Exploring the DME Treatment Decision Tree
Where do the various treatment options fit in managing patients with diabetic macular edema?
There is now a variety of options for treating patients with diabetic macular edema (DME), which at once is a benefit but also a source of potential confusion. What is the best approach to the patient newly diagnosed with DME? What about for patients with chronic, long-lasting edema? Does the inflammatory nature of the disease suggest a role for steroids? And although it has not been studied extensively, is there perhaps a role for combination therapy?
Finding definitive answers to these questions in the absence of a plethora of data from long-term, randomized clinical trials is a Herculean task—and it may well be a Sisyphean endeavor as new options are studied and become available. Yet, physicians are making treatment decisions every day in this information vacuum, decisions that have implications for the health of patients’ vision immediately and into the future.
To begin to explore some of these questions, Retina Today interviewed David Eichenbaum, MD, of Retina Vitreous Associates of Florida, to seek his input on how he manages patients with DME.
Retina Today: What are your decision-making criteria for selecting treatment for a patient with DME?
David Eichenbaum, MD: My typical evaluation of a DME patient includes a dilated examination and optical coherence tomography (OCT), and I do angiography on all my new patients with diabetes to look for the location of leaks. I periodically repeat the angiography, but not very often. The most important thing I am looking for is the location of the edema. Historically, we would rely on criteria derived from the Early Treatment Diabetic Retinopathy Study to determine whether to start therapy, but I am really more concerned with whether the edema is center-involving. If it is center-involved symptomatic edema, I recommend starting with intravitreal therapy regardless of the level of Snellen or ETDRS eye chart acuity. I will sometimes observe asymptomatic mild center-involving DME. My usual first-line approach is to use antiangiogenic agents.
There are options in the choice of anti-VEGF agents with both ranibizumab (Lucentis, Genentech) and aflibercept (Eylea, Regeneron) approved by the US Food and Drug Administration for treatment of DME. Off-label use of bevacizumab (Avastin, Genentech) is an option as well. I usually start with ranibizumab, because the molecule is designed without an FC portion, which probably reduces antibody recirculation. That said, even though I start with anti-VEGF therapy, I am most likely going to use combination therapy with some mix of anti-VEGF, steroid, and laser, and surgical intervention as needed. For example, I use laser following anti-VEGF therapy in patients with persistent noncentral focal leaks, but I almost always use deferred laser because the DRCR.net showed a benefit for deferred laser, especially in longer follow-up. A lot of people still use prompt laser, but I prefer to defer laser at least 4 to 6 months because it is associated with improved visual outcomes.
RT: How do you define treatment failure with anti-VEGF therapy?
Dr. Eichenbaum: There are 3 ways to think about treatment failure with regard to anti-VEGF therapy: (1) failure of response to monthly injections with regards to anatomic drying, which occurs in about 20% of patients; (2) recurrence with less than monthly therapy, which occurs in a higher proportion of patients; or (3) lack of willingness to come in for monthly therapy. The anti-VEGF agents work well, and there is a reduction in the treatment burden after the first 12 to 24 months of treatment, but if the patient cannot make it through those first 12 to 24 months of more frequent therapy there is often going to be chronic low-level edema. We know from the RISE and RIDE trials that if the edema is undertreated, if the macula stays edematous, the probability of visual improvement diminishes over time.
RT: When and why would you consider use of steroids in patients with DME?
Dr. Eichenbaum: Practically speaking, steroids are particularly important for patients with DME who are noncompliant with regular anti-VEGF injection therapy. Noncompliance, it should be noted, is a big reason why many patients develop uncontrolled diabetic center-involved edema in the first place. Many patients who are unwilling to undergo monthly anti-VEGF therapy are on dialysis, have ulcers or other nonhealing wounds, and have a host of other systemic issues going on at the same time. To my way of thinking, this is a primary reason to think about adding a steroid, especially 1 that has sustained release and is therefore not as dependent on patient compliance or associated with a high incidence of severe intraocular pressure elevation. If the patient cannot or will not return for frequent future visits, whether or not that is because he or she is under a huge burden of health care utilization, there has to be something on board to control the edema. Another practical in-the-clinic characteristic that affects my decision to use steroids is lens status. I am more likely to inject a steroid earlier in a pseudophakic patient.
