Perspectives on the Link Between Anti-VEGF Injections and Long-Term Ocular Hypertension

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The question appears straightfor­ward enough: Do repeated intra­vitreal anti–vascular endothelial growth factor (VEGF) injections cause a long-term increase in glaucoma or ocular hypertension (OHT) in patients with neovascular age-related macular degeneration (AMD)?

A review of the literature indicates the answer is not that simple.

While earlier studies showed a mini­mal risk of sustained elevated intraocu­lar pressure (IOP) following intravitreal anti-VEGF injection, a more recent retrospective clinical study demonstrat­ed a significantly increased incidence of OHT and open-angle glaucoma (OAG) related to this treatment.¹

One thing is for certain, according to Ahmad A. Aref, MD, at the University of Illinois Eye and Ear Infirmary in Chicago. “Given the severity of AMD and glaucoma, both of which can lead to irreversible blindness, and the increasing numbers of older patients who will need anti-VEGF intravitreal injection therapy, sustained IOP ele­vation following anti-VEGF injections will continue to be an important area of research.”

Pathophysiology Still Being Explored

Dr. Aref explained that 2 distinguish­able time periods of IOP elevation following intravitreal anti-VEGF injections—short-term and long-term—have been identified.²

Short term. Short-term increases in IOP are seen almost immediately following injection, and from a patho­physiology perspective they are thought to be related directly to an increase in intraocular fluid volume. “Typically, the rise is by virtue of injecting fluid into a restricted space,” he said.

Long term. On the other hand, the pathogenesis of long-term, sustained IOP elevation has been more difficult to ascertain, Dr. Aref said. “Theories in­clude a permanent decrease in outflow facility due to repeated spikes in IOP after each injection that damage the trabecular meshwork; direct pharma­cological toxicity; and chronic trabec­ulitis.”

He pointed to a recent study show­ing that chronic anti-VEGF injections significantly reduced outflow facility in patients with AMD.³ Researchers found a small but statistically signifi­cant decrease in tonographic outflow facility in patients who had undergone 20 or more anti-VEGF injections; this decrease was not observed in patients with 10 or fewer injections. The re­searchers also showed that patients with ocular hypertension in their uninjected eye demonstrated a substantially lower outflow facility in their injected eye.

“The pathogenesis of sustained IOP increases associated with anti-VEGF remains unclear and continues to be the focus of many studies,” he said.

INJECTION. It is generally agreed that the fluid introduced by intravitreal anti-VEGF injection raises IOP over the short term. However, expert opinion differs about the long-term effects of these injections.

A Minimal Concern

Researchers appear to agree that short-term IOP increases after anti-VEGF injections frequently occur. Seenu M. Hariprasad, MD, at the University of Chicago, noted that several papers over the years have described this phenom­enon.

“In each of these studies, a signif­icant elevation in IOP was found 30 minutes after the injection but returned to baseline levels by the first follow-up clinic visit,” Dr. Hariprasad said. “My own research looking at pegaptanib, bevacizumab, and ranibizumab also indicated that the IOP increase we saw roughly 30 minutes after the injection had normalized at the 5- to 7-day fol­low-up visit.”^4-6

While the short-term IOP rise is almost universally understood and ac­cepted, Dr. Hariprasad said, the debate surrounding whether these injections cause long-term elevation in IOP persists. He added that several large clinical trials have demonstrated that intravitreal injections “very rarely” led to a sustained increase in IOP.

This includes the post hoc analysis of the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) and the Anti-VEGF Antibody for the Treatment of Pre­dominantly Classic Choroidal Neo­vascularization in AMD (ANCHOR) ranibizumab trials,⁷ “which showed that most ranibizumab-treated eyes did not experience a sustained elevation of IOP over 24 months,” he said.

New study. “Yet despite these find­ings, a recent survey of retina specialists revealed that 55% believe intravitreal injections may cause sustained IOP ele­vation,”⁸ Dr. Hariprasad said. “Realizing the need for further clarification, we recently published a retrospective study investigating how the number and tim­ing of intravitreal injections in patients with AMD and DME [diabetic macular edema] affected IOP over time.”⁹

Long-term IOP data were collected on 76 AMD patients and 55 DME patients receiving anti-VEGF injections at Dr. Hariprasad’s institution. Time points ranged from 0 to more than 24 months, with patients receiving from 1 to more than 10 injections. “Our data suggested that when using a treat-and-extend dosing regimen, the admin­istration of anti-VEGF intravitreal injections was not a significant risk factor for an increase in IOP—regard­less of how many injections the patient received,” he said.

