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Graefe's Archive for Clinical and Experimental Ophthalmology

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Open Access 01.01.2009 | Review Article

A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

verfasst von: Jan S. A. G. Schouten, Ellen C. La Heij, Carroll A. B. Webers, Igor J. Lundqvist, Fred Hendrikse

Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology | Ausgabe 1/2009

Abstract

Aim

To provide evidence for the effect of bevacizumab on visual acuity (VA) and central retinal thickness (CRT) in exudative age-related macular degeneration

Methods

A systematic review of all articles of bevacizumab for exudative AMD was conducted. Articles published up to March 2008 were identified in Medline, Embase, the Cochrane Controlled Trials Register and references from included articles. Search terms were “Bevacizumab or Avastin” and “Macula* or ARMD or AMD or intra(-)vitreal or intra(-)vitreous”. Three observers participated in the data retrieval and assignment of the quality scores.

Results

A total of 561 articles were retrieved. Three randomised controlled trials (RCT) and 23 before-and-after studies of patients (n = 1,435) who had received bevacizumab were published. Inclusion criteria varied. Lack of masking was the main methodological shortcoming. These RCTs showed that bevacizumab is more effective than PDT. Bevacizumab was given intravenously or as intravitreal injection. The latter was given once, or repeatedly every 4 weeks, and with or without additional injection when a recurrence occurred, mostly based on visual acuity and/or findings from optical coherence tomography. After intravenous administration, the weighted mean change in VA was +12.8 ETDRS letters (range +11 to +14) and the weighted mean change for CRT was −129 μm (range −100 to −202). For the 23 studies with intravitreal injections, the change in VA was +8.6 letters (range +2 to +26) and the change in CRT was −90 μm (range −46 to −190). The incidence of adverse events was low. The change in VA was 2.7 letters higher for studies with a higher quality vs lower quality.

Conclusion

Visual acuity improves and central retinal thickness decreases in patients with exudative AMD after bevacizumab. There is no reasonable doubt that this is caused by bevacizumab. It is likely that a randomised controlled trial will show that bevacizumab is equivalent in effect to ranibizumab, which showed a change in ETDRS of +5.9 letters for occult or minimally classic CNV and +9.8 letters for classic CNV after three monthly injections in two large RCTs.

The authors had no commercial or proprietary interest.

Introduction

Age-related macular degeneration (AMD) is the leading cause of severe blindness in the elderly in Western countries [11, 13]. Exudative macular degeneration is the most severe form with the highest risk of blindness [13]. Vision loss is the result of macular haemorrhage and fluid caused by leakage from subfoveal choroidal neovascularisation (CNV), which is the hallmark of exudative AMD. Vascular endothelial growth factors (VEGF) have a key role in the formation and leakage of CNV [28]. Recently, the anti-VEGFs pegabtanib and ranibizumab became available for the treatment of exudative AMD [12, 36, 38, 43, 45]. In contrast to pegabtanib, intravitreal injections with ranibizumab led to a significant vision improvement. In fact, ranibizumab was the first drug to improve vision in exudative AMD, compared to interventions used earlier which only delayed progression [12, 38]. Major disadvantages of this intervention are the costs and the need to give intravitreal injections repeatedly. Bevacizumab, which is approved for the treatment of colon cancer but not for the treatment of AMD, is closely related to ranibizumab. In contrast to pegaptanib that binds only the VEGF isoforms that are 165 kD (VEGF165) and larger [26], both ranibizumab and bevacizumab bind and inhibit all biologically active forms of VEGF [47]. Bevacizumab is a full-length, humanized monoclonal antibody against VEGF, whereas ranibizumab is a humanized antigen binding fragment against VEGF, and both proteins were genetically engineered from the same murine monoclonal antibody against VEGF. A major advantage of bevacizumab is its price, which is about 1–5% the price of ranibizumab. Mainly for this reason, it is now used worldwide and on a large scale off-label for the treatment of exudative AMD. Its off-label use is obviously controversial, also because the use of anti-VEGF therapy is associated with an increased risk for thromboembolic events. Until now, no systematic review has shown evidence for the therapeutic effect of bevacizumab, or its safety. In this systematic review, the effects of bevacizumab on visual acuity (VA) and central retinal thickness (CRT) are quantified, and the adverse events are reported. Moreover, the various therapeutic strategies are described.

