S:

Ms Jones, 70 years old, initially presented in January 2013 with acute-onset blurry vision and metamorphopsia of the left eye. She has a history of age-related macular degeneration (AMD) that necessitated intravitreal anti-vascular endothelial growth factor (anti-VEGF) treatment every 4 to 5 weeks for 6 years. 

O:

Best-corrected visual acuity (BCVA) was 20/400. Funduscopic examination was remarkable for drusen, pigment epithelial detachment (PED), and macular edema. Optical coherence tomography (OCT) revealed cortical subfield thickness (CST) of 634 µm in the left eye (compared with 277 µm in the right eye) and subretinal fluid (SRF).

A:

Despite standard intravitreal anti-VEGF treatment, SRF persisted, and Ms Jones had persistent fluctuations in visual acuity. The frequency of treatments might have been difficult for her to maintain. 

P:

The newest anti-VEGF agent, brolucizumab, can reduce treatment burden, given its 12- to 15-week dosing interval. Potential risks and benefits of brolucizumab treatment were discussed with the patient. A shared decision was made to initiate treatment with brolucizumab. 

Outcome and Follow-Up

After 13 months of treatment (5 injections), the SRF resolved, BCVA is stable at 20/40, and cortical subfield thickness remains less than 300 µm. 

Case Scenario

Ms Jones is a 70-year-old woman with suspected neovascular AMD who presented in January 2013 complaining of visual blur and distortion in the left eye. A comprehensive eye examination was performed.

BCVA was 20/400. CST was 634 µm in the left eye and 277 µm in the right eye. Funduscopic examination of the left eye was remarkable for drusen, PED, and macular thickening.

A large PED and SRF were seen on OCT.

Ms Jones said that she enjoyed gardening and reading before her vision deteriorated. Other than presbyopia and cataract (removed in 2011), she had no ocular comorbidities. Medical comorbidities included chronic obstructive pulmonary disease, type 2 diabetes, congestive heart failure, and osteoarthritis. She reported daily dietary supplementation with general vitamins and was taking medications for the aforementioned diseases.



Testing, Diagnosis, and Treatment 

The American Academy of Ophthalmology’s Preferred Practice Pattern1 for AMD notes that the initial history should include:

  • Symptoms (metamorphopsia, decreased vision, scotoma, photopsia, dark adaptation);
  • Ocular, medical, family, and social histories; and
  • Medications and nutritional supplements.

Furthermore, binocular slit-lamp biomicroscopy of the fundus might be recommended because this procedure allows the clinician to see small areas of hemorrhage, hard exudates, SRF, macular edema, subretinal fibrosis, and pigment epithelial elevation. 

Diagnostic tests include OCT, which is the primary tool used to determine the anatomic response to treatment. Newer-generation modalities include swept-source OCT and OCT angiography.1 Fluorescein angiography is recommended when the patient complains of unexplained blurred vision or new metamorphopsia. Color fundus images cannot only find landmarks but can be used as baseline reference or to determine the cause of blocked fluorescence. Fundus autofluorescence is recommended to determine areas of geographic atrophy.

At initial presentation, Ms Jones underwent funduscopic examination, fluorescein angiography, and OCT. Fluorescein angiography showed macular neovascularization with leakage under the fovea. As noted, OCT confirmed SRF, but intraretinal fluid was not observed. Treatment was initiated with off-label bevacizumab. Vision improved to 20/100, the SRF resolved, and treatment was continued. Over the course of the next few years, the SRF and visual acuity fluctuated. The patient underwent 3 intravitreal injections of bevacizumab over the course of 3 months but was switched to ranibizumab due to persistent fluctuation in SRF and vision. After 4 intravitreal ranibizumab treatments and some improvement, Ms Jones was switched back to bevacizumab for 8 treatments. Vision again improved, but SRF still fluctuated, especially when the patient missed an appointment. 

Over the subsequent years, Ms Jones’ AMD became refractory to treatment, and she began to have difficulty keeping consistent monthly appointments. The treatment was switched to aflibercept initially at a frequency of every 8 weeks (on-label) and in anticipation of being able to move the patient to a treat-and-extend regimen. She continued with 37 intravitreal aflibercept injections, eventually settling on treatment every 5 weeks because significant fluid would be seen on OCT at 6-week intervals. 

