Guidelines for the Management of Neovascular AMD
Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients.
Age-related macular degeneration (AMD) has been described as the leading cause of legal blindness, affecting 10%–13% of adults over 65 years of age in North America, Europe, Australia and, recently, Asia. AMD is a major medical and socioeconomic challenge worldwide and, based on increased life expectancy and a growing negative impact of environmental risk factors, particularly arteriosclerosis, obesity and smoking, its incidence is expected to at least double by 2020. The Global Burden of Disease Study 2010 reported an exponential increase of 160% in vision-related years lived with disability due to AMD, highlighting the overwhelming burden for societies overall. Moreover, with an impact similar to AIDS, renal failure and stroke, AMD has a profound effect on the quality of life of those affected.
Fortunately, progress in AMD's diagnosis and therapy, based on advances in medical research has recently wrought a substantial paradigm shift in the management of neovascular AMD. Identification of a major pathogenetic feature, that is, the influence of vascular endothelial growth factor (VEGF), has opened an easily accessible therapeutic window. Landmark clinical trials proved that intravitreal inhibition of VEGF-A can efficiently block the pathophysiological process of AMD, restore retinal morphology and increase/maintain neurosensory function in most patients with neovascular AMD. Since the approval of anti-VEGF pharmacotherapy in 2006, the prevalence of legal blindness and visual impairment due to AMD has been considerably reduced, removing neovascular AMD from the list of incurable diseases.
The impressive benefit of antiangiogenic therapy has since been widely recognised. However, real-life outcomes have consistently been found to be less favourable than clinical trial results. The community faces a huge dilemma in the management of AMD, with substantial controversies over the efficacy of substances, choice of therapeutic regimens and adequate monitoring needs. This is further aggravated by exponentially growing costs resulting from highly priced drugs, increasing patient numbers and long-term disease chronicity. At the same time, one of the most successful therapeutic break-throughs in ophthalmology is currently at the centre of an array, of unresolved issues and the standard-of-care is vastly inconsistent.
Evidently, there are enormous variations in clinical practice, and considerable uncertainty about how the scientific evidence should be reduced to clinical practice in widely varying settings. The EURETINA community has, therefore, taken responsibility for bringing together experts in the field to develop a working guidance based on the best available scientific and clinical knowledge. The goal is to provide clinically sound, economically acceptable and unbiased diagnostic and therapeutic recommendations to brighten the horizon for patients and physicians worldwide.
Patients' History, Clinical Examination and Self-monitoring. Rationale: Neovascular AMD is an acute onset and rapidly progressing disease which impacts central vision. Early detection of disease onset and continuous follow-up are mandatory because, visual loss becomes irreversible with delayed diagnosis and treatment. General ophthalmologic examination procedures, such as determination of best-corrected visual acuity (BCVA), stereoscopic ophthalmoscopy and home monitoring between routine visits should be implemented. Whenever neovascular AMD is suspected, advanced diagnostic measures such as fluorescein angiography (FA) and optical coherence tomography (OCT) must follow to confirm the diagnosis. Numerous clinical trials have shown that better final outcomes can be achieved with better initial visual acuity (VA). Unfortunately, in most trials as well as in real life, lesions nowadays are usually detected when there is already considerable visual loss. Therefore, awareness must be raised in individuals aged 50 years and older, and physicians should perform AMD screenings regularly.
The reduced efficacy of anti-VEGF therapy compared with academic trial results is commonly associated with poor initial diagnosis and/or discontinuous follow-up in routine clinical care. Compared with treatment paradigms validated by clinical trials, patients with neovascular AMD received too few injections and only infrequent monitoring in US clinical practice from 2006 to mid-2011. Holecamp et al, found 8767 patients were treated with a mean annual number of 4.7 bevacizumab or 5.0 ranibizumab injections between 2006 and 2007. The mean annual number of injections increased slightly from 2008 to 2010, with 10 259 patients divided between six cohorts receiving 4.6, 5.1 and 5.5, bevacizumab or 6.1, 6.6 and 6.9, ranibizumab injections, but mean numbers of visits to an ophthalmologist and OCT examinations remained low. In a Germany-based, multicentre, retrospective review of data from patients with suspected neovascular AMD visiting ophthalmology clinics over 18 months in 2008–2010, 10 sites collected data from 2498 patients with a mean VA of 0.4±0.3 at the time of diagnosis. The most frequent pathological findings detected by routine ophthalmic examination were fibrotic lesions, indicating late diagnosis of choroidal neovascularisation (CNV). A confirmed diagnosis of neovascular AMD was most frequently based on funduscopy (67.3%) or FA (39.6%).
Disease activity in neovascular AMD is lifelong. Long-term outcomes 7–8 years after initiation of intensive ranibizumab therapy were assessed in patients originally treated with ranibizumab in landmark phase 3 trials (SEVEN-UP). Approximately 7 years after initiation of ranibizumab therapy in the ANCHOR or MARINA trials, one-third of patients had good visual outcomes, whereas another third had poor outcomes. Compared with baseline, almost half the eyes were stable, whereas one-third had declined by 15 letters or more. Hence, even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial additional visual decline. Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing intraocular anti-VEGF treatments.