Material and methods

Searching

The databases searched were MEDLINE, EMBASE, and the Cochrane database. The reference lists of included articles and personal files were also searched until no new articles were found. Search terms for the application in age-related macular degeneration were “Macula*” or “AMD” or “ARMD” or “intra(-)vitreous” or “intra-vitreal” in any field, and for the intervention the search terms were “Bevacizumab” or “Avastin” in any field. All years were included up to March 2008. Published articles on paper, or papers available electronically before publication on paper were included. Language restrictions were English, German, French or Dutch. Two observers, independently of each other, searched the acquired list to identify relevant articles.

Selection

Articles included were randomised controlled trials, non-randomised controlled studies, or before-and-after studies in more than one patient. Studies with systemic or intravitreal therapy were included. Studies were excluded that did not have VA as the primary outcome, had as the primary objective to study differences between subgroups, or included also patients other than patients with exudative AMD. All articles selected by at least one observer were copied or printed. The ultimate selection was based on a discussion between observers.

Data abstraction and validity assessment

Two observers read all the articles and retrieved the data. These observers were not masked for the journal or any other aspect of the article. Data on inclusion criteria, exclusion criteria and adverse events were copied from a HTLM version of the article and edited for the table. One other observer was given only the text of the method section to score quality items. This observer was also given a separate results section to score the baseline and change in ETDRS score and CRT. This observer was blinded for the results of the other observers. Differences between observers were discussed until a consensus was reached. The items scored for quality of the follow-up studies were: prospective follow-up, consecutive case series, loss to follow-up, masked assessment of the outcome, standardized assessment of the outcome and other interventions during the study period. [39] The baseline value of the VA and CRT and these scores at last examination or at the examination with complete follow-up, when possible, were noted.

Study characteristics and outcome

Data included were author and year, type of study and quality issues, inclusion criteria, exclusion criteria, details of the treatment (systemic or intravitreal therapy, dosage, frequency of dosing and criteria for additional injections), number of patients at baseline and at follow-up and follow-up time, baseline ETDRS and CRT and changes in these outcomes and adverse events. The quality of the before-and-after studies was scored according to the following criteria often used to score quality of follow-up studies: prospective study, consecutive cases, loss to follow-up, blind assessment of outcome, standardized assessment of outcome. The criterion “no other intervention” was omitted, since studies that included such intervention were omitted from inclusion.

The quality of the RCTs was scored with the Delphi list, supplemented with criteria from the Dutch Cochrane Centre. The complete list of criteria is shown in Table 2 [44].

Quantitative data analysis

The VA score was converted to the ETDRS score when the ETDRS score was not assessed directly. We used a conversion of 0.1 logmar (one Snellen line) to 5 ETDRS letters (one ETDRS line). The change in ETDRS score was calculated as the difference between baseline value and the value at the last examination, or at the examination when there was no loss to follow-up. A summary for change in ETDRS and CRT was calculated as the weighted mean of the changes. The number of patients at the follow-up examination determined the weight. Calculations were made separately for intravenous injections and intravitreal injections. The RCT arms that included the treatment with only bevacizumab were included in the before-and-after studies. A subgroup analysis was conducted separately for several characteristics for the follow-up studies, which included the following: total quality score, dosage of intravitreal bevacizumab, previous treatment in more than 50% of patients, size of the study, duration of follow-up, and method of assessment for visual acuity (ETDRS or Snellen). The study quality items and results of the RCTs were also presented. The results of the RCTs were presented as described after conversion to ETDRS scores.

Results

The total number of articles retrieved was 561. A large number of articles (n = 535) were not included in the review because of several reasons (Table 1). Ultimately, 26 out of these 561 were suitable and used in the analysis. Three randomised controlled trials were published and presented separately [9, 27, 31]. We also combined in this review the data of the patients of these three RCTs who had received only intravitreal bevacizumab, and the data of patients of 23 before-and-after studies with follow-up of patients who had received bevacizumab for exudative AMD (Tables 2, 3, 4 and 5)[1‐4, 7‐10, 15‐18, 23, 25, 27, 29, 30‐35, 37, 40, 41, 48]. A total of 1,435 patients included at baseline in these studies were included in this review.