The rationale for using steroids in patients with DME is that, at a microbiologic level, diabetes is a lot more than a VEGF-driven disease like an acute vein occlusion or age-related macular degeneration. There are many inflammatory factors, interleukins, and adhesion molecules in addition to VEGF and related vascular proteins affecting the pathogenesis of DME.
The injectable suspension of triamcinolone acetonide (Kenalog-40, Bristol-Myers Squibb) used to be my go-to agent in these cases, but I backed away from that primarily because of the risks of poorly predictable pressure elevations. Plus, it hazes patients’ vision because it is a suspension. I moved away from triamcinolone as soon as anti-VEGF agents became widely used.
However, the availability of the dexamethasone intravitreal implant (Ozurdex, Allergan) has changed my thinking, because it has controlled pharmacokinetics and a predictable release of steroid attributable to the biodegradable Novadur implant. Now, if I have a patient who does not do well with monthly visits or cannot tolerate monthly visits for the first several months, there is a role for dexamethasone therapy in that patient.
RT: Does your thinking change at all for patients with chronic or recalcitrant edema?
Dr. Eichenbaum: There is some literature supporting the notion that patients with chronic edema may have a disease process that is more inflammatory than vascular, so the addition of a steroid may come sooner for a patient with center-involving chronic edema. Most of the patients with DME I see do not have chronic edema, so I am up-front in telling them that they are going to need a lot of anti-VEGF shots in the first 1 to 2 years if the plan is to utilize anti-VEGF monotherapy. I give these patients a trial with anti-VEGF injections without laser, but if the patient has recurrent or persistent center edema and cannot or will not come in for that first 12 to 24 months of higher-burden anti-VEGF therapy, then adding the dexamethasone implant is a reasonable choice.
RT: What do you use to determine the efficacy of treatment response? Do you rely more on functional correlates such as change in visual acuity, or is the anatomic response more important?
Dr. Eichenbaum: I treat toward vision improvement. The OCT is a guide, and it is helpful to know the anatomic response; I want to reduce the burden of the overlying pathology to the give the patient the best chance of a functional improvement. However, as we know in many components of medicine, structure and function do not always align, and I am primarily concerned with visual acuity improvement and vision maintenance more so than with a bone-dry macula. I do go for both, and I will change the treatment plan to dry the macula, but functional vision improvement is my primary goal.
RT: Are there differences in the steroid formulations currently available for use in clinical practice?
Dr. Eichenbaum: There are differences, and they are quite significant. One of the big problems I have with triamcinolone in this indication is that, because it is a suspension, the actual drug volume being injected is unknown. Therefore, the risk of steroid-induced side effects is also unknown because the dose is irregular and the pharmacokinetics are irregular.
In a simple example, if I have a patient whose intraocular pressure (IOP) rose to 30 mm Hg after an injection, I would not really be able to predict if the patient would have a similar response or if the IOP would go up to 35 or 40 mm Hg with the next injection. There is published data showing that the actual injected dose of the triamcinolone suspension is variable in the real world.
With the dexamethasone intravitreal implant, what you get is a predictable and repeatable dose response with regard to increased IOP changes. That is a tremendous benefit from a safety standpoint, and the efficacy seems to be parallel if not slightly longer in duration than triamcinolone.
Another advantage of the dexamethasone implant is that it reduces the treatment burden, and that means not just reducing the number of injections, it also means reducing the patient’s burden of coming to the office. The reason I withhold the dexamethasone implant as an initial treatment is that I want to get to know the patient and the eye(s), and steroid injection does have some risks that anti-VEGF injection does not. I want to know if he or she will come back for follow-up.
If patients are having trouble with follow-up or do not want to come in for regular injections early in their treatment, I tell them I can give them the dexamethasone implant as an option to reduce their overall treatment burden.
RT: It has been suggested that there are different pharmacokinetics among the steroid formulations in addition to a difference in mechanism of delivery. What is the “bolus effect” and what are the implications for safety?
Dr. Eichenbaum: The bolus effect describes a sudden burst following the injection followed by a taper thereafter. There is a bolus effect of triamcinolone or triamcinolone acetonide injectable suspension (Triesence , Alcon), with an initial jolt of steroids and rapidly reduced effect thereafter. With the dexamethasone implant, the Novadur polymer component, which dissolves to glycolic acid and water, is biodegradable; as it degrades, it effects a steady and predictable release of steroid over time. As a result, there is a much more predictable steroid response.
