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Abstract
Purpose To analyse the pooled safety data of intravitreal ziv-aflibercept (IVZ) therapy for various retinal conditions.
Methods This was a retrospective, observational study which included patients from 14 participating centres who received IVZ. The medical records of patients who received IVZ from March 2015 through October 2017 were evaluated. Patient demographics and ocular details were compiled. Ocular and systemic adverse events that occurred within 1 month of IVZ injections were recorded and defined as either procedure-related or drug-related.
Results A total of 1704 eyes of 1562 patients received 5914 IVZ injections (mean±SD: 3.73±3.94) during a period of 2.5 years. The age of patients was 60.6±12.8 years (mean±SD) and included diverse chorioretinal pathologies. Both ocular (one case of endophthalmitis, three cases of intraocular inflammation, and one case each of conjunctival thinning/necrosis and scleral nodule) and systemic adverse events (two cases of myocardial infarction, one case of stroke and two deaths) were infrequent.
Conclusion This constitutes the largest pooled safety report on IVZ use and includes patients from 14 centres distributed across the globe. It shows that IVZ has an acceptable ocular and systemic safety profile with incidences of adverse events similar to those of other vascular endothelial growth factor inhibitory drugs. The analysis supports the continued use of IVZ in various retinal disorders.
- retinal venous occlusion (RVO)
- ziv-aflibercept
- intravitreal ziv-aflibercept (IVZ)
- diabetic macular edema (DME)
- neovascular age related macular degeneration (n-AMD)
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- retinal venous occlusion (RVO)
- ziv-aflibercept
- intravitreal ziv-aflibercept (IVZ)
- diabetic macular edema (DME)
- neovascular age related macular degeneration (n-AMD)
Vascular endothelial growth factor (VEGF) inhibitory drugs have become standard therapy for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular oedema (DME) and macular oedema due to retinal vein occlusions (RVO).1–3 The literature is replete with randomised controlled trials (RCT) and real-life, postapproval data that confirm the efficacy and safety of intravitreal bevacizumab (BVZ) (Avastin; Genentech, South San Francisco, California, USA), ranibizumab (RBZ) (Lucentis; Genentech) and aflibercept (AFL) (Eylea; Regeneron, Tarrytown, New York). Because treatment has become so safe and effective, anti-VEGF injections have become the most commonly performed and one of the most costly ophthalmological procedures worldwide.4 For fiscal year 2013, 2 million anti-VEGF drug claims were filed with the US Medicare part B, representing a total drug cost of more than $2.3 billion.5
The ocular adverse events with anti-VEGF therapy range from relatively insignificant conjunctival haemorrhages, to mild, non-infectious, intraocular inflammation, and to serious vision-threatening complications such as retinal detachment, vitreous haemorrhage and endophthalmitis. Systemic adverse events (SAEs) including thromboembolic events, non-ocular haemorrhages, myocardial infarctions (MI), strokes and systemic arterial hypertension have also been reported in patients receiving intravitreal anti-VEGF injections.6 7
Ziv-aflibercept (Zaltrap; Regeneron), an anti-VEGF agent approved for the treatment of advanced colorectal carcinoma, contains the same molecule as AFL but in a more concentrated solution after the addition of several buffers (ziv-aflibercept: 1000 mOsm/kg; AFL: 300 mOsm/kg).8 Off-label, intravitreal ziv-aflibercept (IVZ) has been used to treat a variety of retinal disorders, with several case reports and case series showing the short-term and long-term (>12 months) safety of IVZ.8–10
In many respects, the intraocular use of IVZ resembles that of BVZ—intravitreal use of both drugs is off-label, and both must be compounded from large, single-use bottles into individual syringes to take advantage of a lower unit cost. All of the safety concerns regarding the aliquoting of BVZ also hold true for IVZ. Clusters of compounding-related endophthalmitis and severe inflammation due to counterfeit products have been reported with BVZ, which have led physicians, institutions and government regulatory agencies to scrutinise both the techniques employed by compounding pharmacies and the integrity of the supply chains.11 Fortunately, these problems are yet to be seen with the intraocular use of ziv-aflibercept.
