Intraocular Pressure Elevations Following Intravitreal Injections of Anti-VEGF Agents

Nurit Mathalone, MD • Orna Geyer, MD

Intravitreal injections of anti-VEGF medications have become a common and widespread treatment for various retinal disorders, including neovascular age-related macular degeneration, diabetic macular edema, and cystoid macular edema following retinal vein occlusions. An increasing number of patients are treated in retina clinics worldwide using intravitreal injections, which are administered routinely. Various reports regarding the relationship between intravitreal injections of anti-VEGF medications and intraocular elevations have been published.

SHORT-TERM IOP ELEVATIONS

Immediate short-term elevations of IOP after such injections are a known phenomenon. The main reason for IOP elevation is the sudden addition of fluid to the relatively small volume of the vitreous cavity. Such elevations are usually transient. Several reports have been published, most of which describe the return of IOP to normal values (less than 25 mmHg) approximately 30 to 60 minutes after injection without any IOP-lowering medications or interventions.^1-4

Several risk factors have been identified for the prompt postinjection IOP elevation, including baseline preinjection elevated IOP,⁵ a short axial length,⁶ and the injection technique.⁷ Other factors, such as age, sex, and the number of previous intravitreal injections, have not been identified as raising the risk for IOP elevation.

In a prospective analysis performed at our retina clinic at the Carmel Medical Center in Haifa, Israel, we analyzed data collected from 90 neovascular AMD patients undergoing intravitreal injections of Avastin (bevacizumab). All of the patients received the standard dose of 1.25 mg Avastin in 0.05 mL injected into the vitreous cavity. For all of the patients, axial length, baseline IOP, and the number of previous injections were recorded. IOP was measured before, immediately after, and 30 minutes after the intravitreal injection.

Although IOP was significantly elevated to a mean of 36 mm Hg (range 13-67 mm Hg) immediately postinjection, it returned to normal values 30 minutes after injections in practically all patients (Figure 1). In contrast to other reports, we found no correlation between immediate IOP elevations and axial length (r = -.0204; P = .19). We did find a significant positive correlation between short-term IOP elevations and baseline IOP (r = 0.467; P = .002) (Figure 2) or the number of previous injections (r = 0.320; P = .036) (Figure 3).

Figure 1. IOP rose significantly immediately postinjection and returned to normal 30 minutes after injection.

Figure 2. A positive correlation was noted between short-term IOP elevations and baseline IOP.

Figure 3. A positive correlation was noted between short-term IOP elevations and the number of previous injections.

SUSTAINED IOP ELEVATIONS

As more patients are treated with intravitreal anti-VEGF medications, reports are being collected describing sustained IOP elevations following intravitreal injections. The cause of such protracted IOP elevation is not completely understood. Several mechanisms have been suggested, including trabecular damage caused by repeated IOP elevations following each injection, a direct toxic effect of the medication on the trabeculum,⁸ trabeculitis⁹ caused by the compounds injected, disrupted drainage of the aqueous humor by proteins or silicone particles, which can be found in the syringes used for the intravitreal injection that penetrate the trabeculum,^10-11 damage to the drainage system caused by repeated acute IOP elevations immediately postinjection, and mechanical injury to the drainage system.

The two major studies that examined the efficacy of Lucentis (ranibizumab) injections in neovascular AMD are the MARINA¹² and ANCHOR¹³ trials. These studies included hundreds of patients who received intravitreal injections of Lucentis at four-week intervals. Interestingly, prolonged IOP elevation was not described as a side effect of the injections. The follow-up period was two years and such sustained IOP elevation was not reported in either study.

However, when post hoc analysis was done for those studies, an elevation of at least 6 mm Hg was found in comparison to the IOP before the initiation of treatment. The MARINA post hoc analysis¹⁴ described an elevation of the IOP to 25 mm Hg and beyond in at least two consecutive follow-up visits in 2.1% of treated eyes, compared to 0.4% of control eyes (treated by sham injection). A similar analysis of the ANCHOR study found IOP elevations in 3.6% of treated eyes, compared to 0% in the control group.

CASE SERIES

Several case series have been published in recent years describing prolonged elevation of IOP following intravitreal injections of anti-VEGF agents for the treatment of AMD. Bakri et al.¹⁵ described a small series of four cases with prolonged elevation of IOP following intravitreal injections of different anti-VEGF agents. In those eyes, IOP rose from an average of 17.5 mm Hg (range 15-22 mm Hg) before injections to an average of 40.0 mm Hg (range 30-50 mm Hg) following injections.