The AMD Detection of Onset of New Choroidal Neovascularisation Study (AMD DOC Study) evaluated the sensitivity of time-domain (TD) OCT relative to FA, in detecting new-onset neovascular AMD within 2 years from onset. The sensitivity of Amsler grid testing, preferential hyperacuity perimetry (PHP), OCT, and FA for detection of CNV was 0.40 for OCT ((95% CI (0.16 to 0.68)), 0.42 for supervised Amsler grid (95% CI 0.15 to 0.72) and 0.50 for PHP (95% CI 0.23 to 0.77)). The AMD DOC Study demonstrated that FA is still the best method for detecting new-onset CNV. Nevertheless, self-monitoring with regular Amsler grid testing is suggested between ophthalmological visits. PHP telemonitoring is a more standardised self-monitoring tool. The HOME study, a prospective, randomised clinical trial found that participants randomised to the home monitor had less vision loss at the time of CNV detection than those in standard care with about 90% maintaining a VAof 20/40 or better at the time of CNV detection. The study also showed that when using the home monitoring device with standard care, CNV detection rates increased statistically significantly, and with smaller lesion size VA at detection was better than standard care alone. With subjective symptom realisation, BCVA at the time of detection was statistically significantly worse than an alert by the device, with a –11.5 letter loss. Increased intraocular pressure (IOP) is another issue in prolonged anti-VEGF therapy. In 528 eyes receiving 1796 intravitreal injections of bevacizumab, IOP was persistently elevated in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/424) with IOP elevated 30–70 mm Hg, 3–30 days after injection. Mean IOP was 42.6 mm Hg (range 30–70); IOP elevations occurred after an average of 7.8 injections of bevacizumab (range 3–13). Injected eyes (19/528) had a significantly higher incidence of elevated IOP than non-injected eyes (fellow eyes), 1/328, p<0.001. Identical observations were published for IOP increases with ranibizumab. Doctors should be aware that IOP might increase after repeated treatments.
Doctors should initially ask patients who present with an onset of decreased vision or metamorphopsia, if they have a family history of AMD, and for their social history including smoking habits. Their complete history should be examined to identify systemic risk factors for anti-VEGF therapy and current medications. Standardised BCVA testing and stereoscopic biomicroscopy/ophthalmoscopy of the macula of both eyes is mandatory, as well as measurement of IOP at least every 6 months. Patients should be instructed to self-monitor their vision between routine office visits. By contrast with current home monitoring strategies, those with intermediate AMD (large drusen in one or both eyes) could benefit from home monitoring with PHP, whenever the device is available. Patients who have received treatment should be monitored at regular intervals, according to a standardised strategy, either monthly or following an individualised pro-re-nata (PRN) or treat-and-extend regimen. Follow-up visits should include examination for new onset of a decrease in vision and nes or persistent metamorphopsia, changes in medical or social history and, most importantly, BCVA tests should be repeated using identical procedures. Further examination by OCT is required if stereoscopic fundus examination reveals clinical signs of retinal oedema, detachment of the retinal pigment epithelium (RPE) or haemorrhage. These recommendations are based on the Age-Related Eye Disease Study and HOME study (evidence level I) and levels II/III data for clinical management of early AMD.
Angiography. Rationale: FA was the main, and for many years, the only diagnostic and follow-up tool for AMD patients. Nowadays, many non-invasive techniques (such as spectral domain (SD) OCT, autofluorescence imaging) can provide detailed anatomical information and precise functional data. In spite of this, FA continues to play a key role in the diagnostic process, for example, providing the base for its clinical classification and the initiation of therapeutic management. The role of FA is to visualise retinal vasculature and neovascular retinal/choroidal proliferations as well as its dynamic features, such as perfusion and exudation. FA has been used in all phase 3 clinical trials for the initial diagnosis of neovascular AMD.
Evidence: In the case of neovascular AMD, leakage of dye from pathological new vessels, into retinal structures appears as hyperfluorescence, which increases in intensity and extension throughout the examination duration. This leakage is classified by its location (subfoveal, juxtafoveal, or extrafoveal) and by its features (classic, occult, or mixed). Classic CNV represents a lesion that has penetrated the RPE layer and is located in the subretinal space (figure 1), whereas occult CNV refers to a neovascular lesion located underneath the RPE (figure 2). In the case of dry AMD, the angiogram will show various grades of drusen (usually seen as early, intensely hyperfluorescence spots) and atrophy (a well-demarcated, hyperfluorescent areas resulting from increased visualisation of the adjacent choroidal fluorescence).
(Enlarge Image)
Figure 1.
Classic choroidal neovascularisation is located above, the retinal pigment epithelium layer and is associated with intraretinal cystoid spaces and/or subretinal fluid. Due to its subretinal location, the neovascular net is delineated with distinct margins. Leakage in late-phase angiography confirms the biologic activity of the lesion (ophthalmoscopy, spectral domain-optical coherence tomography, early fluorescein angiography (FA), late FA).
(Enlarge Image)
Figure 2.
Occult choroidal neovascularisation is located underneath the retinal pigment epithelium layer. By fluorescein angiography (FA), an area of stippled, or pinpoint hyperfluorescence with leakage in late phases, are seen. Indocyanine green angiography (ICGA) (right lower image) may visualise the neovascular pattern of the occult lesion (ophthalmoscopy, early FA, late FA, ICGA).
When assessing a patient with clinical suspicion of neovascular AMD, FA evaluation, if not contraindicated for systemic risks, is routinely mandatory. In fact, it is the only examination that can confirm the mere existence of a CNV, and is also used to evaluate the location and extent of classic and occult forms, particularly when it is coupled with indocyanine green angiography (ICGA). In addition to the location and the area of leakage, FA provides information about the dynamic exudative activity of the lesion. These features, particularly lesion size, have a well-recognised prognostic value and should be clarified in order to plan an appropriate treatment strategy.
