Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview.

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Review

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Introduction

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Molecular and biological mechanism of VEGF function

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VEGF agents: intravitreal use in ophthalmology

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Systemic activity of anti-VEGF Therapeutic profile and systemic safety of anti-VEGF agents

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Discussion

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Conclusion

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Expert opinion

Francesco Semeraro, Francesco Morescalchi, Sarah Duse†, Elena Gambicorti, Mario R Romano & Ciro Costagliola †

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Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration: an overview University of Brescia, Spedali Civili di Brescia, Radiological Specialties and Public Health, Ophthalmology Clinic, Department of Medical and Surgical Specialties, Brescia, Italy

Introduction: Anti-VEGF therapy improved the quality of life for millions of patients suffering from wet age-related macular degeneration (wet-AMD); unfortunately, this therapy involves multiple injections over many years. The administration of anti-VEGF can overcome the blood-retinal barrier with agents entering the systemic circulation and causing a significant decrease in VEGF serum concentration. Although circulating VEGF protects the integrity and patency of vessels, prolonged anti-VEGF treatment has the potential to increase the risk of thromboembolic events. Areas covered: In this review, we discuss the safety data from recent trials involving available anti-VEGF drugs. Expert opinion: During the 2 years of follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients treated with different anti-VEGF drugs. Moreover the arterial thrombotic risk appears sufficiently low when compared with the natural incidence of arterial thrombotic events in this category of elderly patients and acceptably balanced against the advantage of improved vision. Since the use of these drugs is likely to become increasingly widespread and prolonged, it is desirable that the scientific community improves the pharmacovigilance program on all anti-VEGF drugs, expanding knowledge with studies that compares head to head all four compounds belonging to anti-VEGF armamentarium. Keywords: aflibercept, age-related macular degeneration, anti-VEGF, bevacizumab, hypertension, myocardial infarction, pegaptanib, ranibizumab, side effects, stroke Expert Opin. Drug Saf. (2014) 13(6):785-802

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Introduction

Neovascularization is a sight-threatening event characteristic of wet age-related macular degeneration (wet AMD) that causes a progressive and irreversible distortion and blurring of central vision, dramatically affecting the quality of life. Uncontrolled expression of VEGF in retinal tissue leads to growth of new blood vessels that are characterized by fragility and propensity to exudation; this pathological mechanism is involved in development and progression of wet AMD. The strategy of care for wet AMD has recently been revolutionized by the introduction of intravitreal injection of anti-VEGF agents [1]. On 30 June 2006, US FDA approved ranibizumab (Lucentis; Genentech, South San Francisco, CA, USA) for the treatment of exudative AMD [2]. Two years 10.1517/14740338.2014.911284 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Anti-VEGF agents represent a turning point in the treatment of age-related macular degeneration in terms of efficacy. The arterial thrombotic risk appears sufficiently low compared with the natural incidence of arterial thrombotic events in elderly patients, and acceptably balanced against the advantage of improved vision. Rates of serious cardiovascular adverse events were similar in patients treated with different anti-VEGF drugs. All patients undergoing treatment with anti-VEGF agents, however, require long-term general monitoring.

This box summarizes key points contained in the article.

earlier, the parent compound bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA) was approved for use in the treatment of metastatic colon cancer [3], with a large number of patients now receiving this drug off-label for exudative AMD. The work of Ferrara et al., along with other research groups, is revolutionizing the treatment options and drastically improving the quality of life for millions of patients suffering from exudative AMD. Worldwide, approximately one million patients have already received treatment with anti-VEGF antibodies [4]. A great number of others patients are likely to benefit from anti-VEGF treatments in the coming decades, as the frequency of the disease increases due to the aging of the world population. Currently, three anti-VEGF agents have been approved by FDA for the treatment of wet AMD: pegaptanib (Macugen; Eyetech, Inc., FL/ Pfizer, Inc., NY, USA), ranibizumab (Lucentis) and aflibercept (Eylea, Regeneron, Tarrytown, NY, USA; Bayer, Basel, Switzerland). A fourth drug, bevacizumab, also appears to be effective in treating maculopathy, but can only be used off-label at this time (Table 1). The rationale for using VEGF inhibitors in the treatment of wet AMD is based on the assumption that choroidal neovascularization (CNV) can be suppressed without adversely affecting other vessels. Unlike CNV, which requires VEGF as a survival factor, the maintenance, tissue stability and physiological function of normal ocular and systemic vasculature are believed to be largely independent of VEGF [5]. Furthermore, intraocular administration of VEGF inhibitors reduces the required dose and limits the diffusion of treatment agents into the systemic circulation. Assertions of VEGF efficacy and safety have been validated by a number of clinical studies showing intraocular VEGF inhibitor administration to elicit robust suppression of all types of intraocular neovascularizations, with infrequent serious side events. The main disadvantage of these compounds, however, is their short duration of action, necessitating repeated injections over an indefinite period of time. Therefore, the increasing clinical use of anti-VEGF treatments in recent years increases the risk of a 786

prolonged systemic inhibition of VEGF, with possible adverse consequences. The systemic use of anti-VEGF agents like bevacizumab has been associated with an increased risk of hypertension, stroke and myocardial infarction with congestive heart failure. It is not completely clear whether this risk of systemic adverse events is also associated with low doses used in the treatment of wet AMD. The collateral systemic complications are probably related to the intrinsic properties of VEGF. Physiologically, VEGF acts in response to hypoxia to promote vascular repair. The problem of thromboembolic events could become significant when the intraocular injections are performed frequently in the same patient to treat wet AMD or diabetic retinopathy. These ophthalmological conditions are specific for patients that are already at an elevated risk of cardiovascular and cerebrovascular events. Several approved expensive anti-VEGF drugs, including ranibizumab and aflibercept, have become a part of everyday ophthalmological practice. The necessity to prolong the anti-VEGF therapy for years in treating these long-term ocular degenerative conditions is greatly increasing the number of patients who are undergoing treatment with these drugs, thus strongly increasing the economic burden on the healthcare system. We have undertaken a review to evaluate the adverse events associated with the use of VEGF inhibitors in the treatment of wet AMD. Additionally, our review aims to evaluate whether off-label use of bevacizumab is as safe as the use of licensed agents aflibercept or ranibizumab. Finally, we aim to compare the risk of anti-VEGF treatments to determine whether there is sufficient robust evidence to justify offering bevacizumab to patients as a treatment for wet AMD.

Molecular and biological mechanism of VEGF function

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Physiologically, VEGF can play a pathological role, such as in exudative maculopathy, neovascular glaucoma, proliferative diabetic retinopathy, rheumatoid arthritis and cancer [6], and have beneficial effects, such as the promotion of wound healing and cardiac remodeling in adults. VEGF is a growth factor that also exhibits trophic effects on endothelial cells [4]; it promotes angiogenesis and regulates vascular permeability [7,8]. VEGF and its receptors are expressed by a number of ocular cell types, including the cells of the retinal pigment epithelium, endothelial cells, pericytes, glial cells, Mu¨ller cells, ganglion cells and photoreceptors [9-11]. Angiogenesis occurs in response to pathological stimuli such as ischemia [12] or as part of the inflammatory processes, wound healing or tumor formation. Additionally, angiogenesis can also be a part of the homeostatic processes within the tissue, such as the maintenance of the integrity of the cardiovascular system or the growth and maintenance of the ovarian follicle and corpus luteum [13]. Moreover, VEGF is a survival factor for the vascular endothelial cells [14] and inhibits endothelial apoptosis due to serum starvation by blocking

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular AMD

Table 1. Structure, mechanism of action, characteristics and pharmacokinetics of anti-VEGF agents available for the treatment of AMD.