In June 2019, Ms Jones underwent aflibercept injection. At follow-up in August, the OCT reading showed significant fluid (Figure 1a). At that visit, BCVA was 20/30.


Figure 1a.


In October 2019, Ms Jones’ BCVA was 20/30. There was noticeable PED on OCT, and CST was 312 µm. To reduce the treatment burden and improve disease control, treatment was switched to brolucizumab. In January 2020 (14 weeks after the initial injection of brolucizumab), BCVA was 20/30+1, CST had improved to 326 µm, and SRF was undetectable on OCT (Figure 1b). 


Figure 1b.

Ms Jones continued treatment with intravitreal brolucizumab and was monitored closely for disease activity. In May 2020 (15 weeks after the second injection of brolucizumab), SRF was increased, CST had decreased to 443 µm, and BCVA had deteriorated to 20/50+2 (Figure 1c). Safety concerns with brolucizumab — including intraocular inflammation, retinal vasculitis, and retinal artery occlusion — were discussed as more than 85% of reported serious adverse events with this treatment occur in women.2-6 Ms Jones opted to continue with intravitreal brolucizumab injections. At the January 2021 visit (after 3 additional brolucizumab injections), BCVA was 20/30-2, there was no evidence of SRF, and CST was 287 µm (Figure 1d).


Figure 1c.

Figure 1d.

Treatment Approaches

Although anti-VEGF agents are considered an appropriate first-line treatment for neovascular AMD, there does not seem to be a significant difference between aflibercept and ranibizumab in visual and anatomic outcomes, although a 2018 meta-analysis comprising more than 8000 eyes showed equivalent efficacy in BCVA and central macular thickness.1,7 Systemic safety data from the Comparison of AMD Treatment Trials (CATT; ClinicalTrials.gov Identifier: NCT005934650) and Inhibition of VEGF in Age-related choroidal Neovascularization (IVAN; ISRCTNL: 92166560) studies noted similar efficacy for ranibizumab and bevacizumab. Cochrane systematic reviews also concluded that, if any differences in safety exist between these agents, they are minimal, at best.1,8-13 

This means that treatment decisions are often made based on other factors, ranging from response to treatment to insurance coverage to travel considerations. 

Pivotal clinical studies on the newest anti-VEGF agent, brolucizumab, showed that more than one-half of enrolled subjects experienced maintained or improved vision with a 12-week dosing interval; anatomic improvements were seen as early as week 16, and few patients had intraretinal fluid or SRF at the same time point.14,15  The HAWK (ClinicalTrials.gov Identifier: NCT02307682) and HARRIER (ClinicalTrials.gov Identifier: NCT02434328) trials14 reported a higher rate of intraocular inflammation in patients treated with brolucizumab (4%) than in those treated with aflibercept (1%). In addition, reports of retinal vasculitis and retinal artery occlusion were also published after real-world use of brolucizumab.16,17 An independent safety review committee that was established to perform a post-hoc analysis of HAWK and HARRIER data found that the rate of intraocular inflammation was 4.6%.18 Because brolucizumab has a safety profile that is different than other agents, it is used mainly in previously treated patients with worsening disease control with frequent injections, such as the case patient, Ms Jones.

Clinical Learning

This case study highlights several key takeaways about treating AMD.

Frequent dosing with anti-VEGF agents remains the standard of care for patients with neovascular AMD.

