CADTH Health Technology Review

Anti–Vascular Endothelial Growth Factor Drugs for Age-Related Macular Degeneration

Rapid Review

Authors: Qiukui Hao, Sharon Bailey

What Is the Issue?

• Wet age-related macular degeneration (AMD) is a serious health concern that causes reduced vision-related function, poor overall quality of life, and increased health care resource usage.

• Anti–vascular endothelial growth factor (VEGF) drugs are the first-line treatment for wet AMD, and they are injected into the eye. These drugs can slow disease progression but are expensive and require trained medical professionals to administer and monitor treatment response.

• The criteria for initial injection, maintenance, and discontinuation of anti-VEGF drugs in patients with wet AMD remain unclear.

What Did We Do?

• To inform decisions about the appropriate use of anti-VEGF drugs to treat adults with wet AMD, CADTH sought to identify and summarize recommendations about criteria for the diagnosis of wet AMD and best practices for subsequent treatment with anti-VEGF drugs.

• An information specialist searched the peer-reviewed and grey literature for clinical practice guidelines published since 2018.

What Did We Find?

• Three evidence-based guidelines recommend optical coherence tomography (OCT) to assess patients with suspected wet AMD. The National Institute for Health and Care Excellence (NICE) guidelines then strongly recommend fundus fluorescein angiography only when OCT does not exclude neovascular disease.

• The evidence-based guidelines recommend anti-VEGF drugs for wet or neovascular AMD in adults, particularly for patients with recent disease progression. One guideline suggests starting anti-VEGF treatment as soon as possible once the diagnosis of wet AMD is made.

• The NICE guideline suggests that there may not be any clinically significant distinctions in the effectiveness and safety of various anti-VEGF treatments, including aflibercept, bevacizumab, and ranibizumab, indicating a need for an individualized approach when selecting specific anti-VEGF drugs. However, 1 guideline is inconsistent with NICE, as it suggests choosing bevacizumab first.

• During the maintenance phase of using anti-VEGF drugs, it is important to closely monitor the patient's response and the disease activity and adjust the injection intervals accordingly.

• Guidelines recommend taking an individualized approach and emphasizing active patient involvement in switching and discontinuing anti-VEGF drugs for adults with wet AMD.

• Guidelines or guidance documents without a literature search or unclear methods provided generally consistent recommendations with the included evidence-based guidelines.

• We did not identify any evidence-based guidelines regarding the use of faricimab or brolucizumab. However, NICE published technology appraisals supporting the use of recently approved anti-VEGF drugs (faricimab and brolucizumab) as alternative options for patients who meet similar criteria for treatment with bevacizumab or aflibercept, and under agreed pricing conditions.

What Does It Mean?

• All identified guidelines consistently recommend anti-VEGF drugs for adults with wet active AMD, with some providing guidance on the use of OCT and other ophthalmological assessments to identify criteria for starting and adjusting treatment.

• These guidelines recommend personalized and patient-centred approaches for selecting, switching, and discontinuing anti-VEGF medications. Cost is also a crucial factor in decision-making, especially for aflibercept, ranibizumab, and recently approved anti-VEGF drugs such as faricimab and brolucizumab.

• Further research and evidence-based guidelines are necessary to confirm whether newer drugs can be used in similar situations as older drugs.

Context and Policy Issues

What Is Age-Related Macular Degeneration?

Age-related macular degeneration (AMD) is a prevalent eye disease that can lead to permanent central vision loss in older adults.¹ The disease occurs when the retina's central portion (the macula), which is responsible for sharp and straight-ahead vision, is damaged due to aging and other risk factors. AMD may affect 1 eye (unilateral AMD), with a high risk of progressing to both eyes (bilateral AMD) in 5 years.² While advanced age is the primary risk factor for developing AMD, modifiable risk factors like cigarette smoking, increased body mass index, hyperlipidemia, and hypertension are also important.³ Family history and genetic issues also contribute to the development of AMD.³

There are 2 main types of AMD: dry (atrophic) and wet (neovascular or exudative) AMD.³ Dry AMD accounts for approximately 80% to 85% of all cases and may progress to wet AMD, which accounts for the remaining 15% to 20% of AMD and results in the most severe vision loss.³ The progression of AMD varies from person to person and can be slow or fast.⁴ Wet AMD is characterized by the abnormal growth of new blood vessels underneath the macula, which can cause hemorrhaging, fluid leakage, or fibrosis in the inner retinal layers or subretinal space.³

Ophthalmological exams are necessary for diagnosing AMD. These may include measuring best-corrected visual acuity (BCVA), Amsler grids, funduscopic evaluation with dilated pupils, macular layer imaging with optical coherence tomography (OCT), or fluorescein angiography.^1,3 Patients in the early or intermediate stages of dry and wet AMD may not experience noticeable symptoms or suffer from substantial changes in their vision.^1,3 When these vision changes develop, they may include distorted images, increased blurring (especially while reading), loss of visual acuity, central scotoma (blind spot), and decreased contrast sensitivity (ability to detect differences in shades and patterns).^1,3 Wet AMD, also known as neovascular AMD (nAMD) or exudative AMD, typically results in more rapid and severe visual symptoms that may suddenly or gradually worsen, which is the most common form of advanced AMD.^1,3

How Is AMD Managed?