Agent

Structure and mechanism of action

Intravitreal formulation

Characteristics

Pharmacokinetics

PEGAPTANIB Macugen Eyetech Pharmaceuticals FDA approval in 2004

Pegylated aptamer, targeting VEGF-165

ID: 0.3 mg Sterile, solution, single-dose pre-filled syringe

MW: 50 kDa Kd: 49 pmol/l

BEVACIZUMAB Avastin Genentech Off-label use

Humanized monoclonal murine anti--VEGF-A antibody binding all isoforms Recombinant humanized immunoglobulin G1 kappa isotype antibody fragment anti-VEGF-A, targeting all isoforms Fully human, recombinant fusion protein, consisting of portions of human VEGFR1 and VEGFR2 extracellular domains fused to the Fc portion of human IgG1, binding all isomers of the VEGF-A family, VEGF-B and placental growth factor

ID: 1.25 mg Not formuled for intravitreal injection


ID: 0.5 mg or 0.3 mg Sterile, solution, single-use glass vial


T½: 0.5 days Cmax: 0.3 -- 2.5 ng/ml (After a 0.5 mg IV injection)

ID: 2 mg Sterile, aqueous solution single-use glass vial

MW: 115 kDa Kd: 0.49 pmol/l

T½: 5 -- 6 days Cmax: 20 ng/ml (0 -- 54 ng/ml)

RANIBIZUMAB Lucentis Genentech FDA approval in 2006

AFLIBERCEPT Eylea Regeneron Pharmaceutical FDA approval in 2011

T½: 10 days Cmax: 80 ng/ml (After a 3 mg IV injection, 10 times the recommended dose) T½: 20 days Cmax: 59.8 -- 86.5 ng/ml

AMD: Age-related macular degeneration; ID: Intravitreal dose; Kd: Dissociation constant; MW: Molecular weight.

the phosphatidylinositol 3-kinase/Akt-dependent pathway [15]. In vivo, endothelial cells belonging to newly formed vessels were reported to show a strong VEGF dependence, with the coverage of vessels by pericytes identified as an important event associated with the loss of VEGF-A dependence [16,17]. VEGF affects vascular permeability by inducing the formation of pores between endothelial cells and disrupting the intercellular tight junctions, promoting their phosphorylation. Ultimately, the biological outcome of VEGF activity is the extravasation of proteins, fluid and immune cells [18,19]. Evidence indicates that VEGF is also a mediator of tumor angiogenesis [20] and an essential element required for the reperfusion of ischemic myocardial and cerebral tissues after thrombotic accidents [21,22]. It has been demonstrated that intramyocardial injection of VEGF-121 isoform improves myocardial collateral circulation and ameliorates angina in humans [23]. In clinical oncology, VEGF inhibitors were found to predispose treated patients to thrombosis and bleeding by inhibiting the normal turnover of endothelial cells [24]. Anti-VEGF agents elicit changes in both normal and pathologic microvasculature, with fenestrated vessels in particular exhibiting sensitivity to VEGF withdrawal [25,26]. Moreover, anti-VEGF therapy decreases the production of NO and prostaglandin-I2, altering the hematocrit and blood viscosity, increasing the synthesis of erythropoietin, and ultimately

resulting in a destabilization of cholesterol plaques [27-29]. VEGF has many other physiological roles in nervous tissue, such as neurogenesis stimulation and to protect neurons from hypoxia and glutamate toxicity.

VEGF agents: intravitreal use in ophthalmology

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Patients with AMD tend to be older people and have an increased prevalence of stroke, hypertension, myocardial infarction and diabetes compared with patients of similar age without AMD [30,31]. They may also exhibit an elevation in serum VEGF levels, which is a marker of general hypoxia, suggesting that wet AMD could be associated with high cardiovascular risk [32,33]. The standard treatment strategy for the management of wet AMD supported by the randomized clinical trials (RCTs) consists of a monthly injection of ranibizumab and bevacizumab for 2 years, and bimonthly intravitreal injections of aflibercept (after a loading dose of three monthly injections) for 2 years. Such frequent administrations of anti-VEGF agents may be associated with a risk of a chronic pan-VEGF systemic inhibition. Although the monthly injections of anti-VEGF were shown to be the best way to preserve vision, physicians tend to use two alternative treatment approaches, decreasing treatment burden with

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good functional result, the ‘treat and extend’ approach in which the interval between injections are extended until macula remains dry or ‘as needed’ or pro re nata (PRN), meaning ‘as circumstances arise’. The choice to perform a reinjection when treating the patient using PRN strategy depends on the presence of conditions compatible with persistent CNV activity, including central retinal thickness increase of ‡ 100 µm, loss of at least five lines on the visual acuity chart approved by the Early Treatment Diabetic Retinopathy Study, persistent fluid on optical coherence tomography, new onset of classic neovascularization, persistent leakage on fluorescein angiography and presence of new hemorrhage on clinical examination [34-37]. However, most of the patients that underwent the PRN strategy adopted in RCTs also needed to receive a number of intravitreal injections over the 2 consecutive years; for example, in Inhibit VEGF in Age-Related Choroidal Neovascularization (IVAN) study, the PRN group received an average of 13 injections [37]. The anti-VEGF treatment, therefore, should be prolonged beyond the 2-year follow-up to preserve vision. If a sufficient amount of active anti-VEGF drug reaches the circulatory system, it could conceivably lead to a chronic VEGF inhibition throughout the body and cause systemic toxicity.

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Systemic activity of anti-VEGF agents

Physiological levels of VEGF are required to maintain the integrity of the vascular system in particular in response to hypoxia and support its physiological function. Empirical clinical evidence suggests that the systemic suppression of VEGF physiological activity may delay wound healing and cause hypertension, thromboembolic events (stroke and myocardial infarction) and nephrotic syndrome [33,38-40]. Age significantly increases the chance of cardiovascular events such as myocardial ischemia, strokes and thromboembolic accidents. Heart attacks and strokes are important causes of disability and death in industrialized countries [41]. In Italy, 6.5% of the population older than 65 years has experienced a stroke whereas there are 150 cases of myocardial infarction for every 100,000 inhabitants compared with the prevalence of 350/100,000 in the US [42]. Patients affected by wet AMD have an increased prevalence of diabetes, hypertension, myocardial infarction and stroke compared with age- and sex-matched populations without AMD [30,31,33]. The association of wet AMD with high serum VEGF levels and the relationship between VEGF and hypoxia suggest that AMD itself may be a risk factor for cardiovascular accidents [32]. The injection of VEGF inhibitors decreases the systemic VEGF concentration. However, plasma VEGF concentration varies greatly from individual to individual, changes over time in the same individuals and can be altered by the disease states affecting the patient [43,44]. 788