There may not be that initial punch up front,,but often, in real-world settings, this implant is going to be used as 1 element of combination therapy. When used with anti-VEGF injections, the result is a rapid antiangiogenic effect up front combined with durability in treating the inflammatory component with steroid. The dexamethasone implant by itself will deliver a more sustained effect than a bolus injection, but in the context of combination therapy it starts to make even more sense.
RT: What do you tell patients about the safety of the dexamethasone implant?
Dr. Eichenbaum: There are 2 things, really, to be concerned about with the dexamethasone implant: cataract formation and IOP elevation. In the MEAD study, a significant number of patients developed cataracts, and IOP elevation occurred in about a third of patients. These are real, and the discussion of potential side effects has to occur with each and every patient. However, I do believe there is important context to add to both of these items.
There was an appreciable risk cataract progression, especially with multiple injections, in the MEAD trial. There is often an improvement in acuity with cataract extraction that far exceeds baseline visual acuity, and this was shown in the group requiring cataract surgery in the MEAD trial, where the dexamethasone implant was used as monotherapy. I think we can extrapolate from that data that cataract extraction can lead to very good results in patients who are phakic and require steroid therapy as part of a combination therapy approach, as many patients in the clinic will have the dexamethasone implant as part of a treatment regimen with anti-VEGF injections and/or laser as well.
As for IOP response, that 33% incidence of IOP response sounds concerning, but there is important context to that figure as well (see Sidebar). First of all, that IOP response is less significant than we might expect compared with a drug like triamcinolone. Second, a great number of the IOP elevations among subjects in MEAD were subclinical events, meaning they were self-limiting, transient, or otherwise required no action. We have to remember that it was a clinical trial, so the investigators had to report any IOP elevation and lump it into 1 category of “IOP elevation.” Third, even cases in which IOP rose to a concerning level were largely treatable with a single antihypertensive medication. Only 1 patient in the MEAD study required glaucoma surgery.
RT: What do the major clinical trials (MEAD, SHASTA) say about the most likely postinjection timeframe for an IOP elevation to occur?
Dr. Eichenbaum: The interval is well studied. In the MEAD and SHASTA trials, the increase in IOP was most likely to occur around 6 to 8 weeks after the injection. When I inject patients with the dexamethasone implant, I bring them back in 6 to 8 weeks for a pressure check.
RT: What role does the systemic health of patients have in managing their DME?
Dr. Eichenbaum: Paying attention to the systemic health of patients is crucial for 2 reasons. First, in my thinking, the steroid has an especially important role in the patient who has a history of an acute thromboembolic event. I do think about the systemic health of the patient with respect to antiangiogenics. If the patient has had an acute event, I tend to steer clear of anti-VEGF injection, especially if there was a heart attack, stroke, or amputation. The level of systemic distribution of anti-VEGF agents after local injection to the eye is controversial, and there are not good data among patients with DME to parse out the potential risk in patients with recent acute events. The fact that many patients with DME already have a vascular component to their overall disease process leads me to operate on the side of caution. Local injection of a steroid will have some level of systemic distribution, but vascular pathology in the human body would potentially be much less affected by a steroid compared with an antiangiogenic agent.
The other reason I pay attention to the systemic health is that it affects both the systemic and ocular health of that patient. As retina specialists, our purview is the ocular health of the patient, but we are also physicians first, and if we can encourage a patient to attend to his or her blood glucose levels, we are helping that patient along the path to better overall health. Yet there are ocular implications here as well. As I alluded to earlier, poor systemic control is a primary reason patients develop ocular consequences of their disease. Patients have to pay attention to their blood glucose and blood pressure, otherwise there could be chronic or worsening edema despite treatment. Study after study shows that this persistent edema can rob patients of the ability to ever recover visual acuity. Overall improvement in systemic health is how patients see well for decades; the few months to a year during which patients undergo intensive treatment with a retina specialist is really about affording the patient a chance to tune up his or her systemic health to ensure life-long good vision. n
David Eichenbaum, MD, is with Retina Vitreous Associates of Florida, in Tampa Bay, and is a clinical assistant professor of ophthalmology at the University of South Florida. He is a consultant to Allergan, Inc. Dr. Eichenbaum may be reached at firstname.lastname@example.org.