Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema

Zehetner, Claus; Kirchmair, Rudolf; Huber, Stefan; Kralinger, Martina; Kieselbach, G.

doi:10.1136/bjophthalmol-2012-302451

Cited by 146 publications

(109 citation statements)

References 32 publications

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“…In the present study, a similar off-target effect was observed in all patients treated with aflibercept. In both studies, no significant effects on plasma VEGF levels could be detected after intravitreal ranibizumab application (Zehetner et al 2013). The data of our current study for aflibercept are in line with the recent findings of Wang et al (2014) who describe significantly suppressed systemic VEGF levels 1 month after intravitreal aflibercept injection and no significant effects for ranibizumab.…”

Section: Discussionsupporting

confidence: 82%

“…Aflibercept, similar to bevacizumab induces a significant reduction of VEGF in the blood plasma persisting throughout the entire observational period of our study (Matsuyama et al 2010;Carneiro et al 2012;Zehetner et al 2013;Wang et al 2014). VEGF is a multifunctional cytokine that regulates biological functions in endothelial cells in adult vasculature.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that bevacizumab significantly reduces systemic VEGF levels after intravitreal injection (Matsuyama et al 2010;Carneiro et al 2012;Chakravarthy et al 2012;Zehetner et al 2013). Aflibercept contains a Fc fragment like bevacizumab and therefore interacts with the neonatal Fc receptor (FcRn).…”

Section: Introductionmentioning

confidence: 99%

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Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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ABSTRACT.Purpose: To evaluate the changes of vascular endothelial growth factor (VEGF) plasma levels after intravitreal injections of aflibercept or ranibizumab in patients with exudative age-related macular degeneration (AMD). Methods: Thirty-eight patients with exudative AMD were included in this randomised, prospective study. Nineteen patients were randomised to treatment with intravitreal aflibercept (2.0 mg) and 19 to intravitreal ranibizumab (0.5 mg). The concentration of VEGF was measured by ELISA just before the injection, after 7 days and 1 month. Twenty-two age-and sex-matched healthy patients without chorioretinal diseases served as control. Results: The median baseline plasma VEGF concentration was 61.0 pg/ml in the control group, 43.0 pg/ml in the aflibercept group and 59.0 pg/ml in the ranibizumab group (p = 0.127). Seven days after intravitreal injection of aflibercept plasma levels were significantly reduced to values below the minimum detectable dose (MDD) in 17 of 19 patients (89.5%) resulting in a median VEGF concentration of <9 pg/ml (p < 0.001). The reduction persisted throughout 1 month with values below the MDD in 5 of 19 patients (26.3%) and a median measurement of 17.0 pg/ml (p < 0.001). In patients treated with ranibizumab no significant effects could be observed with a baseline VEGF of 59.0 pg/ml, 54.0 pg/ ml at 7 days (p = 0.776) and 58.5 pg/ml at 4 weeks of follow-up (p = 0.670). Conclusion: After intravitreal aflibercept injection, the systemic VEGF levels were significantly reduced throughout the observational period of 4 weeks. No significant systemic effects of intravitreal ranibizumab on plasma VEGF were observed.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

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Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Zehetner

Kralinger

Modi

et al. 2014

Acta Ophthalmologica

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“…However, by measuring serum rather than plasma VEGF, a significant portion of the VEGF measured would include VEGF released by platelets, which artificially increases systemic levels of VEGF measured and may mask subtle changes in VEGF levels. 7,18 Subsequent studies measuring plasma VEGF have also reported significant decreases in plasma VEGF following intravitreal bevacizumab, and non-statistically significant decreases in plasma VEGF following intravitreal ranibizumab, [5][6][7][8][9] which supports the IVAN findings, but remains at odds with data from the oncology literature.…”

Section: Introductioncontrasting

confidence: 47%

“…1 Different anti-VEGF agents also have different molecular structures, different transmissibility across the blood-retinal barrier, and different systemic half-lives, so could potentially have different effects on systemic VEGF levels. 1,[6][7][8][9] Ranibizumab is a recombinantly produced, humanized monoclonal antibody fragment (Fab) designed for intraocular use that binds and inhibits all biologically active isoforms of human VEGF. 10 Its transmissibility across the blood-retinal barrier is lower than that of fulllength molecules, but systemic bioavailability of ranibizumab has been reported post intravitreal injections.…”