There are no curative interventions for AMD. Clinicians usually advise all patients with AMD to pursue lifestyle modifications such as quitting smoking, getting regular physical activity, and changing diet patterns with foods rich in antioxidants or unsaturated fatty acids.^1,3 Available therapies that can help slow down the progression of wet AMD include nutritional supplementation with antioxidants (e.g., vitamin C, vitamin E, copper, lutein, zeaxanthin, and zinc), laser therapy, intravitreal injections with anti–vascular endothelial growth factor (VEGF) drugs, and others.³

Based on the results of major clinical trials in AMD, anti-VEGF drugs have become first-line interventions for wet AMD.^1,3,5,6 VEGF plays a crucial role in the formation and growth of abnormal blood vessels and the leakage of blood plasma components from vessels into the retina.³ Anti-VEGF drugs reduce vessel permeability by blocking VEGF. Available anti-VEGF agents administered by intravitreal injection include ranibizumab, aflibercept, brolucizumab, bevacizumab, and faricimab. Bevacizumab is not approved for treating wet AMD, but clinicians may prescribe it as an off-label treatment.³ Faricimab is a new bispecific antibody (angiopoietin-2 and VEGF) inhibitor, which shows promising results for treating wet AMD in phase II trials and real-world settings.^3,7 It was approved by the FDA and Health Canada for wet AMD in 2022.^8,9

The cost of the approved anti-VEGF treatments (ranibizumab, aflibercept, brolucizumab, and faricimab) is more expensive than bevacizumab.^1,10 A trained health professional is required to administer intravitreal injections of anti-VEGF drugs. Typically, patients with wet AMD need a total of 7 or 8 injections in the first year of treatment.¹ Most patients may need long-term anti-VEGF injections, and the injection interval can be adjusted based on comprehensive assessment.¹ The ophthalmologist and patient usually discuss and select anti-VEGF protocols based on multiple factors, such as patient or clinician preferences, costs, response, and other practical issues.^1,3,6,11

Why Is It Important to Do This Review?

AMD is a leading cause of blindness, responsible for about 9% of global blindness cases.¹ AMD affected approximately 200 million people worldwide in 2020.³ In Canada, almost 1 million people have early AMD, with approximately 25% having advanced forms of AMD.¹² The number is increasing due to the aging population.³ Although AMD does not lead to complete blindness, with the functioning of peripheral vision preserved, it can cause loss of central vision, making it difficult to perform activities of daily living, such as cooking, eating, reading, driving, watching television, and recognizing objects and faces.^3,13 Visual impairment or disability caused by AMD is associated with poor quality of life, depression, falls, and hip fractures in older adults.¹³

In Canada, wet AMD is a serious health concern, causing a significant burden on individuals with the disease.¹⁴ It leads to limitations in vision-related functional abilities, poor overall quality of life, and increased health care resource usage.¹⁴ People with wet AMD also experience higher medical costs, are at a greater risk of falls, and often need more assistance with daily activities, compared to healthy individuals.¹⁴ Therefore, it is crucial to explore evidence-based treatments for wet AMD to prevent vision loss or blindness, which can improve the quality of life and reduce the economic burden associated with this disease. However, there is still ambiguity on how to use anti-VEGF regimens for treating adults with wet AMD in clinical practice, such as criteria for initial injection, maintenance, and discontinuation of the treatment.

Objective

This Rapid Review summarizes evidence-based clinical practice guidelines to support decision-making about using anti-VEGF drugs for wet AMD in adults, including ranibizumab, aflibercept, brolucizumab, faricimab, and bevacizumab.

Research Question

What are the evidence-based guidelines regarding the use of anti-VEGF drugs for adult patients with suspected or confirmed wet AMD?

Methods

Literature Search Methods

An information specialist conducted a literature search on key resources, including MEDLINE, Embase, the Cochrane Database of Systematic Reviews, the International HTA Database, and the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search approach was customized to retrieve a limited set of results, balancing comprehensiveness with relevancy. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. Search concepts were developed based on the elements of the research questions and selection criteria. The main search concepts were wet age-related macular degeneration and anti–vascular endothelial growth factor drugs. CADTH-developed search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, indirect treatment comparisons, and guidelines. The search was completed on August 24, 2023. A supplemental search for guidelines related to wet age-related macular degeneration more broadly was completed on October 20, 2023. Searches were limited to English-language documents published since January 1, 2018.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1: Selection Criteria

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or they were published before 2018. Guidelines, position statements, action papers, and guidance documents with unclear methodology or without a systematic literature search were excluded as well. We also excluded guidelines that only focused on patients with polypoidal choroidal vasculopathy.

Critical Appraisal of Individual Studies

The included publications were critically appraised by 1 reviewer using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument.¹⁵ Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 439 citations were identified in the literature search. Following screening of titles and abstracts, 409 citations were excluded, and 30 potentially relevant reports from the electronic search were retrieved for full-text review. 12 potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, 37 publications were excluded for various reasons, and 5 publications (evidence-based guidelines) met the inclusion criteria and were included in this report. Appendix 1 presents the PRISMA¹⁶ flow chart of the study selection.

We also identified several publications with recommendations, which did not meet our criteria for evidence-based guidelines but provided content relevant to the research question. Appendix 5 presents the characteristics and relevant recommendations from these publications. Appendix 6 presents additional references of potential interest.

Summary of Guideline Characteristics

This report included 5 evidence-based guidelines in which recommendations were developed from a systematic search for relevant evidence.^17-21 The recommendations cover various aspects such as diagnosis, risk factors, referring suggestions, and management. For this report, we have summarized the recommendations that relate to the use of anti-VEGF drugs in treating wet AMD in the sections below.

Appendix 2 presents additional characteristics of the included guidelines.

The guideline development groups were from European¹⁷ and Asia-Pacific countries,¹⁸ the US (American Academy of Ophthalmology),¹⁹ Iran,²⁰ and the UK (National Institute for Health and Care Excellence [NICE]).²¹ We assume that these guidelines are intended to apply to these specific countries. Of these guidelines, 2 provide recommendations for patients with wet or neovascular AMD,^17,18 2 provide recommendations for patients with AMD,^19,21 and the remaining 1 provides guidelines for patients with ocular vascular disease.²⁰ The authors of 2 guidelines^18,21 clearly stated that their recommendations are for adults, while it is assumed that the remaining guidelines^17,19,20 are also for adults, although they do not have a clear description.

