CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL ... · Retinal conditions, such as age related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion

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)

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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?


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


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.


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


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.


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


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.


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.


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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.


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.


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


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


Serious ocular adverse events

All-cause mortality

Wang, 2014,40

China 4 RCTs

AMD patients

Bevacizumab Ranibizumab All-cause mortality


Stroke

Nonfatal MI

Vascular death

Venous thrombotic events

Hypertension






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


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



Patients with any retinal condition requiring anti-VEGF intravitreal injection

Bevacizumab

Ranibizumab

Aflibercept

Pegaptanib

NA Endophthalmitis






Cheung, 2012,6 Canada Retrospective

descriptive study


Patients with any retinal condition who undergone intravitreal injection

Bevacizumab

Ranibizumab


NA Endophthalmitis

Englander, 2013,13

United States



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


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


Patients with any retinal condition who

Bevacizumab

Ranibizumab

Aflibercept

Pegaptanib

NA Endophthalmitis






undergone anti-VEGF intravitreal injection

Hasler, 2015,23

Denmark


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


Traumatic cataract

Intra-ocular hemorrhage

Retinal detachment

Kanchanaranya, 2015,

22 Thailand


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


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






endophthalmitis

Ng, 2012,17

Hong Kong Prospective descriptive case-series study

N = 1,655 injections (392 eyes of 383 patients)


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



Bevacizumab

Ranibizumab


C3F8 gas

NA Endophthalmitis

Rayess, 2016,31

United States

Population based retrospective cohort study


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






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


Souied, 2015,33

United States

Population-based retrospective cohort study


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




Bevacizumab

Ranibizumab

Aflibercept

NA Endophthalmitis

VanderBeek, 2015,5

United States Population based

retrospective cohort study


Patients with any retinal condition who undergone ranibizumab or bevacizumab intravitreal injection

Bevacizumab Ranibizumab Endophthalmitis






Wani, 2016,20

Kuwait Retrospective descriptive study


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)


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


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



Data synthesis was discussed and was appropriate


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








Schmucker, 20127

Pre-specified protocol







Protocol was not published


Method of conducting indirect comparison not well described

Wang, 201440







Lack of a pre-specified and published protocol



Table 3: Strengths and Limitations of Observational Studies using the Modified Downs and Black Checklist


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






Descriptive observational study



No assessment of potential population variability

Data from a single surgeon


Lack of reporting on loss-to-follow-up rates


Biagi, 201439






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


Campbell, 2012a37






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






Appropriate control


Comprehensive description of patients characteristics


Observational case-control non-randomized design

Unable to include patients population not covered in the database used




Casparis, 201412













Cheung, 20126













Englander, 201313














Etminan, 201530






Appropriate comparison and control

Detailed and appropriate study design and statistical analysis

Proper handling of potential confounders

Comprehensive reporting of patients characters


Observational non-randomized design

Lack of reporting on power analysis

Falavarjani, 201514










Data from single centre






Fischer, 201335






Appropriate control





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






Population-based large sample size







Lack of reporting on database validity

Hasler, 201523






Large sample size








Holz, 201325






Large sample size





Lack of reporting validity of database used


Lack of reporting on handling missing values

Kanchanaranya, 201522














Kunavisarut, 201316
















Lyall, 201236






Appropriate comparison and control

Comprehensive description of study design and statistical analysis




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














Ng, 201538






Population based


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


Park, 201318














Rayess, 201631





Lack of reporting on and handling of potential confounders






Appropriate comparison



Multicenter study

Large sample size providing sufficient power to detect differences


Rim, 201632






Appropriate control



Observational cohort non-randomized design


Lack of reference regarding the validity of database used

Schlenker, 20159






Appropriate control







Self-matching control may confound the picture due to the time factor leading to natural progression of potential confounders

Sharma, 20128






Appropriate comparison




Lack of reporting on and handling of potential confounders

Single centre

Small sample size



Simcock, 201424
















Souied, 201533






Appropriate control

Comprehensive and appropriate statistical analysis


Adjustment for potential confounders





Channeling bias may exist favouring ranibizumab since aflibercept is relatively new

Terzic, 201519














VanderBeek, 20155






Appropriate control

Comprehensive and appropriate statistical analysis


Adjustment for potential confounders





Wani, 201620













Xu, 201621
















The dominator of number of injections may not be appropriate for calculating the rate of systemic adverse events


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



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



“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”.



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


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


“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”.



Cheung, 20126

Bevacizumab: 4 cases of endophthalmitis in 5,386 injections (endophthalmitis rate = 0.074%)


Triamcinolone: 2 cases of endophthalmitis in 935 injections (endophthalmitis rate = 0.21%)


“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




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


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



(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


“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-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


Ranibizumab: No cases of endophthalmitis in 190 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




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%)


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)



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.



soxiodemographic-matched control: hazard ratio = 0.95 (95%CI 0.64 to 1.41)

Schlenker, 20159

Bevacizumab N = 33,917


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


“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



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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CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL ... · Retinal conditions, such as age related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusion