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CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL
Anti-Vascular Endothelial Growth Factor Drugs for the Treatment of Retinal Conditions: A Review of the Safety
Service Line: Rapid Response Service
Version: 1.0
Publication Date: February 28, 2017
Report Length: 36 Pages
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 2
Authors: Raywat Deonandan, Sarah Jones
Cite As: Anti-vascular endothelial growth factor drugs for the treatment of retinal conditions: A Review of the Safety. Ottawa: CADTH; 2017 Feb. (CADTH rapid
response report: summary with critical appraisal).
ISSN: 1922-8147 (online)
Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders,
and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document,
the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular
purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical
judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and
Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services.
While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date
the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the
quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing
this document. The views and opinions of third parties published in this document do not necessarily state or reflect those of CADTH.
CADTH is not responsible for any errors, omissions, injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or
conclusions contained in or implied by the contents of this document or any of the source materials.
This document may contain links to third-party websites. CADTH does not have control over the content of such sites. Use of third-party sites is governed by
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has no responsibility for the collection, use, and disclosure of personal information by third-party sites.
Subject to the aforementioned limitations, the views expressed herein are those of CADTH and do not necessarily represent the views of Canada’s federal,
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only, provided it is not modified when reproduced and appropriate credit is given to CADTH and its licensors.
About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada’s health care decision-makers with objective evidence
to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system.
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 3
Context and Policy Issues Retinal conditions, such as age related macular degeneration (AMD), diabetic
macular edema (DME), retinal vein occlusion (RVO), and choroidal
neovascularization due to pathologic myopia (CNV due to PM) are an important public
health concern that threatens the vision of millions of patients in Canada.1 The
mechanism of these conditions involve the new formation of blood vessels in the
retina that eventually leads to loss of vision.2 Anti-vascular endothelial growth factor
(Anti-VEGF) inhibits this growth and allows the restoration of vision.1 Currently in
Canada, two licensed anti-VEGF agents are available in the market; ranibizumab and
aflibercept. Bevacizumab, on the other hand, has been developed as an anti-cancer
drug.3 However, its close molecular resemblance to ranibizumab and identical
mechanism of action has made it a widely used option, especially in environments
that are strained on health resources.4, 5
However, despite the wide use of bevacizumab for retinal conditions, and the
availability of several high-quality randomized controlled trials for its efficacy,2
Bevacizumab still lacks a Health Canada review for retinal indications.1 The
bevacizumab product monograph carries a warning regarding the intravitreal use of
bevacizumab, citing increased risk of ophthalmic complications.3 In addition, the
intravenous use of bevacizumab in cancer patients is often associated with increased
risk of thromboembolic events (e.g. stroke).3
The CADTH therapeutic review titled “Anti–Vascular Endothelial Growth Factor Drugs
for the Treatment of Retinal Conditions” established that the efficacy of bevacizumab
is not different than ranibizumab or aflibercept, and did not observe any signals
indicating issues regarding bevacizumab comparative safety.2 However, the CADTH
recommendation report for the therapeutic review identifies the lack of large
randomized trials powered to detect differences in harms outcomes as a research
gap.1 The statistical power required to detect a difference in harms outcome can
make a randomized clinical trial prohibitive.6 A review of available evidence regarding
safety of bevacizumab from real-world evidence is of high clinical value, as it
represents a useful tool for identifying any potential issues regarding the safety of
bevacizumab for use in treating retinal conditions. A summary and critical appraisal of
studies regarding bevacizumab safety, contrasted with those of ranibizumab and
aflibercept, for the treatment of retinal conditions would allow for a more informed and
evidence-based policy and clinical decision process.
Research Questions 1. What is the comparative safety of bevacizumab versus ranibizumab or
aflibercept for the treatment of retinal conditions?
2. What is the safety of bevacizumab for the treatment of retinal conditions?
3. What is the safety of ranibizumab for the treatment of retinal conditions?
4. What is the safety of aflibercept for the treatment of retinal conditions?
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 4
Key Findings This review included one HTA (health technology assessment) report, four systematic
reviews, seven cohort studies, four case-control studies, one time-series study, and
eighteen descriptive studies of bevacizumab, ranibizumab, and aflibercept for the
treatment of different retinal conditions. The majority of the comparative studies did
not show statistically significant differences in ocular and thromboembolic safety
outcomes between bevacizumab and the other anti-VEGF agents. Furthermore, most
comparative studies also did not show statistically significant differences between
bevacizumab and non-anti-VEGF users in terms of thromboembolic safety outcomes.
The few studies that did show differences are of lower quality than the ones that did
not show such differences.
Descriptive studies indicate that endophthalmitis is a rare outcome associated with
the use of intravitreal anti-VEGF agents, with similar incidence rates across uses of
bevacizumab (ranging from <0.1% to 0.2%), ranibizumab (ranging from <0.1% to
0.423% in one study), and aflibercept (four studies <0.1%).
Methods
Literature Search Methods A limited literature search was conducted of key databases and indices, including
PubMed, The Cochrane Library, University of York Centre for Reviews and
Dissemination (CRD) databases, Canadian and major international health technology
agencies; a focused Internet search was also conducted. Methodological filters were
applied to limit retrieval to health technology assessments, systematic reviews, meta-
analyses, randomized controlled trials, as well as non-randomized studies containing
safety data. Where possible, retrieval was limited to the human population. The
search was also limited to English language documents published between January 1
2012 and January 30, 2017.
Selection Criteria and Methods One reviewer screened citations and selected studies. In the first level of screening,
titles and abstracts were reviewed and potentially relevant articles were retrieved and
assessed for inclusion. The final selection of full-text articles was based on the
inclusion criteria presented in Table 1.
Table 1: Selection Criteria
Population Adult patients with wet age-related macular degeneration, diabetic macular edema, retinal vein occlusion, or choroidal neovascularization due to pathologic myopia
Intervention Bevacizumab, Ranibizumab, or Aflibercept
Comparator No comparator, photodynamic therapy, pegatinib, placebo, ranibizumab, or aflibercept
Outcomes Ophthalmic-related outcomes: intraocular inflammation, endophthalmitis, uveitis, retinal detachment Cardio-thromboembolic outcomes: myocardial infarction, ischemic stroke, hemorrhagic stroke, bleeding, transient ischemic attack, venous thromboembolism, arterial-thromboembolic events
Study Designs Health Technology Assessment (HTA) reports, systematic reviews with meta-analysis, randomized controlled trials (RCT), observational studies
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 5
Exclusion Criteria Articles were excluded if they did not meet the selection criteria outlined in Table 1,
did not asses safety outcomes as a primary outcome, were covered in an included
review, were duplicate publications, were part of an included health technology
assessment or systematic review, or they were published prior to 2012.
Critical Appraisal of Individual Studies Included HTA and systematic reviews reports were assessed using the Assessment
of Multiple Systematic Reviews (AMSTAR) tool.26
The included observational studies
were critically appraised using the modified Downs and Black checklist.27
Summary
scores were not calculated for the included studies; rather, a review of the strengths
and limitations of each included study were described narratively.
Summary of Evidence
Quantity of Research Available A total of 693 citations were identified in the literature search. Following screening of
titles and abstracts, 604 citations were excluded and 89 potentially relevant reports
from the electronic search were retrieved for full-text review. One potentially relevant
publication was retrieved from the grey literature search. Of these 90 potentially
relevant articles, 65 publications were excluded for various reasons, while 35
publications met the inclusion criteria and were included in this report. Appendix 1
describes the PRISMA flowchart of the study selection.
Summary of Study Characteristics Detailed study characteristics can be found in Appendix 2.
