Article
`
`Controversies in the Long-term Management of Neovascular
`AMD
`The role of imaging in clinical decision making
`
`January 1, 2010
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`0
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`Controversies in Long-term AMD Management
`
`The role of imaging in clinical decision making.
`
`SCOTT W. COUSINS, MD
`
`Patients and retinal physicians are extraordinarily fortunate to live in an era where new therapies for neovascular
`AMD have revolutionized recovery of visual acuity. We are approaching the five-year anniversary of the
`introduction of anti-VEGF monotherapy, and the vast majority of patients with neovascular AMD demonstrate
`outstanding initial response. Unfortunately, it is clear that neovascular AMD does not disappear after two years of
`therapy. Further, the major pivotal studies, which followed patients for two years, focused predominantly on
`optimizing visual acuity. However, in the real world, additional therapeutic goals come into play, including
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`minimizing treatment burden and cost and maximizing both ocular and systemic safety. High-quality scientific data
`are lacking to provide guidance for successful long-term management on these issues.
`
`Induction-maintenance has become the standard approach for most retinal physicians. This idea was initially
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`introduced based on the observation of a rapid gain of mean letters of visual acuity during the first three injections
`of ranibizumab (induction), followed by the sub-sequent stable plateau of visual acuity during the next 21 months
`(maintenance). Once induction has been achieved, then what? How is stable long-term visual acuity successfully
`maintained?
`
`Scott W. Cousins, MD is the Robert Machemer Professor of Ophthalmology and Immunology at Duke University
`School of Medicine. He is also vice chair for research and director of the Duke Center for Macular Diseases. His
`research interests include the use of imaging technology to understand the biology of and develop new
`treatments for CNV resistant to anti-VEGF therapy. Dr. Cousins is a consultant for Heidelberg Engineering and
`Genentech. He can be reached at scott.cousins@duke.edu.
`
`Three different long-term maintenance strategies have evolved: (1) scheduled injections (arbitrary injection interval
`based on theoretical pharmacokinetic data); (2) induce and observe (retreatment of recurrent leakage based on
`specific indications); or (3) induce and extend (gradual lengthening of intervals between injections until it recurs
`once; then a regular scheduled injection interval is chosen based on the previous interval before leakage
`occurred). Space limitations prevent a detailed analysis of strengths and weaknesses of the three choices, but
`only the first strategy has been validated scientifically. Strategies two and three are the most commonly used
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`among retinal specialists, but intermittent treatment raises the very real possibility of under treatment. And what is
`an effective way to identify and treat eyes that fail to respond to induction, or eyes that develop recurrence while
`on maintenance therapy?
`
`In the following article, we suggest that imaging technologies in addition to standard optical coherence tomography
`should continue to play a major role in monitoring the patient with neovascular AMD during the maintenance phase
`of anti-VEGF therapy. In particular, we identify four common clinical scenarios, with case examples providing
`anecdotal evidence that spectral-domain OCT, fluorescein angiography and high-speed indocyanine green
`angiography still play an important role in monitoring and treatment of patients in the anti-VEGF therapy era.
`
`REPEAT IMAGING AFTER SCHEDULED INDUCTION: WHAT IS A “SUCCESSFUL”
`INDUCTION?
`
`Implicit in the induction-maintenance paradigm is the assumption that induction (ie, three monthly injections) is
`scientifically validated. Unfortunately, it is not. Further more, even an anatomic definition of induction (ie, continued
`monthly injections until evidence of all leakage has disappeared) is problematic because the meaning of “drying up
`leakage” is dependent on the imaging modality utilized. Nonetheless, we believe that the combined usage of both
`OCT (especially SD-OCT) and FA at the completion of three induction injections is very useful in planning the
`subsequent maintenance phase of therapy.
`
`• Role of OCT: Time-domain vs Spectral-domain OCT Standard (time-domain) OCT has become the main
`imaging modality used in the long-term management of neovascular AMD by most retinal specialists. It has been
`extraordinarily useful in demonstrating the presence of sub-retinal fluid and intraretinal cystic changes that were
`not apparent upon clinical examination or fluorescein angiography. Importantly, OCT-based therapeutic decision
`making was not part of the original pivotal trials.
`1,2
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`In addition, the use of standard OCT to make retreatment decisions, either on the basis of “induce and observe” or
`“induce and extend,” is problematic because of under-sampling across the macula, as well as potential artifacts.