An angiogram is also essential to detect specific forms of AMD that present a more aggressive natural history and requires modification of the therapeutic approach. Retinal angiomatous proliferation (RAP) is characterised clinically by focal haemorrhage, oedema and lipid exudates within retinal layers. In more advanced stages, a serous or vascularised pigment epithelial detachment (PED) is detectable. ICGA reveals the area of focal hyperfluorescence arising from the deep capillary plexus forming the initial angiomatous lesion, which subsequently will form an anastomosis with the choroidal circulation (figure 3). ICGA is therefore vital to distinguish this lesion presentation and should be followed by SD-OCT focused on the lesion site. The other relevant example of a different subtype of exudative AMD is polypoidal choroidal vasculopathy (PCV). It is difficult to distinguish this entity clinically from other forms of occult CNV, even though, it presents more commonly with recurrent serous and haemorrhagic PED. The FA shows an ill-defined occult leakage pattern, whereas ICGA is able to delineate the polypoidal lesions in distinct detail (figure 4). As PCV is more common in patients of Asian and African descent, it should be considered in these patients.
(Enlarge Image)
Figure 3.
A retinal angiomatous proliferation is characterised by an early hyperfluorescent spot at the level of the retinal vasculature, mostly at the site of a focal haemorrhage and progressive intraretinal leakage. The concomitant optical coherence tomography scan reveals a pigment epithelium detachment and intraretinal cystoid expansions.
(Enlarge Image)
Figure 4.
Marked intraretinal exudates and/or haemorrhage seen clinically are associated with multiple hyperfluorescent polyps angiographically in polypoidal chorioidopathy. Indocyanine green angiography (ICGA) is often helpful in delineating the polypoidal components despite haemorrhage (ophthalmoscopy, early fluorescein angiography (FA), ICGA, late FA).
Recommendation: Once the initial diagnosis of CNV is established by FA, the effect of anti-VEGF therapy can be efficiently monitored by non-invasive SD-OCT alone. Nonetheless, FA may be advisable, especially where OCT fails to provide reliable information, such as in high myopia, extrafoveal lesions or when dealing with fresh CNV reactivation at the borders of a fibrotic lesion. Additionally, FA and ICGA should be repeated in the case of a sudden clinical worsening, or in occurrence of haemorrhage or new PED. These recommendations are based on evidence levels II/III.
Optical Coherence Tomography. Rationale: OCT, first used in the 1990s, is based on the properties of light waves reflected from and scattered by ocular tissues, which allows anatomical changes associated with exudative AMD to be visualised and measured. Since its introduction with the initial time-domain technology, the modality has continued to improve, with high-definition SD technology and swept source (SS) OCT, achieving greater resolution, repeatability and applicability than earlier OCT devices. Advanced OCT permits high-speed retina scanning that allows complete coverage of the macular area and generation of three-dimensional retinal images. Within a few years, of its introduction, OCT became a major element in both initial diagnosis and management of patients with exudative AMD. TD-OCT has been used in most of the phase 3 clinical trials for antiangiogenic therapy in AMD either as a second outcome examination for central retinal thickness (CRT) or for retreatment indications in trials with a flexible regimen. SD-OCT has so far been used exclusively in the HARBOR study comparing ranibizumab therapy in a fixed monthly and a flexible PRN regimen. OCT visualises structural changes of the retina and RPE as a high-resolution optical 'histology', in a static mode, however, without identification of vascular features or any representation of dynamic processes such as perfusion or leakage.
Evidence: OCT supports the diagnosis of exudative AMD at initial presentation. Type 1 CNV (also called occult CNV) may have several manifestations in OCT (figure 5): The neovascular membrane is localised behind the RPE, creating a vascularised fibrovascular or serous PED. Subretinal fluid (SRF) presents as a dark virtual space between the retina and the RPE, often with disruption of the external limiting membrane-photoreceptor complex in the outer retina. Intraretinal exudation appears as round, dark, cystoid spaces within the retinal layers, but not all cystoid spaces are exudative features. Persistent cystoid spaces mostly have an irreversible degenerative nature. Pigment epithelium detachments are characterised by elevations of the RPE (figure 6). Serous PED present as a smooth regular and sharply demarcated, dome-shaped hyporeflective RPE elevation, whereas fibrovascular PED appears to be filled with solid layers of material of medium or high reflectivity, separated by hyporeflective clefts. On OCT, RPE tears are typically seen as a discontinuity in a large PED, with the free edge of the RPE often curled under the PED. Type 2 CNV (also called classic CNV) is localised in the subretinal space (figure 7). Most eyes with type 2 CNV present a small 'discrete' PED associated with the highly reflective subretinal lesions (mainly located beneath the subretinal lesion). Increased thickness of the retina, SRF, cystoid spaces and PED are commonly observed. RAP (also called type 3 CNV) is described as small erosion or elevated RPE, a flap sign, or, later, a focal funnel-shaped defect in the RPE, called 'kissing sign', accompanied by subretinal and/or intraretinal fluid (figure 8). In PCV, the branching vascular network appears as RPE elevations, while the polypoidal lesions appear as sharper, dome-shaped protuberances, often associated with exudative findings (figure 9).
(Enlarge Image)
Figure 5.
Spectral domain-optical coherence tomography (SD-OCT) reveals a fibrovascular pigment epithelial detachment and a serous retinal detachment in a patient with age-related macular degeneration affected by a type 1 choroidal neovascularisation (scanning laser ophthalmoscopy, SD-OCT).
(Enlarge Image)
Figure 6.