Study Design
Of the included studies; one study was a health technology assessment (HTA)
following a systematic review and meta-analysis methodology which systematically
reviewed and meta-analysed RCTs. It included a total of 30 RCTs examining anti-
VEGF in different retinal conditions. The literature search in the HTA was conducted
on May 27, 2015 and updated November 13, 2015.2 Four additional included studies
were published systematic reviews and meta-analyses Of these four, one was
published in 2012 and included 11 RCTs,7 two published in 2014 with one including 9
RCTs28
, while the other included 4 RCTs28
; the fourth systematic review and meta-
analysis was published in 2016 and included 10 RCTs along with a separate analysis
of a few non-randomized and observational studies.29
Observational studies included
one that was both of a cohort and case-control design,30
six were of cohort design,5, 8,
9, 31-33 three were of case-control design,
34-36 one was a time-series analysis,
37 18
were descriptive studies with no comparator,6, 10-25, 38
and one study had no clear
study design that compared the odds of a specific adverse outcome in a registry to
other adverse events.39
Country of Origin
There were seven studies from Canada,2, 6, 8, 9, 30, 34, 37
six studies from the United
States,5, 11, 13, 15, 31, 33
two from the United Kingdom,24, 36
two from Italy,28, 39
two from
Thailand,16, 22
two from Korea,18, 32
and two from Singapore.21, 38
Each of the
remaining 12 studies was produced in a different country, including parts of Europe,
Asia, and the Middle East.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 6
Patient Population
All the included studies included patients with retinal conditions that require an anti-
VEGF treatment. Most of the included studies (26 out of 35 studies) included
population with mixed retinal conditions.2, 5, 6, 8-23, 31, 33-37, 39
All of the systematic
reviews (4 studies) only included AMD (age related macular degeneration) patients.7,
28, 29, 40 Five observational studies only included AMD patients.
24, 25, 30, 32, 38
Interventions and Comparators
Of the included studies, six included bevacizumab, ranibizumab, and aflibercept as
part of their intervention/ exposure,2, 11, 12, 15, 19, 21
13 included both bevacizumab and
ranibizumab6, 7, 9, 10, 13, 16-18, 22, 34, 37-39
, 10 only included bevacizumab5, 8, 14, 20, 28-31, 35, 40
five only included ranibizumab,23-25, 32, 36
and one only included aflibercept.33
Most of
the included studies(18) were descriptive in nature and had no comparator.6, 10-25, 38
While the most common comparator was ranibizumab,2, 5, 7, 8, 28, 29, 31, 33, 39, 40
other
comparators included aflibercept,2, 31
photodynamic therapy,29
and control groups for
case-control designed studies and one cohort study.30, 32, 34-36
Some of the unique
comparators were present in the time-series analysis as the period before the
introduction of anti-VEGF to the Canadian market,30
the incidence rate of the
outcomes in the population,38
and self-matching control.9
Outcomes
Outcomes covered in this review can be classified into two major categories: ocular
and systemic. The most commonly reported ocular safety outcome was
endophthalmitis.2, 5, 6, 8, 10-25, 31, 33, 36, 39
The most commonly reported systemic safety
outcome was related to thromboembolic events, such as myocardial infarction (MI)
and stroke.2, 7, 9, 21, 28-30, 32, 34, 35, 37-40
Summary of Critical Appraisal An overview of critical appraisal points for each study can be found in Appendix 3.
The HTA report and the included systematic reviews were, overall, well conducted.
Only the HTA report provided a pre-published protocol and included a search of the
grey literature. Additionally, Schmucker et al7 did not include a clear description of the
methods used to synthesize data, while Mikacic et al29
did not include description of
the method used to extract data and did not report sufficiently on patients
characteristics in the included trials. Cohort studies included in this review were well
conducted and reported. Six of the seven included cohort studies were population-
based studies with a large sample size, thus reducing the risk of selection bias
through minimal selection criteria and wide representation of patients.5, 9, 30-33
The
cohort study conducted by Sharma et al.8 is considered to have a high risk of
selection bias due to the single centre nature of the study, unclear sampling method,
and relatively small sample size (N = 1,584).
The four included case-control studies provided appropriate controls. Two used
population-based database to identify cases and controls; cases were generally
included if a patient received an anti-VEGF for the treatment of a retinal condition,
while controls differed between studies where some included anti-VEGF naïve
patients with retinal conditions controlled for sociodemographic factors, or patients
who received a different anti-VEGF agent.30, 34
The case-control study conducted by
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 7
Lyall et al.36
used estimation methods that were not clearly reported to determine the
denominator.
One time-series analysis by Campbell et al.37
was included. It is an ecological study,
with the limitation that an ecological study cannot be used to inform individual patient
care. However, the study was well designed and conducted to capture changes in
hospitalization rates due to stroke at different time periods corresponding with
different utilization periods of anti-VEGF agents. The study was based on validated
databases, had a clearly described patient population, clearly outlined appropriate
methods to acquire and aggregate data, and provided a clear and appropriate
statistical analysis.
One study conducted by Biagi et al.39
had an unclear study design. The study looked
at adverse events reported to a pharmacovigilance registry, determined the most
common adverse event reported for bevacizumab, ranibizumab, and pegaptanib, and
compared the odds of a specific adverse event in one group (e.g. odds of
endophthalmitis in bevacizumab reported adverse events) to the odds of the same
adverse event in the aggregated two other groups (e.g. to the odds of endophthalmitis
in an aggregate of ranibizumab and pegaptanib). The study does not specify a study
design, nor does it clearly describe the statistical analysis used. While its overall
layout suggests that it is case-control in nature, the denominator used in their
statistical analysis is simply the overall events of a given group, excluding the case
being examined. This would mean that the study’s outcome is the odds of developing
a specific outcome in a population that at least has one adverse event, rather than the
odds of being exposed to an intervention given the outcome exists, which is how a
case-control study’s odds ratio is typically computed. This difference limits the
generalizability of the study.
The included descriptive studies give us an indication of the incidences of specific
outcomes in specific interventions in an examined population of patients with retinal
conditions requiring anti-VEGF treatment. However, such outcomes and rates are
difficult to generalize beyond the population of each descriptive study, as no analyses
of contrast populations are provided.
Throughout the consideration of included studies, attention was given to the sample
sizes, as both examined categories of outcomes are infrequent, thus requiring large
sample sizes to detect meaningful differences. One study has reported that to detect
differences in the outcome of endophthalmitis at an alpha of 0.05 and beta of 80, at
least 25,814 observations would be needed in each group.6 Whether there was
sufficient sample size to detect differences in thromboembolic outcomes is unclear.
With regard to endophthalmitis, however, five studies had sufficient power to detect
statistically significant differences.5, 15, 31, 33, 36
Summary of Findings Detailed findings can be found in Appendix 4.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 8
What is the comparative safety of bevacizumab versus ranibizumab or aflibercept for
the treatment of retinal conditions?
One HTA report conducted by CADTH included 30 randomized clinical trials that did
not show any differences between bevacizumab, ranibizumab, or aflibercept in the
synthesized outcomes of adverse events, serious adverse events, legal blindness,
arteriothrombotic events, and endophthalmitis. However, the report also cautions that
none of the included trials were sufficiently powered to detect differences in harms.2
Of the four systematic reviews and meta-analyses covered in this rapid response, one
has shown a statistically significant difference in the occurrence of serious ocular
events (relative risk [RR] = 2.8; 95% CI 1.2 to 6.5), but not of thromboembolic events
(RR = 0.80; 95%CI 0.30 to 2.13).7 However, this particular systematic review was
published in 2012, and subsequent trials that were included in later systematic
reviews failed to see the same result.28, 29, 40
In the cohort studies comparing bevacizumab to ranibizumab; two large retrospective
population-based cohort studies failed to show a difference in the outcome of
endophthalmitis between the two anti-VEGF agents,5, 31
and between bevacizumab
and aflibercept.31
In contrast, one single centre retrospective cohort study showed
that the rate of enophthalmitis is statistically significantly higher in bevacizumab as
compared to ranibizumab.8 This study, however, has a high risk of selection bias,
mainly due to its nature as a single centre study, where a possible isolated outbreak
of a contaminated anti-VEGF treatment or mishandling of the intravitreal injection can
lead to an ungeneralizable result. This is further compounded by apparent imbalances
in the characteristics of patients in each group, although it is unlikely that these
imbalances may affect the endophthalmitis outcome. These appraisal points are
reflected in the wide confidence interval displayed in the odds ratio of endophthalmitis
in bevacizumab compared to ranibizumab treated group (OR = 11.7, 95%CI 1.5 to
93), indicating a high degree of uncertainty.
With regard to thromboembolic outcomes, two population-based retrospective cohort
studies in Canada and South Korea showed no increased risk compared to non-anti-
VEGF users.30, 32
In contrast, one population-based retrospective cohort study
showed that both bevacizumab and ranibizumab treated-patients have an increased
risk of thromboembolic events compared to self-matched controls, but the risk is
similar in both agents.9 However, this study used a self-matching control that may
confound the outcome due to the natural progression of risk factors over time.9
Of the three case-control studies included in this rapid response, none has identified
bevacizumab as a factor associated with thromboembolic events when compared with
ranibizumab or non-anti-VEGF treatment controls.
