wether a continuation of patient s current anti-vegf treatment with a customized, individualized, treatment approach would have led to similar or better VA. gain.

47 Final Thoughts Halting treatment, should be considered as a treatment option in some patients!

48 Thank you