CONTROVERSIES IN CARE

Primary Treatment of Diffuse DME In Pseudophakic Individuals: Anti-inflammatory or Anti-VEGF?

EDITED BY MICHAEL COLUCCIELLO, MD

Diffuse diabetic macular edema (Figure) is a frequently encountered clinical scenario. Commonly, these individuals are pseudophakic.

Certainly, the cornerstone of treatment involves communication with the patient and the patient’s primary care physician (and endocrinologist, nephrologist, and cardiologist, if available). The need for optimization of systemic status must be emphasized.¹

Considerations will include blood sugar, blood pressure, lipid levels, renal function (and treatment of any anemia associated with nephropathy), cardiac function (including treatment of any congestive heart failure) and treatment of sleep apnea (which may be associated with resistant hypertension).

The BOLT,² RISE, and RIDE³ studies, as well as a DCRC.net study,⁴ indicated that anti-VEGF treatments for DME have advantages versus focal or grid laser monotherapy treatment of the macula. However, challenges in using these agents present themselves.

For instance, how frequently should they be injected? What is the goal of treatment? Which of the anti-VEGF agents is the most efficacious for DME?

The intravitreal dexamethasone (Ozurdex, Allergan) implant has also shown promise in treating DME;⁵ the extended-release nature of its action would seem to favor its use in eyes that have undergone vitrectomy.

However, although the incidence of secondary glaucoma may be less with dexamethasone than the other steroid agents, it remains a consideration.

What is the ideal local (intravitreal) treatment in these patients to protect the macula while systemic treatment is optimized?

Clearly, we need studies to guide our local pharmacological treatment of this common clinical scenario. This month we are fortunate to have comments from Drs. Tarek Hassan and Dante Pieramici to help guide us.

REFERENCES

1. Colucciello M. Diabetic retinopathy: control of systemic factors preserves vision. Postgrad Med. 2004;116:57-64.

2. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT Study): 12-month data report 2. Ophthalmology. 2010;117:1078-1086.e2.

3. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema. Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.

4. Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Threeyear randomized trial results. Ophthalmology. 2012;119:2312-2318.

5. Haller JA, Bandello F, Belfort R Jr, et al; OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema

due to retinal vein occlusion. Ophthalmology. 2010;117.6:1134-1146.

Anti-VEGF Agents for DME

TAREK S. HASSAN, MD

The treatment of chronic DME has become the most challenging day-today management issue we, as retinal specialists, face today. In part, this is because we still face numerous eyes seemingly refractory to all of our treatment attempts.

However, it is also because we have access to more and more treatment options that both improve visual acuity and anatomic outcomes — particularly intravitreal pharmacologic injections of anti-VEGF agents and steroids — and we are now left to try to determine treatment paradigms that make sense to us and that allow for the best potential outcomes.

As outlined below, numerous clinical trials have demonstrated the benefits of intravitreal triamcinolone, bevacizumab (Avastin, Genentech), and ranibizumab (Lucentis, Genentech) in improving vision and reducing mean central retinal thickness, both in the acute and chronic terms. These pharmacologic interventions have proved superior in most cases to focal macular laser given as monotherapy.

Figure. Red-free fundus photograph (left) of proliferative diabetic retinopathy with retinal neovascularization of the disc, “sausage-like” changes in the veins, and cotton wool spots, indicative of retinal ischemia and macular edema with lipid exudates. OCT “macular thickness” protocol image (right) of macular edema (red) and foveal striae (yellow lines) in a patient with diabetic retinopathy .

Unfortunately, for the practical determination of treatment approaches to real-world clinical situations, such comparison trials offer only some benefit. It is only rarely that I find myself approaching vision-threatening or vision-reducing DME with a single mode of treatment.

We know, of course, that some mild cases of central foveal edema do respond well to specific intravitreal anti-VEGF agents, or cases of classically defined “clinically significant DME” outside of the foveal avascular zone, with associated leaking microaneurysms that respond well to specific, focally applied macular laser.

However, the pathogenesis of this condition is generally more complex, and the edema that we treat is often more chronic and is mediated by multiple mechanisms — a number of which we can then target with a variety of treatments.

To me, the most important initial step to take when faced with a patient with vision-threatening or vision-involving DME is to try to ind a specific anatomic abnormality that can be targeted to provide a more definitive and long-lasting treatment.