Finally, this review includes a time-series analysis that compared hospital admissions
due to stroke in patients with retinal condition diagnosis during the period before the
introduction of bevacizumab, to the period where bevacizumab was dominating, and
to the period where ranibizumab was dominating. The study did not find a statistically
significant increase in the rate of hospitalization due to stroke that can be attributed to
the increased use and uptake of either bevacizumab or ranibizumab.37
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 9
What is the safety of bevacizumab for the treatment of retinal conditions?
Further to the previously described comparative evidence, descriptive studies
consistently showed a very low rate of endophthalmitis after bevacizumab use, which
is similar to the endophthalmitis rate seen in other intravitreal injections. The reported
rates of endophthalmitis with bevacizumab use in descriptive studies were: 0.004%,10
0.006%,11
0%,12
0.074%,6 0%,
13 0.012%,
14 0.012%,
15 0.107%,
22 0.053%,
16 0%,
17
0%,18
0.2%,19
0.09%,20
and 0.01%.21
What is the safety of ranibizumab for the treatment of retinal conditions?
Further to the previously described evidence comparing with bevacizumab, the
reported rates in the descriptive studies of endophthalmitis with the use of
ranibizumab were: 0%,10
0%,11
0.008%,12
0.032%,6 0.039%,
13 0.018%,
15 0.036%,
23
0.11%,25
0.423%,22
0%,16
0.21%,17
0%,18
0.04%,24
0%,19
0%,21
What is the safety of aflibercept for the treatment of retinal conditions?
Further to the previously described comparison with bevacizumab, one population-
based retrospective cohort found a statistically significant increase in the risk of
endophthalmitis (termed as “severe ocular inflammation”) with the use of aflibercept
compared to ranibizumab.33
The authors of the paper attributed the observed
increase to the recent introduction of aflibercept, as opposed to the more established
ranibizumab, which health professional were better trained at using.
In addition, the reported rates in the descriptive studies of endophthalmitis with the
use of aflibercept were: 0%,12
0.031%,15
0%,19
0%.21
Limitations Generally, descriptive studies provide little value beyond hypothesis generation.
There is a possibility that a number of the included observational studies are
underpowered and are thus unable to detect meaningful differences in outcomes that
are as infrequent as those observed herein. The HTA report along with the included
systematic reviews and meta-analyses all reported uncertainty in the synthesized
safety outcomes, mainly due to the knowledge that large sample size is needed to
detect meaningful differences in these outcomes. The systematic review conducted
by Schmucker et al.7 was published in 2012 and may need updating as many new
trials have been published since its publication. Similarly, Moja et al.28
and Wang et
al.40
were published in 2014 and may need to include data from newer trials. The
most updated and comprehensive systematic review and meta-analysis was the one
reported in the HTA report.2
A large portion (12) of the observational studies were conducted in North America,5, 6,
8, 9, 11, 13, 15, 30, 31, 33, 34, 37 ensuring a population that can be comparable to the Canadian
population. Interventions of bevacizumab, ranibizumab, and aflibercept were
consistent with minimum variation in the dose.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 10
Conclusions and Implications for Decision or Policy Making While the risk of thromboembolic events and endophthalmitis are present, it seems
that this risk is not more pronounced in one anti-VEGF agent over another. Also, it is
still unclear if this risk is considerably higher in patients treated with anti-VEGF than in
a matching non-anti-VEGF treated population. A definite answer can only be provided
through a properly powered and designed RCT. Such a study is unlikely to be
conducted, however, due to the rarity of the outcome and the requirement of a large
sample size.
The lack of red-flags in this review may encourage policy makers to utilize
bevacizumab as an agent that is comparable in efficacy and safety to ranibizumab
and aflibercept. However, the identified literature concerned with endophthalmitis has
emphasized the importance of proper sterile procedures to prepare bevacizumab into
an intravitreal injection.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 11
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22. Kanchanaranya N, Rojdamrongratana D, Piyasoonthorn P. Incidence of post-intravitreal anti-VEGF endophthalmitis at Thammasat University Hospital. J Med Assoc Thai. 2015;98(5):489-94.
23. Hasler PW, Bloch SB, Villumsen J, Fuchs J, Lund-Andersen H, Larsen M. Safety study of 38,503 intravitreal ranibizumab injections performed mainly by physicians in training and nurses in a hospital setting. Acta Ophthalmol. 2015;93(2):122-5.
24. Simcock P, Kingett B, Mann N, Reddy V, Park J. A safety audit of the first 10 000 intravitreal ranibizumab injections performed by nurse practitioners. Eye (Lond). 2014;28(10):1161-4.
25. Holz FG, Bandello F, Gillies M, Mitchell P, Osborne A, Sheidow T, et al. Safety of ranibizumab in routine clinical practice: 1-year retrospective pooled analysis of four European neovascular AMD registries within the LUMINOUS programme. Br J Ophthalmol. 2013;97(9):1161-7.
26. Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C, et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Med Res Methodol. 2007;7:10.
27. Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. Journal of Epidemiology and Community Health. 1998;52(6):377-84.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 12
28. Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, et al. Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014(9):CD011230.
29. Mikacic I, Bosnar D. Intravitreal Bevacizumab and Cardiovascular Risk in Patients with Age-Related Macular Degeneration: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Observational Studies. Drug Saf. 2016;39(6):517-41.
30. Etminan M, Maberley DA, Babiuk DW, Carleton BC. Risk of Myocardial Infarction and Stroke With Single or Repeated Doses of Intravitreal Bevacizumab in Age-Related Macular Degeneration. Am J Ophthalmol. 2016;163:53-8.
31. Rayess N, Rahimy E, Storey P, Shah CP, Wolfe JD, Chen E, et al. Postinjection Endophthalmitis Rates and Characteristics Following Intravitreal Bevacizumab, Ranibizumab, and Aflibercept. Am J Ophthalmol. 2016;165:88-93.
32. Rim TH, Lee CS, Lee SC, Kim DW, Kim SS. Intravitreal ranibizumab therapy for neovascular age-related macular degeneration and the risk of stroke: A national sample cohort study. Retina. 2016;36(11):2166-74.
33. Souied EH, Dugel PU, Ferreira A, Hashmonay R, Lu J, Kelly SP. Severe Ocular Inflammation Following Ranibizumab or Aflibercept Injections for Age-Related Macular Degeneration: A Retrospective Claims Database Analysis. Ophthalmic Epidemiol. 2016;23(2):71-9.
34. Campbell RJ, Gill SS, Bronskill SE, Paterson JM, Whitehead M, Bell CM. Adverse events with intravitreal injection of vascular endothelial growth factor inhibitors: nested case-control study. BMJ. 2012;345:e4203.
35. Fischer N, Moisseiev E, Waisbourd M, Goldstein M, Loewenstein A. A matched-control comparison of serious adverse events after intravitreal injections of bevacizumab for age-related macular degeneration and cataract extraction. Clin Ophthalmol. 2013;7:621-5.
36. Lyall DA, Tey A, Foot B, Roxburgh ST, Virdi M, Robertson C, et al. Post-intravitreal anti-VEGF endophthalmitis in the United Kingdom: incidence, features, risk factors, and outcomes. Eye (Lond). 2012;26(12):1517-26.
37. Campbell RJ, Bell CM, Paterson JM, Bronskill SE, Moineddin R, Whitehead M, et al. Stroke rates after introduction of vascular endothelial growth factor inhibitors for macular degeneration: a time series analysis. Ophthalmology. 2012;119(8):1604-8.
38. Ng WY, Tan GS, Ong PG, Cheng CY, Cheung CY, Wong DW, et al. Incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy. Am J Ophthalmol. 2015;159(3):557-64.
39. Biagi C, Conti V, Montanaro N, Melis M, Buccellato E, Donati M, et al. Comparative safety profiles of intravitreal bevacizumab, ranibizumab and pegaptanib: the analysis of the WHO database of adverse drug reactions. Eur J Clin Pharmacol. 2014;70(12):1505-12.