The authors of 2 guidelines^17,18 performed a literature search to find relevant systematic reviews, guidelines, and primary studies. They then presented the obtained evidence to a consensus panel for further discussion and development of recommendations.^17,18 For 2 of the guidelines,^19,21 the guideline panel also reviewed health economic evidence. In the remaining guideline,²⁰ the technical committee created scientifically possible answers or scenarios based on the evidence from a systematic search of the literature for each clinical question. The panel members then voted to finalize the recommendations.

One guideline included evidence regarding aflibercept, bevacizumab, brolucizumab, and ranibizumab.¹⁹ The remaining 4 guidelines included evidence regarding aflibercept, bevacizumab, and ranibizumab.^17,18,20,21 No guideline included evidence for faricimab. All guidelines^17-21 based recommendations on visual outcomes such as best-corrected visual acuity (BCVA). However, 2 guidelines^19,21 also considered quality-of-life measures as the main outcomes in developing recommendations.

Summary of Critical Appraisal

All of the included guidelines had clear objectives, guideline questions, and target populations (e.g., patients with wet AMD) and were aimed at health care providers who manage wet AMD in adults.^17-21 All of the guidelines attempted to apply systematic methods to search for evidence and then achieve consensus to finalize recommendations.^17-21 One guideline²⁰ lacked clarity on search methods and another only searched PubMed,¹⁷ potentially missing relevant evidence due to uncomprehensive searches.

Two of the guidelines^19,21 were developed by a team of clinical experts and research professionals. However, it is uncertain whether at least 1 methodology expert was involved in the development of 3^17,18,20 of the 5 included guidelines. Only 1 of the guidelines, from NICE, sought the views or preferences of the target population.²¹ We are also unsure whether the perspectives or preferences of the target populations were sought or had an influence on the recommendations in the remaining 4 guidelines.^17-20 Therefore, the recommendations may not adequately reflect the values and preferences of patients.

Two guidelines^19,21 adopted the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to assess the certainty of evidence, but the certainty of evidence was unclear in the remaining 3 guidelines.^17,18,20 The link between the recommendations and the supporting evidence was unclear in these same 3 guidelines.^17,18,20 In the other 2 guidelines,^19,21 such links were clear for main recommendations. The strength of some or all recommendations in all included guidelines was not clear.^17-21 Two guidelines lacked clarity in explaining the process of transitioning from evidence to recommendation.^17,18 While 3 of the guidelines were published in peer-reviewed journals, none of them described an explicit external review process.^17,18,20 These limitations could limit the internal validity of the guidelines.

The NICE guideline²¹ had good applicability by describing the facilitators and barriers, offering practical tools for implementing the recommendations and considering the potential resources needed to follow the guideline recommendations. Although 2 other guidelines provided algorithms for managing wet AMD,^17,18 the 2 remaining guidelines do not offer advice or tools on how to put the recommendations into practice.^19,20 The relevant recommendations in 3 guidelines were specific and unambiguous,^17,18,21 whereas 2 guidelines provided ambiguous recommendations,^19,20 such as lack of specific information on choosing specific anti-VEGF drugs. These limitations could be a barrier to implementing their recommendations.

All guidelines disclosed the competing interests of their development group.^17-21 It is unlikely that the funding body influenced the contents of the guideline in 3 guidelines.^19-21 However, several authors in the 2 guidelines had received grants or consultation fees from industries, but it is unclear how they addressed these competing interests. The commercial company Novartis, related to 2 anti-VEGF drugs (brolucizumab and ranibizumab), performed the preliminary literature review in 1 guideline.¹⁷ The authors state that the company was not involved in interpreting the search results or developing recommendations. However, the potential impact on the guideline recommendations cannot be ruled out. We are unclear if the competing interests could impact the development of recommendations.

Appendix 3 provides additional details regarding the strengths and limitations of included publications.

Summary of Recommendations

We have summarized the relevant recommendations regarding diagnosis of wet AMD and subsequent treatment with anti-VEGF drugs from the included clinical practice guidelines. This also includes recommendations related to specific drug selection and dosing, initiation of therapy, treatment intervals, and disease monitoring during the maintenance phase, switching and stopping anti-VEGF drugs, and other recommendations. Appendix 4 presents the detailed recommendation statements, along with supporting evidence, certainty of evidence, and strength of the recommendations, if available.

Recommendations for Diagnosis of Wet AMD

Three guidelines^17,19,21 recommend OCT for patients with suspected wet AMD.

One guideline¹⁷ noted that the most important criteria are the morphological parameters observed on OCT, which should be evaluated using the entire stack of images when diagnosing wet AMD. The morphological parameters include subretinal fluid, intraretinal fluid, intraretinal neovascularization (type 3 macular neovascularization [MNV]), subretinal hyperreflective material (type 2 MNV or mixed type 1 and type 2 MNV).¹⁷ Another guideline states that OCT, fluorescein angiography, and optical coherence tomography angiography (OCT-A) are useful diagnostic tests for detecting new or recurrent disease activity and guiding therapy.¹⁹ However, the strength of the recommendations and quality of the supporting evidence were unclear in the 2 guidelines.^17,19

The NICE guideline recommends making an urgent referral to a macula service for people suspected to have late AMD (wet active), even if they do not report any visual impairment.²¹ The referral should be made within 1 working day, but it does not require an emergency referral.²¹ For individuals presenting with visual changes (including micropsia and metamorphopsia) or disturbances, the NICE guideline strongly recommends fundus examination.²¹ The NICE guideline strongly recommends the use of OCT for people who are suspected to have wet active AMD. If OCT does not exclude neovascular disease, then the NICE guideline strongly recommends fundus fluorescein angiography (FFA) to confirm the diagnosis of wet active AMD. However, if clinical examination and OCT exclude neovascularization, then the NICE guideline strongly recommends against offering FFA to people with suspected wet active AMD. These strong recommendations were based on very low- to moderate-quality evidence.

General Recommendations for Use of Anti-VEGF Drugs

All included guidelines^17-21 recommended anti-VEGF drugs for adults with wet AMD. One guideline¹⁹ provided a strong recommendation based on a Cochrane systematic review, and noted that anti-VEGF therapies have become first-line therapy for treating and stabilizing most cases of wet AMD. One guideline²⁰ recommended using bevacizumab and other anti-VEGF drugs to treat wet AMD due to their effectiveness and safety (level I evidence, unclear strength of recommendation).