Despite this, there are few studies in the literature that will verify the concentration of VEGF after intravitreal injection of anti-VEGF drug. For example, some studies like the one conducted by Gu et al. state that there are no significant changes in serum concentration of VEGF in the period from 3 to 30 days following a single intravitreal injection of 0.5 mg of ranibizumab. However, it seems that in the first 24 h there is instead a fall in the levels of VEGF that may have influences on the vascular system [45]. The clinical trials comparing bevacizumab and ranibizumab with control subjects or other treatments have not found an increased risk of cardiovascular events in the patients who received anti-VEGF treatment [46-48]. However, by further analyzing the data from the first clinical trials evaluating ranibizumab, Ueta et al. have found an increased risk of cerebrovascular accidents [49]. Many additional studies and meta-analyses conducted by combining the data from various RCTs have yielded results that were at times controversial, but have neither confirmed nor completely ruled out a possibility of a significant increase in cardiovascular risk with ranibizumab therapy. The results of trials comparing bevacizumab and ranibizumab have generally shown no difference in both ocular and systemic adverse effects [50-52]. Although the adverse events examined were rare, some authors did notice that patients treated with VEGF inhibitors were significantly more likely to experience fatal or nonfatal myocardial infarctions compared with the control subjects from the community [51]. The intravenous injection of bevacizumab used in oncology has been shown to cause an increase in blood pressure, eliciting hypertension in patients treated with bevacizumab with 5-FU ranges from 60 to 67%, compared with 43% in controls [53]. The relationship between anti-VEGF drugs and hypertension likely depends on the reduction of NO production and levels, resulting in vasoconstriction. The comorbidity of AMD with hypertension and thromboembolic events could be clinically relevant for patients treated with anti-VEGF compounds. However, a pilot study did not observe an increase in mean blood pressure, heart rate or pulse pressure following intravitreal bevacizumab administration, despite a decrease in serum VEGF that occurred in individual patients [54]. Data on the actual difference in cardiovascular risk profiles between ranibizumab and bevacizumab, however, are available only from six recent randomized multicenter trials not sponsored by pharmaceutical companies. In the next section, we aim to summarize the major published clinical evidences on the systemic safety of anti-VEGF drugs used to date.

Therapeutic profile and systemic safety of anti-VEGF agents

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Ranibizumab Ranibizumab is the most extensively studied drug in widespread use that has been approved by the US FDA for 5.1




the treatment of exudative AMD. The first ranibizumab Phase III multicenter RCTs (the Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular AMD [MARINA] and Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD [ANCHOR] trials) evaluated different treatment strategies, doses and patient populations, achieving good results with monthly injections, with a mean number of intravitreal injection, over 2 years, of 24 and 21.3 in MARINA and ANCHOR trials, respectively [47,55]. Data from the MARINA study have shown that the percentage of arterial thromboembolic events was slightly higher in ranibizumab-treated than in the sham-treated group after 2 years of observation (4.6 vs 3.8%). After a 2-year follow-up, in the ANCHOR clinical trial, arterial thromboembolic events occurred in 5% of patients treated with 0.5 mg of ranibizumab, compared with 4.4% of patients who received 0.3 mg, and 4.2% in the verteporfin photodynamic therapy (PDT) group. The percentages of myocardial infarction and stroke correspond respectively to 1.3 versus 2.5% in MARINA trial and 3.6 versus 0% in ANCHOR trial [50]. After these trials, other studies have tried to demonstrate that flexible, guided dosing with reduced ranibizumab injections and monthly monitoring maintains the efficacy and positive outcomes. In the FOCUS (RhuFab V2 Ocular treatment combining the Use of visudyne to evaluate Safety) study, patients were randomized to receive ranibizumab or sham injections following PDT [56]. In the PIER (Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration) study, 0.5 mg ranibizumab was given quarterly (every 3 months) to 61 patients for 2 years (an average of six injections). Arterial thrombotic events were reported in 3.3% of the patients after 2 years. In this trial, the incidence of death, arterial thrombotic events and serious adverse events was similar in ranibizumab (0.5 mg) and sham-treated arms [57]. In the EXCITE (Efficacy and Safety of Monthly versus Quarterly Ranibizumab Treatment in Neovascular Age-related Macular Degeneration) study, 0.3 mg ranibizumab was administered monthly for 1 year (an average of 11.4 injections) and the outcomes were compared with 0.5 mg ranibizumab given every 3 months (5.5 injections, on average): arterial thrombotic events were reported in 2% of patients. Patients randomized to quarterly dosing showed worse anatomical outcomes (more retinal thickening) compared with patients treated monthly [58]. In the SUSTAIN (Study of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to AgeRelated Macular Degeneration) study, 0.5 mg ranibizumab was administered as needed to 513 patients (mean 5.6 injections over 1 year). Arterial thrombotic events were reported in 3.7% of the patients after 1 year, with a systemic adverse event rate of 14.2% [35]. Approximately 10% of the patients who had a stroke earlier suffered another stroke in the first

12 months following the beginning of therapy, showing that ranibizumab may potentially lead to a small increase in the incidence of stroke [59]. The rate of thrombotic systemic adverse events in the SUSTAIN study was similar to that reported in patients treated with 0.5 mg intravitreal ranibizumab in the MARINA and ANCHOR studies, in which events were reported in 4.6 and 5% of patients, respectively [46,55]. However, direct comparison of the safety data from SUSTAIN and other previously published studies is complicated by the differences in treatment regimens, systems for classification of adverse events, study designs and because the patients enrolled in the SUSTAIN were not treatment-naive [35]. The SAILOR (Safety Assessment of Intravitreal Lucentis for age-related macular degeneration) study was a large Phase IIIb follow-up study to the MARINA and ANCHOR trials that aimed to evaluate the long-term safety and efficacy of ranibizumab in a population of 4300 patients across all subtypes of CNV (predominantly classic, minimally classic, occult without classic). SAILOR included > 5 times as many ranibizumab-treated patients as the MARINA and ANCHOR studies combined [60]. It is the largest multicenter randomized study to date to evaluate the safety and efficacy outcomes of anti-VEGF treatments in wet AMD. Arterial thrombotic events after an average of 4.6 injections were reported in 2.8% of the patients after 1-year follow-up. This study had two cohorts: cohort 1 subjects were randomized to receive 0.3 mg (n = 1169) or 0.5 mg (n = 1209) intravitreal ranibizumab for 3 months as a loading dose; cohort 2 subjects (n = 1922) received an initial intravitreal dose of 0.5 mg ranibizumab and were treated again at the discretion of the physician. Safety was evaluated at all follow-up visits. The incidences of vascular deaths during the 12-month study in the cohort 1 group were 0.9% (0.3 mg dose) and 0.8% (0.5 mg dose), and 0.7% in cohort 2. The rates of individual ocular serious adverse events in both cohorts were < 1%. The number of vascular and unknown causes deaths did not differ across cohorts or dose groups. Stroke rates were 0.7, 1.2 and 0.6% in cohort 1 (0.3 and 0.5 mg dose groups) and cohort 2, respectively. However, in February 2007, FDA critically observed that the rate of stroke in both dose arms of the SAILOR study was lower than the rate presented in the approval studies, suggesting that the study may have underestimated the systemic effects or selected patients in good health and without significant cardiovascular risk [61,62]. An interim analysis of the SAILOR cohort 1 safety data (October 2006) suggested a higher incidence of stroke in subjects who received 0.5 mg ranibizumab compared with those who received 0.3 mg ranibizumab. The final study data showed a difference in the incidence of stroke between the two doses, with a lower rate observed in the 0.3 mg dose group compared with the 0.5 mg dose group. Due to the small total number of events, the difference was not statistically significant, but suggests that there may potentially be a higher incidence of stroke associated with the 0.5 mg dose, and, therefore, it has been monitored via postmarketing surveillance