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`For instance, the standard Stratus map is based upon the use of six radial B scans (a relatively small sample of
`the total macula) to produce a map that is an interpolation. This scan strategy may fail to detect areas of subretinal
`or intraretinal fluid. In addition, because of errors in segmentation and other artifacts, the quantitative thickness
`measurements in standard OCT can be inaccurate and demonstrate artifactual intertest variability Finally, there is
`a surprisingly poor correlation between OCT responsiveness and ultimate visual acuity Therefore, there is no
`scientific evidence to indicate that using standard OCT based on traditional surface map, quantitative measures, or
`cross-section analysis is an effective way to determine maintenance intervals or retreatment.
`
`Spectral-domain OCT offers the potential advantages of a greater number of sampling scans across the macula.
`Some technologies (Spectralis, Heidelberg) have very robust image registration so that intertest variability is
`reduced. Anecdotal case reports demonstrate that fluid not detected by standard OCT can be imaged by SD-OCT.
`It is attractive to speculate that defining “induction success” by fluid resolution imaged by SD-OCT “full macula
`volume scan,” rather than by standard OCT, would result in better long-term success and fewer recurrences in the
`maintenance phase of therapy (See Figure 1.)
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`Figure 1. Subretinal fluid detected by spectral-domain OCT but not standard OCT. An 81-year-old male
`with occult CNV underwent induction with three monthly injections of ranibizumab, gaining one line of
`vision. Clinical exam and standard OCT (panels A-C) indicated resolution of subfoveal fluid. However, SD-
`OCT (panels D-F) indicated persistence of significant extrafoveal subretinal fluid not imaged by standard
`OCT. Considered to be a partial response to induction, the patient continued on monthly injections until all
`fluid had disappeared.
`
`• Fluorescein Angiography. For 40 years, FA has been the gold standard for diagnosis and monitoring treatment
`responses in neovascular AMD. Although it continues to remain crucial for diagnosis, its role in the long-term
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`management of neovascular AMD has become less clear. As a small, highly charged molecule, fluorescein dye is
`ideally suited for the detection of leakage. Nonetheless, fluorescein leakage can be difficult to interpret in the era of
`digital FA, especially to distinguish fluorescein that remains extravascular but intralesional (ie, stain) vs subretinal
`fluid vs intraretinal fluid. This complexity has lowered the enthusiasm for use of FA for monitoring therapy.
`
`More important than leakage detection, FA remains very useful for determining the size (ie, surface area) of CNV
`and whether area has remained stable, enlarged, or regressed. In a recent study, we observed that, in eyes with
`predominantly classic CNV, 16% demonstrated significant regression after induction with anti-VEGF monotherapy,
`but an equal percentage showed enlargement during treatment. The majority of cases demonstrated only a
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`modest reduction in the surface area, with residual staining of the entire CNV (see Figure 2).
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`Figure 2. Fluorescein angiograms demonstrating different treatment responses after anti-VEGF induction.
`Panel A (left and right) demonstrates inactive but stable CNV, with decreased leakage but persistent
`staining and unchanged area of the lesion. Panel B demonstrates CNV regression, with disappearance of
`both leakage and staining. Panel C demonstrates CNV progression with new hemorrhage and enlargement
`in area, despite receiving three monthly doses of ranibizumab.
`
`We use imaging to determine if the induction regimen has produced any CNV regression. Although speculative, it
`is attractive to postulate that those eyes that showed complete regression of CNV would be more likely to do well
`with extended treatment intervals, whereas those eyes without significant regression will require more frequent
`intervals of treatment. Conversely, CNV that progressed during induction is resistant to anti-VEGF therapy and re
`quires a switch in therapy (see below).
`
`MAINTENANCE PHASE: WHEN TO REORDER IMAGING
`
`The rationale for “induce and observe” with OCT-guided retreatment is based on an uncontrolled prospective study
`using monthly re-evaluation with standard OCT. In this study, patients treated with this protocol were able to
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`maintain the initial visual gains for two years. The interpretation of this study is complicated by the fact that the
`OCT retreatment criteria changed during the course of the study. In addition, reinjection criteria included monthly
`clinical examination, as well as five-letter change in best corrected visual acuity data (the most frequent criteria for
`reinjection). A prospective multicentered study (SAILOR) used similar criteria in a “real-world” setting.