The NICE guideline²¹ provided a strong recommendation based on high-quality evidence regarding using anti-VEGF drugs for wet active AMD for eyes with the following conditions: BCVA is between 6/12 and 6/96; there is no permanent structural damage to the central fovea; the lesion size is less than or equal to 12 disc areas in greatest linear dimension; and there is evidence of recent disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes).

For adults who have wet active AMD and a visual acuity of 6/96 or worse, or better than 6/12, the NICE guideline panel has made weak recommendations based on observational studies.²¹ For those who have a visual acuity of 6/96 or worse, the guideline panel suggests considering anti-VEGF treatment if the treatment is expected to improve the person’s overall visual function (e.g., the affected eye is the person’s better-seeing eye). For those who have a visual acuity better than 6/12, anti-VEGF treatment is effective and may be cost-effective, depending on the regimen used. However, the guideline did not mention a specific anti-VEGF regimen in the recommendation.²¹

Recommendations for Choosing Specific Anti-VEGF Drugs

The NICE guideline²¹ committee agreed that there were no clinically significant differences in the effectiveness and safety of different anti-VEGF treatments (aflibercept, bevacizumab, and ranibizumab). This is a weak recommendation based on moderate-quality evidence.

This guideline makes specific recommendations for ranibizumab and aflibercept but not for bevacizumab, as bevacizumab did not have a UK marketing authorization for treating wet AMD at the time of guideline publication (2018). The NICE guideline recommends ranibizumab and aflibercept as a treatment option for wet AMD, according to their marketing authorizations, and if the manufacturer provides ranibizumab or aflibercept with the discount agreed upon in the patient access scheme. For patients with active wet AMD coexisting with retinal pigment epithelium (RPE), 1 guideline²⁰ recommended intravitreal bevacizumab to improve their visual acuity (supporting evidence level III, unclear strength of recommendation).

Recommendations for Initial Treatment, Dosing, and Intervals

Initial Treatment

The NICE guideline strongly recommends antiangiogenic treatment (anti-VEGF drugs) within 14 days of referral for adults with confirmed wet AMD.²¹

Two guidelines^17,18 made recommendations for initial anti-VEGF treatment with unclear supporting evidence and strength of recommendations. One guideline¹⁷ noted that treatment with anti-VEGF drugs should be initiated as soon as possible once the diagnosis of wet AMD is made; the initiation phase involves at least 2 injections at monthly intervals. The other guideline¹⁸ stated that after a diagnosis of wet AMD, at least 3 consecutive monthly intravitreal anti-VEGF injections should be administered until no disease activity, such as new hemorrhage or fluid on OCT, is observed.

Dosing

One guideline²⁰ provided recommendations for the dosage of using anti-VEGF: bevacizumab (1.25 mg/0.05 mL), aflibercept (2 mg/0.05 mL), and ranibizumab (0.5 mg/0.05 mL).

Intervals

Two guidelines^17,18 recommend using the treat-and-extend (T and E) regimen approach to adjust anti-VEGF injection intervals using algorithms. The 2 guidelines summarized related evidence and recommended 2 algorithms for the management of wet AMD. However, we are unclear on the evidence supporting the recommendations and the strength of recommendations.

One guideline¹⁷ noted the key aspect of the T and E approach is that anti-VEGF treatment should be given proactively at each visit. It emphasizes the OCT measure, and noted that the decisions to modify treatment intervals for subsequent visits should be based on OCT measures of disease activity.¹⁷

We summarized the main points or steps in the 2 algorithms.

• If disease activity is observed:

  • confirm the initial diagnosis of wet AMD and continue at least 2 to 3 additional injections at the minimum interval permitted by the product label, then consider switching to an alternative anti-VEGF drug¹⁷

  • shorten the treatment interval by 2 to 4 weeks (to a minimum of 4 weeks),¹⁷ until intraretinal fluid and/or subretinal fluid are not observed, then the treatment interval can be gradually extended.¹⁸

• If no disease activity is observed, extend the injection interval by 2 to 4 weeks between visits, up to a maximum interval of 16 weeks,^17,18 or potentially more with longer-acting anti-VEGF drugs.¹⁷

Recommendation for Disease Monitoring

One guideline¹⁷ noted that the signs of disease activity in OCT include the following: new subretinal or intraretinal hemorrhage, persistent or increased diffuse retinal thickening, new subretinal fluid or an increase in subretinal fluid, new or increased pigment epithelial detachment or subpigment epithelial detachment fluid, or subretinal hyperreflective material representing a neovascular membrane. The guideline recommends that if disease activity is observed over 3 consecutive anti-VEGF injections with no signs of anatomic or functional improvement, the clinician should reassess the initial diagnosis of wet AMD.¹⁷

One guideline¹⁸ suggests self-monitoring for declining vision; however, the details of self-monitoring, supporting evidence, and the strength of recommendation were unclear.

The NICE guideline strongly recommends close monitoring of individuals with wet active AMD in both eyes using OCT.²¹ If the OCT results appear stable but there is a decline in visual acuity or function, the guideline strongly recommends a fundus examination or colour photography.²¹ For identifying unrecognized neovascularization, a weak recommendation is provided for FFA.²¹ If the OCT results suggest macular abnormalities that are not responding to treatment, the NICE guideline advises using alternative imaging or alternative diagnoses.²¹

Recommendation for Switching or Stopping Anti-VEGF Drugs

Active involvement of patients and personalized approaches are crucial in the decision-making process regarding switching and stopping anti-VEGF. The strength of recommendations regarding switching and stopping anti-VEGF drugs is unclear or weak. The supporting evidence for these recommendations was mostly unclear or limited.