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and ongoing trials of ranibizumab in neovascular AMD. It was suggested that certain subgroups of subjects (e.g., those with prior cardiovascular accidents) might experience higher rates of systemic adverse events. A meta-analysis of ranibizumab systemic safety, based on a pooling of first-year data from MARINA, ANCHOR, PIER, FOCUS and SAILOR trials and on second-year data from MARINA, ANCHOR, PIER and FOCUS, showed that arterial thromboembolic event rates were similar across treatment groups, although side effects appeared to be slightly more frequent in patients treated with higher ranibizumab doses compared with the controls [63]. These analyses suggested that persons with a history of stroke and in those with arrhythmia, stroke risk was higher in those treated with higher doses of ranibizumab [64,65]. Further analysis of these trials, evaluating the data on 859 subjects treated monthly for 2 years, showed that ranibizumab was associated with a higher incidence of stroke (p = 0.045; OR 3.24; 95% CI 0.96 -- 10.95), whereas there was no apparent association with the incidence of myocardial infarction (p = 0.193) [49]. Therefore, the intracranial vasculature appears to be more sensitive than the cardiac circulation, with even a small amount of ranibizumab injected into the vitreous body increasing the risk of adverse event. HORIZON (an Open-Label extension Trial of Ranibizumab secondary to wet-AMD) trial is a 2-year extension study on a select but potentially biased group of patients who completed a 2-year follow-up after MARINA, ANCHOR and FOCUS trials. The treatment was administered at the investigator’s discretion (a mean of 4.4 more injections per patient was performed). The aim of the study was to explore the effects of ranibizumab after 2 years of treatment. A total of 84 patients completed 2 years of follow-up, providing data on 4 -- 5 years of ranibizumab treatment. The results showed a decline in vision (mean -7 letters along the follow-up) after the reduction of the monthly frequency of the injections. In HORIZON, 5.3% of the patients experienced arterial thromboembolic events [66]. In the SECURE study, ranibizumab was administered according to the treatment strategy commonly adopted in Europe (visual acuity-guided flexible dosing regimen) over a 2-year follow-up period [67,68]. This trial is a Phase IV extension study in which a selection of 210 patients previously included in the EXCITE and SUSTAIN studies were managed for up to 3 years with ranibizumab [35,58]. After further mean 6.1 injections per patient over 2 years (counted separately from the injections received in EXCITE and SUSTAIN trials), arterial thromboembolic events, including hemorrhagic cerebrovascular conditions, myocardial infarction, ischemic cerebrovascular disease, arterial thrombotic and embolic events, were recorded in 5.6% of the patients. Similarly to the HORIZON study, the reduction in the frequency of intravitreal injection caused a decline of vision. Statistically significant increases of 11.5 and 3.6% in systolic and diastolic blood pressure were observed in patients. 790

In interpreting the findings of these studies, it is important to emphasize that a direct comparison of the safety data from SUSTAIN and other previously published studies is not entirely possible due to the differences in treatment regimens, adverse event classification systems and study designs. Finally, a key difference is the fact that the patients enrolled in the SUSTAIN study were not treatment-naive. Future contribution to the elucidation of the systemic safety profile of ranibizumab will be made by the LUMINOUS study, a multicenter trial recently initiated as part of the Novartis pharmacovigilance program that aims to assess the long-term safety and effect on the quality of life in patients treated with intravitreal Lucentis (ClinicalTrials.gov identifier: NCT01318941) [69]. This study is designed to have both a retrospective and a prospective part, including a retrospective safety study on ranibizumab, in addition to the abovementioned observational study. The retrospective analysis is conducted on the basis of observations on 1-year data from four European ranibizumab registries. Data collected on 4444 patients showed good systemic safety of the drug. The risk of cerebrovascular accident manifested as the annual incidence of stroke was found to be 0.43%, which is lower than the rate observed with 0.5 mg ranibizumab treatment in the SAILOR study (1.2%). However, the mean number of injections per patient in the analysis was very low (4.3) compared with those reported in SAILOR (4.6 in cohort 1) and SUSTAIN trials (5.6). Additionally, it is lower than the number of treatments in the ranibizumab as-needed arm of the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT) study at 1 year (6.9) [60,70].

Bevacizumab The FDA originally approved bevacizumab in 2004 for chemotherapy, specifically for the treatment of metastatic colorectal cancer, but not for the treatment of eye conditions. It was manufactured for intravenous use in oncology, but intravitreal injections were soon also used off label in ophthalmology. Doses used for the intravitreal injections of bevacizumab are produced by splitting the doses of the cancer drug and making multiple unit doses from a single vial of bevacizumab. The off-label or unlicensed use of bevacizumab in the treatment of wet AMD has emerged in the US in 2005 and has rapidly become a widespread practice among ophthalmologists worldwide. The use of bevacizumab compared with the other anti-VEGF agents is attractive due to its low cost ($50 per dose of bevacizumab compared with $1850 per dose of ranibizumab), particularly considering the number of injections necessary at 4 -- 6-week treatment intervals. Despite its off-label status, bevacizumab is widely used by most of the physicians worldwide because of its efficacy, demonstrated in a number of clinical reports and several randomized controlled clinical trials. Finally, its lower price allows the treating physicians to preserve vision of thousands 5.2




of patients who otherwise would not have access to other anti-VEGF drugs due to their restrictively high cost [71]. Systemic adverse effects have been a long-lasting area of debate surrounding the intravitreal off-label use of bevacizumab. The first large study with 1 year follow-up was conducted by Wu and colleagues in 2008, in which 1173 patients treated with intravitreal bevacizumab were reported to have a low rate of systemic side effects, with adverse events reported in 18 patients (1.5%). Among the adverse events, there were seven hypertensive crises (0.59%), six cerebrovascular accidents (0.5%), five cases of myocardial infarction (0.4%) and five deaths (0.4%) [72]. Many limited studies directly comparing the efficacies of ranibizumab and bevacizumab in retrospective case series concluded that patients treated with either ranibizumab or bevacizumab showed similar improvements in vision and a similar safety profile, which was stable over time [50,57,73-75]. A large retrospective nonrandomized study was performed in 702 patients treated in the Seoul National University Hospital; bevacizumab was given to 610 patients and ranibizumab to 240 patients for a period of 1 year. This study observed systemic adverse events in 7 of the 503 patients (1.4%) in the bevacizumab group and in 3 of the 199 patients in the ranibizumab group (1.5%), without a statistically significant difference [76]. The first prospective comparative case series was carried out in the Eye Institute in Kolkata, India, on 120 patients. The comparison of the efficacy and safety of intravitreal ranibizumab and bevacizumab administration showed equivalent improvements in vision, no thromboembolic events and similar safety profiles [77]. An important contribution was made by a large comparative retrospective study conducted on 146,942 Medicare beneficiaries with wet AMD that received intravitreal pegaptanib, bevacizumab, ranibizumab or PDT. After adjusting for patient characteristics and economic status, and limiting the comparison to newly treated patients in order to alleviate any potential selection bias, no statistically significant differences in safety outcomes were observed between the bevacizumab and ranibizumab groups. The cumulative incidence of myocardial infarction and stroke was 1.3 and 2%, respectively, in the PDT group, 1.3 and 2% in the group treated with pegaptanib, 1.2 and 2.1% in the group treated with bevacizumab, and 1.1 and 1.8% in the group treated with ranibizumab. All patients were older than 65, and no differences in the risk of stroke, myocardial infarction or mortality were observed between bevacizumab treatment and the use of other FDA-approved therapies [78-81]. Another large nested case--control population study was conducted in Canada evaluating 91,378 older patients with retinal disease. The authors observed 7388 serious cardiovascular events, including ischemic stroke (1.6%), myocardial infarction (2.4%), venous thromboembolism (1.2%) and congestive heart failure (2.9%). Controls were matched on the basis of age, sex, history of disease and diabetes. They identified the patients who received ranibizumab and bevacizumab in the case/control groups. The authors found that