Fluorescein angiography (FA) and spectral domain-optical coherence tomography (SD-OCT) identify a minimally classic choroidal neovascularisation with the classic component in the nasal portion of the macular area and the occult component in the temporal area (FA, SD-OCT).
(Enlarge Image)
Figure 7.
Spectral domain-optical coherence tomography (SD-OCT) features of type 2 (classic) choroidal neovascularisation (CNV) associated with exudative age-related macular degeneration are shown: fluorescein angiography (FA) visualises a small type 2 neovascular membrane. On SD-OCT, CNV appears between the retina and the retinal pigment epithelium, associated with some exudative cystoid spaces and increased central retinal thickness. (FA, SD-OCT).
(Enlarge Image)
Figure 8.
In retinal angiomatous proliferation, fluorescein angiography (FA) shows a hot-spot in the macular area. On spectral domain-optical coherence tomography (SD-OCT), a focal pigment epithelial detachment and intraretinal cystoid spaces are the pathognomonic features. (FA, SD-OCT).
(Enlarge Image)
Figure 9.
Spectral domain-optical coherence tomography (SD-OCT) features of polypoidal choroidopathy are shown: Indocyanine green angiography (ICGA) identifies a hyperfluorescent polypoidal lesion. A punctuate haemorrhage associated with the hot-spot on angiography suggests a retinal angiomatous proliferation. SD-OCT shows a dome-shaped elevation, the sign of a polypoidal lesion. (ICGA, scanning laser ophthalmoscopy, SD-OCT).
OCT is currently the most frequently used tool in the long-term management of exudative AMD. Comparisons of macular thickness and morphology over time allow a patient's response to treatment to be assessed. In the MARINA and ANCHOR studies, anti-VEGF intravitreal injections were based on a fixed regimen every 4 weeks and CRT measured by OCT was only a secondary outcome. Subsequently, individualised regimens based on the concept of treating patients only when necessary have since been investigated. Most subsequent clinical trials of anti-VEGF agents have used some variation on a PRN regimen, usually involving three consecutive monthly loading injections followed by further injections as needed, according to predefined retreatment criteria. This concept of individualised or evaluation-based, as-needed therapy is reportedly the most commonly used treatment regimen in current clinical practice in Europe. The most frequent morphologic criterion for retreatment decisions has been defined as an increase in CRT. Recent analyses revealed that CRT does not correlate with BCVA in AMD, because the structure/function correlation is lost during follow-up as early as at month 3. The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study, therefore, suggested patients should be retreated in a 'no tolerance' mode, that is, whenever any fluid was seen on TD-OCT. The same principle of tight retreatment based on any change in OCT was adopted in the HARBOR trial, but, using SD-OCT which usually leads to a higher retreatment frequency due to the increased number of scans potentially revealing intraretinal fluid or SRF. A comprehensive subgroup analysis of the VIEW study correlation of functional and anatomical data revealed that OCT biomarkers, which are generally correlated with reduced vision in neovascular AMD, were intraretinal cystoid spaces (IRC) at baseline, and persistent cystoid spaces at the end of the loading dose. Whenever IRC were present initially, BCVA, and the therapeutical gain in BCVA were limited, while eyes with SRF showed the best visual prognosis. Prognostic for the therapeutic benefit were IRC and fibrovascular PED at initial presentation, where RPE detachment is the primary pathognomonic feature, and secondary cyst formation under discontinued treatment is the biomarker associated with vision loss. These features were independent of the substance and the regimen used.
Recommendation: BCVA alone is insufficient to detect a recurrence of activity of the neovascular membranes in neovascular AMD. FA can also be useful, in addition to OCT, in some ambiguous cases, particularly for type 2 CNV. New haemorrhage on fundus examination is also a sign of CNV activity. Nevertheless, OCT is actually the most useful tool for evaluating morphological changes because it best reflects recurrence of neovascular activity. Two types of assessment for neovascular activity can be distinguished: measurements and qualitative OCT observations. CRT has been the most common measurement used in clinical studies, however, PRN treatment based on these measurements was invariably associated with reduced therapeutical benefit compared with a fixed continuous regimen. There is a large body of evidence that supports qualitative morphology-based OCT data as more sensitive than measurements for detecting of CNV activity. IRC, SRF and RPE detachments are important signs of activity in the neovascular membrane, independent of CRT. In a 'real life' PRN protocol, all these features are usually considered as criteria for reinjection of anti-VEGF substances. Compared with the former TD-OCT technology, current SD-OCT or SS-OCT technologies which provide raster-scanning imaging, are more sensitive for detecting of subtle morphological changes and, thus, permit early treatment of exudative recurrence. The common recommendation is, therefore, to monitor disease activity using SD-OCT, and on a monthly base. The concept of a 'zero tolerance' on OCT criteria is emerging, because of the rapid progression of exudative features and progressive loss of vision when initiation of treatment is delayed. However, persistent IRC should be considered signs of irreversible retinal degeneration and should not trigger further retreatment. These recommendations are based on evidence levels I (CATT, VIEW, HARBOR) and evidence levels II.
