Anti-vascular endothelial growth factor for neovascular age-related macular degeneration

Background
Age-related macular degeneration (AMD) is a common cause of severe vision loss in people 55 years and older. Neovascular AMD, which involves abnormal growth of blood vessels in the back of the eye, accounts for most AMD-related severe vision loss. Injections into the eye of medications, such as pegaptanib, ranibizumab, and bevacizumab, that block this abnormal growth of blood vessels in the back of the eye are the main way to treat this condition. These types of medications are known as anti-vascular endothelial growth factors (anti-VEGFs).

Review question
We aimed to investigate: (1) the effects of anti-VEGF agents injected into the eye for the treatment of neovascular AMD when compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.

Study details
We found 12 randomized controlled trials (RCTs), which included a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus no anti-VEGF treatment; six trials compared bevacizumab with ranibizumab. Four trials were conducted by drug companies; none of the eight studies which evaluated bevacizumab were funded by drug companies. The trials were conducted at various centers on five continents (North and South America, Europe, Asia and Australia). All trials treated and followed-up participants for at least one year. The evidence is current to 27 March 2014.

Key results
Participants treated with any of the three anti-VEGF agents more often experienced improved vision, less often lost vision, and were less likely to be legally blind than participants treated with control interventions after one year of treatment. Participants treated with anti-VEGF agents also showed improvements in structural areas of the eye that doctors use to monitor disease progression and treatment response compared with participants not treated with anti-VEGF agents.

Compared with control treatments, treatment with ranibizumab or bevacizumab yielded larger improvements than pegaptanib. No trial compared pegaptanib directly with other anti-VEGF agents. When bevacizumab and ranibizumab were compared with each other, there were no major differences with respect to vision-related outcomes; there was, however, a large difference in cost between the two agents.

Inflammation and increased pressure in the eye were the most common vision-related adverse events with anti-VEGF agents. Endophthalmitis (inflammation in the inner part of the eye, which can lead to blindness) was reported in fewer than 1% of anti-VEGF-treated participants; no cases were reported in control groups. The occurrence of serious adverse health effects, such as high blood pressure and internal bleeding, was comparable across anti-VEGF-treated groups and control groups; however, the number of events was small relative to the number of people in the studies making it difficult to detect any meaningful differences between groups. Few data were available for visual function (e.g., reading speed and critical print size), quality of life, and economic outcomes.

Quality of the evidence
The overall quality of the evidence was very good, with most trials having an overall low risk of bias (i.e., good methodological quality).

Authors' conclusions: 

The results of this review indicate the effectiveness of anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) in terms of maintaining visual acuity; ranibizumab and bevacizumab were also shown to improve visual acuity. The information available on the adverse effects of each medication do not suggest a higher incidence of potentially vision-threatening complications with intravitreal injection compared with control interventions; however, clinical trial sample sizes may not have been sufficient to detect rare safety outcomes. Research evaluating variable dosing regimens with anti-VEGF agents, effects of long-term use, combination therapies (e.g., anti-VEGF treatment plus photodynamic therapy), and other methods of delivering the agents should be incorporated into future Cochrane reviews.

Read the full abstract...
Background: 

Age-related macular degeneration (AMD) is the most common cause of uncorrectable severe vision loss in people aged 55 years and older in the developed world. Choroidal neovascularization (CNV) secondary to neovascular AMD accounts for most AMD-related severe vision loss. Anti-vascular endothelial growth factor (anti-VEGF) agents, injected intravitreally, aim to block the growth of abnormal blood vessels in the eye to prevent vision loss and, in some instances, improve vision.

Objectives: 

To investigate: (1) the ocular and systemic effects of, and quality of life associated with, intravitreally injected anti-VEGF agents (pegaptanib, ranibizumab, and bevacizumab) for the treatment of neovascular AMD compared with no anti-VEGF treatment; and (2) the relative effects of one anti-VEGF agent compared with another when administered in comparable dosages and regimens.

Search strategy: 

We searched Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to March 2014), EMBASE (January 1980 to March 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to March 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We used no date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 27 March 2014.

Selection criteria: 

We included randomized controlled trials (RCTs) that evaluated pegaptanib, ranibizumab, or bevacizumab versus each other or a control treatment (e.g., sham treatment or photodynamic therapy). All trials followed participants for at least one year.

Data collection and analysis: 

Two review authors independently screened records, extracted data, and assessed risks of bias. We contacted trial authors for additional data. We analyzed outcomes as risk ratios (RRs) or mean differences (MDs). We used the standard methodological procedures expected by The Cochrane Collaboration.

Main results: 

We included 12 RCTs including a total of 5496 participants with neovascular AMD (the number of participants per trial ranged from 28 to 1208). One trial compared pegaptanib, three trials ranibizumab, and two trials bevacizumab versus controls; six trials compared bevacizumab with ranibizumab. Four trials were conducted by pharmaceutical companies; none of the eight studies which evaluated bevacizumab were funded by pharmaceutical companies. The trials were conducted at various centers across five continents (North and South America, Europe, Asia and Australia). The overall quality of the evidence was very good, with most trials having an overall low risk of bias.

When compared with control treatments, participants who received any of the three anti-VEGF agents were more likely to have gained 15 letters or more of visual acuity, lost fewer than 15 letters of visual acuity, and had vision 20/200 or better after one year of follow up. Visual acuity outcomes after bevacizumab and ranibizumab were similar when the same regimens were compared in the same RCTs, despite the substantially lower cost for bevacizumab compared with ranibizumab. No trial directly compared pegaptanib with other anti-VEGF agents; however, when compared with controls, ranibizumab or bevacizumab yielded larger improvements in visual acuity outcomes than pegaptanib.

Participants treated with anti-VEGFs showed improvements in morphologic outcomes (e.g., size of CNV or central retinal thickness) compared with participants not treated with anti-VEGF agents. There was less reduction in central retinal thickness among bevacizumab-treated participants than among ranibizumab-treated participants after one year (MD -13.97 μm; 95% confidence interval (CI) -26.52 to -1.41); however, this difference is within the range of measurement error and we did not interpret it as being clinically meaningful.

Ocular inflammation and increased intraocular pressure after intravitreal injection were the most frequently reported serious ocular adverse events. Endophthalmitis was reported in fewer than 1% of anti-VEGF treated participants; no cases were reported in control groups. The occurrence of serious systemic adverse events was comparable across anti-VEGF-treated groups and control groups; however, the numbers of events and trial participants may have been insufficient to detect a meaningful difference between groups. Data for visual function, quality of life, and economic outcomes were sparsely measured and reported.

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