`Unfortunately, this study failed to demonstrate maintenance of long-term visual gain over the subsequent
`observation period. Furthermore, no scientific data exist to support the treat-and-extend strategy. Bottom line:
`There is high risk for undertreatment of some eyes with “induce and observe” or “induce and extend” maintenance
`strategies. Therefore, we repeat fluorescein angiography every six to nine months to rule out enlargement of CNV
`area or other changes in fluorescein patterns (see Figure 3).
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`Figure 3. Enlargement of CNV area in spite of stable OCT. A 67-year-old male with occult CNV associated
`with hemorrhagic PED (panels A, B and E) underwent induction with ranibizumab. Examination and OCT
`improved (panel F). The patient was observed during the subsequent six months, returning every six
`weeks for exam and standard OCT (Panels G and H). Clinical exam and vision remain unchanged (panel
`C). However, repeat fluorescein at six months postinduction demonstrated significant increase in CNV
`area (panel D), suggesting undertreatment.
`
`RESISTANCE TO MONOTHERAPY: WHAT TO DO WHEN STANDARD THERAPY IS
`INEFFECTIVE?
`
`Another controversy in the management of neovascular AMD is the idea of anti-VEGF therapy resistance.
`Anatomical resistance is defined as the failure to reverse leakage and/or normalize other morphological evidence
`of neovascularization after anti-VEGF induction. The anatomical definition can be based upon clinical examination
`or, more commonly based upon imaging criteria. We define anti-VEGF resistance after induction by FA and OCT
`as: subfoveal CNV that bled or increased in size by FA; subfoveal CNV that show persistent significant residual
`sub-retinal fluid and/or intraretinal cysts by OCT; or serous pigment epithelial detachments (PEDs) that fail to
`flatten by OCT.
`
`Recently, we observed in our “real-world” retina practice (rather than well-defined cases as found in a trial) that
`about 25% of cases demonstrated some form of anatomic resistance. Approximately 5% of eyes that were
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`deemed resistant demonstrated fibrovascular PEDs or occult CNV that failed to resolve subretinal or intraretinal
`fluid. In addition, about 5% of all cases (and 15% of predominantly classic CNV) demonstrated increased size or
`developed new hemorrhage while on induction therapy. However, the majority of cases demonstrating resistance
`were serous PEDs (without RAP lesions) in which the PED failed to flatten.
`
`• Indocyanine Green Angiography. ICGA is very useful in trying to explain and treat cases of anti-VEGF therapy
`resistance. Indocyanine green dye has the property of being predominantly protein bound and therefore tends to
`remain intravascular with less leakage than fluorescein dye. Static ICGA which uses bright-flash illumination with
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`images acquired every two to five seconds, typically evaluates hyperfluorescence (ie, leakage) at 15 and 30
`minutes after intravenous injection. Although initially met with enthusiasm, static ICG angiography has become
`rarely utilized.
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`High-speed ICGA has received renewed interest with the introduction of the Spectralis imaging system
`(Heidelberg Engineering). High-speed ICGA images the transit of intravascular dye in the first one minute after
`intravenous injection, focusing on vascular morphology and flow rate (the rate of filling of the lesion) not leakage,
`presence of vascular remodeling (ie, feeder vessels and arteriolarized CNV), and other unusual features of new
`vessels (ie, polypoidal choroidal vasculopathy). In addition, high-speed ICGA can identify the presence of
`neovascularization not apparent with standard FA. Therefore, in eyes with anti-VEGF resistance, we perform high-
`speed ICG angiography, looking for evidence of feeder vessels, arteriolarized CNV or PCV (see Figure 4).
`
`Figure 4. Serous PED associated with marginal CNV resistant to ranibizumab but responsive to
`photodynamic therapy directed toward vascular pathology, imaged by high-speed indocyanine green
`angiography. A 68-year-old female with serous PED (panel A) and two areas of occult CNV (panel B, red
`arrows) underwent induction with three monthly injections of ranibizumab but without anatomic or visual
`improvement. High-speed indocyanine angiography using HRA2 (Heidelberg Engineering) demonstrated a
`feeder vessel with branching arterioles (Panel C, dotted line) inferonasal to the PED (panel C, asterisk).
`Photodynamic therapy was directed toward the vascular pathology imaged by ICGA, with subsequent
`resolution of the PED (panels D-F) and improvement in vision.