The long-term ocular and systemic safety of IVZ in different retinal conditions in diverse populations is still unknown. To better define the safety profile of intraocular ziv-aflibercept, we have compiled safety data following 5914 injections performed in 14 centres from seven countries.
Methods
The medical records of patients treated with IVZ injections from March 2015 through October 2017 were reviewed retrospectively. Data were received from 14 clinical centres in India, Brazil, Syria, Iran, Lebanon, Ghana and Egypt. The off-label status of IVZ had been explained to each patient prior to use.
IVZ is available as a phial of 4 mL (100 mg) or 8 mL (200 mg) with a concentration of 25 mg/mL. The drug was withdrawn under a laminar flow hood, and a single puncture technique was used to withdraw the drug in multiple 1 mL syringes. Aliquots of 0.1 mL (2.5 mg) were prepared and labelled. A small sample of IVZ was also plated on chocolate agar to identify any bacterial contamination. The syringes containing IVZ were used for intraocular injection as needed and stored at 4°C in refrigerator. The unused syringes were discarded after a period of 2 weeks. The applied concentration was 25 mg/mL. The volume of drug injected intravitreally was 0.05 mL (1.25 mg) in all the centres. Among the 14 centres, 9 centres practised drug injections in a minor operation theatre (OR). Three centres injected the drug in the major OR. However, two centres gave intravitreal injections as an outpatient basis in office settings. Preinjection and postinjection povidone iodine applications were practised in all the centres. None of the centres used preinjection antibiotic drops. However, among the 14 centres, 4 centres used postinjection antibiotics for a period of 1 week.
Collected data
Demographic and treatment information, including patient age, previous treatments, best corrected visual acuity (BCVA) at initial and final visits, details regarding the retinal condition, information on complications related to IVZ (if any), and follow-up periods (in months), was collected. If deemed necessary by the treating physician, a systemic history and evaluation was performed to identify pertinent VEGF-related risk factors. The IVZ injection technique and treatment regimen were at the discretion of each physician.
Adverse events
Disease management details were documented at each site, and ocular and systemic adverse events were documented, investigated and treated as needed. Ocular adverse effects were defined as those ophthalmic complications that occurred within 1 month after an IVZ injection. SAEs were defined as those systemic complications, including thromboembolic episodes, non-ocular haemorrhages or death that occurred within 1 month after an IVZ injection. Complications were defined as either procedure-related or drug-related.
Statistics
The mean and SD of descriptive variables were calculated using SPSS V.22 software.
Results
The average age of study patients was 60.6±12.8 years (mean±SD) and the majority (963; 56.51%) were men. The cohort (1562 patients) comprised patients from diverse geographical locations, including India (1019), Middle East (449), Africa (70) and Brazil (24). A total of 1704 eyes received 5914 IVZ injections (mean: 3.7±3.9) during the 2.5-year study period.
The chorioretinal conditions that were treated are listed in table 1. The most common indications for IVZ therapy were DME (696; 40.84%), nAMD (420; 24.65%) and RVO (366; 21.48%). The patients received IVZ according to three different treatment strategies: pro re nata (1434; 83.15%); treat-and-extend (159; 9.34%); and monthly (111; 6.51%). The adverse events included both ocular and systemic side effects related to either injection procedure or IVZ, and are detailed in the subsequent sections.
Lists of indications for intravitreal ziv-aflibercept injections
Ocular adverse events
Conjunctival necrosis
One patient developed conjunctival thinning at the injection site 1 week after an IVZ injection. There were no accompanying ocular complaints or significant hyperaemia. A conjunctival swab of the suspicious area failed to identify any micro-organisms. The inflammation resolved after 5 days of topical antibiotics. The absence of intraocular inflammation suggests that this event was not drug-related.