Conclusion. Dr. Hariprasad said that after looking at the evidence from these studies, “the argument is very weak that anti-VEGF injections cause a meaningful long-term increase in IOP.” And, although clinical judgment is advised for patients at risk for glaucoma, “clini­cians should use anti-VEGF agents with confidence that long-term IOP eleva­tions are of minimal concern,” he said.

An Important Link

Jeremy B. Wingard, MD, at the Wheaton Eye Clinic in Illinois, was prompted to conduct a controlled retrospective chart review¹ after observing a significant incidence of sustained OHT and OAG in AMD patients receiving anti-VEGF intravitreal injections.

Trends in the clinic. “Wheaton Eye Clinic is one of the largest practices in the Midwest with more than 30 ophthalmologists, including 5 retina specialists and 5 glaucoma specialists,” he said. “Our size and internal referral system allow us to study disease devel­opment in a highly controlled manner and with numbers that vastly exceed other studies looking at individual pa­tient results. Our retina specialists were directly referring their AMD patients to our glaucoma specialists for sustained ocular hypertension, and we wanted to further study this phenomenon.”

The study. Dr. Wingard noted that the retrospective chart review only in­cluded patients who received unilateral anti-VEGF injections but in whom both eyes could be analyzed to deter­mine OHT or OAG development. Of the 1,107 patients who met the study criteria, 43 (3.88%) developed OHT or OAG in only the injected eye, 21 patients (1.90%) developed OHT or OAG in both eyes, and 2 patients (0.18%) developed OHT or OAG only in the untreated eye.

“The most striking finding is that 30 patients received 25 or more injectionsof bevacizumab, and of those 30 pa­tients, 11, or 36.7%, developed OHT or OAG in the treated eye only,” Dr. Wingard noted. “A number of these pa­tients needed surgery to manage their glaucoma. In fact, of the 40 patients who developed glaucoma in the treated eye and were followed by our glaucoma specialists for at least 6 months, 35% required glaucoma surgery to manage their disease, including 17.5% who required filtering surgery. Thankfully, these surgical patients have generally responded well to treatment and have been able to resume anti-VEGF injec­tions as indicated for their AMD.”

Dr. Wingard noted that some earlier, and typically small, studies did not identify this link as they rarely included patients who had more than 25 injec­tions, and yet this population is crucial given the chronic nature of AMD. “You can’t stop delivering the anti-VEGF medication in many of these patients,” he said. “Most retina doctors are trying to extend the time between the injec­tions, but in certain patients, there is a risk to this strategy as well. And the longer patients live, the more injections they will need.”

Conclusion. “It is important to bring this information to light as it supports the hypothesis that intravitreal anti-VEGF injections have a significantimpact on sustained IOP elevations,” he added. “I am personally convinced that there is a cause and effect, and any new anti-VEGF regimens that are tested should prospectively assess patients for the possible development of sustained ocular hypertension and optic nerve damage.”

IOP Rise Uncommon

The 2013 introduction of the Academy IRIS Registry (Intelligent Research in Sight), which includes clinical bench­marks and practice patterns on more than 28 million U.S. patients and 100 million patient visits, has given prac­ticing ophthalmologists new insights through big data, noted Mathew W. MacCumber, MD, PhD, at Rush Uni­versity Medical Center in Chicago.

“Several previous studies have sug­gested a link between intravitreal anti-VEGF injections and sustained IOP,” noted Dr. MacCumber. “We wanted to use the power of real-world big data to gain clarification.”

The study. At the 2017 ARVO meeting in May, Dr. MacCumber and colleagues presented study findings indicating that overall anti-VEGF ther­apy was in fact associated with a small decrease in IOP over time.¹⁰

The study included 23,282 patients in the IRIS Registry with AMD, DME, or branch or central retinal vein occlusion who received bevacizumab, ranibizumab, or aflibercept injections in the right eye from the study period be­tween Jan. 1, 2013, and Dec. 31, 2015.

“When looking at the 3 drugs, IOP was generally higher in bevacizumab-treated eyes compared to aflibercept- and ranibizumab-treated eyes, although the differences were small. Moreover, when looking at the rate of a clinically significant pressure rise [at least a 6 mm Hg IOP rise to over 21 mm Hg], the rate was 2.2% for aflibercept, 2.5% for ranibizumab, and 3% for bevaci­zumab,” Dr. MacCumber said.