Switching Anti-VEGF Drugs

One guideline¹⁷ noted that if a patient is switched to an alternative anti-VEGF therapy due to lack of efficacy (the definition of efficacy was unclear), a new initiation phase is required. The supporting evidence and the strength of the recommendation are not clearly defined. Another guideline more specifically recommends that patients who are unresponsive to bevacizumab may be switched to ranibizumab or aflibercept, based on level I evidence (systematic reviews or randomized controlled trials [RCTs]).²⁰ However, the NICE guideline recommends considering switching anti-VEGF drugs for practical reasons or patient preference, although there may be limited clinical benefits given the committee’s agreement that there are no significant differences in effectiveness and safety between aflibercept, bevacizumab, and ranibizumab (weak recommendations based on very low evidence).²¹

Stopping Anti-VEGF Drugs

The NICE guideline²¹ made weak recommendations for stopping anti-VEGF drugs in the following 2 conditions: the eye develops severe, progressive loss of visual acuity despite treatment as recommended; or the eye develops wet inactive AMD with no prospect of functional improvement. The NICE guideline emphasized the importance of involving patients in treatment decisions regarding switching or discontinuation.²¹ The NICE guideline²¹ also weakly recommends observation without giving anti-VEGF drugs for patients with stable wet AMD (the definition of stable was unclear) based on very low evidence.

One guideline¹⁸ recommends discontinuing anti-VEGF therapy on a case-by-case basis after careful discussion with patients. The guideline suggests that it may be a reasonable choice to discontinue anti-VEGF injections for patients with stable, inactive disease who have been treated at 16-week intervals for consecutive visits, or patients with advanced nAMD who have significant scarring or atrophy. The supporting evidence and strength of these recommendations were not clearly defined. One guideline¹⁷ states that long-term anti-VEGF therapy may not be beneficial for patients with low vision who have certain retinal conditions such as fibrosis, extensive subretinal hemorrhage, subfoveal disruption of the external limiting membrane, or central atrophy of the RPE.

Other Recommendations for Intravitreal Injection of Anti-VEGF

Three guidelines^17,20,21 offer other recommendations for the intravitreal injection anti-VEGF procedure.

One guideline²⁰ advises administering anti-VEGF injections with caution in patients with recent systemic vascular events, such as stroke or myocardial infarction, after appropriate consultation with a health care provider. Although the guideline does not recommend bilateral injection, surgeons can perform it at their discretion. The guideline emphasizes the use of separate equipment for each eye, such as gloves and surgical preps.²⁰ The guideline recommends using a 29-gauge or 30-gauge needle for injections and avoiding postinjection antibiotics.²⁰ Clinicians should perform the injections between the horizontal and vertical rectus muscles at the pars plana (3 mm to 4 mm posterior to the limbus).²⁰ Additionally, the guideline suggests that clinicians monitor for rare retinal detachment risk after each injection, particularly in patients with myopia.²⁰ The guideline authors did not clearly present the strengths of recommendation and the supporting evidence.²⁰

According to the NICE guideline,²¹ administering intraocular injections requires trained health care professionals like ophthalmologists, nurse practitioners, optometrists, and experienced technicians. If a person without medical qualifications is administering the injection, it is important to have plans and resources in place to manage any potential complications.²¹ However, the strength of recommendations and the supporting evidence were unclear.

Limitations

We have identified 5 evidence-based guidelines for the use of anti-VEGF drugs in treating wet AMD in adults.^17-21 However, most of these guidelines have serious limitations, as detailed in the critical appraisal summary section. In these guidelines, unclear reporting in evidence synthesis and recommendation development is a significant issue for 3^17,18,20 of the 5 included guidelines. Specifically, although all included guidelines claimed they conducted the literature search and consensus process, the literature review process and the links between supporting evidence and recommendations were often unclear. The supporting evidence for certain recommendations was either unclear or based solely on expert consensus.^17-21 Therefore, we need to interpret these recommendations with caution.

There were inconsistencies in some of the recommendations. For instance, 1 guideline suggests a minimum of 2 injections at monthly intervals during the initial phase,¹⁷ while another guideline recommends 3 consecutive injections at same injection intervals.¹⁸ Given that the links between the recommendations and the supporting evidence were unclear, it is challenging to determine which recommendation is more reasonable.

We identified some gaps between the available evidence and guideline recommendations. None of the existing guidelines provided recommendations for the newly approved anti-VEGF drug faricimab (approved in 2022 by Health Canada), and only 1 guideline¹⁹ included evidence for brolucizumab (approved in 2020 by Health Canada). We did not find any specific recommendations for these 2 anti-VEGF drugs. To ensure that the latest available evidence is considered, an updated evidence-based guideline on all anti-VEGF drugs for wet AMD is needed.

Additionally, we did not find evidence-based guidelines from Canada. In the included 5 guidelines, the guideline panel members were from European¹⁷ and Asia-Pacific countries,¹⁸ the US,¹⁹ Iran,²⁰ and the UK,²¹ while no panel members were from a Canadian institution. Thus, the generalizability of the findings to settings in Canada was unclear.

Conclusions and Implications for Decision- or Policy-Making

We included 5 evidence-based guidelines,^17-21 including guidelines from NICE and the American Academy of Ophthalmology, in this report.

Three guidelines^17,19,21 provided recommendations regarding measures to diagnose wet AMD, as a preliminary step to pursuing treatment with anti-VEGF drugs. For individuals presenting with visual changes (including micropsia and metamorphopsia) or disturbances, the NICE guidelines strongly recommend fundus examination.²¹ Three guidelines^17,19,21 recommend OCT for patients with suspected wet AMD. The NICE guideline²¹ strongly recommends the use of OCT: if OCT does not exclude neovascular disease, then FFA is strongly recommended, while if clinical examination and OCT exclude neovascularization, then the guideline strongly recommends against offering FFA to people with suspected wet active AMD.

