Seenu M. Hariprasad
We have come a long way in the management of the complications resulting from retinal vein occlusion, especially in the past few years. Prior to 2009, there was no FDA-approved pharmacotherapy to treat macular edema secondary to RVO. However, just in the past 4 years, we have three FDA-approved therapies for this condition. The outcomes are better than they have ever been, and the current treatments carry less morbidity than those that have been described in the past.
Drs. Schneider and Mruthyunjaya tackle the question of whether there is a role for combination therapy in the management of macular edema secondary to RVO. Undoubtedly, the rationale for combination therapy is sound given the multifactorial etiology of this disease. The assigned task is difficult due to the paucity of large-scale prospective clinical trial data. They review the current evidence in this landscape and share insights from their clinical experience.
Eric W. Schneider
In the nearly two decades following the publication of the Branch Retinal Vein Occlusion Study (BVOS) and Central Retinal Vein Occlusion Study (CVOS), pharmacologic therapy for retinal vein occlusion (RVO) was almost nonexistent. However, the introduction of intravitreal therapy — namely corticosteroids and anti-VEGF agents — has provided a host of new pharmacologic options to clinicians. As evidenced by several large-scale clinical trials,1–4 intravitreal monotherapy is effective for the vast majority of patients with RVO and has thus become the predominant therapeutic approach.5
Unfortunately, a small minority of patients display recalcitrant macular edema despite frequent intravitreal monotherapy dosing. In the SCORE trials, 11.6% to 12.0% of patients treated with repeated intravitreal triamcinolone lost at least 15 letters, and more than 20% had central point thicknesses greater than 500 μm at 12-month follow-up.1,2 Although the rate of refractory edema was lower in the BRAVO/CRUISE trial (0.7% to 3.8% lost at least 15 letters, and 6.7% to 15.9% had central foveal thickness greater than 400 μm at 12 months), frequent ranibizumab monotherapy was not universally successful.3,4 Such recalcitrant cases have prompted the search for therapeutic alternatives, most notably combination pharmacologic and pharmaco-laser treatments.
Mechanism of action, pharmacokinetics, and side effect profiles (Table 1) must be considered in discussing the rationale for combination therapy. An additional consideration is whether combination therapy is intended as an alternative in monotherapy-responsive patients — to reduce dosing frequency and intensity, avoid cumulative dose-limiting side effects, or minimize reductions in efficacy due to tachyphylaxis — or as an escalation strategy in monotherapy-resistant cases. In either scenario, the ideal combination regimen would employ agents with activity targeted to disparate components of RVO pathophysiology and possess complementary pharmacokinetic profiles. Such a combination should in theory allow for greater therapeutic efficacy and/or higher trough activity.
In the future, intravitreal cytokine profiling in treatment-naïve RVO patients may provide a greater level of customization of RVO therapy and allow for identification of candidates for initial combination therapy based on a particularly unfavorable intravitreal cytokine milieu.19
Eric W. Schneider, MD, can be reached at Duke University Eye Center, Department of Ophthalmology, 2351 Erwin Road, Box 3802, Durham, NC 27705; 919-684-3316; fax: 919-681-6474; email:
Privthvi Mruthyunjaya, MD, can be reached at Duke University Eye Center, Department of Ophthalmology, 2351 Erwin Road, Box 3802, Durham, NC 27705; 919-684-8434; fax: 919-681-6474; email:
Seenu M. Hariprasad, MD, can be reached at the Department of Ophthalmology and Visual Science, University of Chicago, 5841 S. Maryland Avenue, MC2114, Chicago, IL 60637; 773-795-1326; email:
Disclosures: Drs. Schneider and Mruthyunjaya have no relevant financial disclosures. Dr. Hariprasad is a consultant or on the speakers’ bureau for Regeneron, Takeda, Alcon, Allergan, Bayer, Optos, Ocular…