Dr. MacCumber noted the IRIS Reg­istry findings supported Dr. Wingard’s clinical results to some extent and ex­tended them further for a comparison between the 3 commonly used anti-VEGF drugs. “When we ran numbers on the IRIS Registry data for the 324 patients who had 25 or more injections, we saw that bevacizumab caused more eyes to develop high IOP, 4%-9.5%, not as high as his study at 36%,” Dr. MacCumber added. “The other 2 drugs still caused only 1%-3% of injected eyes to experience a clinically significant pressure rise.”

Dr. MacCumber noted that the over­all lower rates of sustained IOP found in the IRIS Registry data reflected practice patterns from thousands of ophthal­mology practices, unlike the smaller populations seen in clinical trials, which may explain his study’s findings.

Conclusion. “While we agree that there are eye pressure rises associated with anti-VEGF injections, it is gen­erally less common than previously reported,” said Dr. MacCumber.

Implications for Practice

While questions of elevated IOP after anti-VEGF injections continue to be explored, clinicians can take steps now to protect their patients, noted Dr. Aref.

“First, if clinicians are considering starting a patient on anti-VEGF treatment, they should obtain accurate mea­surements of baseline eye pressures and optic nerve status, as well as determine the patient’s risk for glaucoma. If the patient is diagnosed with glaucoma or deemed to be at a substantially increased risk, he or she should be treated accordingly before undergoing the injections.”

Second, if the patient is at an average risk for glaucoma, the clinician should do “whatever it takes” to treat the mac­ular degeneration. “Keep monitoring the IOP,” Dr. Aref added, “and if an IOP increase continues to appear sustained over several months, a different treat­ment strategy should be considered.” This may include changing anti-VEGF medications or switching to a treat-and-extend strategy.

Finally, Dr. Aref stressed that retina specialists should develop strong work­ing relationships with their glaucoma colleagues. “It’s important to get these complicated patients evaluated to de­termine the optimal treatment.”

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1 Houlihan N, Lin J, Gieser J, Delzell D, Wingard J. Poster #135, The relationship between anti-VEGF treatments and the development of glaucoma or ocular hypertension in macular degeneration pa­tients. Presented at: American Glaucoma Society 2017 Annual Meeting; May 4, 2017, Coronado, Calif.

2 Aref AA. Curr Opin Ophthalmol. 2012;23(2):105-110.

3 Wen JC, Reina-Torres E, Sherwood JM, Challa P, Liu KC, Li G, Chang JYH, Cousins SW, Schuman SG, Mettu PS, Stamer WD, Overby DR, Allingham RR. Invest Ophthalmol Vis Sci. 2017;58(3):1893-1898.

4 Hariprasad SM, Shah GK, Binder KJ. Am J Ophthalmol. 2006;141(1):200-201.

5 Mazzulla DA, Hariprasad SM, Jager RD, Mieler WF. Retin Cases Brief Rep. 2008;2(3):234-235.

6 Mojica G, Hariprasad SM, Jager RD, Mieler WF. Br J Ophthalmol. 2008;92(4):584.

7 Bakri SJ, Moshfeghi DM, Francom S, Rundle AC, Reshef DS, Lee PP, Schaeffer C, Rubio RG, Lai P. Ophthalmology. 2014;121(5):1102-1108.

8 Yannuzzi NA, Patel SN, Bhavsar KV, Sugi­guchi F, Freund KB. Am J Ophthalmol. 2014;158(2):319-327.e2.

9 Nariani A, Williams B, Hariprasad SM. Indian J Ophthalmol. 2016;64(9):643-647.

10 Atchison EA, Barry CN, Lum F, Mattox C, MacCumber MW. Poster # A0050, The real world effect of anti-VEGF injections on IOP using the IRIS Registry. Presented at: ARVO Annual Meet­ing; May 7, 2017, Baltimore.

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Dr. Aref is assistant professor of ophthalmology, Glaucoma Service, and director, Residency Training Program, Illinois Eye and Ear Infirmary, Uni­versity of Illinois College of Medicine, Chicago. Relevant financial disclosures: None

Dr. Hariprasad is Shui-Chin Lee Professor of Ophthalmology and Visual Science, chief, Vitreoretinal Service and director, Clinical Research at the University of Chicago Medicine & Biological Sciences. Relevant financial disclosures: Regeneron: C,L.

Dr. MacCumber is professor and associate chair­man for research, Department of Ophthalmol­ogy, Rush University Medical Center, Chicago. Relevant financial disclosures: Genentech: C,S; Regeneron: C,S.

Dr. Wingard specializes in glaucoma and cataract surgery at Wheaton Eye Clinic, Wheaton, Ill. Relevant financial disclosures: None.

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