PEER REVIEWED

Anti-VEGF Debate: Are Intravitreal Agents Associated With Elevated IOP?

A review of the data indicates reasons to be vigilant.

KATELYN EARLS, MD · DAVID L. CUTE, DO

The use of intravitreal injections for ocular diseases continues to increase. In particular, intravitreal injections of anti-VEGF agents are becoming more commonplace.

The versatility of these medications is expanding to include treatment for choroidal neovascularization and macular edema from various causes, such as retinal vascular occlusions and diabetes mellitus.

More recently, these agents have also been used for the treatment of retinopathy of prematurity. Currently, four intravitreal anti-VEGF agents are available:

• pegaptanib (Macugen, Valeant Pharmaceuticals, Bridgewater, NJ; 0.09 mL injected with a 27- or 30-gauge needle);

• ranibizumab (Lucentis, Genentech, South San Francisco, CA; 0.05 mL, 30- or 32-gauge);

• bevacizumab (Avastin, Genentech; 0.05 mL, 30- or 32-g); and

• aflibercept (Eylea, Regeneron, Tarrytown, NY; 0.05 mL, 30-g).

Because these drugs have a limited duration of effect, patients frequently need multiple injections. The interval between injections can vary depending on the mechanism of action and patient response.

This article focuses on the concern for increased IOP associated with intravitreal anti-VEGF agents as a group.

PREVIOUS DATA

Prior research has reported elevated IOP with intravitreal anti-VEGF agent injections in both acute/transient and delayed/sustained settings. Transient IOP elevation is due to the acute increase in intraocular volume the injection causes, a well-documented phenomenon.^1-3 Studies have shown IOP to rise as high as 87 mm Hg,³ although it typically returns to close to baseline within 60 minutes postinjection (Figure 1).^1-3 However, sustained IOP elevation associated with the intravitreal injection of these agents has been heavily debated within the literature (Figures 2-4 [3 and 4 on page 22]).

We review an assortment of published reports surrounding the major variables applicable to elevations in IOP, both acute and delayed. In addition, several articles have validated the elevation in IOP, but they have debated its importance in ocular health.¹

ANTI-VEGF AGENTS

Anti-VEGF agents themselves have multiple properties and processing features that have raised concern. VEGF is a collection of related molecules, which include VEGF-A and placental growth factor (PlGF), the two families most associated with angiogenesis.⁴

In 2004, pegaptanib was the first anti-VEGF drug the FDA approved for treatment of neovascular AMD. Its mechanism of action as an oligonucleotide is in binding to the 165 amino acid isoform of VEGF-A, neutralizing VEGF-A binding activity related specifically to this isoform.

Ranibizumab followed with approval in 2006. This drug is a recombinant monoclonal antibody fragment (Fab) of 48 kDa. It binds to a conserved region on the VEGF-A protein, allowing more isoforms of VEGF-A to be neutralized.

Physicians began using bevacizumab off-label at about the same time ranibizumab was approved. It is a whole antibody of 149 kDa, about three times the size of ranibizumab. This larger size raises concern for possible physical blockage of the trabecular meshwork.

Also, bevacizumab, as a whole antibody, includes the crystalizable fragment region (Fc), which plays a role in immunologic processes. This has the potential for increased intraocular inflammation, both macroscopically and microscopically.

Compounding pharmacies process bevacizumab, which is FDA-approved for intravenous treatment of metastatic colon carcinoma. During processing, transport, and storage, changes may occur that make the agent more apt to cause changes in IOP.⁵ Possible mechanisms include physical blockage of outflow through silicone leaching and protein aggregation, as well as an immune response due to protein aggregation in the trabecular meshwork.

In 2011 the FDA approved aflibercept for treatment of wet AMD. Its total molecular weight is 115 kDa, and it is considered a VEGF-trap design, composed of all human amino acid sequences. Structurally, it consists of a constant Fc region from human immunoglobulin G, fused with two identical arms with sequences consistent with VEGF receptor 1 and VEGF receptor 2.

These sequences correspond to the normal binding site of VEGF-A and PlGF, but they have a higher affinity than naturally occurring sequences.^6,7 This agent is all-human, which decreases its likelihood of causing inflammation, but it is large in size and price.

Figure 1. IOP tends to rise immediately postinjection and then recover within 30 to 60 minutes.

ALL IMAGES COURTESY: NURIT MATHALONE, MD, AND ORNA GEYER, MD

Figure 2. Some studies have noted a positive correlation between baseline IOP and the rise in postinjection IOP.

INJECTION TECHNIQUE

Studies have investigated the number of injections as a risk factor for sustained IOP elevation.⁸ Tseng et al studied 25 eyes with neovascular AMD that displayed increased IOP while receiving “treat-and-extend” interval doses of intravitreal ranibizumab or bevacizumab, or both.

This study found a mean of 20 injections was associated with an increased risk of sustained IOP elevation,⁹ although other studies have not found this association.¹⁰

Studies have also investigated the frequency of injections. Choi and colleagues, in a retrospective review of 155 eyes treated with intravitreal bevacizumab, ranibizumab, or pegaptanib for wet AMD, found both acute and sustained IOP increases. However, data analysis found no association between injection frequency and sustained IOP elevation.¹⁰

Further research involving eyes that received multiple intravitreal injections has focused on structural changes elevated IOP frequently causes. Seth and colleagues reported no statistical significance in optic nerve structure after longterm anti-VEGF treatment.¹¹

In addition, Horsley and colleagues evaluated the effects of multiple intravitreal anti-VEGF injections for wet AMD on temporal-domain retinal nerve fiber layer thickness in patients without glaucoma.