Abstract and Introduction
Abstract
Age-related macular degeneration (AMD) is still referred to as the leading cause of severe and irreversible visual loss world-wide. The disease has a profound effect on quality of life of affected individuals and represents a major socioeconomic challenge for societies due to the exponential increase in life expectancy and environmental risks. Advances in medical research have identified vascular endothelial growth factor (VEGF) as an important pathophysiological player in neovascular AMD and intraocular inhibition of VEGF as one of the most efficient therapies in medicine. The wide introduction of anti-VEGF therapy has led to an overwhelming improvement in the prognosis of patients affected by neovascular AMD, allowing recovery and maintenance of visual function in the vast majority of patients. However, the therapeutic benefit is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management. The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance. Simultaneously, ground-breaking innovations in diagnostic technologies, such as optical coherence tomography, allows unprecedented high-resolution visualisation of disease morphology and provides a promising horizon for early disease detection and efficient therapeutic follow-up. However, definite conclusions from morphologic parameters are still lacking, and valid biomarkers have yet to be identified to provide a practical base for disease management. The European Society of Retina Specialists offers expert guidance for diagnostic and therapeutic management of neovascular AMD supporting healthcare givers and doctors in providing the best state-of-the-art care to their patients.
Introduction
Age-related macular degeneration (AMD) has been described as the leading cause of legal blindness, affecting 10%–13% of adults over 65 years of age in North America, Europe, Australia and, recently, Asia. AMD is a major medical and socioeconomic challenge worldwide and, based on increased life expectancy and a growing negative impact of environmental risk factors, particularly arteriosclerosis, obesity and smoking, its incidence is expected to at least double by 2020. The Global Burden of Disease Study 2010 reported an exponential increase of 160% in vision-related years lived with disability due to AMD, highlighting the overwhelming burden for societies overall. Moreover, with an impact similar to AIDS, renal failure and stroke, AMD has a profound effect on the quality of life of those affected.
Fortunately, progress in AMD's diagnosis and therapy, based on advances in medical research has recently wrought a substantial paradigm shift in the management of neovascular AMD. Identification of a major pathogenetic feature, that is, the influence of vascular endothelial growth factor (VEGF), has opened an easily accessible therapeutic window. Landmark clinical trials proved that intravitreal inhibition of VEGF-A can efficiently block the pathophysiological process of AMD, restore retinal morphology and increase/maintain neurosensory function in most patients with neovascular AMD. Since the approval of anti-VEGF pharmacotherapy in 2006, the prevalence of legal blindness and visual impairment due to AMD has been considerably reduced, removing neovascular AMD from the list of incurable diseases.
The impressive benefit of antiangiogenic therapy has since been widely recognised. However, real-life outcomes have consistently been found to be less favourable than clinical trial results. The community faces a huge dilemma in the management of AMD, with substantial controversies over the efficacy of substances, choice of therapeutic regimens and adequate monitoring needs. This is further aggravated by exponentially growing costs resulting from highly priced drugs, increasing patient numbers and long-term disease chronicity. At the same time, one of the most successful therapeutic break-throughs in ophthalmology is currently at the centre of an array, of unresolved issues and the standard-of-care is vastly inconsistent.
Evidently, there are enormous variations in clinical practice, and considerable uncertainty about how the scientific evidence should be reduced to clinical practice in widely varying settings. The EURETINA community has, therefore, taken responsibility for bringing together experts in the field to develop a working guidance based on the best available scientific and clinical knowledge. The goal is to provide clinically sound, economically acceptable and unbiased diagnostic and therapeutic recommendations to brighten the horizon for patients and physicians worldwide.
Diagnostic Procedures
Patients' History, Clinical Examination and Self-monitoring. Rationale: Neovascular AMD is an acute onset and rapidly progressing disease which impacts central vision. Early detection of disease onset and continuous follow-up are mandatory because, visual loss becomes irreversible with delayed diagnosis and treatment. General ophthalmologic examination procedures, such as determination of best-corrected visual acuity (BCVA), stereoscopic ophthalmoscopy and home monitoring between routine visits should be implemented. Whenever neovascular AMD is suspected, advanced diagnostic measures such as fluorescein angiography (FA) and optical coherence tomography (OCT) must follow to confirm the diagnosis. Numerous clinical trials have shown that better final outcomes can be achieved with better initial visual acuity (VA). Unfortunately, in most trials as well as in real life, lesions nowadays are usually detected when there is already considerable visual loss. Therefore, awareness must be raised in individuals aged 50 years and older, and physicians should perform AMD screenings regularly.
Evidence
The reduced efficacy of anti-VEGF therapy compared with academic trial results is commonly associated with poor initial diagnosis and/or discontinuous follow-up in routine clinical care. Compared with treatment paradigms validated by clinical trials, patients with neovascular AMD received too few injections and only infrequent monitoring in US clinical practice from 2006 to mid-2011. Holecamp et al, found 8767 patients were treated with a mean annual number of 4.7 bevacizumab or 5.0 ranibizumab injections between 2006 and 2007. The mean annual number of injections increased slightly from 2008 to 2010, with 10 259 patients divided between six cohorts receiving 4.6, 5.1 and 5.5, bevacizumab or 6.1, 6.6 and 6.9, ranibizumab injections, but mean numbers of visits to an ophthalmologist and OCT examinations remained low. In a Germany-based, multicentre, retrospective review of data from patients with suspected neovascular AMD visiting ophthalmology clinics over 18 months in 2008–2010, 10 sites collected data from 2498 patients with a mean VA of 0.4±0.3 at the time of diagnosis. The most frequent pathological findings detected by routine ophthalmic examination were fibrotic lesions, indicating late diagnosis of choroidal neovascularisation (CNV). A confirmed diagnosis of neovascular AMD was most frequently based on funduscopy (67.3%) or FA (39.6%).