All included guidelines recommended antivascular drugs for wet AMD in adults, particularly for the affected eyes with the following conditions: the BCVA is between 6/12 and 6/96; there is no permanent structural damage to the central fovea; the lesion size is less than or equal to 12 disc areas in greatest linear dimension; or there is evidence of recent disease progression (blood vessel growth, as indicated by fluorescein angiography, or recent visual acuity changes). For eyes with wet active AMD and visual acuity of 6/96 or worse, NICE provides a weak recommendation for anti-VEGF only if a benefit in the person's overall visual function is expected; for eyes with wet active AMD and visual acuity better than 6/12, anti-VEGF is effective.²¹ One guideline¹⁷ suggests that anti-VEGF drugs should be initiated as soon as possible once the diagnosis of wet AMD is made. For the initial phase of using anti-VEGF drugs, 1 guideline¹⁷ suggests a minimum of 2 injections, while the other guideline recommends¹⁸ at least 3 consecutive injections at monthly intervals at same injection intervals.

The NICE guideline²¹ noted that there are no clinically significant distinctions in the effectiveness and safety of various anti-VEGF treatments, including aflibercept, bevacizumab, and ranibizumab. This recommendation is considered weak due to moderate-quality evidence and did not involve the evidence assessment for faricimab and brolucizumab. They recommend considering either ranibizumab or aflibercept as a treatment option for wet AMD, in accordance with their marketing authorizations, and highlight that the recommendation requires that the manufacturer offer these medications with the agreed-upon discount.²¹ Similarly, 1 guideline¹⁹ does not recommend a specific treatment option, and emphasizes that physicians and patients should discuss and choose an individualized anti-VEGF drug. In contrast, 1 guideline²⁰ suggests using bevacizumab to improve visual acuity in patients with active wet AMD and coexisting RPE, although the recommendation's strength is unclear (evidence level III).

During the maintenance phase of using anti-VEGF drugs, it is important to closely monitor the patient's response and the disease activity. The injection intervals could be adjusted by following a T and E regimen plan, according to 2 guidelines.^17,18 The intervals for anti-VEGF injections should be adjusted based on disease activity: shortened intervals when activity is present, and extended intervals when no disease activity is observed. The NICE guideline strongly recommends close monitoring of individuals with wet active AMD in both eyes using OCT.²¹ For patients with normal OCT but a decline in visual acuity or function, the guideline strongly recommends a fundus examination or colour photography.²¹

The included guidelines^17-21 recommend taking an individualized approach and emphasizing active patient involvement in switching and discontinuing anti-VEGF drugs for adults with wet AMD. The NICE guideline suggests that switching anti-VEGF drugs may have limited clinical benefits and should only be considered for practical reasons, such as patient preference. If a decision is made to switch, it may be necessary to go through a new initiation phase.¹⁷ The evidence for discontinuing anti-VEGF drugs is limited, and the strength of recommendations is unclear or weak. Careful patient discussion can lead to the consideration of discontinuation, especially for those treated at 16-week intervals and having stable, inactive disease.^18,21

Two guidelines provided recommendations related to the intravitreal injection procedure for anti-VEGF drugs. According to the NICE guideline,²¹ intraocular injections should be administered by trained health care professionals, such as ophthalmologists or nurse practitioners. One guideline²⁰ suggests cautious administration in cases of recent systemic vascular issues, employing 29-gauge or 30-gauge needles, and avoiding postinjection antibiotics. They recommend injecting between rectus muscles, and monitoring for rare retinal detachment risk, particularly in patients with myopia.²⁰

Guidelines or guidance documents that were considered as non–evidence-based^22-27 for the purposes of this Rapid Review still provided recommendations that were generally consistent with the evidence-based guidelines that were included. The Ministry of Health Singapore suggests using ranibizumab as an alternative to bevacizumab for treating visual impairment due to wet AMD in adults.²⁴ This non–evidence-based guideline did not conduct a literature search as part of its methods. Two NICE technology appraisal guidance papers,^22,26 based on manufacturer-submitted evidence, recommended the newly approved anti-VEGF drugs faricimab or brolucizumab as options for treating wet AMD in adults with similar situations as bevacizumab and aflibercept, including specific discount agreement. Two expert consensus papers from Taiwan^23,25 and 1 recommendation paper²⁷ for a UK expert panel provided recommendations for a T and E approach for using anti-VEGF drugs. The consensus papers^23,25,27 suggested adjusting injection intervals based on monitoring disease activity or visual function after the loading phase, and recommended initiating a loading phase of 3 consecutive monthly anti-VEGF injections. The suggested frequency is consistent with 1 of the included guidelines.¹⁸

Appendix 5 presents additional details regarding the relevant guidelines with alternative or unclear methodology.

The included guidelines^17-21 used various guideline development frameworks or processes to develop recommendations, resulting in challenges in summarizing and interpreting the recommendations. Although it can be easy to find key recommendations, distinguishing between additional recommendation and nonrecommendation statements can be challenging in 3 guidelines.^17-19 Future guideline development research should prioritize transparency by clearly linking evidence to recommendations and indicating the strength of recommendations. A consistent framework or strict adherence to reporting guidelines may be helpful for guideline users and decision-makers. Evidence-based guidelines with comprehensive literature searches are required to guide use or policy-making regarding the most recently approved anti-VEGF drugs, including faricimab and brolucizumab.