ANATOMIC ABNORMALITIES

Practically speaking, we can diagnose three basic anatomic abnormalities that I feel comfortable attacking with the goal of getting to the specific cause of the acute problem:

• distinct focal microaneurysms outside of the foveal avascular zone associated with macular thickening, which I manage with focal macular laser applied directly to the microaneurysms and a modified grid laser pattern applied in the area of edema;

• widespread midperipheral and peripheral retinal ischemia in the setting of diffuse macular thickening, which I manage with panretinal photocoagulation to the areas of ischemia (generally seen for 360°); and

• evidence of anteroposterior or tangential vitreomacular traction with underlying macular thickening, which I manage with vitrectomy, membrane peeling (including the internal limiting membrane), and PRP, or potentially with the injection of intravitreal ocriplasmin (Jetrea, Thrombogenics). To find these abnormalities, we must obviously look for them. I thus obtain a fluorescein angiogram and spectral-domain OCT on all such patients as part of my evaluation.

If I am unable to demonstrate any of these overtly abnormal anatomic situations, then I feel we are dealing with a more complex etiology of the edema, at which time I turn to more chronic therapies, such as the use of repeated injections of intravitreal anti-VEGF agents or steroids and possibly combination therapeutic approaches.

Role of Ranibizumab

The RISE and RIDE trials demonstrated the benefit of ranibizumab over sham in the treatment of DME when used as monotherapy,¹ and the RESTORE and REVEAL trials demonstrated the benefit of ranibizumab,alone or with macular laser over macular laser alone in reducing edema and improving vision.²’³

I am of the opinion that ranibizumab monotherapy is beneficial for most eyes with center-involving edema but may potentially be enhanced with supplemental macular laser in a significant number of eyes.

The DRCR.net reported that deferring focal/grid macular laser when combined with ranibizumab may be advantageous, rather than applying the laser when initiating ranibizumab therapy.⁴ I generally follow these guidelines when combining my therapies.

I like to give at least three to six monthly ranibizumab injections prior to initiating any additional macular laser. This allows for a more targeted and specifically applied treatment to an area of the retina that is hopefully already under repair.

I will also use intravitreal injections of triamcinolone in some eyes with DME, particularly those with large cystic spaces. Although no large, multicenter, prospective trials have suggested any benefit of the steroid over anti-VEGF agents, I believe some eyes benefit from the combination of both ranibizumab to treat the component of edema that VEGF mediates and steroids to treat the component that other inflammatory mechanisms mediate.

Intravitreal bevacizumab has also been shown to be more effective than sham or macular laser alone in treating DME, and its off-label use is a reasonable alternative to ranibizumab. No significant widespread, long-term, prospective data have compared the two agents in a way we feel can steer us in the use of one agent over the other.

Having said that, it has been my extensive personal experience that ranibizumab offers notably better treatment success than bevacizumab in most diabetic eyes. The other commercially available anti-VEGF agent, aflibercept (Eylea, Regeneron), has not yet been approved for use in the treatment of DME. It is currently being studied in phase 3 trials in the United States, Europe, and Asia, but it has been shown to be much more effective in treating DME than macular laser alone in the phase 2 DA VINCI trial.⁵

We also await the approval of the sustained-release dexamethasone intravitreal office-based injectable implant (Ozurdex, Allergan) for treatment of DME. It is now approved for management of CRVO and BRVO, and we expect it to gain approval for DME because it has proven to be more efficacious than observation in a large, multicenter trial.

Another promising sustainedrelease steroid, an intravitreal, office-based implant that utilizes luocinolone (Retisert, Bausch + Lomb), as opposed to dexamethasone, is currently approved for use in Europe for treatment of DME. It is again under review for approval in the United States. Concern over the development of glaucoma certainly must be kept in mind when considering such long-term steroid implants.

The landscape for the management of DME has changed considerably. The standard of care is indeed intravitreal anti-VEGF agents, but how we integrate their use into a more comprehensive approach to this complex clinical condition is becomingly increasingly interesting as we seek to continue the trend of improving patient outcomes.

REFERENCES

1. Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for diabetic macular edema. Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119:789-801.

2. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE Study Group. The RESTORE Study: Ranibizumab monotherapy or combined with laser versus laser mono-therapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.

3. Ohji M, Ishibashi T Sr; REVEAL Study Group. Efficacy and safety of ranibizumab 0.5 mg as monotherapy or adjunctive to laser versus laser monotherapy In Asian patients with visual impairment due to diabetic macular edema: 12-month results of the REVEAL study. Invest Ophthalmol Vis Sci. 2012;53:ARVO E-Abstract 4664.

4. Diabetic Retinopathy Clinical Research Network; Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Three-year randomized trial results. Ophthalmology. 2012;119:2312-2318.

5. Do DV, Nguyen QD, Boyer D, et al; DA VINCI Study Group. One-year outcomes of the DA VINCI Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119:1658-1665.

6. Haller J, Kuppermann B, Blumenkranz M. Randomized controlled trial of an intravitreous dexamethasone drug delivery system in patients with diabetic macular edema. Arch Ophthalmol. 2010;128:289-296.

A Role for Inflammation

DANTE J. PIERAMICI, MD

Macular edema has many pathophysiological mechanisms, particularly in the diabetic patient. Phase 3 clinical trials have recently demonstrated that ischemia and upregulation of VEGF are important mechanisms in many of our diabetic patients.