40. Wang W, Zhang X. Systemic adverse events after intravitreal bevacizumab versus ranibizumab for age-related macular degeneration: a meta-analysis. PLoS ONE. 2014;9(10):e109744.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 13
Appendix 1: Selection of Included Studies
604 citations excluded
89 potentially relevant articles retrieved for scrutiny (full text, if available)
1 potentially relevant report retrieved from other sources (grey
literature, hand search)
90 potentially relevant reports
65 reports excluded: -irrelevant population (0) -irrelevant intervention (3) -irrelevant comparator (4) -irrelevant outcomes (24) -already included in at least one of the selected systematic reviews (11) -published in language other than English (1) -other (review articles, editorials)(12)
35 reports included in review
693 citations identified from electronic literature search and screened
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 14
Appendix 2: Characteristics of Included Publications Table 1: Characteristics of Included Clinical Studies
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
Health Technology Assessment
CADTH, 2016,2 Canada 30 RCTs
AMD, DME, RVO, and CNV due to PM
Bevacizumab
Ranibizumab
Aflibercept
Bevacizumab
Ranibizumab
Aflibercept
Placebo (Sham)
Serious adverse events
Mortality
Thromboembolism
Endophthalmitis
Retinal detachment
Systematic reviews
Mikacic, 2016,29
Croatia 10 RCTs
1 Non-randomized controlled clinical trial
2 Cohort studies
2 Uncontrolled cohort studies
AMD patients
Bevacizumab Ranibizumab
Photodynamic therapy
All-cause mortality
Vascular death
MI or angina
Stroke
TIA
Arterial thromboembolic events
Moja, 2014,28
Italy 9 RCTs
AMD patients
Bevacizumab Ranibizumab All-cause mortality
All serious adverse events
Fatal MI
Non-fatal MI
Stroke
Arteriothrombotic events
Serious infections
Gastrointestinal disorders
Schmucker, 2012,7
Austria 11 RCTs
AMD patients
Bevacizumab
Ranibizumab
Bevacizumab
Ranibizumab
Any other comparison
Arterial thromboembolic events
Serious ocular adverse events
All-cause mortality
Wang, 2014,40
China 4 RCTs
AMD patients
Bevacizumab Ranibizumab All-cause mortality
Arterial thromboembolic events
Stroke
Nonfatal MI
Vascular death
Venous thrombotic events
Hypertension
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 15
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
Observational Studies
Al-Rashaed, 2016,10
Saudi Arabia
Retrospective descriptive study
N = 22,674 injections
Patients with any retinal condition who undergone Anti-VEGF injections
Bevacizumab
Ranibizumab
NA Endophthalmitis
Bhavsar, 2015,11
Unites States
Retrospective descriptive study
N = 18,839 injections (3,457 patients)
Patients with any retinal condition who undergone Intravitreal injection
Bevacizumab
Ranibizumab
Triamcinolone acetonide
Pegaptanib sodium
Aflibercept
Dexamethasone implants
Dexamethasone sodium phosphate
Ganciclovir
NA Endophthalmitis
Biagi, 2014,39
Italy Analysis of adverse drug reactions registry (WHO-VigiBase)
N = 7,753 drug reaction pairs
Any adverse drug reaction related to intravitreal injection
Bevacizumab
Ranibizumab
Pegaptanib
Bevacizumab
Ranibizumab
Pegaptanib
Endophthalmitis
Uveitis
CVA
MI
Campbell, 2012a,37
Canada
Time series analysis, population based
N = 116,388 patients
Patients with retinal disease diagnosis
Bevacizumab dominated period
Ranibizumab dominated period
Pre-bevacizumab period
Hospitalization for ischemic stroke
Campbell, 2012b,34
Canada
Population based nested case-control study
N = 91,278
Patients with retinal disease diagnosis
Bevacizumab
Ranibizumab
Control Ischemic stroke
MI
Congestive heart failure
Venous thromboembolism
Casparis, 2014,12
Sweden
Retrospective descriptive study
N = 40,011 injections
Patients with any retinal condition requiring anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
Aflibercept
Pegaptanib
NA Endophthalmitis
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 16
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
Cheung, 2012,6 Canada Retrospective
descriptive study
N = 15,895 injections
Patients with any retinal condition who undergone intravitreal injection
Bevacizumab
Ranibizumab
Triamcinolone acetonide
NA Endophthalmitis
Englander, 2013,13
United States
Retrospective descriptive study
N = 10,208 injections
Patients with any retinal condition who undergone intravitreal injection
Bevacizumab
Ranibizumab
NA Endophthalmitis
Etminan, 2015,30
Canada
Population based retrospective cohort study and a nested case-control study
Cohort study N = 8,208
Nested case-control N = 3,443
AMD patients
Bevacizumab Anti-VEGF naïve patients
Control
MI
Stroke
Falavarjani, 2015,14
Iran Retrospective descriptive study
N = 8,037 injections
Patients with any retinal condition who undergone intravitreal bevacizumab injection
Bevacizumab NA Endophthalmitis
Fischer, 2013,35
Israel Retrospective case-control study
N = 130 (65 cases, 65 control)
Patients with any retinal condition who undergone intravitreal bevacizumab injection
Bevacizumab Control Hospital admission due to thromboembolic event
Gregori, 2015,15
United States
Population based retrospective descriptive study
N = 121,285 injections
Patients with any retinal condition who
Bevacizumab
Ranibizumab
Aflibercept
Pegaptanib
NA Endophthalmitis
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 17
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
undergone anti-VEGF intravitreal injection
Hasler, 2015,23
Denmark
Retrospective descriptive study
N = 38,503 injections (4,623 eyes of 3,679 patients)
Patients with any retinal condition who undergone ranibizumab intravitreal injection
Ranibizumab NA Endophthalmitis
Traumatic cataract
Intra-ocular hemorrhage
Retinal detachment
Holz, 2013,25
Germany, Netherlands, Belgium, and Sweden
Retrospective descriptive analysis of ranibizumab AMD safety registries
N = 4,444 patients
AMD patients in ranibizumab registries in four European countries
Ranibizumab NA Endophthalmitis
Traumatic cataract
Intra-ocular hemorrhage
Retinal detachment
Kanchanaranya, 2015,
22 Thailand
Retrospective descriptive study
N = 1,169 injections (519 eyes)
Patients with any retinal condition who undergone bevacizumab or ranibizumab intravitreal injection
Bevacizumab
Ranibizumab
NA Endophthalmitis
Kunavisarut, 2013,16
Thailand
Retrospective descriptive study
N = 2,077 injections (1,006 eyes of 878 patients)
Patients with any retinal condition who undergone anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
Pegaptanib
NA Endophthalmitis
Lyall, 2012,36
United Kingdom
Prospective observational and case-control study
N = 186,972 estimated injections
Patients with reported
Ranibizumab Control (only for risk factors identification)
Endophthalmitis
Possible risk factors associated with endophthalmitis
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 18
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
endophthalmitis
Ng, 2012,17
Hong Kong Prospective descriptive case-series study
N = 1,655 injections (392 eyes of 383 patients)
Patients with any retinal condition who undergone anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
NA Endophthalmitis
Ng, 2015,38
Singapore Population-based descriptive study
N = 1,182 patients
AMD patients treated with Anti-VEGF intravitreal injections
Bevacizumab
Ranibizumab
Incidence rate of outcomes in Singapore population
MI
Stroke
All-cause mortality
Park, 2013,18
Korea Retrospective descriptive study
N = 17,332 injections
Patients with any retinal condition who undergone anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
Triamcinolone acetonide
C3F8 gas
NA Endophthalmitis
Rayess, 2016,31
United States
Population based retrospective cohort study
N = 503,890 injections
Patients with AMD, DME, or RVO
Bevacizumab
Ranibizumab
Aflibercept
Endophthalmitis
Rim, 2016,32
Korea Population-based retrospective cohort study
N = 4,797 (cases = 467, control = 2,330)
Ranibizumab treated AMD patients
Ranibizumab Control Stroke
Schlenker, 2015,9
Canada Population-based
analysis with self-matching historical control
N = 57,919
Patients with any retinal condition who undergone
Bevacizumab
Ranibizumab
Self-matching historical data control
Thromboembolic events
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 19
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
ranibizumab or bevacizumab intravitreal injection
Sharma, 2012,8 Canada Retrospective cohort
study
N = 1,044
Patients with any retinal condition who undergone ranibizumab or bevacizumab intravitreal injection
Bevacizumab Ranibizumab Endophthalmitis
Simcock, 2014,24
United Kingdom
Retrospective descriptive study (safety audit)
N = 11,893
Ranibizumab treated AMD patients
Ranibizumab NA Endophthalmitis
Souied, 2015,33
United States
Population-based retrospective cohort study
N = 432,794 injections
Patients with any retinal condition who undergone ranibizumab or aflibercept intravitreal injection
Aflibercept Ranibizumab Severe ocular inflammation
Antibiotic associated endophthalmitis
Non-antibiotic associated endophthalmitis
Terzic, 2015,19
Bosnia and Herzegovina
Retrospective descriptive study
N = 1,101 injections
Patients with any retinal condition who undergone anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
Aflibercept
NA Endophthalmitis
VanderBeek, 2015,5
United States Population based
retrospective cohort study
N = 383,810 injections
Patients with any retinal condition who undergone ranibizumab or bevacizumab intravitreal injection
Bevacizumab Ranibizumab Endophthalmitis
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 20
First Author, Year, Country
Study/ Patient Characteristics
Intervention/ exposure
Comparator Clinical Safety Outcomes Measured
Wani, 2016,20
Kuwait Retrospective descriptive study
N = 5,429 injections
Patients with any retinal condition who undergone bevacizumab intravitreal injection
Bevacizumab NA Endophthalmitis
Xu, 2016,21
Singapore Retrospective descriptive study
N = 14,001 injections (2,225 patients)
Patients with any retinal condition who undergone anti-VEGF intravitreal injection
Bevacizumab
Ranibizumab
Aflibercept
NA Overall mortality
Fatal thromboembolic events
Non-fatal thromboembolic events
Endophthalmitis
AMD = age related macular degeneration; CADTH = Canadian Agency for Drugs and Technologies in Health; CNV due to PM = choroidal
neovascularization due to pathologic myopia; CVA = cerebrovascular accident; DME = diabetic macular edema; MI = myocardial infarction; NA = not
applicable; RVO = retinal vein occlusion; TIA = transient ischemic attack; VEGF = vascular endothelial growth factor; WHO = world health
organization
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 21
Appendix 3: Critical Appraisal of Included Publications Table 2: Strengths and Limitations of Systematic Reviews and Meta-Analyses using
AMSTAR checklist
Strengths Limitations
CADTH, 20162
Pre-specified and published protocol
Independent and duplicate study selection and data extraction
Included grey literature
Provided a comprehensive list of included studies
Provided comprehensive characteristics of included studies
Assessed and documented the quality and risk of bias in included studies
Data synthesis was discussed in details and was appropriate
Declared any potential conflict of interest
Lack of sufficient number of studies to assess all pre-specified safety outcomes across each designated patient population
Mikacic, 201629
Independent and duplicate study selection