Table 1

Flow chart for the selection of articles

Number of articles after the search		561
Reasons for not including an article
Review, comments, guidelines other reasons	228
Other eye diseases than age-related macular degeneration	133
Adverse events or safety of bevacizumab as primary goal of study outcome	59
Other diseases than eye diseases	34
Other primary study therapy in AMD	28
Basic science or experimental studies	24
Case series	9
Kinetics and dosage study of anti-vegf	7
Study on costs	5
Study conducted to study the differences between subgroups in effect of bevacizumab	3
Follow-up with only OCT	2
Retrospective comparison of bevacizumab with ranibizumab (abstract only)	1
Co-interventions given	1
Not only patients with AMD included	1
Included in the study		26

Table 2

Study quality scores (according to Delphi list supplemented with criteria from the Dutch Cochrane centre) of three randomized controlled clinical trials that included one treatment group with intravitreal bevacizumab

Study characteristics and outcome	[9]	[27]	[30]
Randomization	Yes	Yes	Yes
Allocation concealed	Uk	Uk	Uk
Groups similar at baseline regarding prognostic factors or were adjustments for differences made in the analysis	Uk	Yes	Yes
Eligibility criteria specified	Yes	Yes	Yes
Other interventions applied	No	No	No
Outcome assessor blinded	No	Uk	Yes
Care provider blinded	No	No	No
Patient blinded	No	No	No
Sufficient number with follow-up	Yes	Yes	Yes
Point estimates and measures of variability presented	No	Yes	Yes
Intention to treat analysis	Yes	Yes	Yes
Total quality score	5/11	7/11	8/11

Uk: unknown

Table 3

Results of three randomized controlled trials that included one group that received intravitreal bevacizumab

Study	Intervention	Number of patients	ETDRS baseline	ETDRS change	CRT base-line	CRT change
[9]	Bevacizumab	32	47	12	354	−113
[9]	PDT	30	49	−6	352	−60
[27]	Bevacizumab	10	54	12	371	−138
	PDT + triamcinolone	10	42	−7	346	−132
	PDT + triamcinolone, reduced	10	43	0	286	−78
[30]	Bevacizumab	54	31	8.6 (7.1–10.1)	355	−55 (−64 to −45)
	PDT	50	31	2.5 (0.9–4.1)	356	−54 (−64 to −44)
	PDT + Bevacizumab	52	33	12.3 (10.1–13.9)	349	−65 (−74 to −55)

Table 4

Study characteristics of 23 studies on the effect of bevacizumab in age-related exudative AMD

