Combination Strategies In the Treatment of DME
What the latest clinical trial data say about what approach to use and when.
RITHWICK RAJAGOPAL, MD, PhD · RAJENDRA S. APTE, MD, PhD
The pathogenesis of diabetic macular edema is multifactorial, involving neuronal injury, vascular damage, and induction of complex inflammatory cascades.1 As such, the treatment of DME has evolved to encompass a combination of multi-target treatment approaches.
Retinal physicians often customize treatment to fit each individual patient, based on algorithms that consider various factors, including systemic comorbidities, the morphology of macular involvement, chronicity, and the status of macular perfusion.
Our understanding of the disease process in diabetic retinopathy continues to evolve with the rapidly accumulating new data from randomized clinical trials on combination therapy. Novel pharmacologic targets to treat DME continue to emerge.
Here, we review the recent literature on combined treatment approaches to DME, and we offer our treatment recommendations based on the data.
CONSIDERATIONS FROM CLINICAL TRIAL DATA
Taken together, large clinical trials, such as the DCCT, UKPDS and ACCORD-Eye studies, showed that in both type 1 and 2 diabetics, aggressive glucose control reduced the risk of development and progression of retinopathy, compared to conventional therapy.2-4
The modality of antihyperglycemic regimen may also play an important role. Following case reports of worsening DME with thiazolidinedione use, larger clinical trials have shown an association between this class of diabetes medication and macular edema.5-7
Control of hypertension and management of dyslipidemia also appear to reduce risk of retinopathy progression, as shown in the UKPDS blood pressure trial and the ACCORD trial.8,9
Although it has been the mainstay of DME treatment for decades, laser monotherapy has some important limitations. Intravitreal injections of anti-VEGF agents have recently replaced ETDRS-style macular laser as the choice for initial treatment of center-involving DME in the treatment-naïve patient, likely based on the results of several well-controlled randomized clinical trials.
In recent DRCR.net reports, treatment with modified ETDRS laser resulted in stable or improved vision in a majority of patients, but close to 20% of patients lost >10 letters of visual acuity.10,11
The finding that eyes with diabetic retinopathy have elevated vitreous levels of VEGF provides a mechanistic rationale for anti-VEGF therapy.12 The RISE and RIDE trials, BOLT, and the DAVINCI studies have since demonstrated superior efficacy benefits for the use of ranibizumab (Lucentis, Genentech, South San Francisco, CA), bevacizumab (Avastin, Genentech), and aflibercept (Eylea, Regeneron, Tarrytown, NY), respectively, in the treatment of DME.13-15
Drawbacks to Monotherapy
However, anti-VEGF monotherapy also has its drawbacks. For one, it is not uniformly effective in all patients, as seen in the BOLT, DAVINCI, and RISE, and RIDE trials.
In addition, even in responders, anti-VEGF monotherapy has significant practical limitations, because patients require monthly evaluation and frequent retreatment with the potential for rare but serious ocular and systemic adverse events.16,17
Doctors have used intraocular steroids extensively to treat DME. They offer the potential advantage of greater duration of action than current anti-VEGF therapy. Large randomized trials have also provided evidence for steroid monotherapy, especially in pseudophakic patients.18-20
However, elevated IOP and cataract-related events were more frequent with steroid and confounded the analysis of effect of treatment on visual outcomes.
EVIDENCE FOR COMBO THERAPY
Several recent trials have provided good evidence to support combined treatment modalities for the treatment of DME.
The RESTORE trial was a European-conducted, multicenter, randomized study that compared monthly treatment with ranibizumab plus sham laser, ranibizumab combined with laser, and laser with sham injections.21 The READ 2 trial was a similarly designed trial conducted in the United States.22 Both trials showed the superiority of combination treatment to laser alone.
The RESTORE protocol applied laser at the beginning of the trial, with retreatments no less than three months apart, per ETDRS guidelines. The protocol called for injections administered monthly, with as-needed treatment beginning after month 3.
With regard to the primary outcome measurement, both ranibizumab-treated groups gained significantly more vision (approximately six ETDRS letters gained), compared to the group receiving laser treatment alone (0.8 letters gained) at 12 months.
Macular thickness also improved significantly more in the two ranibizumab groups compared to laser alone. The mean number of injections was the same for both the monotherapy arm and the combination arm.
However, the mean treatment-free interval during the study was two months for the ranibizumab monotherapy arm and 2.5 months for the combination arm. Slightly more patients in the monotherapy arm required monthly treatment (8%) than in the combination group (7.6%).
