FormalPara Key Summary Points

Why carry out this study?

Anti-vascular endothelial growth factor (VEGF) agents for treating retinal diseases are given by intravitreal injection using single-use vials or prefilled syringes (PFS).

We performed a systematic review of the literature to assess procedural efficacy, health care resource use, patient and clinician experiences, and the safety outcomes associated with approved anti-VEGF injections administered using PFS versus single-use vials.

What was learned from the study?

Compared with vials, PFS are associated with increased procedural efficacy, improved safety, and greater clinician preference.

The time saving and safety benefits of PFS have positive implications for clinic capacity.

Introduction

The introduction of anti-vascular endothelial growth factor (VEGF) agents from the mid-2000s onwards was a landmark development in the history of treating retinal diseases, including neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusion [1, 2]. Pegaptanib, since discontinued, was the first anti-VEGF to be approved in 2004, closely followed by ranibizumab in 2006, aflibercept in 2011, and brolucizumab in 2019. Most recently, in 2022, faricimab, a dual angiopoietin-2/VEGF inhibitor, was also approved. These treatments have allowed patients to achieve improvements in vision and retinal anatomy, which are clear life-changing outcomes [3].

Anti-VEGF treatments for retinal diseases have traditionally been administered via vial-based intravitreal injection. Vial-based administration is a multistep process, which, in brief, comprises disinfecting the single-use vial, withdrawing the drug into a syringe using a sterile transfer needle, replacing the transfer needle with an injection needle, removing air bubbles and adjusting volume (as necessary), and then injecting [4]. In a subsequent significant development in the field of anti-VEGF intravitreal injection, a single-dose, prefilled ranibizumab 0.5-mg syringe was first approved for use by the US Food and Drug Administration in 2016. Approvals for ranibizumab 0.3 mg (2018), aflibercept 2.0 mg (2019), and brolucizumab 6.0 mg (2019) followed thereafter. The process of intravitreal injection using prefilled syringes (PFS) comprises attaching an injection needle, inspecting for air bubbles and adjusting the dose as necessary, and injecting [5,6,7,8,9,10]. Hence, a number of preparation steps are removed with PFS versus vial-based administration, with obvious time-saving implications for busy ophthalmology clinics. The reduced number of steps involved, and by association decreased likelihood of contamination, has also been purported to result in improved procedural safety, specifically the risk of endophthalmitis [11]. Increased accuracy of dosing has also been suggested to be a benefit of PFS anti-VEGF injection [11].

To date, there has been no comprehensive summary of the available evidence concerning the use of PFS for intravitreal injection of anti-VEGF treatments. Hence, we performed a systematic review of the literature to evaluate the procedural efficacy, health care resource use, patient and clinician experiences, and the safety outcomes associated with approved anti-VEGF injections administered using PFS versus single-use vials.

Methods

This systematic literature review was carried out in accordance with the PRISMA guidelines [12]. The search protocol was prospectively registered on February 2, 2024 on the INSPLASY International Platform of Registered Systematic Review and Meta-analysis Protocols (INPLASY202420007).

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Data Sources

MEDLINE, EMBASE, and The Cochrane Library were searched on February 8, 2024. Search strategy details are provided in the Supplementary Material.

Websites from the following organizations were also searched using free-text terms to identify relevant gray literature: US Food and Drug Administration, European Medicines Association, National Institute for Health and Care Excellence, Scottish Medicines Consortium, Pharmaceutical Benefits Advisory Committee, Canadian Agency for Drugs and Technologies in Health, The Professional Society for Health Economics and Outcomes Research, EconLit Database, American Society of Retinal Specialists, European Society of Retina Specialists, The Association for Research and Vision in Ophthalmology, American Academy of Ophthalmology, The Retina International World Congress of Ophthalmology, The American Macular Degeneration Foundation, The Royal Australian and New Zealand College of Ophthalmologists, Asia-Australia Controversies in Ophthalmology, The Royal College of Ophthalmologists, and United Kingdom Ophthalmology Alliance.

Reference lists were hand searched to identify additional potentially relevant literature.

Study Screening and Selection

Eligibility criteria for inclusion in the systematic review were defined according to the Population, Intervention, Comparator, Outcome, and Study Design (PICOS) framework and are summarized in Table 1. Any literature reporting on the outcomes of interest in patients treated with intravitreal injections using PFS containing ranibizumab, aflibercept, or brolucizumab, or literature reporting on health care providers preparing and administering such injections were considered for inclusion. The databases were searched on February 8, 2024 and were restricted to literature published from 2015 onwards.

Table 1 Systematic literature review eligibility criteria
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After removal of duplicates, abstracts were screened by two reviewers to determine eligibility.

Data Extraction and Quality Assessment

A single reviewer extracted relevant information/data from each eligible publication into a prespecified Excel spreadsheet. The quality of publications was assessed using the Joanna Briggs Institute Critical Appraisal Checklists for Analytical Cross-Sectional Studies, Case Series, and Expert Opinion [13,14,15].