References

1.Stahl A. The diagnosis and treatment of age-related macular degeneration. Dtsch Arztebl Int. 2020;117(29-30):513-520. PubMed

2.Joachim N, Colijn JM, Kifley A, et al. Five-year progression of unilateral age-related macular degeneration to bilateral involvement: The Three Continent AMD Consortium report. Br J Ophthalmol. 2017;101(9):1185-1192. PubMed

3.Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration. Med Clin North Am. 2021;105(3):473-491. PubMed

4.Heesterbeek TJ, Lores-Motta L, Hoyng CB, Lechanteur YTE, den Hollander AI. Risk factors for progression of age-related macular degeneration. Ophthalmic Physiol Opt. 2020;40(2):140-170. PubMed

5.Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: A review. Clin Interv Aging. 2017;12:1313-1330. PubMed

6.Flores R, Carneiro A, Vieira M, Tenreiro S, Seabra MC. Age-related macular degeneration: Pathophysiology, management, and future perspectives. Ophthalmologica. 2021;244(6):495-511. PubMed

7.Nicolo M, Ferro Desideri L, Vagge A, Traverso CE. Faricimab: An investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert Opin Investig Drugs. 2021;30(3):193-200. PubMed

8.Stanga PE, Valentin-Bravo FJ, Stanga SEF, Reinstein UI, Pastor-Idoate S, Downes SM. Faricimab in neovascular AMD: First report of real-world outcomes in an independent retina clinic. Eye (Lond). 2023;37(15):3282-3289. PubMed

9.CADTH reimbursement recommendation: Faricimab (Vabysmo). Can J Health Technol. 2022;2(8). https://www.cadth.ca/sites/default/files/DRR/2022/SR0719REC-Vabysmo.pdf. Accessed 2023 Sep 28.

10.Meer EA, Oh DH, Brodie FL. Time and distance cost of longer acting anti-VEGF therapies for macular degeneration: Contributions to drug cost comparisons. Clin Ophthalmol. 2022;16:4273-4279. PubMed

11.Khanani AM, Thomas MJ, Aziz AA, et al. Review of gene therapies for age-related macular degeneration. Eye (Lond). 2022;36(2):303-311. PubMed

12.Cruess AF, Berger A, Colleaux K, et al. Canadian expert consensus: Optimal treatment of neovascular age-related macular degeneration. Can J Ophthalmol. 2012;47(3):227-235. PubMed

13.Wysong A, Lee PP, Sloan FA. Longitudinal incidence of adverse outcomes of age-related macular degeneration. Arch Ophthalmol. 2009;127(3):320-327. PubMed

14.Cruess A, Zlateva G, Xu X, Rochon S. Burden of illness of neovascular age-related macular degeneration in Canada. Can J Ophthalmol. 2007;42(6):836-843. PubMed

15.Agree Next Steps C. The AGREE II Instrument. [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf.

16.Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1-e34. PubMed

17.Kodjikian L, Parravano M, Clemens A, et al. Fluid as a critical biomarker in neovascular age-related macular degeneration management: Literature review and consensus recommendations. Eye (Lond). 2021;35(8):2119-2135. PubMed

18.Chaikitmongkol V, Sagong M, Lai TYY, et al. Treat-and-extend regimens for the management of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy: Consensus and recommendations from the Asia-Pacific Vitreo-Retina Society. Asia Pac J Ophthalmol (Phila). 2021;10(6):507-518. PubMed

19.Flaxel CJ, Adelman RA, Bailey ST, et al. Age-Related Macular Degeneration Preferred Practice Pattern®. Ophthalmology. 2020;127(1):P1-P65. PubMed

20.Nikkhah H, Karimi S, Ahmadieh H, et al. Intravitreal injection of anti-vascular endothelial growth factor agents for ocular vascular diseases: Clinical practice guideline. J Ophthalmic Vis Res. 2018;13(2):158-169. PubMed

21.National Institute for Health and Care Excellence. Age-related macular degeneration (NICE guideline NG82). 2018; https://www.nice.org.uk/guidance/ng82. Accessed 2023 Sep 9.

22.National Institute for Health and Care Excellence. Faricimab for treating wet age-related macular degeneration (Technology appraisal guidance TA800). 2022; https://www.nice.org.uk/guidance/ta800. Accessed 2023 Sep 10.

23.Cheng CK, Chen SJ, Chen JT, et al. Optimal approaches and criteria to treat-and-extend regimen implementation for neovascular age-related macular degeneration: Experts consensus in Taiwan. BMC Ophthalmol. 2022;22(1):25. PubMed

24.Agency for Care Effectiveness (ACE). Ranibizumab for treating age-related macular degeneration, diabetic macular oedema and retinal vein occlusion. 2022; https://www.ace-hta.gov.sg/healthcare-professionals/ace-technology-guidances/details/ranibizumab-for-treating-age-related-macular-degeneration-diabetic-macular-oedema-and-retinal-vein-occlusion. Accessed 2023 Sep 9.

25.Yeung L, Hsieh YT, Yang CH, et al. Management of neovascular age-related macular degeneration: Taiwan expert consensus. J Formos Med Assoc. 2021;120(12):2061-2071. PubMed

26.National Institute for Health and Care Excellence. Brolucizumab for treating wet age-related macular degeneration (Technology appraisal guidance TA672). 2021; https://www.nice.org.uk/guidance/ta672. Accessed 2023 Sep 10.

27.Ross AH, Downey L, Devonport H, et al. Recommendations by a UK expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration. Eye (Lond). 2020;34(10):1825-1834. PubMed

Appendix 1: Selection of Included Studies

Figure 1: Selection of Included Studies

Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Guidelines

AMD = age-related macular degeneration; GRADE = Grading of Recommendations Assessment, Development and Evaluation; nAMD = neovascular age-related macular degeneration; NICE = National Institute for Health and Care Excellence; OCT = optical coherence tomography; QoL = quality of life; RCT = randomized controlled trial; SIGN = Scottish Intercollegiate Guideline Network; T and E = treat-and-extend; VEGF = vascular endothelial growth factor.

Note that this table has not been copy-edited.

Appendix 3: Critical Appraisal of Included Publications

Table 3: Strengths and Limitations of Guidelines Using AGREE II¹⁵

NICE = National Institute for Health and Care Excellence.

Note that this table has not been copy-edited.

Appendix 4: Main Study Findings

Note that this appendix has not been copy-edited.