This study provides a rationale for ranibizumab over laser monotherapy, but it failed to show an outright advantage of combination therapy over ranibizumab monotherapy.
However, the follow-up in this trial was only 12 months. As such, it remains possible that a synergistic approach, incorporating laser photocoagulation into the anti-VEGF therapeutic regimen, may have a positive influence on long-term durability.
Figure 1. Improvement of DME following discontinuation of pioglitazone. Despite several monthly injections with bevacizumab,this patient had no improvement in vision, which remained 20/60 with persistent macular edema (A). Three months after discontinuation of pioglitazone, her vision was 20/40 with improvement on OCT (B).
Entry criteria for READ 2 were similar to the RESTORE study, but the READ 2 investigators chose to give injections every two months in the ranibizumab group. Importantly, in the combination group, patients received focal laser a week after injection, which differs from the RESTORE trial, which applied combined treatment on the same day.
Investigators could repeat focal or grid laser every three months if necessary. At month 24, VA gains were similar between the ranibizumab and combination therapy groups (approximately 7 letters) and both were superior to laser alone.23 These gains persisted at three years of follow-up.24
Improvement in thickness on OCT was similar among the groups, even through three years of follow-up. Interestingly, in the READ 2 study, by year 3 of treatment, 50% of patients in the ranibizumab group met the retreatment criteria at more than six visits, and they needed continued injections, while 18% required no further injections in the final year.
In the combination group, only 8% met the retreatment criteria at more than six visits, and 46% did not need retreatment in the year 3. So by two years, although both monotherapy and combination therapy with laser showed similar visual outcomes, the combination group required fewer treatments.
Protocol I Study
The DRCR.net’s Protocol I study also investigated combination therapy involving ranibizumab or triamcinolone with focal laser.25 The study included patients with central DME. Patients were randomized to receive treatment with sham injection plus prompt laser (within one week), intravitreal ranibizumab plus prompt laser, intravitreal ranibizumab plus deferred laser (at least 24 weeks after initial treatment), or intravitreal triamcinolone plus prompt laser.
The inclusion of a “deferred laser” arm is one of the unique features of this study. It allowed the investigators to test the theory that macular laser, when delivered after anti-VEGF agents had reduced macular thickness, would be more effective.
The primary outcomes measured in this study were VA and safety at one year. However, investigators also recorded macular thickness, and we now have follow-up data for three years.
In the initial report of results from this study, both treatment groups that received ranibizumab fared better with regard to the primary VA endpoint, with gains of 9 letters in both ranibizumab groups vs 4 letters in the laser-only group. Macular thickness, as assessed by OCT, was also similarly decreased in both groups.
Treatment with triamcinolone plus prompt laser produced a transient improvement in VA in the first few months that was comparable to ranibizumab treatment. However, these gains were not sustained at the one-year visit.
By two years, VA improvement remained similar in both ranibizumab-treated groups (seven letters in the prompt laser group and nine in the deferred laser group), but was significantly worse in the triamcinolone and laser-only groups (two and three letters, respectively).26
By three years, VA scores had improved more in the ranibizumab plus deferred laser group compared to prompt laser (9.7 letters vs 6.8 letters).27 In a subset analysis, VA gains in patients who were pseudophakic at baseline were similar among patients treated with ranibizumab (5 letters for prompt group, 9 letters for deferred) or triamcinolone (8 letters), suggesting that cataract formation or subsequent cataract surgery played a major role in the lack of visual improvement in the steroid-treated arm.
Although longer follow-up is necessary, the three-year results of this study would suggest that the combination of these therapies, applied in such a specified temporal relationship, is better than monotherapy. This is in contrast to the RESTORE trial, which did not provide a clear advantage for combination therapy.
Furthermore, the DRCR.net trial validated combination therapy with laser and triamcinolone, at least for a subset of patients. Another interesting aspect of the DRCR.net study was the diminishing need for injections with long-term adherence to the protocol regimen, from a mean of roughly eight injections in the first year to three during the second year and ultimately to two in the third year of the study. No significant differences occurred in the number of injections between prompt or deferred laser groups.
However, practical limitations exist to the protocol described in both the DRCR.net trial and the RESTORE trial. Most notably, patients are seen monthly through the first year or more of treatment. Such a follow-up schedule is not sustainable for most retina practices given the high prevalence of DME. Furthermore, a significant portion of patients did not enjoy two-line gains in VA despite strict adherence to such frequent visits and treatments.
Steroids offer the potential advantage of longer duration of action. Rather than repeated bolus delivery of steroid, sustained-delivery devices have undergone development and testing for treatment of macular edema.