Results

Overview

A total of 36 publications from the databases searches met the criteria for the systematic literature review (Table 1) and were included (Fig. 1). Of these, the majority were cross-sectional studies (n = 26) [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41], with a small number of reviews (n = 4) [4, 11, 42, 43], case series (n = 3) [44,45,46], surveys (n = 2) [47, 48], and opinion (n = 1) [49] publications. Overall, 17 publications reported comparisons of ranibizumab PFS with ranibizumab or aflibercept vials [17,18,19,20,21,22,23,24,25, 27,28,29,30,31, 33, 34, 41], 10 publications reported comparisons of aflibercept PFS with aflibercept vials [26, 35, 37,38,39,40, 44,45,46, 48], and two publications reported comparisons of ranibizumab and aflibercept PFS and ranibizumab and aflibercept vials [32, 36].

Fig. 1
figure 1

Study selection flow diagram. AFL aflibercept, BRZ brolucizumab, BVZ bevacizumab, PFS prefilled syringe

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Quality Assessment

Most of the publications in the review included the key information as stipulated in the Joanna Briggs Institute Critical Appraisal Checklists (Tables S1, S2, and S3). Exceptions (where the majority of checklist items were marked either “unclear” because of a lack of information or “no”) were published abstracts [16, 17, 20, 29,30,31, 37, 38]. The majority of publications (19 of 27) reporting results from cross-sectional studies did not disclose strategies to deal with potential confounding factors.

Procedural Efficiency Outcomes

Overall, 11 publications [16,17,18,19,20, 23, 29, 30, 41, 48, 49] included outcomes related to the procedural efficiency of PFS (Table 2). Five publications [18,19,20, 29, 30] reported preparation times for ranibizumab PFS compared with vial-based ranibizumab and/or aflibercept preparation. For each comparison, preparation times for PFS (40.3–57.9 s) were significantly faster than vial-based preparation times (ranibizumab, 62.8–98.0 s; aflibercept, 71.9–79.5 s) [18, 20, 29, 30]. Subhi et al. [19] also reported significantly faster preparation times for PFS versus vial-based preparation times; however, the times for both (ranibizumab PFS, 16.9 s; ranibizumab vial, 40.3 s; aflibercept vial, 45.1 s) were considerably faster than the range of times reported in the other studies. Two publications [16, 17] reported that there were no differences in product stability between ranibizumab PFS and vials and two publications [16, 41] described the ease of use of ranibizumab PFS. Some publications [48, 49] reported problems with the aflibercept PFS in terms of lack of tactile responsiveness when injecting, potentially affecting accuracy of dosing.

Table 2 Systematic literature review results: procedural efficiency outcomes
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Health Care Resource Use Outcomes

No publications reported on health care resource use.

Patient and Clinician Experience Outcomes

Six publications reported outcomes related to clinician experiences with PFS (Table 3) [18,19,20, 41, 47, 48]. Clinicians, including physicians, retinal specialists, ophthalmologists, and nurses consistently reported that intravitreal injection using PFS was easier, faster, and had increased safety compared with vial-based intravitreal injection [18, 19, 41, 48]. Clinicians also expressed either increased satisfaction or a preference for using PFS over vials [18, 20, 47].

Table 3 Systematic literature review results: clinician experiences outcomes
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No publications reported on outcomes related to patient experiences.

Safety Outcomes

A total of 21 publications [21, 22, 24,25,26,27,28, 31,32,33,34,35,36,37,38,39,40, 44,45,46, 48] reported outcomes related to the safety of PFS (Table 4), including endophthalmitis rate [21, 22, 24, 25, 28, 31, 33, 34, 36, 38, 40], vision and transient vision loss [24, 35, 38, 45, 46, 48], intraocular pressure (IOP) after injection [26, 32, 37, 39, 48], the presence of intravitreal air bubbles [27], ocular hypertension [37], and intraocular inflammation rate [40]. Endophthalmitis rates per injection were consistently lower (and generally statistically significantly) with PFS injection (ranibizumab, 0–0.02% [0 to ~ 1 in 5000]; aflibercept, 0.01–0.02% [~ 1 in 10,000 to ~ 1 in 5000]) compared with vial-based injection (ranibizumab, 0.02–0.05% [~ 1 in 5000 to ~ 1 in 2500]; aflibercept, 0.02–0.06% [~ 1 in 5000 to ~ 1 in 1600]) [21, 22, 24, 25, 28, 31, 33, 34, 36, 38]. When evaluated, the difference between ranibizumab PFS injection and vial-based injection of ranibizumab or aflibercept was also evident for rates of culture-positive endophthalmitis [24, 34]. One publication [27] reported a lower rate of intravitreal air bubbles after ranibizumab PFS injection compared with vial-based aflibercept injection.

