Ophthalmic Surgery, Lasers and Imaging Retina

Practical Retina 

Combination Therapy for Macular Edema Secondary to Retinal Vein Occlusion

Eric W. Schneider, MD; Prithvi Mruthyunjaya, MD; Seenu M. Hariprasad

Abstract

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

Prithvi Mruthyunjaya

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: eric.schneider@duke.edu.

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: prithvi.m@dm.duke.edu.

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: retina@uchicago.edu.

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…

Seenu M. Hariprasad

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

Eric W. Schneider

Prithvi Mruthyunjaya

Prithvi Mruthyunjaya

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.

Rationale for combination therapy

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.

Characteristics of Candidate Combination Therapy Agents

Table 1: Characteristics of Candidate Combination Therapy Agents

As seen in Table 1, there is significant diversity in the mechanism of action of the various candidate combination agents, providing an opportunity for synergistic treatment effects. For example, combination therapy with corticosteroids and anti-VEGF agents target both the inflammatory (via decreased leukotriene/prostaglandin production and ICAM-1 expression) and ischemic (via robust VEGF inhibition) drivers of RVO-related macular edema. And from a pharmacokinetic standpoint, combining agents with differing intravitreal half-lives may allow for a prolonged treatment effect of rapid, short-acting agents (eg, corticosteroids and anti-VEGF agents) and/or a shortening of effect latency for delayed, longer-acting therapies (eg, laser). Moreover, early intervention with a rapid, short-acting agent such as intravitreal triamcinolone (IVTA), bevacizumab (IVB), or ranibizumab (IVR) — which, unlike laser, can be administered regardless of the extent of associated macular hemorrhage or edema — may allow for earlier adjunctive laser therapy.

In monotherapy-responsive patients, combination therapy may also be applied to limit the burdens of frequent treatments visits and/or adverse effects related to cumulative exposure. Some investigators have suggested that repeated intravitreal therapy, in addition to the psychosocial and financial burden associated with frequent re-treatment, can lead to diminishing anatomic and functional improvement due to tachyphylaxis, which appears to be mediated by upregulation of VEGF receptors.6 Additionally, repeated monotherapy may also increase the incidence of certain adverse effects due to increased cumulative toxicity. This may be particularly problematic with intravitreal steroid therapy in which rates of cataract and possibly ocular hypertension or glaucoma have been linked with more frequent administration. There appear to be fewer safety concerns regarding repetitive anti-VEGF dosing, but there remain theoretical concerns related to the potential for increased rates of arteriothrombotic events and glaucoma with frequent dosing.7

Evidence to date

In light of the many potential pitfalls of repeated monotherapy detailed above, clinicians are increasingly exploring combination therapy. Unfortunately, the currently available data have lagged somewhat behind clinical practice. Of the handful of studies published to date, many are small, short-term, and retrospective, limiting the ability to draw firm conclusions. For the sake of brevity, noncomparative retrospective studies will not be included in the following review.

Combined anti-VEGF, corticosteroid therapy

Primary corticosteroid and anti-VEGF combination therapy was compared to anti-VEGF monotherapy in two prospective studies with mixed results. In the first study, combination of IVB and IVTA (2 mg) was not superior to IVB alone in terms of visual outcome, macular edema reduction, frequency of re-treatment, or IOP-related adverse effects in patients with CRVO.8 In contrast, posterior sub-Tenon’s kenalog (40 mg) plus IVB was found to result in significantly greater visual acuity improvement and macular edema reduction with significantly fewer injections in BRVO patients when compared to IVB alone.9

The use of the longer-acting dexamethasone implant (Ozurdex; Allergan, Irvine, CA) in conjunction with anti-VEGF therapy was recently examined in a small prospective, noncomparative trial. In this study, robust visual acuity gains were achieved up to 6 months (12.3 to 16.8 letters gained), with infrequent re-treatment (mean time to re-treatment: 125.9 ± 25.5 days).10 Anatomic improvement was excellent through 3 months but waned in the final 3 months of the study.

Combined anti-VEGF, laser therapy

Two prospective studies looked at combined anti-VEGF and laser therapy and compared it to either IVB alone11 or macular grid laser (MGL) alone12 in patients with BRVO-related macular edema. Interestingly, anti-VEGF plus MGL combination therapy was found to result in significantly greater visual and anatomic improvement compared to IVB alone,11 although no such superiority was found when this combination was compared to MGL alone.12 Combined therapy was also associated with significantly fewer injections over the study period when compared to IVB alone.