In the FAME trial, investigators used fluocinolone acetonide vitreous inserts (Iluvien, Alimera Sciences, Alpharetta, GA) to treat subjects with center-involving DME who had failed at least one prior macular laser.28 The investigators compared two doses of steroid (0.2 and 0.5 µg/day) to sham injections.
Both treatment groups showed larger gains in VA compared to the sham group, with 4.4 and 5.4 letters gained at two years in the low- and high-dose groups, respectively, compared to a gain of 1.7 letters in the controls.
The differences were more pronounced in favor of the steroid group in patients with chronic DME of more than three years’ duration. Cataract progression was significant among steroid-treated patients.
A subset analysis of patients who were pseudophakic at baseline showed an increase of 7 letters at month 24. Sustained elevation of IOP was also a major adverse event, with 8.1% of patients in the high-dose group and 3.7% in the low-dose group needing glaucoma surgery, compared to 0.5% of the controls.
CHAMPLAIN and PLACID
Investigators have also tested implantable dexamethasone for the treatment of DME in clinical trials. In the CHAMPLAIN study, the investigators administered a single dexamethasone injectable implant (Ozurdex, Allergan, Irvine, CA) in a cohort of patients with refractory DME and prior vitrectomy.29
Figure 2. Response to combined macular laser and anti-VEGF therapy. A type 2 diabetic woman with initial visual acuities of 20/80 OD and 20/100 OS presented with center-involving DME in both eyes. Shown are an initial color photograph of her right eye (A) and correspondingangiogram (B). Her initial OCT shows thick cystic edema andsignificant subretinal fluid (C, D). Eighteen months later,after 10 anti-VEGF injections and three sessions of macular laser photocoagulation to each eye, her vision improved to 20/30 OD and 20/40 OS with marked improvement of her OCT appearance (E, F).
The study showed that dexamethasone improved macular thickness and vision but that its peak effect was at two months postinjection. However, the study was limited by its lack of a control group, and both cataract and glaucoma-related events occurred in a significant portion of patients.
The more recent PLACID study randomized eyes with central diffuse DME to treatment with dexamethasone implant combined with macular laser or to sham injection with macular laser.30 Investigators treated eligible patients with either the 0.7-mg dexamethasone injectable implant or with a sham injection. Patients were eligible for laser retreatment every three months and dexamethasone every six months.
No difference emerged between the groups in terms of VA at one year. However, at months 1 and 9, the percentage of patients achieving a 10-letter gain was greater in the combination group.
In fact, analysis of VA curves from the study showed peak effects at one month and seven months into the study, corresponding to one month after the initial injection and one month after reinjection, respectively. Improvement in foveal thickness also exhibited a similar dual-peak curve.
Steroid-treated patients demonstrated improved patterns of leakage on FA that continued through month 12. Although increased IOP was more common in the steroid-treated group, no patients required glaucoma surgery.
DME WITH VITREOMACULAR TRACTION
On occasion, patients with DME will present with vitreomacular traction (VMT). The DRCR.net examined the role of vitrectomy and membrane peeling in the treatment of DME with a tractional component in a small, prospective cohort study by the DRCR.net.31 The investigators evaluated 87 eyes with DME and VMT. All patients underwent vitrectomy, with removal of membranes at the surgeon’s discretion.
At six months postoperatively, VA improved by more than 2 lines in 38% of eyes and worsened by 2 lines or more in 22% of eyes. The mean decrease in macular thickness on OCTwas 160 µm, with 43% of patients having macular thickness of less than 250 µm.
Although a preponderance of clinical data exist to guide the treatment of DME, much remains to be understood about the pathology of the disease, leaving much room for improvement in our treatment strategies.
Several limitations exist of the studies outlined previously. First, many of these studies did not include patients with very poor glucose control, so they may not be applicable to poorly controlled diabetics.
Further, the investigators almost never included patients with VA worse than 20/320. They did not test combinations of anti-VEGF and steroid. Follow-up in most studies was frequent, usually monthly, which may be difficult to adhere to in real practice.
Finally, investigators did not always consider the chronicity of macular edema or the role of vitreoretinal interface abnormalities, so the results above may not be universally applicable to those patients with long-standing DME or those with vitreous related adhesion and traction.
RECOMMENDATIONS FOR REAL-WORLD PRACTICE
In our practice, we regularly utilize a multimodal approach to the diagnosis and treatment of DME. An assessment of patients’ systemic risk factors is critical for treatment and prognosis. We record baseline blood pressure, lipid panel, and glycated hemoglobin levels, usually through correspondence with the primary care physician.