Patients received an average of 16 injections of some combination of pegaptanib, bevacizumab, or ranibizumab. They exhibited no significant RNFL changes.¹² This study was limited, however, because it only evaluated the mean RNFL thickness and not sectoral RNFL thickness.

Figure 3. The number of prior injections seems to correlate with postinjection IOP.

Figure 4. A study by Mathalone and Geyer found IOP elevation was greater when the interval between injections was eight weeks or less.

A study by Martinez-de-la-Casa and colleagues also studied RNFL thickness in patients with no history of glaucoma receiving intravitreal anti-VEGF injections for wet AMD. The study monitored RNFL with spatialdomain technology and found a loss of 5.2% in thickness compared to baseline at one year. Although this is probably not significant for patients with normal RNFL thickness, it may be important for patients with an already compromised RNFL.¹³

Other factors the study reviewed included the needle gauge and reflux from injection site. The smaller the needle bore, the larger the acute increase in IOP due to less reflux at the injection site.³

THE EYE’S ANATOMIC STRUCTURE

The injection causes an abrupt increase in intraocular volume, which in turn causes an acute elevation in IOP. So one would expect eyes with shorter axial lengths to experience larger IOP elevations immediately postinjection compared to longer, more myopic eyes.¹⁴

Besides the size of the globe, scleral thickness and rigidity also likely play roles. The sclera becomes more rigid as the eye ages, leading possibly to a greater IOP increase with volume addition. One should also consider these factors as anti-VEGF agents begin to be used in ROP treatment.

Although the globes of younger ROP patients typically have a shorter axial length early on, the sclera is likely more pliable, mitigating any significant, acute IOP rise.

HISTORY OF GLAUCOMA

Specific concerns arise in patients with a history of glaucoma. These eyes already may have a compromised outflow system and optic nerves more susceptible to elevations in IOP.

Kim et al’s study retrospectively reviewed 120 eyes with various indications for injections. Eyes with a history of glaucoma had higher immediate postinjection IOP and took a longer time to normalize IOP acutely postinjection, but the IOP normalized in all injected eyes (glaucomatous or not) by 30 minutes.³

Hoang et al found no association between a history of glaucoma and an increased risk of sustained elevated IOP.⁸ In contrast, Good et al retrospectively reviewed 215 eyes being treated for wet-AMD with ranibizumab or bevacizumab, or both. This study compared eyes with and without a history of glaucoma. Results showed that patients with a history of glaucoma had a higher prevalence of sustained elevated IOP, which occurred after fewer total injections. The authors hypothesized that eyes with already compromised outflow may be at greater risk.⁵

DISCUSSION

Although the body of literature regarding IOP elevation in anti-VEGF therapy is growing, interpreting the data continues to be difficult for many reasons. First, no one mechanism has been consistently found to be a direct causal factor between anti-VEGF intravitreal injections and IOP elevation.

Among the mechanisms authors have suggested for sustained IOP elevation are the agent or syringe contaminant directly blocking the trabecular meshwork, direct drug toxicity, injection technique, microscopic inflammation, and already susceptible eyes (ie, those with a history of glaucoma).

Because the injections occur over months to years, conclusively targeting intravitreal agents as the cause proves difficult. In addition, the four anti-VEGF agents have developed over time. Many patients have had injections with multiple agents, so interpreting the effect anti-VEGF agents have on IOP is difficult.

For example, Bakri and colleagues found ocular hypertension following ranibizumab injections, although several patients had also previously received pegaptanib. Could the elevated IOP have been a late response to pegaptanib or only from the ranibizumab, or both?

Further complicating the data are case reports of patients developing sustained IOP elevation after only one injection.¹⁵ Yet other patients have received 40 or more intravitreal injections without any sustained rise in IOP.

POINTS TO CONSIDER

After a review of the data, several points are worth considering with regard to IOP in the setting of intravitreal anti-VEGF injections. First, treating physicians should remain aware of the evidence for the possibility of a sustained elevation in IOP following injections (regardless of the number or frequency of previous injections, or agent). The consent process should include a description of this possible side effect.

Second, consider the patient’s baseline IOP and optic nerve status. In a patient with severe pre-existing glaucomatous optic nerve damage, the treating physician should specifically counsel on the risk of an abrupt rise in IOP and a sustained IOP increase, with their possible consequences.

In such a patient, consider pretreating the eye with topical IOP-lowering agents, although doing so might not be necessary if the IOP is well controlled, either medically or via previous glaucoma surgery, such as trabeculectomy or a glaucoma drainage implant, or both medically and surgically.

Besides documenting an appropriate level of vision immediately postinjection, as should be done in all treated patients, a good practice may be to also check IOP at 30 minutes postinjection to ensure it is within a safe range.

If vision immediately postinjection is quite poor, or the IOP remains greater than a safe level for that given patient at 30 minutes postinjection, consider further intervention to lower IOP.

Doctors should consider performing an anterior-chamber paracentesis to lower the IOP to an appropriate level, if necessary. Some research even recommends considering a pre-injection anterior-chamber paracentesis in eyes with severe axial hyperopia, vascular compromise,¹⁴ and advanced glaucoma¹ to reduce the likelihood of a significant acute elevation in IOP immediately following the injection.

Further, because compounding pharmacies supply bevacizumab, doctors must be aware of the pharmacies’ procedures for handling the drug. Consider monitoring patients more closely if the injection volume is greater than 0.05 mL or a smaller-gauge needle is used.

CONCLUSION

The research in this field continues to grow as anti-VEGF agents have been used now for almost 10 years. Newer agents are being engineered (to increase interval times and decrease side-effect profiles), and the technology for monitoring the side effects of the medication continues to improve.

These points notwithstanding, we urge physicians to continue to remain aware of this research and its implications for their patients. RP

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