Study	Inclusion criteria	Prospective	Consecutive cases	Loss to follow-up	Blind assessment	Standardized assessment	Previous treatment >50%
[34, 35]	CNV location: subfoveal	Yes	No	No	No	Yes
[34, 35]	Lesion composition: all lesion types if recent progression.	Yes	No	No	No	Yes
[10]	CNV location: nn	Yes	Yes	No	No (yes for OCT)	Yes
[10]	Lesion composition: pigment epithelial detachment.	Yes	Yes	No	No (yes for OCT)	Yes
[23]	CNV location: nn	Yes	No	No	No	Yes
[23]	Lesion composition: all lesion types.	Yes	No	No	No	Yes
[1]	CNV location: nn	Yes	No	No	No	No	No
[1]	Lesion composition: all lesion types.	Yes	No	No	No	No	No
[7]	CNV location: subfoveal	Yes	No	No	No	No	No
[7]	Lesion composition: all lesion types, except minimally classic CNV >4 disk areas or those with CNV that is more than 50% obscured by blood	Yes	No	No	No	No	No
[23]	CNV location: subfoveal	Yes	No	No	No	Yes	No
[23]	Lesion composition: all active lesion types.	Yes	No	No	No	Yes	No
[3]	CNV location: nn	Nr	Yes	No	No	Yes	No
[3]	Lesion composition: pure or predominantly occult + recent progression.	Nr	Yes	No	No	Yes	No
[4]	CNV location: subfoveal CNV	No	Yes	Possible	No	No	No
[4]	Lesion composition: all lesion types.	No	Yes	Possible	No	No	No
[30]	CNV location: subfoveal lesion	Yes	No	Possible	No	Yes	No
[30]	Lesion composition: Minimally classic, occult with active leakage by FAG and OCT.	Yes	No	Possible	No	Yes	No
[37]	CNV location: nn	No	No	No	No	No	No
[37]	Lesion composition: all lesion types	No	No	No	No	No	No
[40]	CNV location: subfoveal	No	Yes	Yes	No	No	No
[40]	Lesion composition: Initially patients who responded poorly on other treatments, later large minimally classic or occult CNV.	No	Yes	Yes	No	No	No
[48]	CNV location: subfoveal	No	No	No	No	Yes	No
[48]	Lesion composition: all types.	No	No	No	No	Yes	No
[29]	CNV location: subfoveal CNV	No	No	No	No	Yes	No
[29]	Lesion composition: all lesion types	No	No	No	No	Yes	No
[15]	CNV location: nn	Yes	Yes	No	No	No	No
[15]	Lesion composition: all lesion types	Yes	Yes	No	No	No	No
[2]	CNV location: subfoveal	No	No	Possible	No	No	No
[2]	Lesion composition: all lesion types	No	No	Possible	No	No	No
[41]	CNV location: some part of the lesion had to involve the fovea.	No	Yes	Yes	No	No	Yes
[41]	Lesion composition: submacular hemorrhage of >50% of the lesion size.	No	Yes	Yes	No	No	Yes
[27]	CNV location: subfoveal	Yes	Yes	Yes	No	Yes	No
[27]	Lesion composition: 5 occult type, 2 classic, 3 minimal classic	Yes	Yes	Yes	No	Yes	No
[18]	CNV location: subfoveal	No	No	No	No	Yes	Yes
[18]	Lesion composition: all lesion types	No	No	No	No	Yes	Yes
[16]	CNV location: subfoveal	No	Yes	Yes	No	Yes	Yes
[16]	Lesion composition: Refractory pigment epithelial detachment (PED) and occult CNV	No	Yes	Yes	No	Yes	Yes
[9]	CNV location: subfoveal	Yes	No	Yes	No	Yes	No
[9]	Lesion composition: Predominantly classic CNV.	Yes	No	Yes	No	Yes	No
[8]	CNV location: Subfoveal	Yes	No	No	No	Yes	No
[8]	Lesion composition: all types except retinal angiomatous proliferation (RAP)	Yes	No	No	No	Yes	No
[31]	CNV location: subfoveal	Yes	No	No	No	Yes	No
[31]	Lesion composition: minimally classic or occult.	Yes	No	No	No	Yes	No
[33]	CNV location: Mainly subfoveal	No	Yes	No	No	Yes	No
[33]	Lesion composition: All lesion types.	No	Yes	No	No	Yes	No
[17]	CNV location: subfoveal CNV	No	Yes	No	No	No	No
[17]	Lesion composition: all types	No	Yes	No	No	No	No
[25]	CNV location: nn	Yes	No	Yes	No	No	Yes
[25]	Lesion composition: nn	Yes	No	Yes	No	No	Yes
[32]	CNV location: subfoveal	Yes	No	No	No	No	No
[32]	Lesion composition: all active lesion types	Yes	No	No	No	No	No

nn: not noted, CNV: choroidal neovascularisation; FAG: fluorescein angiography; OCT: optical coherence tomography.

Table 5

Summary of exclusion criteria of the 23 studies on the effect of bevacizumab in age-related exudative AMD

Exclusion criteria mentioned in the various articles	Reference numbers
Uncontrolled hypertension	[1‐4, 23, 25, 34, 35, 37, 41, 48]
Thromboembolic events: MI, CVA	[1‐4, 8, 10, 23, 25, 29, 34, 35, 37, 41, 48]
Renal abnormalities	[3, 10, 23, 34, 35]
History of bleeding and / or coagulation abnormalities	[1, 8, 23, 25, 34, 35]
Recent or planned surgery	[1, 3, 8, 23, 25, 34, 35]
Any ocular condition that may affect vision	[1, 7, 23]
Recent ocular surgery or laser	[1, 23, 28]
Prior treatment for CNV	[8, 9, 27]
No exclusion criteria mentioned	[15‐17, 30, 32, 33, 40]

The three RCTs all showed that bevacizumab is more effective than PDT (with or without triamcinolone) [9, 27, 31]. The RCTs were of a poor-to-reasonable quality and lack of masking was the main methodological problem.