In an effort to reduce the source of VEGF production, investigators have explored the use of panretinal photocoagulation (PRP) in conjunction with anti-VEGF therapy. In CRVO patients, IVB plus subsequent (7 to 14 days) PRP was found to result in a significant reduction in the need for re-treatment, although no functional or anatomical difference was found.13 In contrast, a follow-up study found no difference in injection frequency after PRP in 10 CRVO patients with peripheral nonperfusion who received PRP plus as-needed IVR treatment after 6 months of IVR monotherapy.14

Combined corticosteroid, laser therapy

In a prospective, noncomparative analysis, significant functional and anatomic improvements were noted in patients with BRVO-related macular edema undergoing MGL within 3 weeks of IVTA.15 This occurred after a mean of 1.13 IVTA injections over 6 months.

The use of the dexamethasone implant in combination with MGL was prospectively examined in two abstracts presented in 2012. Both reported significant improvement in retinal thickness at all analyzed time points,16,17 but only one study found similar improvements in visual acuity.16 No data were available regarding the impact of combining therapies on injection frequency.

In the sole prospective, comparative study to date, the combination of a single IVTA injection and subthreshold micropulse grid laser was found to result in significantly greater visual gains as compared to micropulse grid laser alone in patients with BRVO-related macular edema.18 Both groups achieved significant improvement in foveal thickness, without intergroup differences detected. IOP higher than 21 mm Hg requiring medical therapy occurred in 55% of IVTA-treated patients; the rate of IOP elevation in the micropulse grid laser–alone cohort was not given.

Conclusions

There appears to be no compelling evidence to date to support the use of combination pharmacologic and pharmacolaser therapy as a primary treatment in RVO. The well-established efficacy of intravitreal monotherapy, particularly with anti-VEGF agents, warrants at the very minimum a trial of either anti-VEGF or corticosteroid monotherapy. Such an approach will continue to be standard of care until a large-scale randomized clinical trial demonstrates clear superiority of combination therapy over intravitreal monotherapy.

There is, however, enough evidence to recommend combination therapy in patients in whom monotherapy is failing as well as in patients for whom frequent re-treatments have become an overwhelming social or financial burden or in whom dose-limiting adverse effects are a significant concern. Currently, specific recommendations regarding the ideal combination approach fall largely to individual providers, who are tasked with creating treatments customized for individual patients based on available clinical data, with particular attention paid to previously documented responses to component agents, preexisting adverse effects or predisposition to adverse effects, and angiographic data documenting extent of ischemia (Table 2). Of note, the addition of PRP to treat patients with documented nonperfusion on wide-field angiography appears to be a promising approach to reducing the frequency of intravitreal anti-VEGF administration.13

Pros and Cons of Pharmacologic and Pharmaco-Laser Therapies

Table 2: Pros and Cons of Pharmacologic and Pharmaco-Laser Therapies

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: eric.schneider@duke.edu.

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: prithvi.m@dm.duke.edu.

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: retina@uchicago.edu.

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 Therapeutix, and OD-OS.

