Description of the condition
Age-related macular degeneration (AMD) is a progressive, degenerative disease of the central retina, known as the macula, that can result in central vision loss. It is the leading cause of irreversible vision loss in industrialized countries and the third major cause of blindness globally (Bourne 2014; WHO 2016). The main risk factor for AMD is age (Klein 1992; Leibowitz 1980); other risk factors include cigarette smoking, Caucasian race, and genetic variation (Christen 1996; Evans 2005; Friedman 1999; Friedman 2004; Miller 2013; Seddon 1996; Swaroop 2007). There are two main forms of AMD: non-neovascular, known as 'dry' or 'non-exudative,' and neovascular, known as 'wet' or 'exudative,' types.
This review will focus on neovascular AMD (nAMD). Approximately 20% of dry AMD cases transform to exudative disease through development of choroidal neovascularization (CNV), the abnormal proliferation of blood vessels in the inner choroid layer (AAO 2010). Defects in Bruch's membrane and the retinal pigment epithelium (RPE) enable extension of choroidal blood vessels into the sub-pigment epithelial space and eventually the subretinal space. Leakage or bleeding from these vessels causes exudative or hemorrhagic retinal detachments, triggering fibrosis. The resulting scarred retina has significantly decreased visual capacity (AAO 2010; Solomon 2014).
Fluorescein angiography (FA) findings are the gold standard for diagnosing CNV. Fluorescein dye is injected into a vein and travels into the eye; characteristic patterns of hyperfluorescence and hypofluorescence outline pathology. CNV diagnosis is supported by hyperfluorescent lesions in the macula that increase in intensity and size over time. Another useful nAMD imaging modality is spectrum-domain optical coherence tomography (OCT), which provides cross-sectional views of the layers of the retina that are especially useful for monitoring disease and evaluating treatment response (AAO 2015).
CNV represents pathologic angiogenesis, the development of new capillaries, in the choroid. In nAMD, chronic exposure to hypoxia, ischemia, and/or inflammation tips the balance between angioinhibitors and angioactivators toward the formation of new blood vessels (Bressler 2009; Gunda 2013). The natural progression of nAMD without effective treatment eventually results in an end-stage subretinal disciform scar and loss of vision.
Description of the intervention
The current mainstay treatment for nAMD is intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. VEGF is an endothelial cell-specific mitogen that promotes the proliferation of new vessels and increased vascular permeability (Ferrara 2004). It is upregulated in nAMD and is a key factor in the pathogenesis of CNV. Anti-VEGF agents, including ranibizumab, bevacizumab, and aflibercept, target this angioactivator in their treatment of nAMD (Bressler 2009; Ferrara 2004; Gunda 2013).
Ranibizumab, a monoclonal antibody fragment against VEGF-A, was approved by the United States Food and Drug Administration (FDA) for the treatment of nAMD in 2006. Its efficacy and safety were demonstrated in two pivotal trials, ANCHOR and MARINA (ANCHOR 2009; MARINA 2006). Bevacizumab, a monoclonal antibody against VEGF-A, has been used alongside ranibizumab as a cheaper anti-VEGF alternative. Although it is FDA approved only for the treatment of colorectal cancer, non-small cell lung cancer, cervical cancer, glioblastoma, and renal cell carcinoma, it is used off-label to treat nAMD. Several trials have demonstrated comparable efficacies and safeties between these two anti-VEGF agents (CATT 2012; GEFAL 2013; IVAN 2012; MANTA 2013; Moja 2014; Solomon 2014). However, the marketed dosage of bevacizumab is too large for use in the eye. The appropriate dose of bevacizumab for intravitreal injection has to be compounded by pharmacies, which introduces contamination risk. Its use in the eye is not regulated by the FDA. A third anti-VEGF intravitreal agent, aflibercept, was approved by the FDA in 2011 for the treatment of nAMD. It is a decoy receptor that blocks VEGF-A, VEGF-B, and placental growth factor (PIGF). VIEW 1 and VIEW 2 trials demonstrated the non-inferiority of aflibercept efficacy when compared to ranibizumab (Sarwar 2016; VIEW 2012).
The first FDA approved anti-VEGF drug, pegaptanib (VISION 2006), is no longer in use because of the better visual acuity results from ranibizumab, bevacizumab, and aflibercept (Sarwar 2016; Solomon 2014). Photodynamic therapy (PDT) decreases rates of visual loss from subfoveal nAMD and still has clinical application in rare cases (TAP 2001; VIP 2001; Wormald 2007; Yonekawa 2015). Our review will focus on treatment regimens using ranibizumab, bevacizumab, and aflibercept intravitreal injections.
There is currently no standard regimen for injection frequency after the initial three monthly loading doses. Ophthalmologists administer anti-VEGF injections at frequencies that vary based on physician practice and individual cases after the first three injections. Intravitreal injections of ranibizumab were administered monthly in the MARINA and ANCHOR trials (ANCHOR 2009; MARINA 2006). With a higher binding affinity and thus longer therapy window than ranibizumab, aflibercept's non-inferior effects were demonstrated with bimonthly injections after three initial monthly loading doses (VIEW 2012).