`
`For cases with well-defined feeder arteries or polypoidal choroidal vasculopathy, we offer combination therapy with
`anti-VEGF therapy plus intravitreal triamcinolone, together with verteporfin photodynamic therapy, directing the
`PDT treatment to the major arteriolarized vascular structures observed by ICGA, rather than areas of leakage
`defined by FA. In our series of over 34 eyes with resistant CNV caused by either serous PED or subfoveal CNV
`associated with arteriolarized vessels, we showed greater than 80% anatomic response. In eyes without
`arteriolarization by ICGA, or which are not good candidates for PDT, several choices are possible, including
`switching to another anti-VEGF agent, adding intravitreal triamcinolone, increasing the anti-VEGF dose (ie, 0.1 cc
`of ranibizumab or bevacizumab), or injecting more frequently (two to three weeks).
`
`RECURRENCES
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`Recurrences are defined anatomically as reaccumulation of fluid or new hemorrhage after “successful” induction. It
`is tempting to assume that recurrent leakage simply signifies underdosing, and simply shortening of the injection
`interval is adequate to regain anatomic and visual stability. Sometimes, however, recurrence indicates that the
`CNV has increased in size or changed in some other way (ie, losing VEGF responsiveness or undergoing
`maturation). Therefore, it is reasonable to suggest that upon recognizing recurrence, that repeat FA should be
`performed. If any indication of anti-VEGF resistance is observed (ie, increase in CNV area), then ICGA is useful
`(see Figure 5).
`
`Figure 5. Recurrence during maintenance developing progressive increase in CNV area during
`reinduction. A 77-year-old female underwent successful induction for subfoveal occult CNV and was
`subsequently observed every six to eight weeks. About nine months later, she developed a new OCT
`cystic thickening and a new hemorrhage temporal to the initial lesion. She was reinduced with two
`monthly bevacizumab injections, with improvement of OCT thickening but worsening of vision.
`Fluorescein angiography demonstrated progressive increase in surface area of the CNV. High-speed
`indocyanine angiography using Spectralis demonstrated that the recurrence was arteriolarized, with a
`large-caliber feeder vessel (red arrows) and many branching arterioles (dotted line). This CNV was treated
`with PDT directed toward the feeder artery, with good long-term results (not shown).
`
`CONCLUSION
`
`Although the anti-VEGF therapies have revolutionized the treatment of neovascular AMD, significant challenges
`remain, especially trying to balance maximizing visual acuity against treatment burden and safety. In this
`complexity, FA and high-speed ICGA will continue to play important roles in the management of neovascular AMD.
`RP
`
`REFERENCES
`
`1. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: Phase III clinical trial results. Ophthalmol Clin North Am.
`2006;19:361–372.
`2. Dadgostar H, Ventura AA, Chung JY, Sharma S, Kaiser PK. Evaluation of injection frequency and visual
`acuity outcomes for ranibizumab monotherapy in exudative age-related macular degeneration.
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`Ophthalmology. 2009;116:1740–1747.
`3. Ray R, Stinnett SS, Jaffe GJ. Evaluation of image artifact produced by optical coherence tomography of
`retinal pathology. Am J Ophthalmol. 2005;139:18–29.
`4. Gass JDM. Stereoscopic Atlas of Macular Diseases: Diagnosis and Treatment. 4th ed. St. Louis, MO; C.V.
`Mosby; 1997.
`5. Cousins S, Csaky K Patterns of CNV fluorescein and indocyanine green angiographic regression responses
`after anti-VEGF monotherapy or anti-VEGF plus anti-PDGF combotherapy. Inv Opthalmol Vis
`Sci.2009;50(Suppl):1261.
`6. Lalwani GA, Rosenfeld PJ, Fung AE, Dubovy SR, Michels S, Feuer W, Davis JL, Flynn HW Jr, Esquiabro M.
`A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration:
`year 2 of the PrONTO Study. Am J Ophthalmol. 2009;148:1–3.
`7. Cousins SW, Nelson M, Schuman S. The Arteriolarized CNV: Resistance to anti-VEGF therapy and
`Response to ICG-directed PDT, ASRS Annual Meeting, 2007.
`8. Hassenstein A, Meyer CH. Clinical use and research applications of Heidelberg retinal angiography and
`spectral-domain optical coherence tomography – a review. Clin Experiment Ophthalmol. 2009;37:130–143.
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`Retinal Physician, Issue: Jan / Feb 2010
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