In recent years, a number of medical options have become available for treating retinal disease. As understanding of the disease processes in the retina has increased, it has become clear that many of the conditions for which we treat our patients are multifactorial in nature. For example, there are data showing that choroidal neovascularization (CNV), although an important factor in agerelated macular degeneration (AMD), is not the only component to this disease and that the inflammatory response and cellular proliferation in AMD should also be considered as potential therapeutic targets.1,2 Similarly, combination therapy has been explored for the treatment of diabetic macular edema (DME). Thus, some diseases may respond better to combination therapy rather than to a single therapeutic agent. Because corticosteroids target the inflammatory cells and also decrease the production of inflammatory cytokines,3 they may be useful adjuncts for some cases. This hypothesis has been tested in several published studies. This article provides an overview summary.

PDT + STEROIDS FOR AMD
One of the earliest combination therapies investigated was verteporfin photodynamic therapy (PDT; Visudyne, Novartis) with intravitreal triamcinolone acetonide (IVTA). In 2005, Spaide et al4 published 12-month results with this combination for CNV secondary to AMD. Twenty-six eyes of 26 patients were included in this noncomparative case series. Half of the patients in the study were treatment naïve and the other half had visual loss during prior PDT treatment. All patients were treated with PDT and then immediately given intravitreal injections of 4-mg IVTA (Kenalog, Bristol-Myers Squibb). The retreatment criteria were based on leakage seen with fluorescein angiography.

At 12 months, the newly treated group had an average of 2.5 lines of visual acuity improvement (P=.011). The previously treated patients had an average of 0.44 lines improvement in visual acuity (P=.53). Ten patients in the study required intraocular pressure (IOP)-lowering medication.

Augustin and Schmidt-Erfurth5,6 demonstrated similar results with PDT and IVTA for CNV secondary to AMD. In their investigations, a method of applying PDT and then injecting 25-mg IVTA 16 hours after the PDT procedure was used. Additionally, both studies reported lower-than-expected retreatment rates. One case series included 184 patients and the second case series included 41 patients. The mean visual acuity improvement in the first case series was significant at 1.22 lines (P<.01).

Further study has shown an adjunctive effect with IVTA plus PDT.7-9

Piermarocchi et al,10 despite finding an early positive response with PDT plus IVTA in an 84-patient study comparing patients randomized to PDT (n=41) or IVTA followed by PDT (n=43), did not find functional benefits over the long-term follow-up. Additionally, a study by the NAPP (Neovascular Age-Related Macular Degeneration, Periocular Corticosteroids, and Photodynamic Therapy) Trial Research Group did not find a reduction in leakage upon fluorescein angiography after a single treatment with IVTA and PDT compared with PDT alone.11

ANTI-VEGF + STEROIDS FOR DME
There are fewer published studies investigating the effect of combined anti-VEGF agents with corticosteroids, but many studies are currently underway. Soheilian et al12 reported 12-week results for 103 eyes of 97 patients enrolled in a study to evaluate the effects of intravitreal bevacizumab (IVB; Avastin, Genentech, Inc.) with or without IVTA vs laser photocoagulation for the primary treatment of DME. The 12-week results demonstrated significantly better visual acuity results for patients treated with IVB or IVB/IVTA at 6 weeks (P<.0001) than those treated with laser photocoagulation, but did not find an adjunctive effect with IVTA; further, the significant improvement in visual acuity was only seen in the IVB-alone group at 12 weeks (P=.024).

In a more recent report by Soheilian et al,13 150 eyes of 129 patients were randomized in a similar fashion to IVB injections, IVB/IVTA injections, and focal or modified grid laser. The visual acuity data showed a significant visual acuity improvement at 6 and 12 weeks for both the IVB and IVB/IVTA groups (P<.001 and P=.012, respectively) and for all follow-up time points for the IVB group. An anatomical effect of central macular thickness (CMT) reduction, although significant at 6 weeks for all groups, was not seen in any of the groups at 12 and 24 weeks.

Another study by the same group evaluated the effect of three injections of IVB on both CMT and visual acuity in patients with refractory DME. The first injections of IVB were combined with IVTA or sham.14 At 24 weeks, the CMT for both treatment groups was significantly reduced compared with the sham group (IVB: P=.012; IVB/IVTA: P=.01). At 24 weeks the visual acuity differences between the IVB and sham groups were significant (P=.01) as were those between the IVB/IVTA and sham groups (,em>P=.006). The difference in visual acuity between the IVB and IVB/IVTA groups was not significant; however, visual acuity improvement was initiated earlier (at 6 weeks) in the IVB/IVTA group than in the IVB only group (12 weeks). IOP rise was seen in 8% of the IVB/IVTA group. Investigators concluded that, although combined IVB and IVTA appeared to result in an earlier improvement in visual acuity, the long-term results did not support an adjunctive effect.