Table 4 Systematic literature review results: safety outcomes
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Several publications [35, 45, 46, 48] reported increased rates of transient vision loss after aflibercept PFS injection compared with vial-based aflibercept injection. There was mixed evidence regarding the effect of aflibercept PFS injection on IOP, with several publications reporting no differences in the proportion of patients experiencing an IOP increase of at least 30 mmHg or sustained IOP increases after injection [32, 37, 39]. In contrast, one publication [26] reported a significantly higher rate of patients with an IOP increase greater than 20 mmHg after aflibercept PFS injection versus vial-based aflibercept injection, and another reported a significantly higher proportion of patients with at least one IOP spike after aflibercept PFS injection compared with vial-based aflibercept injection [48].

Discussion

The aim of this systematic review was to summarize the available evidence regarding the use of PFS for intravitreal injection of approved anti-VEGF treatments for retinal diseases. Overall, we identified 36 publications reporting relevant evidence, including that related procedural efficiency, clinician experiences, and safety outcomes. Five publications reported that the preparation time for intravitreal injection was significantly faster (approximately 50%) for PFS compared with vial-based injections, and two publications reported no differences in product stability between PFS and vials. Another noteworthy finding in the literature is that clinicians have expressed positive opinions regarding PFS, including ease of use, speed, and safety. Furthermore, on the topic of safety, a large number of publications have reported data demonstrating a significantly lower risk of endophthalmitis following intravitreal injection with PFS compared with vials. This is likely because of the inadvertent transfer of contaminants from the rubber bung to the injection fluid when the drug is withdrawn from the vial and the lack of clear guidance on adequate disinfection procedures [50, 51]. Several publications noted an increased frequency of post-injection transient vision loss with aflibercept PFS versus vials. These instances of transient vision loss are likely a consequence of acute retinal arterial occlusion due to a sharp rise in IOP, which may necessitate emergency paracentesis. As this has not been reported with other PFS, it is thought to be related to the aflibercept PFS design, including the wide barrel diameter and the lack of tactile responsiveness associated with the high dead-space plunger design, affecting dosing accuracy [35, 44, 46, 52].

We did not identify any publications specifically reporting on health care resource use outcomes; hence, this represents a gap in the literature. The faster preparation time and decreased rate of endophthalmitis with PFS use have implications for clinic capacity and economics. The need to spend less time preparing injections and treating post-injection endophthalmitis would free up time for clinicians to spend with other patients and/or on other clinic-related activities. As an example, nearly 45,000 intravitreal injections were administered at Moorfields Eye Hospital (UK) in 2019 [53]. If this number of injections were administered via PFS rather than vial, the time saved (assuming 30 s saved per PFS vs. vial injection) would be approximately 375 h. Less experienced clinicians may particularly appreciate the less complicated PFS injection process, which may increase their treatment capacity. Furthermore, the use of PFS means that, in some settings, nurses/ancillary staff may no longer be required to disinfect the vial and transfer the injection fluid to the syringe. In addition to reducing the risk of endophthalmitis, this decreases the number of staff required during the treatment process and enables nurses/ancillary staff to prepare for the next patient, thereby optimizing patient flow. Because of the nature of the process (i.e., number of steps potentially involving multiple clinic staff and the need for communication between such staff), there would appear to be an increased likelihood of medication wastage during drug preparation with vials compared with PFS. There is also a possibility of insufficient medication being withdrawn from the vial on the first attempt because of the viscosity of the drug; use of PFS means that this complication is avoided. The decreased number of materials required for PFS injection may be of benefit in situations where the supply of medical consumables is limited. For example, the COVID-19 pandemic severely disrupted the National Health Service supply chain in the UK, leading to a shortage of needles and syringes, which are required for vial-based injection. The economic effects of the purported benefits of PFS use warrant investigation.

Another gap in the available literature is the absence of evidence on patient experiences with PFS. We hypothesize that differences in preparation time and safety would have an effect on patient satisfaction (e.g., decreased treatment contact time with PFS injection may decrease anxiety) and hence adherence. Given the increasing importance of patient-reported outcomes, studies are required to examine these possibilities and obtain a comprehensive understanding of the patient perspective regarding PFS injection.

The results of our systematic review are limited by the fact that the available evidence comes predominantly from non-randomized studies and case series. To our knowledge, no randomized controlled trials have compared outcomes between PFS and vial-based intravitreal injection approaches. Nevertheless, the main findings of increased procedural efficiency and decreased rates of endophthalmitis with PFS versus vial-based administration were consistently reported across publications. As for all systematic reviews, another limitation is the possibility that relevant literature were not identified in the search or were published after the search was completed. Given the relatively small body of literature on this topic, we are confident that all relevant publications were captured.

Conclusions

The results of our systematic review of the literature demonstrate that the use of PFS for intravitreal injection has benefits over vial-based intravitreal injection for the clinician, patients, and health care systems. Compared with vials, PFS are associated with increased procedural efficacy, improved safety (specifically decreased rates of endophthalmitis), and greater clinician preference, all of which support the use of PFS for administering intravitreal treatments. The time saving and safety benefits of PFS have positive implications for capacity, an important consideration for increasingly busy ophthalmology clinics.