Section: Introductionmentioning

confidence: 99%

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

Shao

Sivagnanavel

Dabbagh

et al. 2015

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Purpose To investigate whether intravitreal ranibizumab injections administered to a child alter systemic plasma levels of total and free VEGF 165. Methods A 9-year-old child sustained a choroidal rupture from blunt trauma. He subsequently developed a secondary choroidal neovascular membrane, which was treated with five ranibizumab injections over a period of 8 months. Peripheral venous blood samples were taken at each visit over a period of 12 months and plasma was extracted. Plasma VEGF 165 levels were determined using enzyme-linked immunosorbent assay and were assayed both pre-and post-immunodepletion to remove complexed VEGF. Results Plasma VEGF 165 levels proved labile following intravitreal injection of ranibizumab. Levels increased by 30% above baseline following the first intravitreal ranibizumab injection, but then returned to baseline despite two subsequent injections. There was then a rebound increase of 67% in total plasma VEGF levels following a further injection, which remained above baseline for 12 weeks despite two further intravitreal ranibizumab injections. Baseline levels were re-attained 26 weeks after the final injection. Conclusions These results suggest intravitreal ranibizumab injections can cause significant, multiphasic changes in systemic VEGF levels. This may be of particular clinical significance in children as VEGF is known to be vital in the development of major organs, in addition to its role in the maintenance of normal organ function in adults.

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Cardiovascular Events and Bleeding Risk Associated With Intravitreal Antivascular Endothelial Growth Factor Monoclonal Antibodies

et al. 2014

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IMPORTANCE Few data exist regarding the systemic safety of intravitreal antivascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb).OBJECTIVE To conduct a systematic review and meta-analysis to evaluate the risk of major cardiovascular and nonocular hemorrhagic events in patients with neovascular age-related macular degeneration (AMD), diabetes mellitus-associated macular edema (DME), or retinal vein occlusions (RVOs) who receive intravitreal anti-VEGF mAbs.DATA SOURCES The MEDLINE and Cochrane Central databases were searched for potentially eligible studies.STUDY SELECTION Randomized clinical trials comparing ranibizumab or bevacizumab with no anti-VEGF treatment, as well as those comparing ranibizumab with bevacizumab in patients with AMD, DME, or RVOs. DATA EXTRACTION AND SYNTHESISWe used a fixed-effects model and report the results as odds ratios (ORs) and 95% CIs. MAIN OUTCOMES AND MEASURESPrimary end points were major cardiovascular and nonocular hemorrhagic events. Secondary end points were all-cause mortality, cardiovascular mortality, stroke, myocardial infarction, venous thromboembolic events (VTEs), and hypertension.RESULTS Twenty-one trials that evaluated 9557 patients were retrieved. Anti-VEGF mAbs did not significantly increase the risk of major cardiovascular events (OR, 1.18; 95% CI, 0.81-1.71) or nonocular hemorrhagic events (OR, 1.42; 95% CI, 0.95-2.13) in treatment groups compared with control populations. Bevacizumab did not increase the risk of major cardiovascular events (OR, 0.94; 95% CI, 0.59-1.52) or nonocular hemorrhagic events (OR, 2.56; 95% CI, 0.78-8.38) compared with ranibizumab, but significantly increased VTEs (OR, 3.45; 95% CI, 1.25-9.54). Subgroup analysis showed a significant increase of nonocular hemorrhagic events in patients with AMD in ranibizumab vs control trials (OR, 1.57; 95% CI, 1.01-2.44). Anti-VEGF mAbs did not significantly increase overall mortality, cardiovascular mortality, stroke, myocardial infarction, VTEs, or hypertension. CONCLUSIONS AND RELEVANCEWe showed that intravitreal anti-VEGF-mAbs were not associated with significant increases in major cardiovascular or nonocular hemorrhagic events, but studies and meta-analyses were not powered enough to correctly assess these risks. Increased risks of VTEs with bevacizumab and nonocular hemorrhagic events in older patients with AMD with ranibizumab should be cautiously interpreted because more safety data are needed.

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Plasma levels of vascular endothelial growth factor before and after intravitreal injection of bevacizumab, ranibizumab and pegaptanib in patients with age-related macular degeneration, and in patients with diabetic macular oedema

Abstract: Bevacizumab significantly reduces the level of VEGF in the blood plasma for up to one month in patients with DME as well as in those with ARMD. No significant systemic effects of intravitreal ranibizumab or pegaptanib on plasma VEGF could be observed.

Cited by 146 publications

References 32 publications

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

Multiphasic changes in systemic VEGF following intravitreal injections of ranibizumab in a child

Cardiovascular Events and Bleeding Risk Associated With Intravitreal Antivascular Endothelial Growth Factor Monoclonal Antibodies

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