We thoroughly review medications, with an emphasis on antihyperglycemics, antihypertensives, and lipid-lowering agents. Although rarely used today, we have seen improvement in macular edema with subsequent visual gains in patients whom we discontinued treatment with thiazolidinediones, including pioglitazone, illustrating the importance of systemic review (Figure 1, page 48).
We routinely utilize both widefield FA and high-resolution OCT for baseline assessment of patients. Patients with long-standing visual complaints, vision worse than 20/400, or evidence of either significant macular nonperfusion on angiography or severe outer band disruption on OCT may have guarded prognoses.
We initiate a dialogue with each patient so that he or she has a thorough understanding of the nature of the condition and long-term prognosis, and make an informed decision regarding the recommended therapeutic regimen.
In the treatment-naïve patient, we often consider initial laser photocoagulation in eyes with circumscribed, noncenter-involving edema without any tractional elements identified on OCT. We direct treatment at microaneurysms and other treatable lesions within the area of edema and titrate the burn intensity to achieve mild blanching, as per the modified ETDRS guidelines.
If the edema is center-involving, whether focal or diffuse, we recommend therapy with either intravitreal bevacizumab or ranibizumab. We also initially treat center-threatening diffuse edema with anti-VEGF injections.
We repeat biomicroscopic examination with ancillary diagnostic testing every four weeks to assess the patient’s response to therapy. We continue anti-VEGF therapy with possible additional focal laser until macular edema resolves (Figure 2), until it becomes clinically nonsignificant, or until futility criteria are reached as in the DRCR.net’s Protocol I.
Treatment for Poor Responders
For poorly responsive patients, we consider re-evaluation one to two weeks after injection to assess the VA and OCT response. If we see objective improvement, we continue monthly anti-VEGF therapy with the intent to consider applying focal laser photocoagulation once quantitative improvement occurs in the macular volume.
In fact, application of focal laser as soon as one or two weeks postinjection, as performed in the READ 2 trial, may be an attractive approach. In such cases, we resume anti-VEGF agents in the laser postoperative period as a “staged” treatment for persistent edema.
For patients who remain unresponsive to anti-VEGF therapy or who are pseudophakic and at slow risk for glaucoma, we consider treatment with intraocular steroids, especially if they desire an initial treatment associated with fewer intravitreal injections. As discussed, we also consider focal laser photocoagulation as a synergistic treatment with steroids. We can perform a topical steroid challenge before intraocular administration to identify some steroid responders.
In Case of Failure
If these approaches fail, we obtain widefield angiography to assess peripheral and macular nonperfusion. Based on anecdotal evidence of peripheral ischemia driving persistent DME, we consider targeted PRP to areas of nonperfusion to reduce the ischemic burden.
In those cases that remain refractory to treatment, the next step in the therapeutic algorithm is PPV with ILM removal. In eyes with refractory edema and taut ILM, significant ERM, or vitreous adhesion and VMT, we often consider vitrectomy with peeling early in the course of treatment with adequate intravitreal pharmacotherapy in the perioperative period. Postoperatively, we can treat eyes with persistent edema with laser and intraocular pharmacotherapy based on the guidelines discussed previously.
The currently available clinical data favor combination therapies, but the physician should customize specific combinations of treatment to the individual patient given the complexity of this disease.
Clinical trials for combination therapy in DME continue. The phase 3 VISTA trial is in progress to assess the efficacy of aflibercept, compared to laser alone, in the treatment of center-involving DME. A DRCR.net randomized trial (Protocol T) is also under way to evaluate the comparative efficacy of the currently available anti-VEGF agents (bevacizumab, ranibizumab, and aflibercept) in the treatment of DME.
A recent phase 1 study of subconjunctival and intravitreal sirolimus also showed encouraging results, and larger follow-up studies are ongoing.32 The future remains promising with additional clinical trials being planned to evaluate novel treatments such as Raf kinase inhibitors.
Emerging data will inevitably change the manner in which we approach the patient with DME. RP
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Rajendra S. Apte, MD, PhD, is Paul A. Cibis Distinguished Professor of Ophthalmology and Developmental Biology at Washington University in St. Louis, MO. Rithwick Rajagopal, MD, PhD, is assistant professor of Ophthalmology & Visual Sciences at WUSTL. Dr. Apte reports moderate financial interest in Regeneron and Genentech and minimal financial interest in Novartis, Bayer, Alimera, Thrombogenics, and Ophthotech. Dr. Rajagopal reports no financial interest in any of the products mentioned here. Dr.Apte can be reached via e-mail at firstname.lastname@example.org