Disease activity in neovascular AMD is lifelong. Long-term outcomes 7–8 years after initiation of intensive ranibizumab therapy were assessed in patients originally treated with ranibizumab in landmark phase 3 trials (SEVEN-UP). Approximately 7 years after initiation of ranibizumab therapy in the ANCHOR or MARINA trials, one-third of patients had good visual outcomes, whereas another third had poor outcomes. Compared with baseline, almost half the eyes were stable, whereas one-third had declined by 15 letters or more. Hence, even at this late stage in the therapeutic course, exudative AMD patients remain at risk for substantial additional visual decline. Active exudative disease was detected by spectral-domain OCT in 68% of study eyes, and 46% were receiving ongoing intraocular anti-VEGF treatments.
The AMD Detection of Onset of New Choroidal Neovascularisation Study (AMD DOC Study) evaluated the sensitivity of time-domain (TD) OCT relative to FA, in detecting new-onset neovascular AMD within 2 years from onset. The sensitivity of Amsler grid testing, preferential hyperacuity perimetry (PHP), OCT, and FA for detection of CNV was 0.40 for OCT ((95% CI (0.16 to 0.68)), 0.42 for supervised Amsler grid (95% CI 0.15 to 0.72) and 0.50 for PHP (95% CI 0.23 to 0.77)). The AMD DOC Study demonstrated that FA is still the best method for detecting new-onset CNV. Nevertheless, self-monitoring with regular Amsler grid testing is suggested between ophthalmological visits. PHP telemonitoring is a more standardised self-monitoring tool. The HOME study, a prospective, randomised clinical trial found that participants randomised to the home monitor had less vision loss at the time of CNV detection than those in standard care with about 90% maintaining a VAof 20/40 or better at the time of CNV detection. The study also showed that when using the home monitoring device with standard care, CNV detection rates increased statistically significantly, and with smaller lesion size VA at detection was better than standard care alone. With subjective symptom realisation, BCVA at the time of detection was statistically significantly worse than an alert by the device, with a –11.5 letter loss. Increased intraocular pressure (IOP) is another issue in prolonged anti-VEGF therapy. In 528 eyes receiving 1796 intravitreal injections of bevacizumab, IOP was persistently elevated in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/424) with IOP elevated 30–70 mm Hg, 3–30 days after injection. Mean IOP was 42.6 mm Hg (range 30–70); IOP elevations occurred after an average of 7.8 injections of bevacizumab (range 3–13). Injected eyes (19/528) had a significantly higher incidence of elevated IOP than non-injected eyes (fellow eyes), 1/328, p<0.001. Identical observations were published for IOP increases with ranibizumab. Doctors should be aware that IOP might increase after repeated treatments.
Recommendation
Doctors should initially ask patients who present with an onset of decreased vision or metamorphopsia, if they have a family history of AMD, and for their social history including smoking habits. Their complete history should be examined to identify systemic risk factors for anti-VEGF therapy and current medications. Standardised BCVA testing and stereoscopic biomicroscopy/ophthalmoscopy of the macula of both eyes is mandatory, as well as measurement of IOP at least every 6 months. Patients should be instructed to self-monitor their vision between routine office visits. By contrast with current home monitoring strategies, those with intermediate AMD (large drusen in one or both eyes) could benefit from home monitoring with PHP, whenever the device is available. Patients who have received treatment should be monitored at regular intervals, according to a standardised strategy, either monthly or following an individualised pro-re-nata (PRN) or treat-and-extend regimen. Follow-up visits should include examination for new onset of a decrease in vision and nes or persistent metamorphopsia, changes in medical or social history and, most importantly, BCVA tests should be repeated using identical procedures. Further examination by OCT is required if stereoscopic fundus examination reveals clinical signs of retinal oedema, detachment of the retinal pigment epithelium (RPE) or haemorrhage. These recommendations are based on the Age-Related Eye Disease Study and HOME study (evidence level I) and levels II/III data for clinical management of early AMD.
Angiography. Rationale: FA was the main, and for many years, the only diagnostic and follow-up tool for AMD patients. Nowadays, many non-invasive techniques (such as spectral domain (SD) OCT, autofluorescence imaging) can provide detailed anatomical information and precise functional data. In spite of this, FA continues to play a key role in the diagnostic process, for example, providing the base for its clinical classification and the initiation of therapeutic management. The role of FA is to visualise retinal vasculature and neovascular retinal/choroidal proliferations as well as its dynamic features, such as perfusion and exudation. FA has been used in all phase 3 clinical trials for the initial diagnosis of neovascular AMD.
Evidence: In the case of neovascular AMD, leakage of dye from pathological new vessels, into retinal structures appears as hyperfluorescence, which increases in intensity and extension throughout the examination duration. This leakage is classified by its location (subfoveal, juxtafoveal, or extrafoveal) and by its features (classic, occult, or mixed). Classic CNV represents a lesion that has penetrated the RPE layer and is located in the subretinal space (figure 1), whereas occult CNV refers to a neovascular lesion located underneath the RPE (figure 2). In the case of dry AMD, the angiogram will show various grades of drusen (usually seen as early, intensely hyperfluorescence spots) and atrophy (a well-demarcated, hyperfluorescent areas resulting from increased visualisation of the adjacent choroidal fluorescence).
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Figure 1.
Classic choroidal neovascularisation is located above, the retinal pigment epithelium layer and is associated with intraretinal cystoid spaces and/or subretinal fluid. Due to its subretinal location, the neovascular net is delineated with distinct margins. Leakage in late-phase angiography confirms the biologic activity of the lesion (ophthalmoscopy, spectral domain-optical coherence tomography, early fluorescein angiography (FA), late FA).
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Figure 2.
Occult choroidal neovascularisation is located underneath the retinal pigment epithelium layer. By fluorescein angiography (FA), an area of stippled, or pinpoint hyperfluorescence with leakage in late phases, are seen. Indocyanine green angiography (ICGA) (right lower image) may visualise the neovascular pattern of the occult lesion (ophthalmoscopy, early FA, late FA, ICGA).