Two articles showed the results of the same study [34, 35]. Of these two, the article with the largest series of patients and longest follow-up period was included in this review [35]. In this study the effect of intravenous bevacizumab in AMD was studied. Two other studies included patients who had received intravenous bevacizumab [10, 23]. The data of these three studies were included in the summary of the effect of intravenous injections. After intravenous bevacizumab the weighted mean change in ETDRS score was +12.8 (range +11 to +14) and the weighted mean change in CRT was −129 μm (range −100 to −202).

Twenty-three articles, including the patients in the RCTs who received bevacizumab, reported the change in VA after intravitreal bevacizumab (see Table 2) [1‐4, 9, 15‐18, 23, 25, 27‐33, 37, 40, 48]. The weighted mean change after intravitreal injections was 8.6 (range 2 to 26), and for the CRT −90 (range −46 to −190). The data are summarised in Tables 5 and 6. Inclusion criteria varied, and were composed of: age range, VA range, recent disease progression, poor response to previous treatment including PDT or pegaptanib, not eligible for PDT, previous treatment, and type of CNV. A summary of the various exclusion criteria in these studies is displayed in Table 5. Mostly, intravitreal injections of 1.25 mg bevacizumab were given. The strategy for additional injections differed and two main strategies could be discerned: 1) monthly injections irrespective of the results, or 2) additional injections when vision loss reoccurred or when macular fluid reoccurred on OCT. The mean number of patients included at baseline who received intravitreal injections per study was 61 (range 10–266). The weighted mean follow-up time was 15 weeks (range 4–48). The ocular or systemic adverse events that were reported in a total of 1,435 patients who had received an intravitreal injection, and a total of several thousand intravitreal injections, are summarized in Table 6. Table 7 summarizes the incidence of reported presumed adverse events.