Provided a comprehensive list of included studies
Assessed and documented the quality and risk of bias in included studies
Data synthesis was discussed and was appropriate
Declared any potential conflict of interest
Lack of a pre-specified and published protocol
Lack of reporting on data extraction method
Lack of inclusion of grey literature
Lack of reporting on detailed list of study characters
Moja, 201428
Pre-specified and published protocol
Independent and duplicate study selection and data extraction
Provided a comprehensive list of included studies
Provided comprehensive characteristics of included studies
Assessed and documented the quality and risk of bias in included studies
Data synthesis was discussed in details and was appropriate
Declared any potential conflict of interest
Lack of inclusion of grey literature
Schmucker, 20127
Pre-specified protocol
Independent and duplicate study selection and data extraction
Provided a comprehensive list of included studies
Provided comprehensive characteristics of included studies
Assessed and documented the quality and risk of bias in included studies
Data synthesis was discussed in details and was appropriate
Declared any potential conflict of interest
Protocol was not published
Lack of inclusion of grey literature
Method of conducting indirect comparison not well described
Wang, 201440
Independent and duplicate study selection and data extraction
Provided a comprehensive list of included studies
Provided comprehensive characteristics of included studies
Assessed and documented the quality and risk of bias in included studies
Data synthesis was discussed in details and was appropriate
Declared any potential conflict of interest
Lack of a pre-specified and published protocol
Lack of inclusion of grey literature
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 22
Table 3: Strengths and Limitations of Observational Studies using the Modified Downs and Black Checklist
Strengths Limitations
Al-Rashaed, 201610
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential variability
Data from a single centre
Insufficient power to detect difference in different exposures
Lack of reporting on follow-up rates
Lack of comprehensive reporting on patients characters
Bhavsar, 201511
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from a single surgeon
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Biagi, 201439
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Retrospective observational study
Unclear specific study design
Statistical analysis not well described
Lack of a description for the denominator
Lack of adjustment for potential confounders
Lack of reporting on the validity of dataset used
Lack of comprehensive reporting on patients characters
Campbell, 2012a37
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Detailed and appropriate statistical analysis
Large sample size provides sufficient power
Provided references for validity of database used
Ecological observational non-randomized study design
Study design cannot adjust for potential confounders
Ecological study results are not appropriate for patient-level inference
Campbell, 2012b34
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Detailed and appropriate statistical analysis
Comprehensive description of patients characteristics
Large sample size provides sufficient power
Observational case-control non-randomized design
Unable to include patients population not covered in the database used
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 23
Strengths Limitations
Provided references for validity of database used
Casparis, 201412
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Cheung, 20126
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Englander, 201313
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from a single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Etminan, 201530
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate comparison and control
Detailed and appropriate study design and statistical analysis
Proper handling of potential confounders
Comprehensive reporting of patients characters
Provided references for validity of database used
Observational non-randomized design
Lack of reporting on power analysis
Falavarjani, 201514
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 24
Strengths Limitations
Fischer, 201335
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Detailed and appropriate statistical analysis
Comprehensive description of patients characteristics
Observational case-control non-randomized design
Unable to include patients population not covered in the database used
Small sample size
Insufficiently powered to detect differences
Lack of reference to validity of database used
Lack of reporting handling of missing values
Lack of reporting on loss-to-follow-up rate
Gregori, 201515
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Population-based large sample size
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Lack of reporting on database validity
Hasler, 201523
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Large sample size
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Data from a single centre
Holz, 201325
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Large sample size
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Lack of reporting validity of database used
Lack of comprehensive reporting on patients characters
Lack of reporting on handling missing values
Kanchanaranya, 201522
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Kunavisarut, 201316
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 25
Strengths Limitations
Clearly described exposure
Captured specified outcomes
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Lyall, 201236
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate comparison and control
Comprehensive description of study design and statistical analysis
Comprehensive reporting of patients characters
Provided references for validity of database used
Observational non-randomized design
Denominator (control) were extrapolated from a single region into the whole population
Lack of reporting on power analysis
Lack of comprehensive reporting of patients characters
Lack of reporting on lost-to-follow-up rate
Lack of describing handling missing data
Lack of describing methods to account for potential confounders
Small sample size for assessment of some risk factors
Ng, 201217
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Ng, 201538
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Population based
Descriptive observational study
Qualitative comparison with the population incidence of outcome
Lack of description on how the study handled potential confounders
Lack of references regarding the validity of database used
Lack of power assessment
Lack of comprehensive reporting on patients characters
Park, 201318
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Rayess, 201631
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Observational non-randomized design
Lack of reporting on and handling of potential confounders
Lack of reporting on lost-to-follow-up rate
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 26
Strengths Limitations
Clearly described exposure
Captured specified outcomes
Appropriate comparison
Comprehensive description of study design and statistical analysis
Comprehensive reporting of patients characters
Multicenter study
Large sample size providing sufficient power to detect differences
Lack of describing handling missing data
Rim, 201632
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Detailed and appropriate statistical analysis
Comprehensive description of patients characteristics
Observational cohort non-randomized design
Unable to include patients population not covered in the database used
Lack of reference regarding the validity of database used
Schlenker, 20159
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Detailed and appropriate statistical analysis
Comprehensive description of patients characteristics
Large sample size provides sufficient power
Provided references for validity of database used
Observational case-control non-randomized design
Unable to include patients population not covered in the database used
Self-matching control may confound the picture due to the time factor leading to natural progression of potential confounders
Sharma, 20128
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate comparison
Comprehensive description of study design and statistical analysis
Comprehensive reporting of patients characters
Observational non-randomized design
Lack of reporting on and handling of potential confounders
Single centre
Small sample size
Lack of reporting on lost-to-follow-up rate
Lack of describing handling missing data
Simcock, 201424
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 27
Strengths Limitations
Souied, 201533
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Comprehensive and appropriate statistical analysis
Comprehensive description of patients characteristics
Adjustment for potential confounders
Large sample size provides sufficient power
Provided references for validity of database used
Observational case-control non-randomized design
Unable to include patients population not covered in the database used
Channeling bias may exist favouring ranibizumab since aflibercept is relatively new
Terzic, 201519
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
VanderBeek, 20155
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Appropriate control
Comprehensive and appropriate statistical analysis
Comprehensive description of patients characteristics
Adjustment for potential confounders
Large sample size provides sufficient power
Provided references for validity of database used
Observational case-control non-randomized design
Unable to include patients population not covered in the database used
Wani, 201620
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
Data from single centre
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
Xu, 201621
Clearly stated hypothesis
Clearly described outcomes
Clearly described patient population
Clearly described exposure
Captured specified outcomes
Descriptive observational study
Lack of comparative group (uncontrolled)
Inability to adjust for potential confounders
No assessment of potential population variability
Data from single centre
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 28
Strengths Limitations
Insufficient power to detect difference in different exposures
Lack of reporting on loss-to-follow-up rates
Lack of comprehensive reporting on patients characters
The dominator of number of injections may not be appropriate for calculating the rate of systemic adverse events
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 29
Appendix 4: Main Study Findings and Author’s Conclusions Table 4: Summary of Findings of Included Studies
Main Study Findings Author’s Conclusion
Health Technology Assessment
CADTH, 20162
Throughout the different study population covered in 30 included RCTs, 17 of which compared bevacizumab to either ranibizumab of aflibercept, no statistically significant difference was found between ranibizumab, bevacizumab, or aflibercept in terms of adverse events, serious adverse events, withdrawal due to adverse events, increased intraocular pressure, thromboembolic events, or endophthalmitis.