When assessing a patient with clinical suspicion of neovascular AMD, FA evaluation, if not contraindicated for systemic risks, is routinely mandatory. In fact, it is the only examination that can confirm the mere existence of a CNV, and is also used to evaluate the location and extent of classic and occult forms, particularly when it is coupled with indocyanine green angiography (ICGA). In addition to the location and the area of leakage, FA provides information about the dynamic exudative activity of the lesion. These features, particularly lesion size, have a well-recognised prognostic value and should be clarified in order to plan an appropriate treatment strategy.
An angiogram is also essential to detect specific forms of AMD that present a more aggressive natural history and requires modification of the therapeutic approach. Retinal angiomatous proliferation (RAP) is characterised clinically by focal haemorrhage, oedema and lipid exudates within retinal layers. In more advanced stages, a serous or vascularised pigment epithelial detachment (PED) is detectable. ICGA reveals the area of focal hyperfluorescence arising from the deep capillary plexus forming the initial angiomatous lesion, which subsequently will form an anastomosis with the choroidal circulation (figure 3). ICGA is therefore vital to distinguish this lesion presentation and should be followed by SD-OCT focused on the lesion site. The other relevant example of a different subtype of exudative AMD is polypoidal choroidal vasculopathy (PCV). It is difficult to distinguish this entity clinically from other forms of occult CNV, even though, it presents more commonly with recurrent serous and haemorrhagic PED. The FA shows an ill-defined occult leakage pattern, whereas ICGA is able to delineate the polypoidal lesions in distinct detail (figure 4). As PCV is more common in patients of Asian and African descent, it should be considered in these patients.
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Figure 3.
A retinal angiomatous proliferation is characterised by an early hyperfluorescent spot at the level of the retinal vasculature, mostly at the site of a focal haemorrhage and progressive intraretinal leakage. The concomitant optical coherence tomography scan reveals a pigment epithelium detachment and intraretinal cystoid expansions.
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Figure 4.
Marked intraretinal exudates and/or haemorrhage seen clinically are associated with multiple hyperfluorescent polyps angiographically in polypoidal chorioidopathy. Indocyanine green angiography (ICGA) is often helpful in delineating the polypoidal components despite haemorrhage (ophthalmoscopy, early fluorescein angiography (FA), ICGA, late FA).
Recommendation: Once the initial diagnosis of CNV is established by FA, the effect of anti-VEGF therapy can be efficiently monitored by non-invasive SD-OCT alone. Nonetheless, FA may be advisable, especially where OCT fails to provide reliable information, such as in high myopia, extrafoveal lesions or when dealing with fresh CNV reactivation at the borders of a fibrotic lesion. Additionally, FA and ICGA should be repeated in the case of a sudden clinical worsening, or in occurrence of haemorrhage or new PED. These recommendations are based on evidence levels II/III.
Optical Coherence Tomography. Rationale: OCT, first used in the 1990s, is based on the properties of light waves reflected from and scattered by ocular tissues, which allows anatomical changes associated with exudative AMD to be visualised and measured. Since its introduction with the initial time-domain technology, the modality has continued to improve, with high-definition SD technology and swept source (SS) OCT, achieving greater resolution, repeatability and applicability than earlier OCT devices. Advanced OCT permits high-speed retina scanning that allows complete coverage of the macular area and generation of three-dimensional retinal images. Within a few years, of its introduction, OCT became a major element in both initial diagnosis and management of patients with exudative AMD. TD-OCT has been used in most of the phase 3 clinical trials for antiangiogenic therapy in AMD either as a second outcome examination for central retinal thickness (CRT) or for retreatment indications in trials with a flexible regimen. SD-OCT has so far been used exclusively in the HARBOR study comparing ranibizumab therapy in a fixed monthly and a flexible PRN regimen. OCT visualises structural changes of the retina and RPE as a high-resolution optical 'histology', in a static mode, however, without identification of vascular features or any representation of dynamic processes such as perfusion or leakage.
Evidence: OCT supports the diagnosis of exudative AMD at initial presentation. Type 1 CNV (also called occult CNV) may have several manifestations in OCT (figure 5): The neovascular membrane is localised behind the RPE, creating a vascularised fibrovascular or serous PED. Subretinal fluid (SRF) presents as a dark virtual space between the retina and the RPE, often with disruption of the external limiting membrane-photoreceptor complex in the outer retina. Intraretinal exudation appears as round, dark, cystoid spaces within the retinal layers, but not all cystoid spaces are exudative features. Persistent cystoid spaces mostly have an irreversible degenerative nature. Pigment epithelium detachments are characterised by elevations of the RPE (figure 6). Serous PED present as a smooth regular and sharply demarcated, dome-shaped hyporeflective RPE elevation, whereas fibrovascular PED appears to be filled with solid layers of material of medium or high reflectivity, separated by hyporeflective clefts. On OCT, RPE tears are typically seen as a discontinuity in a large PED, with the free edge of the RPE often curled under the PED. Type 2 CNV (also called classic CNV) is localised in the subretinal space (figure 7). Most eyes with type 2 CNV present a small 'discrete' PED associated with the highly reflective subretinal lesions (mainly located beneath the subretinal lesion). Increased thickness of the retina, SRF, cystoid spaces and PED are commonly observed. RAP (also called type 3 CNV) is described as small erosion or elevated RPE, a flap sign, or, later, a focal funnel-shaped defect in the RPE, called 'kissing sign', accompanied by subretinal and/or intraretinal fluid (figure 8). In PCV, the branching vascular network appears as RPE elevations, while the polypoidal lesions appear as sharper, dome-shaped protuberances, often associated with exudative findings (figure 9).
