Off-Label Use of Bevacizumab in Age-Related Macular Degeneration: Protocol for a Systematic Review and Meta-Analysis

Abstract Background: Age-related macular degeneration (AMD) is considered the leading cause of vision loss in elderly people. Taking into account the phenomenon of aging worldwide, the prevalence of AMD is expected to increase gradually in the future. AMD can be divided into early, intermediate and late stages, where early and intermediate are mainly asymptomatic and, late-stage can be classified in non-vascular AMD and vascular AMD. Current pharmacological treatment in vascular AMD is associated with the administration of anti-VEGF agents, such as ranibizumab, pegaptanib, and aflibercept. Additionally, it has been reported the off-label use of bevacizumab, commonly associated with oncology, in this condition through intravitreal administrations, demonstrating efficacy allied with a lower cost in comparison to other agents used, which makes it a new possible pharmacological approach. In this sense, this review aims to evaluate the off-label use profile of bevacizumab in the treatment of neovascular AMD. Methods/design: To identify and select relevant articles present in current literature, it will be developed a highly sensitive search strategy. To develop this search, it will be used MEDLINE via the Pubmed platform. It will be only considered clinical studies, where it is compared the use of bevacizumab with another pharmacological agent, such as ranibizumab, or even a placebo, in patients aged 50 years and older, diagnosed with vascular AMD.Discussion: This review will provide a synthesis of the current information and underlying evidence, about the influence of the off-label use of bevacizumab in this disease. Altogether, it will allow having a clearer vision on a new possible accepted pharmacological approach for the treatment of vascular AMD.Systematic review registration: The protocol for this review will be submitted and registered with the International Prospective Register of Systematic Reviews (PROSPERO).

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Off-label use of bevacizumab for wet age-related macular degeneration in Europe

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-019-04569-8 ◽

2019 ◽

Vol 258 (3) ◽

pp. 503-511

Author(s):

Tomas Bro ◽

Magdalena Derebecka ◽

Øystein Kalsnes Jørstad ◽

Andrzej Grzybowski

Keyword(s):

Macular Degeneration ◽

European Countries ◽

Age Related Macular Degeneration ◽

Off Label Use ◽

Off Label ◽

Age Related ◽

Governmental Institutions ◽

Very High ◽

Wet Amd ◽

Label Use

Abstract Purpose To analyse current off-label use of bevacizumab for wet age-related macular degeneration (AMD) in Europe. Methods The study was conducted as a combined survey and literature review. It included the 22 most populous countries in Europe. In each country, ophthalmologists with particular knowledge about off-label treatment responded to a questionnaire. Results Answers were obtained from twenty European countries. The off-label use of bevacizumab for wet AMD greatly differed between nations; the bevacizumab proportion varied from non-existent (0%) to very high (97%). There were also large disparities within single countries (e.g. 0–80%), which were attributable to differences in regional decision-making. Both governmental institutions and national ophthalmological societies expressed highly diverging opinions on the use of off-label treatment. Intravitreal administration of bevacizumab had been a matter of legal dispute in several countries. The question about responsibility for off-label therapy mainly remained unanswered. Conclusions There was a highly varying utilization of bevacizumab between European countries. Despite an intention of a consistent approach to medical regulations, Europe has not yet reached a professional or political consensus on the ophthalmic off-label use of bevacizumab.

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Off-Label Use of Bevacizumab for the Treatment of Age-Related Macular Degeneration

Drugs & Aging ◽

10.2165/00002512-200926040-00002 ◽

2009 ◽

Vol 26 (4) ◽

pp. 295-320 ◽

Cited By ~ 18

Author(s):

Focke Ziemssen ◽

Salvatore Grisanti ◽

Karl Ulrich Bartz-Schmidt ◽

Martin S. Spitzer

Keyword(s):

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Off Label Use ◽

Off Label ◽

Age Related ◽

Label Use

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Changes in aqueous and vitreous inflammatory cytokine levels in neovascular age-related macular degeneration: A systematic review and meta-analysis

10.26226/morressier.5e61463c250f7ee26aeb41ed ◽

2020 ◽

Author(s):

Samuel Minaker

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Inflammatory Cytokine ◽

Meta Analysis ◽

Age Related Macular Degeneration ◽

Age Related ◽

Cytokine Levels

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Systematic review and meta-analysis of the association between complementary factor H Y402H polymorphisms and age-related macular degeneration

Human Molecular Genetics ◽

10.1093/hmg/ddl220 ◽

2006 ◽

Vol 15 (18) ◽

pp. 2784-2790 ◽

Cited By ~ 139

Author(s):

Ammarin Thakkinstian ◽

Pearline Han ◽

Mark McEvoy ◽

Wayne Smith ◽

Josephine Hoh ◽

...

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Meta Analysis ◽

Factor H ◽

Age Related Macular Degeneration ◽

Complementary Factor ◽

Age Related

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Efficacy Comparison of Intravitreal Anti-VEGF Therapy for Three Subtypes of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis

Journal of Ophthalmology ◽

10.1155/2018/1425707 ◽

2018 ◽

Vol 2018 ◽

pp. 1-10 ◽

Cited By ~ 4

Author(s):

Jianqing Li ◽

Jiayi Xu ◽

Yiyi Chen ◽

Jiaju Zhang ◽

Yihong Cao ◽

...