patients affected by ischemic stroke, acute myocardial infarction, venous thromboembolism and congestive heart failure were not more likely than controls to have been exposed either to bevacizumab or ranibizumab. Further analysis has shown that patients treated with bevacizumab or ranibizumab showed no clinically relevant increase in the risk of ischemic stroke, myocardial infarction, venous thromboembolism or congestive heart failure [82]. The CATT and the IVAN trials were two noninferiority studies comparing visual outcomes in patients randomly assigned to intravitreal ranibizumab or bevacizumab on a monthly schedule or on an as-needed regimen. CATT was a multicenter, randomized controlled trial conducted in the US including 1208 patients with a median age of 80 years and affected by AMD that were randomized to four treatment groups: bevacizumab or ranibizumab given every month or bevacizumab or ranibizumab given PRN. The number of intravitreal injections for the PRN regimen groups in the CATT was 7.7 injections for bevacizumab treatment and 6.9 for ranibizumab treatment per year, whereas the patients in monthly dosing groups received 13 injections. At 1 year, there were no significant differences in the therapeutic efficacy between all the arms of the study, whereas serious systemic adverse events occurred in 24.1% of bevacizumab-treated and 19.0% of ranibizumab-treated (p = 0.004) patients. The elevated rate of complications observed in both groups could be explained by the high median age (80 years) and by the fact that AMD patients are more frequently affected by serious systemic problems. After 2 years, serious systemic adverse events occurred in 31.7% of the ranibizumab group compared with 39.9% in bevacizumab group. The number of patients affected by the arterial thrombotic events was similar in the bevacizumab-treated patients (5.0%) and in the ranibizumab-treated patients (4.7%, p = 0.89). Additionally, the rate of venous thrombotic events was not significantly different between the treatment groups, occurring in 1.7% of bevacizumab-treated patients and in 0.5% of ranibizumabtreated patients (p = 0.054). Although the rate of general serious adverse events for bevacizumab-treated patients was higher than in patients treated with ranibizumab in year 1 or 2, with the relative risk increased by 1.30, most adverse events appeared not to be specifically caused by the antiVEGF therapy and could have been random occurrences or a reflection of imbalances between groups not captured in multivariate modeling [36,70]. Both drugs elicited equivalent risk of arterial thrombotic events, whereas venous thrombosis was slightly more frequent in patients treated with bevacizumab. Multivariate analysis of the data suggested that the eyes of patients managed with continuous monthly dosing showed greater improvements, both anatomical and functional (gain of 1.7 letters) compared with the patients managed with PRN dosing. The mean numbers of intravitreal injections for the PRN regimen groups were 14.1 (bevacizumab-treated group) and 12.6 (ranibizumab-treated group) during 2 years. Switching from monthly


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treatment to the PRN regimen in the second year resulted in a slight worsening of visual performance, with a loss of 1.7 and 3.6 letters in the ranibizumab and bevacizumab groups, respectively. The IVAN multicenter randomized, controlled trial was conducted at 23 centers across the UK and included 610 patients affected by AMD that were randomized to four treatment groups similar to the division used in CATT: bevacizumab 1.25 mg and ranibizumab 0.5 mg, given either as a continuous monthly injections or within a PRN regimen. In the PRN-treated group, three injections were performed monthly after a loading dose of three monthly injections if the requirements for further treatment were met. At 2 years, there was no difference between the drugs in any of the primary or secondary efficacy outcomes. Data from this trial demonstrated that bevacizumab was not inferior to ranibizumab when assessed following 2 years of either continuous or discontinuous treatment, with respect to visual acuity. Although the trials had similar findings at 1 year, incorporation of the data on systemic adverse events occurring in the second year in the IVAN trial shifted the 2-year odd ratio almost to unity. Considering the indices of safety in the IVAN trial, the rate of arterial thrombotic event or heart failure hospitalization was not significantly different between ranibizumab and bevacizumab (6 vs 4%; OR 1.69, 95% CI 0.80 -3.57) or between continuous and as-needed (PRN) administration (4 vs 7%; OR 0.56, 95% CI 0.27 -- 1.19). After 2 years, the mortality rate was similar between the two drugs, but it was lower with continuous treatment, with borderline significance (OR 0.47, 95% CI 0.22 -- 1.03). For both drugs, monthly injections resulted in less CNV and slightly better visual acuity than following the as-needed treatment. Pooling the results of CATT and IVAN trials, the authors concluded that no difference exists between bevacizumab or ranibizumab treatments in the incidence of death or arterial thrombotic events at 2 years [37,83]. Ranibizumab was associated with a lower likelihood of having any systemic serious adverse event compared with bevacizumab (OR 0.76, 95% CI 0.63 -- 0.93), and continuous administration was associated with a lower mortality rate (OR 0.49, 95% CI 0.27 -- 0.86) and a trend toward higher risk of any systemic serious adverse event (p = 0.063). As stated by the researchers, ‘The comparisons between the drugs after 2 years are reassuring, with no suggestion of any difference in mortality or arterial thrombotic events, which have previously been suggested to be related to use of anti-VEGF drugs’. The ideal choice of agent and frequency of administration remains unclear because both studies were not designed and, sufficiently, powered to detect drug-specific differences in rates of rare adverse events. Bevacizumab and ranibizumab appeared to have similar systemic collateral effects, with the main difference between treatments observed in the comparison between continuous and discontinuous treatments. Visual function was slightly better in continuous than in discontinuous treatment, 792

although this improvement was not reflected in the measures of self-reported health-related quality of life. However, neither of the two trials was adequately powered to ascertain with certainty whether any potential statistically significant differences in safety exist between ranibizumab and bevacizumab treatments. Various other multicenter comparative clinical trials were recently conducted in Europe (the VIBERA study in Germany, LUCAS study in Norway, GEFAL study in France and MANTA study in Austria). The results of these trials are consistent with the findings of the CATT and IVAN studies, establishing that the two drugs are equivalent in clinical efficacy and safety [84-86]. Aflibercept Aflibercept (VEGF Trap-eye) is the most recent addition to the anti-VEGF armamentarium, having received FDA approval in November 2011 [87]. Two Phase III clinical trials of VEGF Trap-eye, VIEW 1 and VIEW 2 (VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD), were successfully conducted to assess whether VEGF Trap-eye was not inferior and clinically equivalent to ranibizumab, considered the standard against which all other drugs are compared. Arterial thrombotic adverse events at 1-year follow-up were reported in 2.3% of the cases treated with aflibercept (n = 610) and in 1.5% of patients treated with ranibizumab 0.5 mg (n = 595). No difference with regard to the safety profile and the frequency of systemic adverse events was found in comparison with ranibizumab [88,89]. In January 2014, 96-week results of the VIEW studies were published. After a first-year fixed-dosing regimen, patients received their original dosing assignment in the second year but using a PRN regimen. Incidence of adverse events was similar among groups from baseline to week 96. Specifically, the percentage of adverse events between 0.5 mg monthly bevacizumab and 2q8 (2 mg aflibercept every 8 weeks after three initial monthly injections followed by PRN in the second year) was 3.2 and 3.6%, respectively [90]. The safety data emerged from VIEW1 and VIEW2 are today subject of debate for what concern cerebrovascular risk. Some authors, such as Beaumont and Ueta, point out that recently the Committee for Medicinal Products for Human Use drew attention to a potential increased risk in cerebrovascular events with aflibercept. Taking into account the fact that aflibercept has a higher binding affinity for VEGF-A isoforms and a greater potency in vitro than ranibizumab or bevacizumab and that almost 20% of drug substance goes through the systemic circulation, we must consider the theoretical increase in the potential risk of systemic events. In the study of the elderly population (the subgroups ‡ 85 years), in year 1, there were 20 cases of stroke recorded in the four subgroups of treatement with aflibercept versus one in the ranibizumab group. Therefore, this difference seems to have no particular clinical relevance, according to the FDA, the safety profile 5.3