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Figure 5.
Spectral domain-optical coherence tomography (SD-OCT) reveals a fibrovascular pigment epithelial detachment and a serous retinal detachment in a patient with age-related macular degeneration affected by a type 1 choroidal neovascularisation (scanning laser ophthalmoscopy, SD-OCT).
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Figure 6.
Fluorescein angiography (FA) and spectral domain-optical coherence tomography (SD-OCT) identify a minimally classic choroidal neovascularisation with the classic component in the nasal portion of the macular area and the occult component in the temporal area (FA, SD-OCT).
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Figure 7.
Spectral domain-optical coherence tomography (SD-OCT) features of type 2 (classic) choroidal neovascularisation (CNV) associated with exudative age-related macular degeneration are shown: fluorescein angiography (FA) visualises a small type 2 neovascular membrane. On SD-OCT, CNV appears between the retina and the retinal pigment epithelium, associated with some exudative cystoid spaces and increased central retinal thickness. (FA, SD-OCT).
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Figure 8.
In retinal angiomatous proliferation, fluorescein angiography (FA) shows a hot-spot in the macular area. On spectral domain-optical coherence tomography (SD-OCT), a focal pigment epithelial detachment and intraretinal cystoid spaces are the pathognomonic features. (FA, SD-OCT).
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Figure 9.
Spectral domain-optical coherence tomography (SD-OCT) features of polypoidal choroidopathy are shown: Indocyanine green angiography (ICGA) identifies a hyperfluorescent polypoidal lesion. A punctuate haemorrhage associated with the hot-spot on angiography suggests a retinal angiomatous proliferation. SD-OCT shows a dome-shaped elevation, the sign of a polypoidal lesion. (ICGA, scanning laser ophthalmoscopy, SD-OCT).
OCT is currently the most frequently used tool in the long-term management of exudative AMD. Comparisons of macular thickness and morphology over time allow a patient's response to treatment to be assessed. In the MARINA and ANCHOR studies, anti-VEGF intravitreal injections were based on a fixed regimen every 4 weeks and CRT measured by OCT was only a secondary outcome. Subsequently, individualised regimens based on the concept of treating patients only when necessary have since been investigated. Most subsequent clinical trials of anti-VEGF agents have used some variation on a PRN regimen, usually involving three consecutive monthly loading injections followed by further injections as needed, according to predefined retreatment criteria. This concept of individualised or evaluation-based, as-needed therapy is reportedly the most commonly used treatment regimen in current clinical practice in Europe. The most frequent morphologic criterion for retreatment decisions has been defined as an increase in CRT. Recent analyses revealed that CRT does not correlate with BCVA in AMD, because the structure/function correlation is lost during follow-up as early as at month 3. The Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) study, therefore, suggested patients should be retreated in a 'no tolerance' mode, that is, whenever any fluid was seen on TD-OCT. The same principle of tight retreatment based on any change in OCT was adopted in the HARBOR trial, but, using SD-OCT which usually leads to a higher retreatment frequency due to the increased number of scans potentially revealing intraretinal fluid or SRF. A comprehensive subgroup analysis of the VIEW study correlation of functional and anatomical data revealed that OCT biomarkers, which are generally correlated with reduced vision in neovascular AMD, were intraretinal cystoid spaces (IRC) at baseline, and persistent cystoid spaces at the end of the loading dose. Whenever IRC were present initially, BCVA, and the therapeutical gain in BCVA were limited, while eyes with SRF showed the best visual prognosis. Prognostic for the therapeutic benefit were IRC and fibrovascular PED at initial presentation, where RPE detachment is the primary pathognomonic feature, and secondary cyst formation under discontinued treatment is the biomarker associated with vision loss. These features were independent of the substance and the regimen used.
Recommendation: BCVA alone is insufficient to detect a recurrence of activity of the neovascular membranes in neovascular AMD. FA can also be useful, in addition to OCT, in some ambiguous cases, particularly for type 2 CNV. New haemorrhage on fundus examination is also a sign of CNV activity. Nevertheless, OCT is actually the most useful tool for evaluating morphological changes because it best reflects recurrence of neovascular activity. Two types of assessment for neovascular activity can be distinguished: measurements and qualitative OCT observations. CRT has been the most common measurement used in clinical studies, however, PRN treatment based on these measurements was invariably associated with reduced therapeutical benefit compared with a fixed continuous regimen. There is a large body of evidence that supports qualitative morphology-based OCT data as more sensitive than measurements for detecting of CNV activity. IRC, SRF and RPE detachments are important signs of activity in the neovascular membrane, independent of CRT. In a 'real life' PRN protocol, all these features are usually considered as criteria for reinjection of anti-VEGF substances. Compared with the former TD-OCT technology, current SD-OCT or SS-OCT technologies which provide raster-scanning imaging, are more sensitive for detecting of subtle morphological changes and, thus, permit early treatment of exudative recurrence. The common recommendation is, therefore, to monitor disease activity using SD-OCT, and on a monthly base. The concept of a 'zero tolerance' on OCT criteria is emerging, because of the rapid progression of exudative features and progressive loss of vision when initiation of treatment is delayed. However, persistent IRC should be considered signs of irreversible retinal degeneration and should not trigger further retreatment. These recommendations are based on evidence levels I (CATT, VIEW, HARBOR) and evidence levels II.