Since the introduction of the anti-VEGF agents, blindness resulting from AMD has decreased by 50%.11,19 To maintain vision, it is well accepted that patients with AMD must be treated frequently, although therapy needs to be individualized. Approximately 10% to 20% of patients are able to extend an intravitreal anti-VEGF treatment regimen out to every 10 to 12 weeks; another 10% to 20% of patients continue to need monthly injections to maintain vision.20 In addition, some patients do not respond to a particular agent, and some regress after years of treatment.21,22 

The AURA study (ClinicalTrials.gov Identifier: NCT01447043) found that the number of injections, baseline visual acuity score, age when starting intravitreal therapy, and number of ophthalmoscopies and OCT images were all significant prognostic factors for both vision maintenance and vision gain.23 When Solomon and colleagues looked at 12 trials comprising 5496 participants with neovascular AMD treated with anti-VEGF, they found that compared with control arms, patients who received any anti-VEGF agent were more likely to:

  • Have gained 15 letters or more of visual acuity;
  • Have fewer than 15 letters of visual acuity; and
  • Have vision 20/200 or better after 1 year of follow-up.11

Because most patients with AMD are older, this treatment burden can become overwhelming. One study found that patients spent an average of 12 hours per visit (preappointment preparation, travel, waiting time, treatment time, and postappointment recovery),24 which might be a contributing factor to the high percentage of patients lost to follow-up. Patients with AMD who are lost to follow-up are approximately 6 years older than patients who are adherent to treatment.25,26 

Patients lost to follow-up have a poorer prognosis for vision than those who maintain clinic visits.27 This finding is of particular concern in older patients with AMD, given that functional decline and impaired vision are significant drivers of depression, which only further compounds disability and isolation.28 

The need remains for neovascular AMD treatments that (1) have longer durability or (2) are equally potent to treatments on the market, or both.

Better durability of anti-VEGF agents has been discussed for almost a decade.29 Several studies underscore the need for longer durability. The ATLAS study (ClinicalTrials.gov Identifier: NCT01773954) evaluated aflibercept in a treat-and-extend approach in which patients were treated every 4 weeks until signs of macular exudation were absent. A median gain of 11 letters was sustained through the second year of the study. A 12-week interval was achieved in only 35% of patients during the first year and in 41% during the second year.30,31 

The PrONTO study (ClinicalTrials.gov Identifier: NCT00344227) evaluated patients treated with 3 monthly injections of ranibizumab who were then dosed as needed. Gains in visual acuity were maintained, and most patients were able to halve their monthly dosing schedule.32 

More recently, the TREX-AMD group (ClinicalTrials.gov Identifier: NCT01748292) found that a treat-and-extend regimen produced visual and anatomic outcomes that are comparable to those produced by monthly dosing.33,34 Ohnaka and coworkers suggested that a treat-and-extend regimen with aflibercept produced good functional and vision outcomes with as few as 4.5 injections over 12 months.35 In 2 clinical studies, Dugel and colleagues showed that 30% of patients were able to maintain a gain in vision of at least 15 letters at 1 year when dosed every 12 weeks with brolucizumab.14 

Of potential concern for treating clinicians are reports of retinal vasculitis and retinal vascular occlusion after treatment with brolucizumab; for some affected patients, the outcome was severe, irreversible vision loss.3,16,17,36,37 Underlying causes of these adverse effects are being evaluated and investigated, but treatment can still be valuable, particularly in patients who have unresolved fluid or in whom a longer treatment interval is appropriate, or both.

Undertreatment remains a concern; newer treatment options might help overcome this problem with longer durability.

Undertreatment remains a concern for clinicians. Ciulla and coworkers found direct correlation between mean letters gained and number of injections over the course of 1 year. Better vision, they reported, was associated with more frequent visits.38 

Regrettably, results of clinical trials often are not replicable in the real world.12,22 A leading reason for the vision disparity is undertreatment. A 2019 Preferences and Trends survey found that more than one-half of respondents believe that patients undergo fewer injections than experienced by those in the trials.39 This belief is bolstered by the work of Holekamp and colleagues, who found that real-world patients receive, on average, only 4.6 to 6.9 injections.40

In the SEVEN-UP study (ClinicalTrials.gov Identifier: NCT01256827), patients received, on average, 6.8 ranibizumab injections each year. Only one-half of those eyes were stable at 1 year; 33% had declining vision. Yet, patients who received at least 11 injections gained vision.39 

Conclusion

Based on Ms Jones’ response to her current anti-VEGF treatment, she will continue to receive this therapy every 12 weeks.

References

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Reviewed July 2021