Additional studies have investigated ranibizumab, bevacizumab, and aflibercept efficacy using a variety of monthly and non-monthly injection regimens. Non-monthly dosing has included: loading doses (monthly for the first three months) followed by as needed, every eight weeks, quarterly, crossover from monthly to as needed, or formula-based (that is treat-and-extend protocol) (Abedi 2014; CATT 2012; CLEAR-IT 2 2011; EXCITE 2011; HARBOR 2014; IVAN 2012; PIER 2010; PrONTO 2009; SECURE 2013; SUSTAIN 2011; VIEW 2012). Although all investigations have supported the use of anti-VEGF agents, it is unclear which dosing regimen is superior with respect to efficacy and safety.
The ideal treatment protocol would minimize the number of injections in order to decrease side effects and maximize therapeutic outcomes. The potential side effects are rare but may have serious consequences for vision from the procedure and the drug itself. Serious risks from the injection process include endophthalmitis, retinal hemorrhage, retinal detachment, RPE detachment, retinal edema, and vitreous detachment (CATT 2012; CLEAR-IT 2 2011). Potential adverse drug events include systemic arterial thromboembolic events such as myocardial infarction and cerebral vascular accident (CATT 2012). Although Solomon et al found the occurrence of systemic adverse events to be comparable across anti-VEGF and control groups and between ranibizumab and bevacizumab when given the same injections schedules, the number of participants in the trials included in their review may have been insufficient to detect meaningful differences in adverse events (Solomon 2014). Furthermore, their review did not compare dosing regimens. Inclusion of more studies in our review may reveal other adverse systemic effects of individual anti-VEGF agents in addition to those risks posed by the injection procedure.
Delivering injections more frequently than therapeutically required also imposes an unnecessary cost burden on individuals and on national healthcare systems. Our intervention aims to evaluate the current literature to compare non-monthly with monthly injection regimens to identify the optimal anti-VEGF injection schedule for people with nAMD among those that have been implemented and reported to date.
How the intervention might work
Pivotal anti-VEGF studies followed monthly injection regimens to investigate drug efficacy. Initial trials of ranibizumab, bevacizumab, and aflibercept used monthly administration of the drugs (ANCHOR 2009; CATT 2012; CLEAR-IT 2 2011; IVAN 2012; MARINA 2006). Mean change of best-corrected visual acuity (BCVA) after two years was +8.1, +7.8, and +9 for monthly 0.5 mg ranibizumab, 1.25 mg bevacizumab, and 2.0 mg aflibercept, respectively (ANCHOR 2009; CATT 2012; CLEAR-IT 2 2011).
Subsequent studies have investigated ranibizumab, bevacizumab, and aflibercept efficacy using a variety of monthly and non-monthly injection regimens. The VIEW trials compared bimonthly injection of aflibercept 2.0 mg after three initial monthly doses with monthly injections. Results demonstrated comparable effects on BCVA due to aflibercept's longer therapy window than ranibizumab (CLEAR-IT 2 2011; VIEW 2012; Yonekawa 2015). Trials also have investigated as needed, quarterly, crossover from monthly to as needed, and formula-based (that is treat-and-extend protocol) dosing regimens. Effects on BCVA from these studies have been mixed (Abedi 2014; CATT 2012; CLEAR-IT 2 2011; EXCITE 2011; HARBOR 2014; IVAN 2012; PIER 2010; PrONTO 2009; SECURE 2013; SUSTAIN 2011; VIEW 2012). Schmucker et al performed a systematic review and meta-analysis of injections as required versus monthly injections of anti-VEGF in 2015; the review and meta-analysis, which included reports from three studies with more than 2000 participants (CATT 2012; HARBOR 2014; IVAN 2012), found that those on as-needed treatment had slightly but statistically significantly worse BCVA and an increased risk of systemic adverse events compared to those given monthly injections (Schmucker 2015). As their findings were based on only three studies, it is not known which dosing regimen satisfies therapeutic standards while minimizing injection frequency to eliminate unnecessary risk of adverse events and to control cost.
Why it is important to do this review
Although nAMD is less prevalent than non-exudative disease, it accounts for 80% of severe vision loss due to AMD (worse than 20/200 Snellen acuity) (Leibowitz 1980). Risk factors for conversion from non-exudative AMD to nAMD include a decrease in visual acuity to less than or equal to 75 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from a baseline of more than 85 letters and older age (Friberg 2012).
As global populations age, the number of individuals affected by AMD is expected to rise. Approximately 1.25 million individuals with nAMD were reported in the USA in 2004. By 2020, the prevalence of nAMD is expected to increase to an estimated 1.875 million cases (Friedman 2004). AMD imposes a significant decrement in patients' quality of life, with the impact from severe AMD likened to that of end-stage cancer or a stroke requiring constant nursing care (Brown 2006). Several studies have suggested AMD as a risk factor for depression, a major cause of disability (Casten 2004). Thirty percent of people with AMD have depression, compared with 15% of adults aged 65 years and older who have clinically significant depressive symptoms in the USA and internationally (Casten 2004; Fiske 2009). Neovascular AMD not only has negative effects on individual patients, but also has negative social and economic consequences. Using utility analysis, researchers have estimated a gross domestic product (GDP) cost of USD 5.396 billion per year due to lost productivity (Brown 2005).
Previous Cochrane reviews have investigated and demonstrated the efficacy and safety of intravitreal anti-VEGF agents for the treatment of nAMD (Solomon 2014). However, ever-growing burdens on the patient and healthcare systems necessitate cost-effective therapies for nAMD. It remains unknown which treatment schedule is optimal when balancing efficacy, safety, and cost.