21.3

24§

NR

0 1.4%

2.5%

0

3.6%

1.3%

1.3%

0

Anchor 5%

11.2

1.4%

0.7%

2.1%

4.3%

Ranibizumab 0.5 mg

Anchor

0

Marina 4.6%

NR

NR

Pier 3.3%

NR

NR

NR

NR

NR

NR

NR

Ranibizumab 0.5 mg

Ranibizumab 0.5 mg

0%

Marina

Pier

z

Monthly 11.7 As needed 6.9 Catt 4.7% p = 0.89 1.5% p = 0.80 1.3% p=1 2.0% p = 0.70 Monthly 22.4 As needed 12.6z

2.2% p = 0.85 0.8% p = 0.73 0.7% p=1 0.7% p = 0.38

Ranibizumab

Bevacizumab

Monthly 23.4 As needed 14.1z

2.4%

1.4%

1.2%

5%

Monthly 11.9 As needed 7.7

z

1.2%

0.7%

0.5%

2.4%

Catt

*2 mg of aflibercept every 8 weeks after three monthly injection for the first year, followed by PRN regimen for the second year. z Patients treated with the same dosing regimen for 2 years. § As reported in the study design but the endless exact mean number of injections is not reported in the results. NR: Not reported in the published manuscript.

Death from vascular causes Mean number of injections

24 months Arterial thrombotic events Nonfatal myocardial infarction Nonfatal stroke

Death from vascular causes Mean number of injections

Arterial thrombotic events Nonfatal myocardial infarction Nonfatal stroke

12 months

Ivan 4% p = NR 1% p = NR 2% p = NR 1% p = NR 18

1.9% p = NR 0.6% p = NR 1% p = NR 0.3% p = NR 10

Ranibizumab

19

1%

1%

1%

3%

11

0%

0%

0.3%

0.3%

Bevacizumab

Ivan

View 3.2% p = NR 2% p = NR 0.8% p = NR 0.5% p = NR 16.5

1.6/1.7% p = NR 1.3/0.7% p = NR 0/ 0.7% p = NR 0.3/0.3% p = NR NR/NR

Ranibizumab

11.2

1.8%

0.8%

1.1%

3.6%

7.5/7.5

1.3/0.3%

0.3/0.7%

0.3/1.6%

2/2.6%

Aflibercept (2q8*)

View 1/View 2

Table 2. Percentage of patients experiencing systemic thromboembolic adverse events and mean number of injections at 1 and 2 years in mean randomized control trials.



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of aflibercept appears to be similar to ranibizumab because the analysis of data on global thromboembolic events is the same when we consider the Antiplatelet Trialists’ Collaboration criteria. In addition, as we show in Table 2, at 2 years of follow-up in VIEW trials, there is an incidence of nonfatal stroke of ~0.8% either in ranibizumab group or in 2q8 VEGF TRAP group (i.e., in the regimen that is subjected to a major number of injections). Finally, we have to consider that reducing injection frequency we may reduce the risk of drug and procedure-related complications. However, further pharmacovigilance research is needed to investigate the systemic effects of long-term aflibercept intravitreal therapy, with a special attention on cerebrovascular events [91,92]. Pegaptanib The VEGF Inhibition Study in Ocular Neovascularization study enrolled 1208 patients who were randomly assigned to receive either intravitreal injections of pegaptanib (0.3, 1 or 3 mg) or sham injections every 6 weeks [93]. The study demonstrated the absence of systemic collateral effects related to VEGF inhibition. At 2 years follow-up, the analysis performed on 425 patients detected no differences in the incidence of cardiovascular accidents [94]. The higher safety of a selective VEGF-165 blocker such as pegaptanib could reflect the inability of the drug to interfere with the positive effects of VEGF-21 and VEGF-189 isoforms. However, this study excluded patients with a history of myocardial infarction or stroke, or those with peripheral vascular diseases [95,96]. In 161 subjects receiving active therapy (every 6 weeks) with pegaptanib for 3 years, no thromboembolic cerebrovascular accidents were reported, with only two subjects experiencing myocardial infarctions (2%) and one patient reporting an occurrence of angina (1%). The incidence of these cardiovascular events was the same in a cohort of 422 subjects treated with pegaptanib for 3 years [97]. In 2011, the Pegaptanib Sodium Multi-Center Study Group reported a number of thromboembolic adverse events, including one event of hypertension and arteriosclerosis obliterans each among 61 patients (1.6%) after a 2-year follow-up period [98]. Finally, Rinaldi et al., in two studies performed on both diabetic and myopic patients, did not find ocular or systemic adverse events throughout a 48-month follow-up [99,100]. 5.4

6.

Discussion

The anti-VEGF therapy was the first treatment of wet AMD able to prevent a moderate visual acuity loss (loss of three or more lines) in most of the patients, instead showing a moderate visual gain (gain of three or more lines) in almost one-third of patients treated monthly. Unfortunately, this treatment strategy is far from satisfactory because it implies certain costs and must be prolonged indefinitely to maintain the vision improvement in many cases. The results of almost 794

all RCTs confirmed that vision gains achieved following regular treatment (monthly for ranibizumab and bevacizumab, bimonthly for aflibercept) tend to decline when patients are switched to the less frequent dosing regimens with less frequent follow-up. Vision deterioration in the long term is accompanied by macular geographic atrophy that may be caused by the natural progression of the disease or the toxicity of the drug. Other causes of treatment failure with anti-VEGF agents include the development of resistance to the drug, insufficient anti-VEGF activity and drug tachyphylaxis [101]. In addition to the possible incomplete effects of anti-VEGF therapy, concern exists regarding the possibility of deleterious cumulative effects associated with the systemic reduction of VEGF activity. Assessment of the impact of anti-VEGF drugs on the cardiovascular system is complicated by the advanced age of the affected population. Vascular stiffening and other rheological phenomena related to aging already predispose this patient population to ischemic events in the short term. In a prospective cohort study that followed over 10,405 persons between 49 and 73 years of age, Wong et al. reported that middle-aged persons with signs of early-stage AMD are at an elevated risk for stroke, independent of the traditional stroke risk factors. In this study, there were 508 cases of AMD in the cohort and 241 persons had a stroke over a 10-year period. After adjusting for age, ethnicity, sex and site, the authors found that persons with early-stage AMD had a higher cumulative annual incidence of stroke compared with the individuals without the disease (4.08 vs 2.14%) [102]. In large comparative trials, there are many possible variables related to the health of the individual patients that may affect the homogeneity of the compared populations and influence the conclusions. The data from the first randomized trials of pegaptanib, ranibizumab and aflibercept, especially the trial data used in the process of securing FDA approval, may have underestimated the systemic risk by selecting patients in good health and without significant cardiovascular risk. The low mortality and low incidence of arterial thrombotic events in a number of ranibizumab trials suggest that high-risk patients with wet AMD and concomitant cardiovascular diseases may have been under-recruited. Moreover, a direct comparison of the safety data from published studies evaluating the effects of ranibizumab is not entirely possible due to the differences in treatment regimens, adverse events classification systems, study designs and proportion of treatment-naive patients. Some lingering concerns remain in light of the larger amount of safety data on ranibizumab suggesting elevated incidence of stroke with the 0.5 mg treatment compared with the 0.3 mg dose, raising the concern that the effect on VEGF concentration could increase the risk of cerebrovascular events in the long period. SAILOR data showed that patients with a history of stroke or heart disease may have a slightly increased risk of stroke, especially at the 0.5 mg dose of ranibizumab. Long-term results of RCTs that investigated ranibizumab for at least 2 years showed that the rate of arterial