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Meta Analysis ◽

Age Related Macular Degeneration ◽

Cochrane Library ◽

Anti Vegf ◽

Age Related ◽

Significant Difference ◽

The Mean

Purpose. Intravitreal antivascular endothelial growth factor (anti-VEGF) therapy has been widely used for the treatment of neovascularization (NV) secondary to age-related macular degeneration (AMD). This study aimed to compare the efficacy among different subtypes of neovascular age-related macular degeneration (nAMD). Methods. PubMed, Embase, and the Cochrane Library were searched for eligible studies. We performed meta-analysis using Review Manager 5.3 and Stata/SE 12.0. Results. A total of 24 studies met our inclusion criteria and were included in the systematic review. At 3 months, the mean logarithm of the minimum angle of resolution (logMAR) improvements were −0.09, −0.18, and −0.23 for type 1, 2, and 3, respectively, while the mean macular thickness (MT) changes were −104.83, −130.76, and −196.29 μm. At 12 months, the mean changes in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters were 6.38, 8.12, and 9.37, while the MT decrease was 126.51, 126.52, and 139.85 μm, respectively. However, statistically significant difference was only found between type 1 and 3 in vision improvement, both in the short term (p=0.0002) and long term (p=0.01). Conclusions. The reactivity to VEGF inhibitors varied among different subtypes of nAMD. The efficacy of intravitreal anti-VEGF therapy in type 3 nAMD was statistically better than type 1 when considering vision improvement at 3 and 12 months. Thus, the lesion subtype is a predictor for the treatment outcome which can help guide prognosis.

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Prevalence and incidence of age-related macular degeneration in Europe: a systematic review and meta-analysis

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-314422 ◽

2019 ◽

Vol 104 (8) ◽

pp. 1077-1084 ◽

Cited By ~ 11

Author(s):

Jeany Q Li ◽

Thomas Welchowski ◽

Matthias Schmid ◽

Matthias Marten Mauschitz ◽

Frank G Holz ◽

...

Keyword(s):

Systematic Review ◽

Macular Degeneration ◽

Meta Analysis ◽

Resource Planning ◽

Classification Systems ◽

Age Related Macular Degeneration ◽

Population Projections ◽

Age Related ◽

Pooled Prevalence ◽

Incidence Studies

Background/AimsAge-related macular degeneration (AMD) is the main cause of visual impairment and blindness in Europe. A further increase in the number of affected persons is expected and current European data are needed for healthcare resource planning.MethodsWe performed a systematic review on the prevalence and incidence of AMD based on the meta-analysis of observational studies in epidemiology guideline. Meta-analysis and meta-regression on time-trends, age, countries, regions, sex and classification systems for AMD were performed. Based on Eurostat population projections, the pooled prevalence estimates were extrapolated to the year 2050.ResultsTwenty-two prevalence and four incidence studies published since 1996 were included. Our pooled prevalence estimate of early or intermediate AMD and any late AMD in those 60 years and older was 25.3% (95% CI 18.0% to 34.4%) and 2.4% (95% CI 1.8% to 3.3%), respectively. A significant increase in prevalence was seen in older populations. In the meta-analysis of incidence, the pooled annual incidence of any late AMD was 1.4 per 1 000 individuals (95% CI 0.8 to 2.6). Overall, the number of EU inhabitants with any AMD is expected to increase from 67 to 77 million until 2050. Incident late AMD is estimated to increase from 400 000 per year today to 700 000 per year in 2050.ConclusionsApproximately 67 million people in the EU are currently affected by any AMD and, due to population ageing, this number is expected to increase by 15% until 2050. Monitoring and treatment of people with advanced disease stages will require additional healthcare resources and thorough healthcare planning in the years and decades to come.

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Apixaban for Stroke Prevention in Atrial Fibrillation: Why are Event Rates Higher in Clinical Practice than in Randomized Trials?—A Systematic Review

Thrombosis and Haemostasis ◽

10.1055/s-0040-1713889 ◽

2020 ◽

Vol 120 (09) ◽

pp. 1323-1329 ◽

Cited By ~ 1

Author(s):

Tim A. C. de Vries ◽

Jack Hirsh ◽

Ke Xu ◽

Imaad Mallick ◽

Vinai C. Bhagirath ◽

...

Keyword(s):

Systematic Review ◽

Clinical Practice ◽

Thromboembolic Event ◽

Meta Analysis ◽

Patient Characteristics ◽

Thromboembolic Events ◽

Off Label Use ◽

Off Label ◽

Event Rates ◽

Label Use

Abstract Background Recent reports suggest an important contribution from frequent off-label use of apixaban 2.5 mg twice daily to the higher rates of thromboembolic events observed in observational studies (OSs) relative to in randomized controlled trials (RCTs), and consequently, advocate against such use in all patients. Objectives To examine factors contributing to the higher thromboembolic event rates, we estimated the prevalence of off-label use in contemporary practice, and compared patient characteristics and rates of stroke/systemic embolism, major bleeding, and mortality by apixaban dose and by study design in a systematic review and meta-analysis. Results and Discussion We identified 18 OSs and 2 RCTs that included 155,228 and 11,928 patients, respectively. Patients in OSs more often received apixaban 2.5 mg twice daily (31.3% vs. 5.1%), were older (mean age 73.8 vs. 69.8 years), and had higher CHA2DS2-VASc scores (mean 3.6 vs. 2.9) versus those in RCTs. We observed a consistent pattern of higher rates of thromboembolic events, bleeding, and mortality in patients treated with 2.5 versus 5 mg twice daily apixaban in both OSs and RCTs. Conclusion The higher risk profiles of patients in OSs versus RCTs, and higher rates of both bleeding and mortality not attributable to thromboembolism in patients treated with apixaban 2.5 versus 5 mg twice daily suggest that differences in patient characteristics are additional important contributors to the higher than expected thromboembolic event rates in clinical practice.

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