A larger series was described by Tseng et al.,¹⁶ who followed 25 eyes of 23 patients for an average of 47.9 weeks. In all eyes preinjection, IOP was normal and rose from an average of 16.9 mm Hg (range 14-21 mm Hg) to 35.8 mm Hg (range 23-58 mm Hg) postinjection. IOP increases occurred after an average of 20 (range 8-40) injections of Lucentis, Avastin, or a combination of both.

Eyes that suffered from IOP elevation and needed additional anti-VEGF injections required hypotensive treatment to maintain normal IOP, and three even underwent glaucoma surgery. In eyes that did not need further injections, IOP stabilized without medical treatment, suggesting that IOP elevation following intravitreal injections might be temporary.

INCIDENCE OF SUSTAINED IOP ELEVATION

Papers describing the occurrence of protracted IOP elevation among patients undergoing anti-VEGF intravitreal injections have reported diverse findings. Adelman et al.¹⁷ found prolonged elevation in four out of 116 patients (3.45%) treated with recurrent intravitreal Lucentis or Avastin. None of the patients who suffered from IOP elevations had a history of glaucoma or ocular hypertension. Average IOP rose from 13 mm Hg (range 8-15 mm Hg) before the initiation of injections to 31.75 mm Hg (range 28-36 mm Hg) after treatment.

Another analysis was published by Choi et al.,¹⁸ who reviewed 155 eyes of 127 AMD patients who received one to 39 intravitreal injections of anti-VEGF agents, including Lucentis, Avastin, and Macugen (pegaptanib sodium). The length of follow-up was 30 to 1,759 days.

In 12 patients (14 eyes, 9.4% of all eyes), an IOP greater than 25 mm Hg was measured postinjections. In seven of those patients, IOP stabilized by topical glaucoma medication (eight eyes) or surgery (one eye). This analysis did not identify the number or frequency of injections as risk factors for IOP elevation. This paper was the first to describe IOP elevation after Macugen injections.

Subsequently, a post hoc analysis of the VISION study,¹⁹ which investigated intravitreal injections of Macugen for the treatment of neovascular AMD, was presented at the 2011 American Academy of Ophthalmology meeting. This analysis included 114 subjects who received an average of 17 injections over two years and 107 control subjects treated with sham injections.

Elevated IOP was defined as a pressure of 22 mm Hg and higher. No differences were found in IOP elevations between the two groups, and none of the patients had to undergo glaucoma surgery or discontinue participation in the study following uncontrolled IOP or advancement of pre-existing glaucoma.

A recent publication by Hoang et al.²⁰ investigated 207 patients treated with intravitreal injections of anti-VEGF agents for AMD. Elevated IOP was defined as a rise in IOP of more than 5, 10, and 15 mm Hg in two consecutive visits compared to preinjection pressure, and treated eyes were compared to nontreated eyes that served as controls. The frequency of IOP elevation of greater than 5 mm Hg was 11.6% of treated eyes, compared to 5.3% of control eyes.

In this study, the investigators found a correlation between the number of injections and the risk for IOP elevation. In eyes that received 29 and more injections, the risk was 20% — 5.75 times the risk for eyes that received 12 or fewer injections (4.2%) and for the control group (5.3%). Of all the risk factors studied, only the number of injections was found to have a significant relationship with an increase in IOP. Pre-existing glaucoma, which was identified as a risk factor in other studies, was not found to be a significant factor in this one.

LUCENTIS VS AVASTIN

All those papers discuss IOP changes following intravitreal injections of anti-VEGF medications in general and do not distinguish Lucentis from Avastin. Avastin is currently the most commonly injected drug globally for the treatment of AMD because of its lower cost.

The number of Avastin injections will probably increase in the future following the expanding number of indications for intravitreal injections, and the recent CATT²¹ two-year results reported similar effects on visual acuity of Avastin and Lucentis in AMD patients. Therefore, the effect of Avastin specifically is important.

One study that investigated Avastin injections specifically was the PACORES trial.²² This study investigated the safety of intravitreal Avastin injections over a 12-month period and found a low rate (0.16%) of temporary IOP increases. In all cases, IOP was stabilized using medical hypotensive treatment.