Table 6

Reported results of 23 studies on the effect of bevacizumab in exudative AMD

Study	Treatment	No. patients/eyes at follow-up; time at follow-up in weeks	Mean ETDRS letters at baseline; mean change in ETDRS letters	Mean central retinal thickness at baseline (μm); mean change in retinal thickness (μm)	Adverse events
[34, 35]	Intravenous. Two to three at 2 weeks interval. Additional therapy according to criteria	n = 18; 24 weeks	54; +14	392; −112	No serious ocular or systemic adverse events. Increase in systolic and diastolic blood pressure.
[10]	Intravenous. Three with 2 weeks in between	n = 9; 12 weeks	54; +12.7	Not reported; −202	No serious ocular or systemic events.
[23]	Intravenous. Three with 2 weeks in between	n = 12; 12 weeks	58.5; +11	337; −100	No severe adverse events
[1]	Single intravitreal injection of 2.5 mg. No additional injections.	n = 39; 4 weeks	29 (median); +15	388 (median); −141	A mild inflammatory response in the anterior chamber was the most common side effect observed in eight eyes (20.5%), followed by subconjunctival haemorrhage in 3 patients
[7]	Three monthly intravitreal injections of 2.5 mg. No additional injections	n = 17; 12 Weeks	31; +26	362; −151	No serious ocular or systemic events
[23]	Three monthly intravitreal injections of 1 mg. No additional injections.	n = 12; 12 weeks	46.6; +8.3	402; −154	No severe adverse events
[3]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 30; 14 weeks	46; +10	420 (median); −190	No serious ocular or systemic events.
[4]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 50; 8 weeks	36; +10	not reported; −92	No serious ocular or systemic events.
[30]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 80; 12 weeks (range 6–24)	32, +8	378, change at 18 weeks −56	RIP in two patients. Ten PVD. No serious ocular or systemic events.
[37]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 50; 12 weeks	38.1; +7.9	351; −99.6	No serious ocular or systemic events.
[40]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 141; 12 weeks	38; +11	340; −127	At 1 month, two patients had mild vitritis, and one patient at 2 months, who had a history of recurrent uveitis. No endophthalmitis, increased intraocular pressure, retinal tear, or retinal detachment occurred. One patient had MI after third injection, one treated for TIA stopped anti-coagulants by himself and developed TIA. Another possible TIA, One death of MI (smoker with emfysema).
[48]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 48; 24 weeks	36.9; +5.3	339; −73	No serious ocular or systemic events
[29]	Single intravitreal injection of 1.25 mg or 1.5 mg. Additional injections according to criteria	n = 80; 12 week	48.5; +8.6	337; −93	No serious ocular or systemic events.
[15]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 102; 10 weeks	56; +10	251; −46	No adverse ocular or systemic events.
[2]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 17; 18 weeks (mean follow-up)	Not reported; +5.5	404; −124	No serious ocular or systemic events.
[41]	one injection of 1 mg / 0.04 ml. Additional injections according to criteria	n = 21, 16 weeks	55;+4	299;−62	No serious ocular or systemic adverse events
[27]	Three monthly intravitreal injections of 1 mg. No additional injections.	n = 10, 12 weeks	54;+12	371;−138	No serious ocular or systemic adverse events
[18]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 68, 12 weeks	51;+4	304;−68	No serious injection-related adverse events.
[16]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria	n = 10, 16 weeks	21;+15	Not quantified	No systemic or ocular adverse events
[9]	Three monthly intravitreal injections of 2.5 mg bevacizumab. Additional injections according to criteria	n = 32, 24 weeks	47;+12	354;−113	No systemic or ocular adverse events
[8]	Three monthly intravitreal injections of 2.5 mg bevacizumab. Additional injections according to criteria.	n = 51, 48 weeks	45.7;+7.4	327;−100	No serious ocular or systemic events.
[31]	Single injection with 1.25 mg bevacizumab. No repeated injections.	n = 54, 12 weeks	31;+8.6	355;−55	Three pigment epithelial ruptures, 12 PVD, four cataract progression. Some patients reported blurred vision during a few days.
[33]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria.	n = 43, 24 weeks	48.5;+5.6	346;−87	One case of endophthalmitis. One patient developed a retinal pigment epithelial rip 2 weeks after treatment. No patient had thromboembolism or any other systemic adverse events.
[17]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria.	n = 103, 8 weeks	44;+6	CRT not in every patient conducted	One case of endophthalmitis, three submacular hemorrhages, and three RPE tears.
[25]	Three monthly intravitreal injections of 1.25 mg bevacizumab.	n = 27, 12 weeks	50;+2	373;−94	Two transient corneal epitheliopathy. Two patients discontinued treatment due to RPE tears. No other systemic or ocular adverse events.
[32]	Single intravitreal injection of 1.25 mg. Additional injections according to criteria.	N = 48; 15.4 weeks	32;+8	389;−51	No adverse ocular or systemic events.

MI: myocardal infarction. RPE: retina pigment epithelium

Table 7

Reported adverse events in the 23 follow-up studies with intravitreal injections of bevacizumab for exudative AMD, in a total of 1,396 patients who received one or more injections

Event	Number of reported case	Cumulative incidence per 100 patients
Posterior vitreous detachment	24	1.7
Pigment epithelial rupture	15	1.1
Vitritis/uveitis	8	0.56
Subconjunctival hemaorrhage	3	0.21
Submacular hemaorrhage	3	0.21
Cataract progression	4	0.18
Endophthalmitis	2	0.14
Corneal epitheliopahty	2	0.14
Myocardial Infarction (MI)I	2 (one 88 years old, 2 months after third injection);	0.14
TIA	1 (stopped anti-coagulants himself)	0.07
MI death	1 (smoker with emphysema)	0.07
CVA	1 (83 years old, 34 days after second injection)	0.07
Blurred vision during few days	Some patients

Studies differed in quality (Tables 4 and 8). The difference in change in VA between subgroups according to differences in quality was no more than 1.9 letters (Table 8). The change in ETDRS score was 2.7 letters higher for the studies with a higher quality. No study had a blinded assessment of the outcome, except for one study (but blinded only for the assessment of the CRT [10]. The highest difference between two groups was for those who had a higher dosage compared to those with a lower dosage (Table 8).