References

  1. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 2009;127(9):1101–1114. doi:10.1001/archophthalmol.2009.234 [CrossRef]
  2. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular Edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 2009;127(9):1115–1128. doi:10.1001/archophthalmol.2009.233 [CrossRef]
  3. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology. 2011;118(8):1594–1602. doi:10.1016/j.ophtha.2011.02.022 [CrossRef]
  4. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology. 2011;118(10):2041–2049. doi:10.1016/j.ophtha.2011.02.038 [CrossRef]
  5. Jumper JM, Mittra RA. Preferences and trends survey 2011 [Online]. http://www.asrs.org/asrs-community/pat-survey/pat-survey-archive. Accessed 27 January 2013.
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  7. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013;33(1):179–187. doi:10.1097/IAE.0b013e318261a6f7 [CrossRef]
  8. Wang HY, Li X, Wang YS, et al. Intravitreal injection of bevacizumab alone or with triamcinolone acetonide for treatment of macular edema caused by central retinal vein occlusion. Int J Ophthalmol. 2011;4(1):89–94.
  9. Cho A, Choi KS, Rhee MR, Lee SJ. Combined therapy of intravit-real bevacizumab and posterior subtenon triamcinolone injection in macular edema with branch retinal vein occlusion. J Korean Ophthalmol Soc. 2012;53(2):276–282. doi:10.3341/jkos.2012.53.2.276 [CrossRef]
  10. Singer MA, Bell DJ, Woods P, et al. Effect of combination therapy with bevacizumab and dexamethasone intravitreal implant in patients with retinal vein occlusion. Retina. 2012;32(7):1289–1294.
  11. Donati S, Barosi P, Bianchi M, Al Oum M, Azzolini C. Combined intravitreal bevacizumab and grid laser photocoagulation for macular edema secondary to branch retinal vein occlusion. Eur J Ophthalmol. 2012;22(4):607–614. doi:10.5301/ejo.5000085 [CrossRef]
  12. Azad R, Vivek K, Sharma Y, Chandra P, Sain S, Venkataraman A. Ranibizumab as an adjunct to laser for macular edema secondary to branch retinal vein occlusion. Indian J Ophthalmol. 2012;60(4):263–266. doi:10.4103/0301-4738.98701 [CrossRef]
  13. Shimura M, Yasuda K, Nakazawa T, Takeshita T, Shiono T, Sakamoto T. Combination therapy for retinal vein occlusion. Ophthalmology. 2010;117(9):1858, 1858e1851–1853. doi:10.1016/j.ophtha.2010.03.077 [CrossRef]
  14. Spaide RF. Prospective study of peripheral panretinal photocoagulation of areas of nonperfusion in central retinal vein occlusion. Retina. 2013;33(1):56–62. doi:10.1097/IAE.0b013e3182641875 [CrossRef]
  15. Riese J, Loukopoulos V, Meier C, Timmermann M, Gerding H. Combined intravitreal triamcinolone injection and laser photocoagulation in eyes with persistent macular edema after branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol. 2008;246(12):1671–1676. doi:10.1007/s00417-008-0898-0 [CrossRef]
  16. Fernandes JK, Patel R, Hariprasad SM. Combination Therapy of an Intravitreal Dexamethasone Implant (OzurdexTM) Plus Prompt Focal Laser for Macular Edema Secondary to Retinal Vein Occlusions - 12 Month Follow-up [abstract]. Invest Ophthalmol Vis Sci. 2012;53((Suppl)):922.
  17. Cetin EN, Scanlon C, Akduman L. Outcomes of Combined Treatment with Ozurdex Implant and Grid Laser Photocoagulation for Macular Edema in Branch Retinal Vein Occlusion (abstract). Invest Ophthalmol Vis Sci. 2012;53:913.
  18. Parodi MB, Iacono P, Ravalico G. Intravitreal triamcinolone acetonide combined with subthreshold grid laser treatment for macular oedema in branch retinal vein occlusion: a pilot study. Br J Ophthalmol. 2008;92(8):1046–1050. doi:10.1136/bjo.2007.128025 [CrossRef]
  19. Noma H, Mimura T, Eguchi S. Association of inflammatory factors with macular edema in branch retinal vein occlusion. JAMA Ophthalmol. 2013;131(2):160–165. doi:10.1001/2013.jamaophthalmol.228 [CrossRef]

Characteristics of Candidate Combination Therapy Agents

CorticosteroidsAnti-VEGFMacular Grid Laser
Mechanism of Action↓ leukotriene/prostaglandin productionVEGF inhibition↓ retinal O2 consumption
↓ inflammatory markers (ICAM-1)↓ vascular permeability↑ inner retinal oxygenation
↓ vascular permeability, ↑ permeability of RPE barrier ↓ permeability of RPE barrier ↓ VEGF production↑ permeability of RPE barrier↓ permeability of RPE barrier ↓ hydrostatic pressure in capillaries/venule

Elimination Half-Life18.6dIVR: 7.19d IVB: 9.92dN/A

Latency to Peak EffectMinimalMinimalLong

Adverse EffectsCataractGlaucoma↑ macular ischemia
GlaucomaCardiovascular eventsParacentral scotoma

Pros and Cons of Pharmacologic and Pharmaco-Laser Therapies

ProsCons

Allows for synergist effects based on differential mechanism of action of component therapies

May overcome tachyphylaxis

May allow for reduced effective dosages

May allow for reduced dosing frequency

Takes advantage of different pharmacokinetic profiles of component therapies

May allow for reduced dosing frequency

No added technical difficulty in administration Component therapies are well-studied in large prospective clinical trials Alternative for monotherapy-resistant patients Alternative for patients with dose-limiting adverse effect or practical limitations on dosing frequency
Large-scale prospective clinical trial data not available Guidelines regarding re-treatment intervals not established Volume of injected agents limited if concurrent administration desired (unless combined with aqueous removal) Non-concurrent administration requires two closely spaced office visits

10.3928/23258160-20130909-02

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