thrombotic events varied from 3 to 5%; 3.3% in PIER, 4 and 4.7% in IVAN and CATT studies, 4.6 and 5% in MARINA and ANCHOR studies and 3.2% in the VIEW study (Table 2). Extension of the follow-up for 3 -- 5 years in a subset of patients yielded a rate of arterial thrombotic events of 5.3 and 5.6% in the HORIZON and SECURE studies, respectively. The risk appears sufficiently low compared with the natural incidence of arterial thrombotic events in this population of elderly patients and acceptable when balanced against the advantage of improved vision. Aflibercept trials provided strong evidence of the drug’s noninferior efficacy and safety, in comparison with ranibizumab. The safety of aflibercept in the VIEW studies at 1 and 2 years was excellent and comparable with that of the ranibizumab group. Severe nonocular adverse events (stroke and myocardial infarction) in both VIEW trials occurred with similar frequencies in patients receiving aflibercept (0.7 and 2.6%, respectively) and ranibizumab (1.6 and 2.6%, respectively). After 96 weeks of follow-up, similar improvements in visual acuity were observed between the aflibercept 2q8 and ranibizumab groups, but the former required five less injections. It is feasible that fewer injections may substantially decrease the cumulative population risk of systemic adverse events, considering that millions of injections are given each year [103]. Whereas the selectivity against VEGF 165 likely makes pegaptanib a safer medication, its effectiveness in the wet AMD is lower compared with other drugs and it is no longer widely used in most countries [97,98,104]. Unlike other anti-VEGF drugs, bevacizumab did not receive the same scientific and economic support from the pharmaceutical companies. The discovery of bevacizumab effectiveness and its low cost may translate to utility in a large number of eye conditions in addition to the treatment of wet AMD, such as neovascular glaucoma, diabetic retinopathy, branch retinal vein occlusion, myopic maculopathy and other diseases with effectiveness shown in numerous but limited studies. National RCTs are recently performed comparing bevacizumab with ranibizumab; the first two large trials, completing 2 years of followup, were CATT and IVAN, which provided robust level 1 evidence supporting the use of bevacizumab treatment in wet AMD. However, neither CATT nor IVAN was large enough to detect clinically relevant differences in adverse outcomes such as stroke. Other RCTs conducted in Europe or Asia and long-term postmarketing surveillance will provide detailed information. 7.

Conclusion

Many additional studies and meta-analyses conducted by combining the data from various RCTs have yielded results that were at times controversial, but have neither confirmed nor completely ruled out a possibility of a significant increase in cardiovascular risk with ranibizumab therapy. Pooling the results of CATT and IVAN, the authors concluded that rates

of arterial thromboembolic events and death were similar and relatively low for both bevacizumab and ranibizumab [83]. The comparisons between the two drugs after a 2-year follow-up are reassuring, with very little difference observed in mortality or the incidence of arterial thrombotic events, which have previously been suggested to be related to treatment with anti-VEGF drugs. With the use of both drugs, differences in safety profiles were found between the discontinuous and continuous administration, with the latter being associated with a lower mortality rate (OR 0.49, 95% CI 0.27 -- 0.86) and a trend toward a lower risk of any systemic serious adverse event (p = 0.063). Continuous administration, however, was found to be associated with an enlargement of geographic atrophy. A number of factors make it difficult to decide whether the difference in the incidence of adverse events between the two drugs justifies the preference for the use of ranibizumab. Results from RCTs that investigated bevacizumab for 2 years showed that the rates of arterial thrombotic events were 5% in CATT and 3.37% in IVAN, which are not significantly better than the rate detected in the ranibizumab cohort. Although the head-to-head comparison trials provided evidence of clinical equivalence between ranibizumab and bevacizumab, some authors maintain that providers should use ranibizumab instead of bevacizumab because bevacizumab carries an increased risk of serious systemic and ocular adverse effects. The results of CATT and IVAN trials showed that the rates of serious ocular adverse effects were low (< 1.5%). The arterial thrombotic risk appears sufficiently low compared with the natural incidence of arterial thrombotic events in this category of elderly patients, and acceptably balanced against the advantage of improved vision. The main cause of current safety concerns surrounding bevacizumab use is the increased RR of systemic adverse events in the bevacizumab-treated patients reported in the CATT trial, which was higher by a factor of 1.30 in comparison with ranibizumab. To facilitate the understanding of this finding, one should consider that smokers have an RR > 17 to develop lung cancer compared with nonsmokers. Additionally, users of 300 mg of aspirin have a RR of 1.62 to suffer a hemorrhagic stroke compared with nonusers, whereas benefiting from a protection against ischemic cardiopathy. Adverse side effects must be weighed relative to the disease being treated; wet AMD is not a life-threatening disease but remains a serious illness, both in consideration of its impact on the patient’s quality of life or the social and economic implications [105,106]. Considering the impact on the quality of life, ~33% of subjects with wet AMD and visual acuity < 0.52 logmar suffer from major depression. The quality of life perceived by a patient suffering for a bilateral moderate visual loss due to AMD is comparable with that perceived by patients requiring renal dialysis. A severe bilateral visual loss caused by AMD results in a reduction of the coefficient of the quality of life by 63% and is comparable to the impact of a heart attack, a stroke or advanced prostate cancer. In cases


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of severe disability caused by AMD, the impact is so severe that afflicted people have stated that they would be willing to give up half of the remaining life-years in order to recover normal vision [69,107]. Additionally, it is ethical to consider which treatment option confers the greatest value from a societal perspective. Among the four options available for the treatment of neovascular AMD tested in the CATT and IVAN trials, bevacizumab administered on a PRN dosing schedule maintains its value for the treatment of neovascular AMD, even considering the slight systemic safety risks, and the concern for potential ocular adverse events caused by the improper bevacizumab compounding procedures. The comparisons between the drugs after a 2-year follow-up in the CATT and IVAN trials and after 1 year of MANTA, VIBERA, LUCAS, and GEFAL studies are reassuring, with no suggestion of difference in mortality or thrombotic events, which have previously been supposed to be related to the use of anti-VEGF drugs. The high cost of the on-label drugs limits their use not only in the disadvantaged communities or in developing countries, where patient income levels are low, but even in the developed countries, because of their high burden on the national healthcare system. Without access to affordable anti-VEGF therapies, many people are likely to be condemned to a progressive loss of vision. Another risk is undertreatment, which is reported to be happening in Europe [108], where, primarily due to economic or legal considerations, the healthcare system limits the regular access to on-label anti-VEGF therapies, causing a delay in the sequence of treatments. The number of patients that should be treated for wet AMD is increasing every year due to the need of prolonged treatments and the aging of the global population. A year of monthly treatments with ranibizumab at US $1615 per injection would cost US$485 million, whereas a year of monthly bevacizumab administrations would cost US$13 million per year, resulting in savings of US$472 milllion [109]. These savings could instead help millions of people maintain or save their eyesight or simply help curtail the rapidly rising healthcare costs. Due to the limited resources available for healthcare, there is an opportunity to relieve the burden by choosing therapies that are relatively cheaper, despite the presence of a small risk that is well balanced by the benefit of restored vision. Today, the opportunity to use different drugs including less-expensive options to treat wet AMD should be a benefit and not a subject of controversy, inappropriately perpetuated for economic or legal reasons. All anti-VEGF drugs act with the same mechanism of action, and there is no need to rely on only one drug for the treatment of all patients. The possibility to switch from one drug to another could reduce the possibility of chronic exposure to a single drug eliciting an immune reactions and tachyphylaxis. As presented in our discussion of the outcomes observed after a 2-year follow-up in the most relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar 796