Scleral nodule
One patient with nAMD who had previously received three RBZ injections developed a scleral nodule at the inferotemporal injection site 4 days after an IVZ injection. Scleral scrapings failed to identify micro-organisms and the nodule resolved after a course of topical antibiotics and steroids (figure 1).
A patient with diabetic macular oedema who had received three ranibizumab injections in the past was later switched to intravitreal ziv-aflibercept (IVZ).The patient reported to the emergency 4days following IVZ injection. Clinical examination using slit lamp (diffuse illumination) showed presence of scleral nodule at injection site (A). Scleral scraping showed no growth in microbiology. Following 4 weeks of topical antibiotics and steroid, there was resolution of nodule with focal whitening (B). He received one more IVZ injection on subsequent visits and did not have any further complications.
Intraocular inflammation
Three patients developed intraocular inflammation after injections. A patient with DME who had previously received several BVZ (1) and IVZ (8) injections developed mild anterior uveitis after his ninth IVZ injection. This was successfully treated with topical corticosteroids. The reason for the inflammation is not known. The patient subsequently received IVZ injections without additional adverse events.
A patient with nAMD who had previously received seven IVZ injections developed sterile vitritis. The inflammation resolved after a brief course of oral and topical corticosteroids. Another patient with macular oedema due to a central retinal vein occlusion (CRVO) developed corneal oedema, but no anterior chamber cells or flare, following his second IVZ injection. No treatment was administered and the oedema resolved during the subsequent follow-up visits (table 2).
Summary of significant ocular and systemic adverse events in patients receiving IVZ injections
Endophthalmitis
A patient with peripapillary CNVM who had previously received three IVZ injections developed endophthalmitis 2 days after his fourth injection. Staphylococcus epidermidis grew from a vitreous specimen and the patient was treated with intravitreal antibiotics. After resolution of the infection, the patient received three additional IVZ injections and had a BCVA of 20/400 at the 10-month follow-up examination.
Increased intraocular pressure
Elevated intraocular pressure was measured in nine eyes of nine patients (0.5%), but only one had a history of glaucoma. The pressure was successfully lowered with topical medications in eight of the patients and only one patient required incisional glaucoma surgery.
Vitreous haemorrhage
Three patients developed vitreous haemorrhages after IVZ injections. In all three patients the vitreous haemorrhage appeared related to the underlying ocular disease and not to the injection of IVZ.
Subconjunctival haemorrhage
Twelve patients developed subconjunctival haemorrhages following IVZ injections. The haemorrhages resolved with conservative management with no long-term sequelae. None of the patients had underlying bleeding disorders or were on prior anticoagulants. These haemorrhages were likely due to the injection procedure itself.
Cataracts
Cataract progressed after IVZ injections in three patients. In none of the cases was lens damage noted during intravitreal injections and the cataracts may not have been related to IVZ.
A patient with CRVO had previously received 24 anti-VEGF injections before receiving 18 IVZ injections. Visually significant cataract was noted later during the course of treatment and cataract surgery was planned. Another patient with diabetes mellitus had previously received five BVZ injections and two sustained-release dexamethasone inserts (Ozurdex, Allergan, Dublin, Ireland). The patient subsequently received three IVZ injections. During the follow-up visits, the patient was noted to have posterior subcapsular cataract (PSC) and eventually underwent cataract surgery.
The third patient, a case of nAMD, had received nine IVZ injections over the course of 22 months. He underwent cataract surgery later once progression of PSC was noted.
Central retinal artery occlusion
Two patients developed central retinal artery occlusion (CRAO) after IVZ Injections. The first patient who had received five IVZ injections for DME developed a CRAO 5 days after the last injection. A systemic evaluation failed to identify an embolic source or predisposing condition.
The second patient was a case of DME who had received 10 IVZ and 1 BVZ injection prior to developing CRAO. A systemic evaluation failed to identify an embolic source or predisposing condition. After the CRAO, this patient continued to receive IVZ injections for DME in the fellow eye without additional adverse events.