Table 8

Change in ETDRS score and central retinal thickness after intravitreal bevacizumab stratified according to different study characteristics

Study characteristic	Value of study characteristic	Number of patients for ETDRS change calculation	ETDRS change	ETDRS difference between the two groups	Number of patients included for CRT change calculation	CRT Change	CRT difference between the two groups
Prospective study	Yes	494	9.7	1.9	494	78	−24
Prospective study	No	661	7.8		548	102
Consecutive inclusion of patients	Yes	510	9.0	0.7	397	99	14
Consecutive inclusion of patients	No	645	8.3		645	85
Loss to follow-up	Yes	478	7.9	−0.4	677	86	−10
Loss to follow-up	No	677	9.7		478	96
Standardized assessment of visual acuity	Yes	540	7.8	−1.5	530	86	−9
Standardized assessment of visual acuity	No	615	9.3		512	95
Quality score†	≥4 out of 5	196	10.9	2.7	186	92	2
Quality score†	<4 out of 5	959	8.2		856	90
Dosage	≥2 mg	139	13.3	5.3	139	120	34
Dosage	<2 mg	1016	8.0		903	86
Study size	>50 patients	801	8.4	−0.8	344	83	−22
Study size	≤50 patients	354	9.2		698	105
Follow-up duration	≥12 weeks	790	8.0	−1.9	780	95	17
Follow-up duration	<12 weeks	365	9.9		262	78
Previous treatment	<50% of patients	621	9.0	0.8	518	93	5
Previous treatment	≥50% of patients	534	8.2		524	88
Method of VA assessment	ETDRS	530	7.2	−2.6	530	81.6	−1.2
Method of VA assessment	Snellen	625	9.8		615	82.8

† as defined by the presence of >4 out of 5 of the following: prospective follow-up, consecutive case series, loss to follow-up, masked assessment of the outcome, standardized assessment of the outcome

Discussion

This systematic review shows that after administration of bevacizumab in patients with exudative age-related macular degeneration, an improvement in both the VA and CRT are reported. Moreover, bevacizumab is more efficacious than PDT. The weighted mean increase in VA after intravitreal bevacizumab injections in 1,396 patients is 8.6 letters on the ETDRS score. The weighted mean decrease in CRT is 90 μm. The incidence of adverse events was low. All studies showed an impressive effect, and the three RCTs showed superiority of bevacizumab to PDT with or without intravitreal triamcinolon.

The observed change in the follow-up studies of bevacizumab is similar to the change observed after monthly intravitreal injections of ranibizumab in exudative age-related macular degeneration. The mean change in ETDRS letters after monthly injections of 0.5 mg ranibizumab varied between +5.9 for occult or minimally classic CNV and +9.8 for classic CNV after 3 months [13, 38]. The observed increase in VA is also closely similar to the increase of 10.8 ETDRS letters after ranibizumab three times and additional injections when necessary based on OCT and VA change [21]. It is interesting to see that in the 1-year follow-up study of Bashur et al., fewer injections were needed than in the 1-year follow-up study on ranibizumab of Fung et al., with almost the same criteria for reinjection, knowing that the intravenous half-life of bevacizumab is 150% that of ranibizumab in rabbit eyes [5, 6, 8, 21]. However, the dosage in Bashur’s study was 2.5 mg bevacizumab.

The similarity in effect between bevacizumab and ranibizumab is also supported by a non-randomised, single centre comparative study in which these two drugs were compared [42]. Baseline patient characteristics were similar in both groups of 44 eyes in the bevacizumab group and the 53 eyes in the ranibizumab group. After 113 days of follow-up and a mean of 1.8 injections in the bevacizumab group the mean increase in VA was 0.8 lines. After 44 days of follow-up and a mean of 2.0 injections of ranibizumab, the mean increase in VA was 0.7 lines (p = 0.87). The improvement in VA is also observed in a study that compared starting with bevacizumab to starting with pegaptanib followed by bevacizumab [19]. In the latter group, no statistically significant difference from baseline was observed.

