Treatment Strategies for Macular Edema: An Update on Theory and Practice

Treatment Strategies for Macular Edema: An Update on Theory and Practice

Executive Summary

This briefing document synthesizes current perspectives on the theory and practice of treating macular edema resulting from Diabetic Macular Edema (DME) and Retinal Vein Occlusion (RVO). The primary therapeutic approach for vision-impairing macular edema with foveal involvement is intravitreal anti-VEGF therapy. A key principle for success across both conditions is a prompt and intensive initiation of treatment, followed by consistent, long-term management.

Individualized treatment regimens, such as Pro-re-nata (PRN) and Treat-and-Extend (T&E), are crucial for balancing therapeutic efficacy with treatment burden. However, real-world outcomes often fall short of clinical trial results, largely due to poor patient adherence. Non-adherence is a significant challenge, particularly in the diabetic population, and is driven by factors including the high frequency of injections, time commitment, and patient anxiety.

To address the unmet need for reduced treatment burden, newer anti-VEGF agents with extended duration of action have been developed. While Brolucizumab and Faricimab have shown efficacy with less frequent dosing, they are associated with concerns regarding intraocular inflammation (Brolucizumab) and study designs that limit direct comparability (Faricimab). The recent introduction of high-dose Aflibercept 8 mg, supported by the PHOTON study, demonstrates comparable visual acuity gains to the 2 mg formulation but with significantly extended treatment intervals (≥12 weeks for nearly 90% of patients), offering a promising option to reduce injection frequency without compromising safety or efficacy.

For RVO, the treatment paradigm also emphasizes intensive initial therapy to prevent irreversible vision loss. The condition demands a high, long-term treatment load for many patients, with studies showing a majority requiring 30 or more injections over five years. Treatment interruptions are particularly detrimental, leading to permanent visual acuity decline. Early and aggressive treatment, however, can lead to successful resolution, as RVO lacks the chronic underlying pathology of DME.

1. Management of Diabetic Macular Edema (DME)

Macular edema is a primary cause of vascular-related vision loss and can arise from diabetic retinopathy. When the edema involves the fovea, intravitreal anti-VEGF therapy is the first-line treatment.

1.1. Diagnostic and Therapeutic Principles

A critical initial step is to differentiate between DME with foveal involvement and DME without foveal involvement.

• Without Foveal Involvement: Laser coagulation remains a valuable and relevant treatment option.
• With Foveal Involvement: Intravitreal injections (IVOM) with anti-VEGF agents are the recommended first-line therapy.

The German professional societies (BVA, RG, DOG), in their 2019 guidelines, recommend an intensive loading phase consisting of six consecutive monthly anti-VEGF injections. This intensive start is considered crucial for achieving optimal therapeutic outcomes.

1.2. Individualized Treatment Strategies

Following the initial loading phase, therapy should be individualized to balance treatment efficacy with patient burden, following the principle of "as much as necessary, but as little as possible." Consistent monitoring is essential to maintain patient adherence.

The two most common individualized regimens are:

• Pro-re-nata (PRN): Patients attend monthly follow-up appointments but receive an injection only when disease activity is detected.
• Treat-and-Extend (T&E): Patients receive an injection at every visit, but the interval between visits is extended (typically in 2- or 4-week steps) if the disease is stable or shortened if activity recurs. The T&E schema is noted as being particularly effective for patients with unilateral disease.

1.3. Challenges in Real-World DME Management

A significant gap exists between the visual acuity outcomes observed in pivotal clinical trials and those achieved in routine clinical practice. Real-world data shows that patients often do not achieve the same level of vision gain, primarily because they receive fewer injections than their counterparts in clinical trials. This under-treatment is largely a consequence of poor patient adherence.

Patient Non-Adherence:

Non-adherence is a critical issue in DME management, even more so than in other retinal diseases like AMD or RVO.

• A study from the Freiburg University Clinic found that 44% of DME patients demonstrated insufficient adherence within the first year of treatment.
• The reasons for non-adherence are multifaceted and include both physician-related factors (e.g., insufficient appointment availability) and patient-related factors.
• Fear and Anxiety: A significant number of patients experience anxiety related to injections. One study highlighted that:
• More than 50% of patients could not relax before an injection.
• 25% experienced sleep disturbances.
• The most common patient desire (42%) is to receive fewer injections while maintaining the same therapeutic results.

2. Advances in Anti-VEGF Therapeutics for DME

The high treatment burden associated with DME has driven the development of new drugs designed to extend the interval between injections.