Retinal pigment epithelium tear
A patient with a fibrovascular pigment epithelial detachment (PED) developed retinal pigment epithelium tear after a single IVZ injection. The BCVA dropped from 20/30 to 20/80 and the patient was subsequently planned for repeat IVZ injection.
Systemic adverse events
Eleven patients experienced SAEs and two patients died while receiving IVZ.
A case of nAMD who had previously received eight BVZ injections died from complications of pneumonia after his third IVZ injection. A patient with DME and kidney disease died from complications of chronic renal disease after three IVZ injections. The IVZ was not believed to have contributed to either of these events.
Three patients experienced non-fatal thromboembolic events: MI (2) and a cerebrovascular accident (CVA) (1). A case of DME with a family history of MI experienced an acute MI after her fourth IVZ injection. Her DME was subsequently treated with subthreshold micropulse laser and her cardiac disease remained stable until the last visit. A case of nAMD, who had received four BVZ injections before receiving four IVZ injections, experienced an acute MI. The patient’s cardiac disease remained stable through 22 months of follow-up.
Six patients developed uncontrolled systemic arterial hypertension while receiving IVZ therapy. Two of these patients were successfully managed with oral antihypertensive medications, but the remaining four patients required admission to intensive care units. None of the hypertensive episodes proved to be fatal, and satisfactory control of blood pressure was achieved in all patients.
Discussion
Anti-VEGF drugs have been used extensively over the last decade to treat a variety of chorioretinal vascular disorders. Scores of prospective studies, meta-analyses and population studies have established the ocular safety.1–3 8 10 Not surprisingly, however, a variety of ocular and systemic adverse effects, related to either the injection procedure or the drugs, have been associated with intravitreal injections.6 7 The treating physician needs to be aware of the adverse events, which although rare can be vision-threatening and rarely life-threatening.
Reluctance to administer ziv-aflibercept intravitreally has been, in part, due to concerns over its highly concentrated, buffered solution. However, the short-term and 1-year safety of IVZ (1.25, 2 and 2.5 mg) has been established through electroretinographic testing.12–14 The standard dose of IVZ (1.25 mg/0.05 mL) is less compared with AFL (2 mg/0.05 mL). In the present study, we report the largest number of patients who experienced ocular adverse events with IVZ. Our incidence of cataract (0.07%) was similar to previously reported rates with other anti-VEGF drugs (from 0.009% to 0.14%).15 16 CRAO, although rare, has been reported following the use of anti-VEGF agents. The main mechanism leading to CRAO could be the disturbance in Virchow’s triad leading to vasoconstriction and disturbed autoregulation of retinal microcirculation. In our cohort, among the two patients who developed CRAO, one patient continued to receive IVZ in the fellow eye with no ocular complications for the next 6 months. The incidence of endophthalmitis after intravitreal BVZ, RBZ and AFL injections varies from 0.004% to 0.4%.17 18 Consistent with these low incidence rates, we observed only one case of endophthalmitis after 5914 IVZ injections. The infection resolved satisfactorily with intravitreal antibiotics and the patient received additional IVZ injections subsequently.
Intraocular inflammation remains one of the most important ocular side effects of anti-VEGF drugs, and inflammation also appears to be associated with ziv-aflibercept. We identified three cases of intraocular inflammation ( one case each of anterior uveitis, corneal oedema and sterile vitritis), one case of conjunctival thinning and one case of a localised scleral nodule. Our case of conjunctival thinning, which we think represented focal necrosis, may have been due to localised conjunctival inflammation at the injection site, without associated involvement of the anterior chamber and vitreous cavity. This may have been due to the injection procedure and a breach in asepsis, and probably cannot be attributed to ocular toxicity from IVZ.19 This rate of intraocular inflammation (0.08%) appears acceptable considering the reported incidence ranging from 0.05% to as high as 2.9%.6 7 Similarly, Hahn et al 20 have reported an incidence of 0.05% (15 in 30 000) with intravitreal AFL injections.