“Our study did not reveal any notable differences with respect to the potential for aflibercept, bevacizumab, and ranibizumab to do harm to patients with retinal conditions, both for non-specific safety outcomes as well as harms of special interest, such as bacterial endophthalmitis and retinal detachment. However, safety data were limited, and this conclusion is therefore highly uncertain”.
Systematic reviews
Mikacic, 201629
Data from five RCTs of bevacizumab compared to ranibizumab showed no statistically significant differences
All-cause mortality: OR = 1.103 (95%CI 0.641 to 1.898)
Vascular mortality: OR = 1.380 (95%CI 0.476 to 3.997)
MI: OR = 0.551 (95%CI 0.265 to 1.146)
Stroke: OR = 0.657 (95%CI 0.260 to 1.660)
TIA: OR = 1.536 (95%CI 0.444 to 5.313)
Atherothrombotic events: OR = 1.007 (95%CI 0.641 to 1.593)
Venous thromboembolism: OR = 2.325 (95%CI 0.963 to 5.612)
Observational data did not demonstrate any differences
“Published data on IVTB (intravitreal bevacizumab) in ARMD (age related macular degeneration) provide only a low level of evidence on its cardiovascular safety and do not support any finite conclusions”.
Moja, 201428
Data from nine RCTs of bevacizumab compared to ranibizumab showed no statistically significant differences except with relation to gastrointestinal disorders
Death: RR = 1.10 (95%CI 0.78 to 1.57)
Systemic serious adverse events: RR = 1.08 (95%CI 0.90 to 1.31)
Gastrointestinal disorders: RR = 1.19 (95%CI 1.06 to 3.19)
“This systematic review of non-industry sponsored RCTs could not determine a difference between intravitreal bevacizumab and ranibizumab for deaths, All SSAEs, or specific subsets of SSAEs in the first two years of treatment, with the exception of gastrointestinal disorders. The current evidence is imprecise and might vary across levels of patient risks, but overall suggests that if a difference exists, it is likely to be small. Health policies for the utilisation of ranibizumab instead of bevacizumab as a routine intervention for neovascular AMD for reasons of systemic safety are not sustained by evidence. The main results and quality of evidence should be verified once all trials are fully published”.
Schmucker, 20127
Direct evidence from 4 RCTs showed higher risk with bevacizumab compared to ranibizumab in serious ocular adverse events and gastrointestinal disorders but not in thromboembolic events
Indirect evidence of bevacizumab compared to ranibizumab synthesized from five RCTs showed increased risk of serious ocular events with bevacizumab compared to ranibizumab,
“Evidence from head-to-head trials raises concern about an increased risk of ocular and multiple systemic AE with bevacizumab. Therefore, clinicians and patients should continue to carefully weight up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 30
Main Study Findings Author’s Conclusion
and an increased in ranibizumab risk of non-ocular hemorrhage compared to bevacizumab
Serious ocular adverse events (direct): RR = 1.3 (95%CI 1.0 to 1.7)
Serious ocular adverse events (indirect): RR = 1.7 (95%CI 1.1 to 8.9)
Arterial thromboembolism: RR = 0.8 (95%CI 0.3 to 2.1)
Death: RR = 1.7 (95%CI 0.8 to 3.8)
Gastrointestinal disorder: RR = 1.3 (95%CI 1.0 to 1.7)
Non-ocular hemorrhage (for ranibizumab): relative risk = 1.7 (95%CI 1.1 to 2.7)
detected in this systematic review”.
Wang, 201440
Pooled data from four RCTs did not show significant differences between bevacizumab and ranibizumab
Death: RR = 1.11 (95%CI 0.77 to 1.61)
Arteriothrombotic events: RR = 1.03 (95%CI 0.69 to 1.55)
Stroke: RR = 0.84 (95%CI 0.39 to 1.80)
Nonfatal MI: RR = 0.97 (0.39 to 1.80)
Vascular death: RR = 1.24 (95%CI 0.63 to 2.44)
Venous thromboembolism: RR = 2.38 (95%CI 0.94 to 6.04)
Hypertension: RR = 1.02 (95%CI 0.29 to 3.62)
“The meta-analysis shows that both treatments are comparably safe. However, the findings from our study must be confirmed in future research via well-designed cohort or intervention studies because of the limited number of studies”.
Observational Studied
Al-Rashaed, 201610
Bevacizumab: 1 case of endophthalmitis in 21,387 injections (endophthalmitis rate = 0.004%)
Ranibizumab: No cases of endophthalmitis in 1,287 injections (endophthalmitis rate = 0%)
“The rate of endophthalmitis after IVT bevacizumab and ranibizumab was very low. We recommend following a standardized injection protocol, adherence to sterile techniques, and proper patient follow-up are determinant factors for low incidence rates. In addition, endophthalmitis after IVT bevacizumab and ranibizumab have poor visual outcomes despite prompt treatment”.
Bhavsar, 201511
Bevacizumab: 1 case of endophthalmitis in 15,479 injections (endophthalmitis rate = 0.006%)
Ranibizumab: No cases of endophthalmitis in 1,014 injections (endophthalmitis rate = 0%)
“A low incidence of endophthalmitis can be achieved when topical antibiotics are omitted”.
Biagi, 201439
The denominator here is the collective adverse events reported for each drug, and not the population who received an intravitreal injection of the drug
Bevacizumab N = 2,069
Ranibizumab N = 5,130
Pegaptanib N = 554
Reported OR of endophthalmitis in bevacizumab compared to ranibizumab pooled with pegaptanib: 1.90 (95%CI 1.48 to 2.43)
Reported OR of uveitis in bevacizumab compared to ranibizumab pooled with pegaptanib: 10.62 (95%CI 6.62 to
“Our data showed an elevated disproportionality for cardiovascular ADRs (adverse drug reaction) in patients treated with ranibizumab and for infective ocular reactions in those treated with bevacizumab. No relevant safety issues were identified for pegaptanib. These findings suggest bevacizumab as a suitable choice for AMD therapy due to its effectiveness similar to that of ranibizumab, its favourable safety profile and for its lower cost”.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 31
Main Study Findings Author’s Conclusion
17.05)
Reported OR of CVA in ranibizumab compared to bevacizumab pooled with pegaptanib: 1.54 (95%CI 1.14 to 2.10)
Reported OR of MI in ranibizumab compared to bevacizumab pooled with pegaptanib: 1.73 (95%CI 1.18 to 2.53)
Campbell, 2012a37
Pre-bevacizumab period N = 30,187
Bevacizumab dominant therapy period N = 44,797
Ranibizumab dominant therapy period N = 60,415
No statistically significant increase in hospitalization due to ischemic stroke was noted when pre-bevacizumab period was compared with bevacizumab dominant period and ranibizumab dominant period
“The rapid uptake of vascular endothelial growth factor (VEGF) inhibitors for AMD was not associated with a change in the rate of hospitalization for stroke among Ontario seniors with retinal disease. Furthermore, stroke rates in the bevacizumab and ranibizumab periods were not different. These population-level results complement the findings of a recently published trial comparing bevacizumab and ranibizumab, and may assist clinicians and policy makers as they balance the comparative efficacy, safety, and cost of these 2 closely related treatments”.