Table 4: Summary of Recommendations in Included Guidelines

AMD = age-related macular degeneration; CI = confidence interval; CMT = central macular thickness; CNV = choroidal neovascularization; FDA = US FDA; IRF = intraretinal fluid; IVB = intravitreal bevacizumab; IVR = intravitreal ranibizumab; MD = mean difference; MNV= macular neovascularization; nAMD = neovascular age-related macular degeneration; NEI-VFQ-25 = National Eye Institute 25-Item Visual Function Questionnaire; NICE = National Institute for Health and Care Excellence; NR = not reported; OCT = optical coherence tomography; PCV = polypoidal choroidal vasculopathy; RCT = randomized controlled trial; RPE = subretinal pigment epithelium; RR = risk ratio; RRD = rhegmatogenous retinal detachment; PRN = pro re nata; SRF = subretinal fluid; T&E = treat-and-extend; VEGF = vascular endothelial growth factor.

Appendix 5: Other Relevant Guidelines with Alternative or Unclear Methodology

Note that this appendix has not been copy-edited.

Description

We have compiled recommendations from guidelines or guidance documents that are considered non–evidence-based, as identified in our literature search. The development methods of these guidelines were either unclear or used nonsystematic methods (alternative methodology). These publications were not critically appraised using AGREE II.¹⁵ Refer to Table 5 for more information on the Characteristics of Guidelines with Alternative or Unclear Methodology.

The Ministry of Health Singapore suggests using ranibizumab as an alternative to bevacizumab for treating visual impairment due to wet AMD in adults.²⁴ The certainty of supporting evidence and the strength of the recommendation are unclear. Two NICE technology appraisal guidance papers^22,26 recommended the newly approved anti-VEGF drugs, faricimab or brolucizumab, as potions for treating wet AMD in adults with similar situations as bevacizumab and aflibercept only if, the best-corrected visual acuity is between 6/12 and 6/96; there is no permanent structural damage to the central fovea; the lesion size is 12 disc areas or less in greatest linear dimension, there is recent presumed disease progression (for example, blood vessel growth, as shown by fluorescein angiography, or recent visual acuity changes), and the manufacturer provides these drugs according to the commercial arrangement with confidential discount. Two expert consensus papers from Taiwan^23,25 and 1 recommendation paper²⁷ for a UK expert panel provided recommendations for a treat-and-extend (T and E) approach using anti-VEGF drugs. The consensus papers^23,25,27 recommend initiating a loading phase of 3 consecutive monthly anti-VEGF injections, followed by adjusting the injection intervals based on monitoring disease activity or visual functions. Table 6 presents the Summary of Recommendations from Guidelines with Alternative or Unclear Methodology.

Table 5: Characteristics of Guidelines with Alternative or Unclear Methodology

AMD = age-related macular degeneration; nAMD = neovascular age-related macular degeneration; NICE = National Institute for Health and Care Excellence; NR = not reported; RCT = randomized controlled trial; T and E = treat-and-extend; VEGF = vascular endothelial growth factor.

Table 6: Summary of Recommendations From Guidelines With Alternative or Unclear Methodology

AMD = age-related macular degeneration; BCVA = best-corrected visual acuity; CRT = central retinal thickness; ETDRS = Early Treatment Diabetic Retinopathy Study; HF = hyperreflective foci; IRF = intraretinal fluid; nAMD = neovascular age-related macular degeneration; NICE = National Institute for Health and Care Excellence; NV = neovascular; OCT = optical coherence tomography; PED = pigment epithelial detachment; PRN = pro re nata; SHRM = subretinal hyperreflective material; SRF = subretinal fluid; sub-RPE = subretinal pigment epithelium; T and E = treat-and-extend; VEGF = vascular endothelial growth factor.

Appendix 6: References of Potential Interest

Note that this appendix has not been copy-edited.

Systematic Reviews of Clinical Practice Guidelines

Han X, Chen Y, Gordon I, et al. A systematic review of clinical practice guidelines for age-related macular degeneration. Ophthalmic Epidemiol. 2023;30(3):213-220. PubMed

Additional References

Editorial

Sivaprasad S, Barnes B, Barrett T, et al. The Royal College of Ophthalmologists Commissioning guidelines on age macular degeneration: Executive summary. Eye (Basingstoke). 2022;36(11):2078-2083. PubMed

Tuuminen R, Sipilä R, Komulainen J, Saarela V, Kaarniranta K, Tuulonen A. The first ophthalmic Choosing Wisely recommendations in Finland for glaucoma and wet age-related macular degeneration. Acta Ophthalmol. 2019;97(5):e808-e810. PubMed

Guidance Paper for Administrating Brolucizumab in Unclear Population

Fonollosa A, Gallego-Pinazo R, Sararols L, Adán A, López-Gálvez M, Figueroa MS. Guidance on brolucizumab management recommendations. Arch Soc Esp Oftalmol (Engl Ed). 2022:S2173-5794(22)00084-6.

Action Paper Based on Included NICE Guidelines

Gale RP, Mahmood S, Devonport H, et al. Action on neovascular age-related macular degeneration (nAMD): Recommendations for management and service provision in the UK hospital eye service. Eye (Lond). 2019;33(Suppl 1):1-21. PubMed

Publication Excluded for Unclear Recommendation

Amoaku W, Balaskas K, Cudrnak T, et al. Initiation and maintenance of a Treat-and-Extend regimen for ranibizumab therapy in wet age-related macular degeneration: Recommendations from the UK Retinal Outcomes Group. Clin Ophthalmol. 2018;12:1731-1740. PubMed

Liang L-N, Xie L-K, Wu X-W. International clinical practice guideline of Chinese medicine-age-related macular degeneration. World J Tradit Chin Med. 2022;8(4):556-564.

Sadda SR, Guymer R, Holz FG, et al. Consensus definition for atrophy associated with age-related macular degeneration on OCT: Classification of atrophy report 3. Ophthalmology. 2018;125(4):537-548. PubMed

Recommendation for Monitoring the Fellow Eyes in Patients With Wet AMD

Wong TY, Lanzetta P, Bandello F, et al. Current concepts and modalities for monitoring the fellow eye in neovascular age-related macular degeneration: An expert panel consensus. Retina. 2020;40(4):599-611. PubMed