Various SAEs, such as thromboembolic episodes (TEE), acute MI, CVA including transient ischaemic attacks and stroke, gastrointestinal haemorrhages, and systemic arterial hypertension, are often attributed to low systemic VEGF concentrations. The incidence of SAE with commonly used anti-VEGF drugs ranges from 0.6% to 2.7% in major clinical trials.6 21 22 In a meta-analysis that included 26 360 patients from 42 ‘real life’ nAMD studies, Kim et al 22 reported TEE and death rates of 0.6% and 0.7%, respectively. The lower incidences of adverse events from these studies, compared with those reported in randomised control trials, may be due to incomplete capture of data.
The Comparison of Age Related Macular Degeneration Treatments Trials reported that 42 patients (7.6%) developed TEE while taking RBZ, compared with 24 patients (4.5%) receiving BVZ (p=0.04), and the incidences of other adverse events were similar between the two drugs.23 The IVAN trial reported no significant difference in adverse events for patients receiving RBZ or BVZ.24 A meta-analysis of six DME trials (READ2, RESOLVE, RESTORE, DRCR.net Protocol I, RISE and RIDE) concluded that RBZ injections in patients with DME were safe and that the rates of TEE in diabetic populations were similar to those reported with other treatment methods.25
We observed two cases of acute MI, one case of CVA and six cases of elevated blood pressure in patients receiving IVZ. Among the first three patients, one patient developed malignant hypertension that warranted admission to an emergency room. This patient was subsequently treated with BVZ injections and did not experience additional blood pressure changes. Although the patients in this study with diabetes, hypertension and coronary artery disease were evaluated by physicians before IVZ was injected, SAEs in these patients may have been under-reported.
The current study included IVZ injections from 14 clinical centres scattered across the globe. When interpreting these results, the differences in practice pattern among the participating physicians should be considered. Several factors, such as the preinjection and postinjection use of topical antibiotics, the techniques used to compound IVZ and perform injections, the training and expertise of personnel administering the injections, and the frequency of follow-up visits and duration of therapy determine the final outcome. The limitations of this study include its retrospective design and non-standardised treatment protocols. The data, however, suggest that IVZ is generally safe when used in different patient populations across the globe, and support continued investigation of IVZ for ocular use. Future prospective RCTs can further validate both the safety and efficacy of IVZ.
The ocular and systemic complications of 5914 intravitreal ziv-aflibercept (IVZ) injections are highlighted in this multicentre study, thereby establishing the safety profile of IVZ.
References
Footnotes
Collaborators Mudit Tyagi, Rajeev Reddy Pappuru, Taraprasad Das, Padmaja Kumari Rani, Raja Narayanan, Vivek Pravin Dave, Subhadra Jalali, Divya Balakrishnan, Hitesh Agrawal, Komal Agrawal, Mohammed Abdul Rasheed, Ahmadreza Baghi, Mehdi Yaseri, Chintan Dedhia, Chetan Videkar, Muchai Gachago, Bhushan Uplanchiwar, Kushal Agrawal, Remya Paulose, Mahima Jhingan, Vishal Govindhari, Rushil Kumar Saxena, Avadesh Oli, Ravi Sharma, Avantika Dogra, Rajan Gupta, Nallamasa Rohit.
Contributors SRS, MA, AMM, MEF and JC were involved in the design of the study. GC, MA, AS, MED, NW, CS, AmM, SR, IZB, MHJB, AR, JRdOD, GCdA, AnM, EBR and AB were involved in the collection of data. SRS, GC, MA and JC were responsible for interpretation and analysis of the data. SRS, MA, AMM, AmM, MWS, MED and AB were involved in manuscript writing. MWS, MA, AR, MS, JRdOD, MEF, AB and JC reviewed the article. All the authors conducted the study and equally contributed in the preparation, review and approval of the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent Obtained.
Ethics approval L V Prasad Eye Institute Institutional Review Board. Prior institute review board (IRB) approval of the study was obtained from each centre and the study adhered to the tenets of the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.
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