2.1. Brolucizumab

• Efficacy: The KITE and KESTREL studies demonstrated that Brolucizumab could achieve comparable visual and morphological outcomes to Aflibercept 2 mg with less frequent injections.
• Safety Concerns: A notable issue with Brolucizumab is the risk of intraocular inflammation, which, although relatively rare, can lead to severe vision loss. The speaker noted seeing two such cases in Heidelberg. To mitigate this risk, it is critical to dilate the pupil and carefully inspect for signs of inflammation before every injection; if inflammation is present, the injection should be withheld.

2.2. Faricimab

• Efficacy: The YOSEMITE and RHINE studies showed that Faricimab, administered at 12- or 16-week intervals, achieved results similar to Aflibercept 2 mg administered every 8 weeks.
• Comparability Issues: German professional societies have issued a supplementary statement noting a key limitation of these trials: the Aflibercept 2 mg comparator arm was not permitted to extend treatment intervals. This study design prevents a direct efficacy comparison with other agents under typical, flexible treatment strategies like T&E.

2.3. Aflibercept 8 mg (High-Dose)

The PHOTON study evaluated a high-dose (8 mg) formulation of Aflibercept, which became available in Germany in early 2024.

PHOTON Study Design & Results:

The 96-week study randomized treatment-naïve DME patients into three arms:

1. Aflibercept 2 mg every 8 weeks (2q8)
2. Aflibercept 8 mg every 12 weeks (8q12)
3. Aflibercept 8 mg every 16 weeks (8q16)

Safety Profile:

The safety profile of Aflibercept 8 mg was comparable to the well-established profile of the 2 mg dose.

• There were no new safety signals, including with regard to intraocular inflammation.
• Fears that the higher injection volume would lead to significant increases in intraocular pressure (IOP) were not substantiated. Incidences of IOP increase were similar across all arms, and a rise to ≥35 mmHg was numerically slightly more frequent in the 2 mg group.

3. Management of Retinal Vein Occlusion (RVO)

RVO is the second most common cause of vascular-related vision loss, affecting an estimated 300,000 people in Germany. While Branch RVO (BRVO) is more common, Central RVO (CRVO) is associated with more severe complications. A study from Birmingham, UK, showed that nearly one-third of RVO patients develop macular edema.

3.1. Treatment Principles and Guidelines

For RVO-associated macular edema, the core principle is prompt, intensive, and sustained therapy to prevent permanent photoreceptor damage and vision loss.

• Initial Therapy: German guidelines recommend initiating treatment with a loading dose of three consecutive monthly anti-VEGF injections.
• Continued Therapy: After the initial series, if a clinically relevant edema persists, treatment must be continued. The guidelines allow for another series of three monthly injections. After the sixth month, individualized regimens like T&E or PRN can be employed.

3.2. Long-Term Treatment Burden and Adherence

RVO necessitates a high and prolonged treatment intensity for many patients.

• The CRYSTAL study found that patients treated under a PRN regimen received a median of 15 injections over 24 months.
• A 5-year retrospective analysis revealed that 60% of RVO patients required 30 or more injections over that period.
• Consequences of Interruption: A study of patients lost to follow-up for over six months found that while retinal thickness could be reduced upon restarting therapy, the associated vision loss was permanent. This underscores the importance of continuous treatment.

3.3. Real-World Evidence and Treatment Switching

Real-world data confirms that good outcomes are achievable with consistent therapy.

• The "Fight Retinal Blindness!" registry showed that after three years, patients gained a mean of 10 letters, with 44% gaining ≥15 letters.
• While 69% of patients remained on monotherapy, 19% were switched to another anti-VEGF agent or a steroid. The switching group achieved similar vision gains but with fewer injections.
• The AURIGA study, a large observational study, found that switching to Aflibercept resulted in significant vision gains, particularly for patients with CRVO.
• A clinical observation is that persistent, intensive therapy is the most critical factor for success, potentially regardless of the specific agent used.

3.4. Prognostic Factors and Potential for Resolution

Unlike DME, which stems from a chronic systemic disease, RVO is an acute event. This offers a chance for complete resolution and cessation of therapy in some patients.

• Predictors of Good Outcome:
• A significant reduction in central retinal thickness within the first six months.
• A good best-corrected visual acuity at the six-month mark.
• Early Intervention: Treating patients at the earliest sign of edema, even in cases of venous stasis retinopathy, can lead to a rapid response and the ability to successfully discontinue therapy after a T&E taper.
• Role of T&E in RVO: The T&E regimen is considered an excellent strategy for RVO. While it may not necessarily reduce the total number of injections, it is highly effective for achieving a stable, functionally superior, and uninterrupted therapeutic result.

The QUASAR study is currently investigating the efficacy and safety of Aflibercept 8 mg for patients with RVO.