Campbell, 2012b34
Bevacizumab = 7,388
Control = 35,962
No statistically significant difference was noted between bevacizumab or ranibizumab exposure and the study outcomes when compared to the control group
Exposure to Bevacizumab OR (95%CI) in: o Ischemic stroke = 0.95 (0.68 to 1.34) o MI = 1.04 (0.77 to 1.39) o Venous thromboembolism = 0.81 (0.49 to
1.34) o Congestive heart failure = 1.21 (0.91 to 1.62)
Exposure to Ranibizumab OR (95%CI) in: o Ischemic stroke = 0.87 (0.68 to 1.10) o MI = 0.90 (0.72 to 1.11) o Venous thromboembolism = 0.88 (0.67 to
1.16) o Congestive heart failure = 0.87 (0.70 to 1.07)
Bevacizumab compared to Ranibizumab, OR (95%CI): o Ischemic stroke = 1.03 (0.67 to 1.60) o MI = 1.23 (0.85 to o 1.77) o Venous thromboembolism = 0.92 (0.51 to
1.69) o Congestive heart failure = 1.35 (0.93 to 1.95)
“Intravitreal injections of bevacizumab and ranibizumab were not associated with significant risks of ischaemic stroke, acute myocardial infarction, congestive heart failure, or venous thromboembolism”.
Casparis, 201412
Bevacizumab: No cases of endophthalmitis in 3,518 injections (endophthalmitis rate = 0%)
Ranibizumab: 3 cases of endophthalmitis in 36,398 injections (endophthalmitis rate = 0.008%)
Aflibercept: No cases of endophthalmitis in 89 injections (endophthalmitis rate = 0%)
Pegaptanib: No cases of endophthalmitis in 6 injections (endophthalmitis rate = 0%)
“The risk of EO (endophthalmitis) after IVI (intravitreal injection) performed under the sterile conditions of the operating room was very low”.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 32
Main Study Findings Author’s Conclusion
Cheung, 20126
Bevacizumab: 4 cases of endophthalmitis in 5,386 injections (endophthalmitis rate = 0.074%)
Ranibizumab: 3 cases of endophthalmitis in 9,453 injections (endophthalmitis rate = 0.032%)
Triamcinolone: 2 cases of endophthalmitis in 935 injections (endophthalmitis rate = 0.21%)
Pegaptanib: No cases of endophthalmitis in 121 injections (endophthalmitis rate = 0%)
“The overall rate of intravitreal injection-related endophthalmitis is greater with the use of topical antibiotics, given immediately or for 5 days after the injection, compared with no antibiotics”.
Englander, 201313
Bevacizumab: No cases of endophthalmitis in 2,315 injections (endophthalmitis rate = 0%)
Ranibizumab: 3 cases of endophthalmitis in 7,768 injections (endophthalmitis rate = 0.039%)
Pegaptanib: No cases of endophthalmitis in 57 injections (endophthalmitis rate = 0%)
Triamcinolone: 2 cases of endophthalmitis in 68 injections (endophthalmitis rate = 0%)
“Acute endophthalmitis is a rare potential complication after intravitreal injection. Further studies are required to elucidate the best prophylactic and aseptic techniques to prevent this rare complication”.
Etminan, 201530
Bevacizumab cohort N = 5,644
No anti-VEGF comparison cohort N = 2,564
Cases N = 313
Control N = 3,130
Adjusted RR for MI in bevacizumab users compared to non-users: RR = 0.70 (95%CI: 0.50 to 1.00)
Adjusted RR for MI in bevacizumab users receiving more than 3 injections compared to less than 3: RR = 0.71 (95%CI: 0.41 to 1.22)
Adjusted RR for stroke in bevacizumab users receiving more than 3 injections compared to less than 3: RR = 0.81 (95%CI: 0.39 to 1.65)
“Single or repeated doses of intravitreal bevacizumab were not shown to increase the risk of myocardial infarction or stroke in patients with wet AMD”.
Falavarjani, 201514
Bevacizumab: One case of endophthalmitis in 8,037 injections (endophthalmitis rate = 0.012%)
“The risk for endophthalmitis after resident-performed IVB injection is low and similar to that of the supervising surgeons performing the procedure”.
Fischer, 201335
Bevacizumab N = 65
Control N = 65
Hospital admissions in the bevacizumab-treated group 32.3% compared to control 15.3% (p-value 0.039)
Hospital admissions due to arteriothrombotic events in bevacizumab treated group 4.6% compared to control 1.5% (p-value 0.629)
“The results suggest that intravitreal bevacizumab is not associated with an increased risk of arteriothrombotic SAEs. Its widespread use for the treatment of AMD appears to be systemically safe”.
Gregori, 201515
Bevacizumab: 8 cases of endophthalmitis in 67,043 injections (endophthalmitis rate = 0.012%)
Ranibizumab: 6 cases of endophthalmitis in 33,134 injections
“Endophthalmitis after anti-VEGF injection was uncommon in our institution and in the population-based database. Treatment outcomes were variable but generally fared better
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 33
Main Study Findings Author’s Conclusion
(endophthalmitis rate = 0.018%)
Aflibercept: 6 cases of endophthalmitis in 19,103 injections (endophthalmitis rate = 0.031%)
Pegaptanib: 0 cases of endophthalmitis in 2,005 injections (endophthalmitis rate = 0%)
in the culture-negative cases”.
Hasler, 201523
Ranibizumab: 14 cases of endophthalmitis in 38,503 injections (endophthalmitis rate = 0.036%)
“Intravitreal ranibizumab injection performed by nurses and physicians without preinjection topical antibiotics was associated with a rate of injection-related adverse events of 0.044%”.
Holz, 201325
Ranibizumab N = 4,444
Ranibizumab-treated (percentage of patients): o Endophthalmitis = 0.11% o Retinal tear = 0.07% o Retinal detachment = 0.02% o Stroke = 0.43% o TIA = 0.11% o MI = 0.11% o Non-ocular hemorrhage = 0.11% o Venous thromboembolism = 0.09%
“Ranibizumab demonstrated favourable 1-year safety profile for NV-AMD in this routine clinical practice sample, consistent with previous reported trial data. Additional data from a larger patient population are needed to better describe the long-term safety profile of ranibizumab in routine clinical practice and further evaluate risk for infrequent but serious events in ‘real-life’ settings. The 5-year LUMINOUS prospective observational study will address this need”.
Kanchanaranya, 201522
Bevacizumab: 1 cases of endophthalmitis in 933 injections (endophthalmitis rate = 0.107%)
Ranibizumab: 1 cases of endophthalmitis in 236 injections (endophthalmitis rate = 0.423%)
“Acute endophthalmitis is a rare potential complication after intravitreal injection. Prognosis of endophthalmitis varies widely depending upon the severity of the infection, the organism involved and the amount of damage the eye sustains from inflammation and scarring. Further studies are required to clarify the best prophylactic techniques to prevent this rare complication”.
Kunavisarut, 201316
Bevacizumab: 1 case of endophthalmitis in 1,878 injections (endophthalmitis rate = 0.053%)
Ranibizumab: No cases of endophthalmitis in 190 injections (endophthalmitis rate = 0%)
Pegaptanib: No cases of endophthalmitis in 9 injections (endophthalmitis rate = 0%)
“The use of IVT injection of anti-VEGF is increasing, especially the use of bevacizumab. Incidence of ocular and systemic complications after IVT injection of anti-VEGF was low with no significant difference among the three anti-VEGFs agents”.
Lyall, 201236
Ranibizumab N = 77
Control N = 200
The OR of ranibizumab exposure given the outcome of endophthalmitis compared to control was 0.237 (95%CI 0.0 to 9.246)
“The incidence of PIAE (post-intravitreal anti-VEGF endophthalmitis) in the United Kingdom is comparable to other studies at a rate of 0.025%. The most common causative organisms were Gram positive. Measures to minimise the risk of PIAE include treatment of blepharitis before injection, avoidance of subconjunctival anaesthesia, topical antibiotic administration immediately after injection with consideration to administering topical antibiotics before injection”.
Ng, 201217
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 34
Main Study Findings Author’s Conclusion
Bevacizumab: No cases of endophthalmitis in 1,184 injections (endophthalmitis rate = 0%)
Ranibizumab: 1 case of endophthalmitis in 471 injections (endophthalmitis rate = 0.21%)
“Although many centres aliquot multiple syringes from a single vial to be kept in a refrigerator for use, the current study shows that so long as proper sterile techniques are implemented, there were no cases of endophthalmitis from using the same vial, which was reused for a maximum of 10 consecutive injections. For intravitreal injection, bevacizumab costs approximately US$50 to US$100 per dose, as opposed to US$2000 per dose for ranibizumab. Sharing multiple doses of bevacizumab from a single vial can substantially reduce the cost of treatment”.