Adverse events were rare in the 1,396 patients who received a total of several thousand intravitreal injections. Moreover, some adverse events are the result of the procedure (endophthalmitis, retinal detachment, cataract progression), others are mild (vitritis), or an event may also occur as a result of the natural course of AMD itself or with other therapies such as photodynamic therapy and ranibizumab [14, 24]. Although the reported thromboembolic events could have been caused by bevacizumab, the time frame between injection and the event, the presence of additional risk factors, the age of the population, or the increased risk of cardiovascular diseases in patients with AMD make this less likely. On the other hand, patients at risk of a thrombo-embolic event were excluded in some studies.

These results confirm the results of an internet surveillance program in which the follow-up for adverse events in 5,228 patients and 7,113 intravitreal injections with bevacizumab from 70 centres in 12 countries was reported [20]. Adverse events reported were corneal abrasion, lens injury, endophthalmitis, retinal detachment, inflammation or uveitis, cataract progression, acute vision loss, central retinal artery occlusion, subretinal haemorrhage, retinal pigment epithelium tears, blood-pressure elevation, transient ischaemic attack, cerebrovascular accident and death. None of the adverse event rates exceeded 0.21% [22]. These results are also confirmed by a 12-month follow-up study of 1,265 consecutive patients with various diagnoses, including exudative AMD, who received 4,303 intravitreal injections of bevacizumab [46]. Systemic adverse events occurred in eighteen patients (1.5%). These were: acute elevation of blood pressure (0.59%), cerebrovascular accidents (0.5%), myocardial infarction (0.4%), iliac artery aneurysms (0.17%), toe amputation (0.17%) and deaths (0.4%). Ocular adverse events were bacterial endophthalmitis (0.16%), tractional retinal detachment (0.16%), uveitis (0.09%), rhegmatogenous retinal detachment (0.02%) and vitreous haemorrhage. Some of the adverse events may have been the result of the underlying disease. The type and incidence of the reported adverse events in the bevacizumab studies does not seem to be very different from the reported type and incidence from two large RCTs of ranibizumab [12, 38]. The frequency of injections in the two ranibizumab RCTs was monthly for a period of 1 year, while in the studies included in this review only a single intravitreal injection, or three monthly injections with or without repeated injections were given. This treatment will ultimately lead to fewer injection-related adverse events in the latter case.

It is known that Snellen and ETDRS visual acuities don’t match exactly. One shortcoming of this review, therefore, was that Snellen acuities as reported in the various studies were converted to ETDRS scores using a conversion of 0.1 logmar (one Snellen line) to 5 ETDRS letters (one ETDRS line). On the other hand, for patients with macular degeneration in the lower vision range, it was recently shown that visual acuity measurement with Snellen charts may underestimate VA as compared to measurements with ETDRS charts [19]. This implies that the visual acuity results of this systematic review, which included several studies using Snellen charts only, may underestimate visual acuity improvement after bevacizumab as compared to the ETDRS assessments in the ranibizumab trials. [20]

We conclude that bevacizumab is effective in improving VA in exudative AMD, and that its effect is likely to be equivalent to ranibizumab. According to current reports severe adverse events for bevacizumab are rare in the short term.

Open Access

This article is distributed under the terms of the Creative Commons Attribution NonCommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

Open AccessThis is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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Titel: A systematic review on the effect of bevacizumab in exudative age-related macular degeneration
verfasst von: Jan S. A. G. Schouten
Ellen C. La Heij
Carroll A. B. Webers
Igor J. Lundqvist
Fred Hendrikse
Publikationsdatum: 01.01.2009
Verlag: Springer-Verlag
Erschienen in: Graefe's Archive for Clinical and Experimental Ophthalmology / Ausgabe 1/2009
Print ISSN: 0721-832X
Elektronische ISSN: 1435-702X
DOI: https://doi.org/10.1007/s00417-008-0952-y

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A systematic review on the effect of bevacizumab in exudative age-related macular degeneration

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