for patients who received any of the available anti-VEGF drugs. Much remains to be understood about CNV pathogenesis, biomolecular mechanisms involved in the progression of the disease and possible new therapeutic interventions. CNV is a multifactorial disease in which angiogenesis, inflammation, gene activation and other factors are involved [110]. There is a strong rationale for applying multiple combined therapies in the treatment of wet AMD. Continuing to use monthly injections of anti-VEGF drugs is not a winning strategy and one would hope that the use of combination of other therapies in the future could give equally effective but more definitive results. A number of studies have been conducted with anti-VEGF drugs such as ranibizumab, pegaptanib and bevacizumab in combination with standard light fluence or reduced light fluence PDT with Visudyne [111-121] and steroids, such as triamcinolone acetonide [122] and dexamethasone. The possibility to switch from one anti-VEGF treatment to another or to use combination therapy could be beneficial for both the patients and the healthcare system. There is a strong rationale for applying multiple combined therapies in the treatment of wet AMD. Continuing to use monthly injections of anti-VEGF drugs is not a winning strategy, and combining other therapies in the future could give equally effective but more definitive results. 8.

Expert opinion

The development of VEGF inhibitors for the treatment of neovascular AMD has revolutionized the treatment of retinal disease, conducting ophthalmologists in a new and unforeseen era. Before the year 2000, treatment was limited to focal laser photocoagulation, a destructive procedure that produced a permanent scar in an effort to limit the spread of CNV. It turned out to be only really viable for treating extrafoveal CNV, and even then, it was not entirely effective. PDT with verteporfin represented the first treatment proven to reduce the risk of vision loss in subfoveal CNV. However, its efficacy was limited to classic or small CNV, and even though it is a relatively nondestructive form of therapy, it failed to improve vision in patients with AMD in clinical trials [123]. Thus, antiVEGF agents undoubtedly represent a turning point in the treatment of AMD in terms of efficacy. The safety profiles of the different drugs have been established to varying degrees. Following evaluation of the outcomes observed after a 2-year follow-up in the relevant clinical trials, the rates of serious adverse events such as stroke, heart attack and death were similar for patients who received any of the available anti-VEGF drugs. Perhaps, the small doses used for eye disease seem to be safe despite the effectiveness of these agents. Results of ongoing head-to-head studies, such as the IVAN study in Great Britain and the CATT study in the US, have demonstrated that bevacizumab was noninferior to ranibizumab for visual acuity at 1 year, with similar safety profiles. More




recently, the GEFAL Study Group, in a multicenter, prospective, noninferiority, double-masked, RCT performed in 38 French ophthalmology centers, obtained the same results [85]. However, intravitreal anti-VEGF compounds expose patients to a suppression of plasma VEGF levels, with moderate effects on the cardiovascular system. As recently raised by Avery [124], the question is: Are VEGF levels reduced after intravitreal injection? In cancer patients, who receive doses hundreds or even a thousand fold higher than intravitreal ones, the side effects are tolerable. Thus, the role of VEGF compounds in systemic disease may be more complex than in the eye, and it is conceivable that fluctuations in VEGF levels are of more concern than chronic suppression. So all patients undergoing treatment with anti-VEGF agents require long-term general monitoring. In fact, the lowering of overall cardiovascular risk would result in a benefit on the ocular disease itself, as acting on modifiable risk factors, such as control of hypertension, maintaining or achieving an ideal weight and smoking cessation, should be to make it a primary prevention on wet AMD. Finally, the doctor--patient relationship has been and remains a keystone of care: the health and well-being of patients depends upon a collaborative effort between physician and patient. Patients share with physicians the responsibility for their own healthcare. The patient--physician Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

2.

3.

4.

5.

6.

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relationship is of greatest benefit to patients when they bring medical problems to the attention of their physicians in a timely fashion, provide information about their medical condition to the best of their ability and work with their physicians in a mutually respectful alliance. Thus, the knowledge of the disease, the potential systemic adverse effects secondary to anti-VEGFs therapy, the discussion about the benefits, risks and costs of appropriate treatment alternatives regarding their disease are recommended to give the right value to these uncommon adverse events. Due to the bias deriving from the comorbidity (arterial hypertension, diabetes, chronic obstructive pulmonary disease, etc.), further studies are needed to well establish the risk for systemic adverse events secondary to intravitreal injection of VEGF inhibitors.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Affiliation Francesco Semeraro1, Francesco Morescalchi1, Sarah Duse†1, Elena Gambicorti1, Mario R Romano2,3 & Ciro Costagliola2 † Author for correspondence 1 University of Brescia, Spedali Civili di Brescia, Radiological Specialties and Public Health, Ophthalmology Clinic, Department of Medical and Surgical Specialties, Piazzale Spedali Civili 1, 25123 Brescia, Italy Tel: +39 0303995308; Fax: +39 0303388191; E-mail: [email protected] 2 University of Molise, Ophthalmology Clinic, Department of Health Science, Campobasso, Italy 3 Istituto Clinico Humanitas, Department of Ophthalmology, Milano, Italy

802


Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: a meta-analysis.

Intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration.

Intravitreal aflibercept in neovascular age-related macular degeneration previously treated with ranibizumab.

Refractory subretinal fluid in patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: visual acuity outcome.

Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab.

or Ranibizumab for Neovascular Age-Related Macular Degeneration.

Variability of disease activity in patients treated with ranibizumab for neovascular age-related macular degeneration.

Long-term longitudinal study of patients treated with ranibizumab for neovascular age-related macular degeneration.

REFRACTORY INTRARETINAL OR SUBRETINAL FLUID IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION TREATED WITH INTRAVITREAL RANIZUBIMAB: Functional and Structural Outcome.

Induction with intravitreal bevacizumab every two weeks in the management of neovascular age-related macular degeneration.

Reasons for discontinuation of intravitreal vascular endothelial growth factor inhibitors in neovascular age-related macular degeneration.

Visual and anatomical outcomes of intravitreal aflibercept for treatment-resistant neovascular age-related macular degeneration.

Subfoveal choroidal thickness changes after intravitreal bevacizumab therapy for neovascular age-related macular degeneration.

Intravitreal Aflibercept for Treatment-Resistant Neovascular Age-Related Macular Degeneration: 12-Month Safety and Efficacy Outcomes.

Two-year outcomes of "treat and extend" intravitreal therapy for neovascular age-related macular degeneration.

Aflibercept for neovascular age-related macular degeneration.

The role of epiretinal membrane on treatment of neovascular age-related macular degeneration with intravitreal bevacizumab.

Comparison of intravitreal ranibizumab in phakic and pseudophakic neovascular age-related macular degeneration patients with good baseline visual acuity.

Long-term outcome of intravitreal pegaptanib sodium as maintenance therapy in Japanese patients with neovascular age-related macular degeneration.

Aflibercept in the treatment of neovascular age-related macular degeneration in previously treated patients.

VEGF gene polymorphism and response to intravitreal ranibizumab in neovascular age-related macular degeneration.

Response of pigment epithelial detachments to intravitreal aflibercept among patients with treatment-resistant neovascular age-related macular degeneration.

Bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration.

Clinical outcomes after switching treatment from intravitreal ranibizumab to aflibercept in neovascular age-related macular degeneration.