Meta-Analysis to Determine Optimal Therapy Strategies in Macular Degeneration

Background of this Study

Neovascular age-related macular degeneration (nAMD) affects as many as 196 million people worldwide, and is a major cause of severe vision problems including blindness. Despite its prevalence, disagreements about the treatment options still exist.

In nAMD patients, vision loss is thought to occur when choroidal neovascularization (CNV) disrupts the function of the macula. Anti-vascular endothelial growth factor (anti-VEGF) therapies have been widely used in recent years as intravitreal injections to treat CNV in nAMD. This article highlights the largest known comprehensive meta-analysis of randomized controlled trials focused upon evaluating the safety and efficacy of anti-VEGF regimens.

Some of the most common anti-VEGF agents used to treat CNV in nAMD patients include:

• Pegaptanib (Macugen)
• Bevacizumab (Avastin)
• Ranibizumab (Lucentis)
• Aflibercept (Eylea)

Combination therapy with anti-VEGF treatments is common as monotherapy has efficacious limits. Treatments used with anti-VEGF therapy are: photodynamic therapy (PDT), radiation therapy, NSAIDs, and steroids. More than forty therapeutic strategies have been described using different combinations of anti-VEGF and supportive agents.

The purpose of this study was to evaluate all different therapeutic regimens of these CNV treatments in order to lay the foundation for a solid reference to aid the decision-making of practicing ophthalmologists.

Results

Outcomes of this study are chiefly presented as answers to four main questions posed regarding current treatment strategies.

1. What are the optimal anti-VEGF dosing strategies for CNV treatment?
   Previously accepted opinions that maximum benefit is achieved from taxing monthly treatments were not validated. The results of this study show that T&E strategy provided patients with the best outcomes in BCVA changes as well as gain of three lines or more of best-corrected visual acuity (BCVA).
2. Are combination treatments providing best patient outcomes?
   Ranibizumab plus NSAIDs therapy resulted in the best central retinal thickness (CRT) reductions, and results show superiority in comparison with anti-VEGF treatment alone. This combination treatment also had a high ranking in BCVA changes. Radiation or PDT also got high ranking in CRT reduction, but had no or even detrimental effects on visual improvement, suggesting monotherapy might be superior to these combination therapies.
3. Is bevacizumab safe and effective to treat nAMD (this treatment costs less and is off-label)?
   Across all studied treatment strategies, this agent did not increase the incidence of adverse drug events in this study. Ocular or cardiocerebral vascular events were noted specifically.
4. Which is the most safe and effective anti-VEGF agent?
   For the same treatment strategy like treat and extend (T&E), there were no significant differences in efficacy or safety between the anti-VEGF agents. The efficacy of treatment was shown, throughout this study, to depend more on the strategy applied rather than the particular agent.

The results of these study questions indicate, for the first time, that the T&E treatment strategy provides a positive effect on visual improvements for patients with nAMD. Concerns about the comparative safety and efficacy among anti-VEGF agents have not been confirmed from in trial data. Topical NSAID therapy has been shown to be an effective adjunct to treatment.

Methods

PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases were searched for randomized controlled trials focused on the dosing of anti-VEGF agents and strategies employed. These results were from 47 randomized controlled trials and 17,872 patients that were included in this meta-analysis. This was a network meta-analysis, a new method for statistical analysis of data which improves precision and increases statistical power when compared with pair-wise meta-analysis that has been used historically.

This study was performed in accordance with PRISMA guidelines for meta-analysis. PRISMA is an evidence-based minimum set of items for reporting in systematic reviews and meta-analyses. PRISMA focuses on the reporting of reviews evaluating randomized trials, but can also be used as a basis for reporting systematic reviews of other types of research, particularly evaluations of interventions.

This study was also registered with an international prospective register of systematic reviews called PROSPERO (CRD42020156353). PROSPERO accepts registrations for systematic reviews, rapid reviews and umbrella reviews. PROSPERO does not accept scoping reviews or literature scans. Sibling PROSPERO sites register systematic reviews of human studies and systematic reviews of animal studies.

The primary outcome of efficacy considered was positive changes in BCVA at one year follow up. The primary safety outcome was the incidence of severe adverse drug events of the eye. Secondary outcomes included patient percentage that gained three or more lines of BCVA, CRT changes, and other non-severe adverse drug events.

Inclusion criteria

Selection inclusion criteria for the included randomized controlled trials were as follows:

Clinical trial data presented in the English language

CNV presentation secondary to nAMD

Anti-VEGF injection therapy was given to the patient

Various doses or therapeutic strategies or combination therapy with anti-VEGF agent were used

At least one of the following indices at one year follow up:

• Visual acuity
• Lines of visual acuity improvement
• CRT
• Incidence of severe ocular adverse drug events
• Incidence of cardiocerebral vascular adverse events

Exclusion criteria

Studies evaluating an unapproved agent or one used in combination with pars plana vitrectomy

Insufficient data to determine odds risk or standardized mean difference

Redundant publications

Bias and limitations

These results are from direct and indirect network meta-analysis, which is highly accepted, but which should never be a substitute for large-scale randomized controlled trials.

The results reported include only a one year follow up interval.

27.7% of studies were rated with low risk of bias, the rest were unclear of the bias risk. No included studies were thought to have high bias risk.

All included studies have acceptable adverse drug event risk.

Odds ratio and its 95% confidence interval were calculated for dichotomous data.

Standardized mean difference and its 95% confidence interval were calculated for continuous data.

Data for 1mg and 1.25mg of bevacizumab were combined.

Global inconsistency, local inconsistency and heterogeneity were all not significant between the direct and indirect comparison of evidence in both the primary and secondary outcomes.

Asymmetry was not identified.

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