In contrast, Kahook et al.²³ presented a retrospective series of six patients with neovascular AMD who were treated with intravitreal Avastin and suffered IOP elevations posttreatment. Two of the patients had pre-existing glaucoma, but all had normal preinjection IOP. IOP increases were recorded after one to 10 injections and reached 42 mm Hg in one of the cases. All of the patients had to start topical hypotensive treatment, which reduced IOP to normal levels in all cases.

Good et al.²⁴ presented a study that included 215 eyes that were treated with Lucentis, Avastin, or both. IOP elevation was defined as an IOP of 22 mm Hg or greater with an elevation of 6 mm Hg or more, compared to pressure before the initiation of treatment, recorded in two consecutive measurements and lasting 30 days or more.

Such persistent elevation was found in 6% of all eyes and required either topical treatment or laser trabeculoplasty. The average IOP in those eyes was 29 mm Hg (range, 23-36 mm Hg). The incidence of sustained IOP elevation was considerably greater in eyes with balanced pre-existing glaucoma (33%), compared to eyes without glaucoma (3.1%).

Of the 101 eyes that were treated with Avastin alone, 9.9% exhibited prolonged IOP elevation, compared to 3.1% of the 96 eyes that were treated with Lucentis alone. The number of injections and the interval between injections were not identified as risk factors. This was the only study that compared and found differences in IOP increases between Lucentis and Avastin injections.

FREQUENCY OF ANTI-VEGF INJECTIONS

Our group recently published a retrospective analysis of IOP following Avastin injections, comprising the largest group of eyes reviewed in the literature for sustained IOP elevation. We collected data from 201 eyes of 174 patients undergoing Avastin injections for neovascular AMD.

All of the patients were treated with the standard dose of 1. 25 mg in 0.05 mL Avastin administered intravitreally.²⁵ We monitored IOP for all patients prior to treatment and at all follow-up visits. Sustained IOP elevation was defined as an IOP of 22 mm Hg or greater, combined with a rise of 6 mm Hg or more lasting 30 days or more, compared to baseline.

We found a significant IOP increase in 22 of 201 eyes examined (11%). There was no significant difference between IOP increases in eyes with pre-existing glaucoma (6.7%; one of 15 eyes) compared to eyes without glaucoma (11.3%; 21 of 186 eyes, P = .9). In eyes that exhibited sustained IOP elevation, the average pressure was 26 mm Hg.

A subanalysis of this group found IOPs greater than 25 mm Hg in 10 eyes, greater than 30 mm Hg in three eyes, and an IOP of 36 mm Hg in one eye.

Among the group with sustained elevation, two patients were treated bilaterally and suffered from bilateral IOP elevation. IOP in all 22 eyes that suffered prolonged IOP elevation returned to normal with topical treatment, with none of the eyes requiring laser trabeculoplasty or glaucoma surgery. No relationship was found between IOP elevation and the number of injections prior to IOP increase.

The interval between injections was the most remarkable risk factor for IOP elevation identified in this study. We found a significantly greater rate of IOP elevation in eyes with intervals <8 weeks (17.6%) than ≥8 weeks (6%, P = .009) (Figure 4). Apparently, close monitoring of IOP is required in patients undergoing intravitreal Avastin injections, especially in those patients receiving frequent injections, to prevent further ocular damage, in addition to the underlying retinal disease.

Figure 4. IOP elevation was significantly greater when the average interval between injections was less than eight weeks compared to average intervals of eight weeks or more.

CONCLUSIONS

Evidence collected in recent years demonstrates that intravitreal injections may produce short- and/or long-term elevations in IOP. Although IOP elevations are uncommon, treating physicians should be aware of this possible complication. In glaucoma patients or people suffering from ocular hypertension, preventive measures, such as topical hypotensive treatment or anterior-chamber decompression prior to injection, should be considered.

Intraocular pressure in patients treated with Avastin injections should be closely monitored, especially in patients receiving frequent injections. In subjects developing sustained IOP elevations PRN, treatment should be considered to minimize the number and frequency of injections. Additionally, close supervision of syringe preparation procedures in Avastin injections is vital because of the risk of particle penetration, as well as the influence of freezing and thawing procedures on IOP in treated eyes. RP

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