Ng, 201538
Bevacizumab-treated (percentage of patients): o MI = 1.6% o Stroke = 1.5% o All-cause mortality = 4.0% o Any adverse event = 6.3%
Anti-VEGF age-adjusted incidence rate: o MI = 350.2 per 100,000 person-years o Stroke = 299.3 per 100,000 person-years o Mortality = 778.9 per 100,000 person-years
“The incidence rate of MI, stroke, and death in this cohort of AMD patients treated with anti-VEGF was low, and was not significantly higher than the age-adjusted incidence rate of these events in the Singapore population”.
Park, 201318
Bevacizumab: 2 cases of endophthalmitis in 9,125 injections (endophthalmitis rate = 0%)
Ranibizumab: No cases of endophthalmitis in 7,061 injections (endophthalmitis rate = 0%)
Triamcinolone acetonide: No cases of endophthalmitis in 849 injections (endophthalmitis rate = 0%)
C3F8 gas: 1 case of endophthalmitis in 297 injections (endophthalmitis rate = 0.337%)
“All 3 endophthalmitis patients had not taken prophylactic preinjection topical antibiotics, but the difference in the rates of endophthalmitis between those who received a multiday course of preinjection antibiotics and those who did not was not statistically significant. The rate of endophthalmitis after intravitreal injection using aseptic techniques in the clinical practice setting is similar with or without the use of preinjection antibiotics. Preinjection antibiotic use confers no additional benefit in the treatment of endophthalmitis compared to without preinjection antibiotics”.
Rayess, 201631
OR (95%CI) of developing endophthalmitis with bevacizumab compared to ranibizumab: 1.11 (0.81 to 2.01)
OR (95%CI) of developing endophthalmitis with bevacizumab compared to aflibercept: 1.12 (0.63 to 2.01)
Bevacizumab: 60 cases of endophthalmitis in 153,812 injections (endophthalmitis rate = 0.039%)
Ranibizumab: 109 cases of endophthalmitis in 309,722 injections (endophthalmitis rate = 0.035%)
Aflibercept: 14 cases of endophthalmitis in 40,356 injections (endophthalmitis rate = 0.035%)
“Endophthalmitis following intravitreal bevacizumab, ranibizumab, and aflibercept injection appears to occur at similar rates and have comparable visual outcomes. This study suggests that the choice of anti-VEGF agent should be primarily based on efficacy and patient response rather than concern for risk of infection”.
Rim, 201632
Ranibizumab N = 467
Control (socio-demographic matched) N = 2,331
Control (comorbidity matched) N = 2,330
Incidence of stroke in ranibizumab treated patients compared comorbidity-matched control: hazard ratio = 0.88 (95%CI 0.60 to 1.30)
Incidence of stroke in ranibizumab treated patients compared
Ranibizumab treatment for neovascular age-related macular degeneration did not increase the overall risk of stroke, compared with comorbidity-matched controls or sociodemographic-matched controls.
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 35
Main Study Findings Author’s Conclusion
soxiodemographic-matched control: hazard ratio = 0.95 (95%CI 0.64 to 1.41)
Schlenker, 20159
Bevacizumab N = 33,917
Ranibizumab N = 24,002
After initiation of anti-VEGF treatment, the absolute change in risk of thromboembolic emergencies increased from 10.7 to 18.6 per 1000 patients annually (rate ratio = 1.74 [95%CI 1.58 to 1.92])
13
These increased rates persisted regardless of bevacizumab or ranibizumab treatment
“Intravitreal anti-vascular endothelial growth factor medications ranibizumab and bevacizumab may contribute to systematic thromboembolic events in patients aged 65 years or older”.
Sharma, 20128
OR (95%CI) of developing intraocular inflammation with bevacizumab compared to ranibizumab: 11.71 (1.5 to 93)
OR (95%CI) of developing arterial thromboembolic events with bevacizumab compared to ranibizumab: 4.26 (0.44 to 41)
Bevacizumab: 9 cases of intraocular inflammation in 693 injections (rate = 1.3%)
Ranibizumab: 1 case of intraocular inflammation in 891 injections (rate = 0.11%)
“Significant concern still exists regarding the safety of off-label use of intravitreal bevacizumab. Patients receiving bevacizumab should be counselled regarding a possible increased risk of serious adverse events”.
Simcock, 201424
Ranibizumab: 4 cases of endophthalmitis in 10,006 injections (endophthalmitis rate = 0.04%)
“Carefully selected and well-trained NPs (nurse practitioner) are capable of delivering a safe and effective wAMD injection treatment service. This work demonstrates how such a service can be established and provides safety data that other units can use as a benchmark when evaluating their own practice”.
Souied, 201533
Adjusted RR (95%CI) of developing severe ocular inflammation (endophthalmitis) with aflibercept compared to ranibizumab: 1.65 (1.34 to 2.04)
Aflibercept: 189 cases of endophthalmitis in 179,147 injections (rate = 0.10%)
Ranibizumab: 162 case of intraocular inflammation in 253,647 injections (rate = 0.064%)
“Severe ocular inflammation was more frequent following intravitreal injection with aflibercept than with ranibizumab during routine clinical use in patients with nAMD. This highlights the importance of real-world, post-approval, observational monitoring of novel medicines, and may aid clinical decision-making, including choice of anti-VEGF agent”.
Terzic, 201519
Bevacizumab: 2 cases of endophthalmitis in 986 injections (endophthalmitis rate = 0.2%)
Ranibizumab: no cases of endophthalmitis in 55 injections (endophthalmitis rate = 0%)
Aflibercept: no cases of endophthalmitis in 60 injections (endophthalmitis rate = 0%)
“The results suggest that a low rate of endophthalmitis can be achieved by means of a protocol. This is a very important study as it is the first of this kind in B&H that documents the incidence of endophthalmitis after intravitreal application. Currently, bevacizumab in B&H is most frequently used intravitreal anti-vascular endothelial growth factor due to very low price”.
VanderBeek, 20155
Adjusted OR (95%CI) of developing endophthalmitis with bevacizumab compared to ranibizumab: 0.66 (0.39 to 1.09)
Bevacizumab: 49 cases of endophthalmitis in 296,565
“The results of this study suggest bevacizumab as currently used across the United States does not increase the risk for endophthalmitis; therefore, additional regulations on the use
SUMMARY WITH CRITICAL APPRAISAL Anti-Vascular Endothelial Growth Factor Drug Safety 36
Main Study Findings Author’s Conclusion
injections (rate = 0.017%)
Ranibizumab: 162 case of intraocular inflammation in 87,245 injections (rate = 0.025%)
of repackaged bevacizumab may be unnecessary”.
Wani, 201620
Bevacizumab: 5 cases of endophthalmitis in 5,429 injections (rate = 0.09%)
“The incidence of endophthalmitis after intravitreal injection of bevacizumab using aliquots prepared in the operating room is comparable to other studies. There were no clusters of endophthalmitis cases”.
Xu, 201621
Bevacizumab (n = 9,992 injections) o Endophthalmitis: 1 event (0.01%) o Non-fatal thromboembolic event: 6 events
(0.06%) o Death from any cause: 10 events (0.10%)
Ranibizumab (n = 3,306 injections) o Endophthalmitis: 0 events (0%) o Non-fatal thromboembolic event: 1 event
(0.03%) o Death from any cause: 4 events (0.12%)
Aflibercept (n = 703) o Endophthalmitis: 0 events (0%) o Non-fatal thromboembolic event: 0 events
(0%) o Death from any cause: 1 events (0.14%)
“Rates of death and thromboembolic events were similar among ranibizumab (lucentis), bevacizumab (avastin) and aflibercept (Eylea). The systemic and ocular complications associated with intravitreal injections among Asian patients at a tertiary eye center are relatively low and reflect the safety of the treatments”.
AMD = age related macular degeneration; CADTH = Canadian Agency for Drugs and Technologies in Health; CI = confidence interval; CNV due to PM = choroidal neovascularization due to pathologic myopia; CVA = cerebrovascular accident; DME = diabetic macular edema; MI = myocardial infarction; NA = not applicable; OR = odds ratio; RR = relative risk; RVO = retinal vein occlusion; TIA = transient ischemic attack; VEGF = vascular endothelial growth factor; WHO = world health organization
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