Today, the use of VEGF inhibitors is the first-line therapy for most patients with center-involved DME. However, the “one size fits all” approach is not ideal for many of our patients.

It is important that the treating physician explore the various potential mechanisms, with complete ocular evaluation including OCT and fluorescein angiography. Additionally, one must consider the patient’s systemic health, with particular attention to diabetic and hypertensive control, as well as renal status.

In a patient with macular edema who is pseudophakic, particularly one who has recently undergone cataract surgery, I always consider the possibility that the macular edema is pseudophakic-associated or inl ammatory in nature.

This can be further corroborated with OCT and angiographic findings that include a petalloid pattern of cystoid edema and associated hyperfluorescence of the disc.

Despite this testing, differentiating the edema may be diffcult. One might initially coinsider a trial of topical NSAIDs and steroids.

When pseudophakic edema has been excluded or treated without success, one must consider other mechanisms. OCT and FA can be particularly helpful in ruling out cases of edema that are associated with vitreomacular adhesions, such as an associated epiretinal membrane or area of vitreomacular traction. In such patients, surgical or nonsurgical vitreolysis may be appropriate and necessary to eliminate the edema.

However, initiating treatment with anti-VEGF agents may also be appropriate because the ischemic mechanism may be the overriding influence and the VMA a less significant factor.

The location of the edema is also an important consideration in cases of DME. When the edema is clinically significant and noncenterinvolved, the traditional approach has been to treat with laser photocoagulation to reduce the chance of moderate vision loss (ETDRS studies). In the era of anti-VEGF therapy, one might consider observing such edema and treating if it progresses to involve the fovea.

The RIDE/RISE, RESTORE, or DRCR Protocol I did not include patients with noncentered edema, so the role of anti-VEGF agents in center-threatening edema is unclear. The DRCR Network will be taking up this issue in a future trial.

I personally tend to err on the side of treating center-threatening edema with laser photocoagulation, if the area is well defined and I identify obvious leaking microaneurysms.

Center-involved DME

In most cases of diffuse, or for that matter nondiffuse center-involved DME, I start with anti-VEGF agents. I favor a regimen similar to that of DRCR.net Protocol I, which is a modified PRN schedule.

I begin treatment with monthly injections and OCTs. If the patient is non-responsive after four to six consecutive treatments, I discontinue the therapy and then consider alternatives, such as intraocular steroids or laser.

If the OCT and/or vision shows progressive improvement, I continue the treatment until the retina is normalized on OCT or further improvement plateaus. At this point, I withhold treatment and reinitiate it only if significant edema recurs.

Monitoring the vision and the retinal edema may not be the only parameters to follow in these cases, as there is also compelling evidence from the phase 3 DME trials that anti-VEGF agents may reverse the level of retinopathy in some patients so that their benefits seem to go beyond simply reducing retinal edema.

ANTI-VEGF DRUGS

Currently, the available anti-VEGF agents for DME patients include ranibizumab and bevacizumab. We can draw on much prospective, randomized clinical data and extensive clinical experience to support the use of either agent (BOLT, RISE, RIDE, DRCR I, RESTORE).

An ongoing trial in the DRCR.net is recruiting patients and comparing ranibizumab, bevacizumab, and aflibercept to determine the relative safety and efficacy of these agents in the treatment of center-involved DME.

My clinical experience and the results of our investigator-initiated clinical trial (REEF study) suggest that in some patients, ranibizumab may be more effective for DME than bevacizumab. In incomplete responders or nonresponders, I will consider a trial of ranibizumab, but have had no luck with the inverse.

In patients who have little or incomplete response to anti-VEGF therapy, I tend to add standard laser photocoagulation. Intraocular steroids are another option in this group.

At times, the effect of intraocular triamcinolone can be rapid and impressive, supporting an alternative mechanism of the edema in these cases. The DRCR.net Protocol I study demonstrated a benefit of steroids similar to that of anti-VEGF agents in the subgroup of pseudophakic patients. A phase 3 trial investigating intravitreall fluocinolone in DME (FAME trial) confirmed a larger benefit of intraocular fluocinolone in cases of more chronic or longstanding DME. The investigators hypothesized that inflammation may be a dominant mechanism driving the DME in longstanding, laser-unresponsive cases.

Phase 3 clinical trials provide us with insights and guidelines for the treatment of our patients. The results of such trials instruct us about the average responses in a population.

In the case of the pseudophakic diffuse DME, we must use our clinical judgment and a bit of “trial and error” to select the best course of treatment for the individual patient.

In our rush to treat the macular edema, let us not forget about the importance of the systemic health of the patient and that our efforts may be futile in the setting of poor diabetic and hypertensive control. RP