LASER + STEROIDS FOR DME
The recent DRCR Study Group report15 comparing preservative free triamcinolone acetonide 4 mg intravitreal injection with macular laser treatment showed superiority of laser treatment over 2 years of follow-up. Over the first several months, however, triamcinolone acetonide therapy demonstrated an improvement in vision not observed with macular laser treatment; this study did not address combination treatment for DME and it is possible that combination therapy may afford improved efficacy. Prospective studies are in progress.

The results of studies evaluating IVTA and sub-Tenon's injection of triamcinolone acetonide are variable. Shimura et al16 showed a protective effect with a posterior sub- Tenon's injection of TA prior to grid laser photocoagulation for diffuse DME by allowing for lower intensity laser spots and decrease in central visual field sensitivity. Using similar methods, Chung et al17 also found that visual outcomes in diffuse DME were better when triamcinolone TA was administered via sub-Tenon's injection prior to laser. Unoki et al,18 in an 82-eye study, found that posterior sub-Tenon's injection of TA prior to laser resulted in a significant improvement in vision at 6 months compared with laser alone (P=.04). The investigators determined that the improved vision in this study was directly linked to TA's effect of reducing macular thickening, which was also significant in this study (P=.03).

In Lam et al,19 111 eyes of 111 patients were randomized to laser, 4 mg IVTA, or IVTA followed by laser approximately 1 month later. The reduction in central foveal thickness in the IVTA and the IVTA/laser was significant initially (P<.01) but the difference was not significant between groups by month 6. Macular thickening seemed to be delayed in the combined group, suggesting that the laser prolonged the effect of TA.

There was no significant difference in best-corrected visual acuity among the treatment groups. The study authors concluded that there were no differences in the IVTA group and combination group, but that TA yielded better effects than laser when injected alone or in conjunction with laser.

TRIPLE THERAPY FOR AMD
Since 2006, there have been several reports of clinical research into triple therapy for AMD. Liggett et al20 first reported the 6-month results of high-dose IVTA (10 mg), PDT, and pegaptanib sodium (Macugen, Eyetech). The study reviewed the records of 16 patients and 22 eyes; 13 eyes had previous IVTA and PDT treatment, and nine eyes had been newly diagnosed with CNV. Mean visual acuity improvement for both groups was 2.2 lines, which was significant in the newly treated group (P=.013); however, improvement in the previously treated group was not considered significant, suggesting that triple therapy may be more beneficial for treatment-naïve patients.

Augustin et al21 performed a prospective, noncomparative case series in 104 patients to evaluate triple therapy with reduced light-dose PDT, IVB, and intravitreal dexamethasone (IVD) for CNV in AMD. The mean increase in visual acuity among patients at 40 weeks was 1.8 lines (P<.01) and the mean decrease in CRT was 182 µm (P7lt;.01). Further, many of the patients in the study had visual acuity improvement after a single cycle of treatment.

Bakri et al,22 also used reduced-fluence PDT, IVD, and IVB for a study on same-day triple therapy for wet AMD in 31 patients, 18 of whom had received previous treatment and 13 of whom were treatment naïve. The follow-up in this study was an average of 13.7 months. Treatment-naïve patients had a mean baseline visual acuity of 20/60, which improved to 20/40 at final follow-up (P=.31). Previously treated patients had a baseline visual acuity of 20/100, which remained at final follow-up. Baseline and final CMT for treatment-naïve patients was 249 µm and 218 µm, respectively (P=.34). Baseline and final CMT for previously treated patients was 325 µm and 265 µm, respectively (P=.10). For all patients the baseline CMTs and CMTs at final follow-up were 293 µm and 245 µm, respectively (P=.053). The treatment-naïve patients required fewer anti- VEGF injections than those who had received prior treatment. The study authors concluded that triple therapy may reduce the frequency of injections for some patients and stabilize vision in patients who are unresponsive to anti-VEGF therapy alone.

Another study by Yip et al23 used a single session of PDT, IVB, and IVTA for 36 eyes. At 6 months, 61.6% had either stable or improving vision and 27.8% gained three or more lines. CNV resolved after the single tripletherapy session in 77.8% of eyes. The authors concluded that triple therapy may be a good treatment option for CNV in AMD, but that the complications associated with IVTA, such as cataract and increased pressure, should be considered.

Finally, a recent paper by Koss et al,24 investigated the efficacy and safety of vitrectomy, IVB, and IVTA over the course of 6 months. The prospective case series included 106 patients with CNV. The gain in best-corrected visual acuity compared with baseline at 2, 4, and 6 months were significant; visual acuity declined in 20 of 96 patients at month 6, remained stable in 38 patients, and improved in 31 patients. Pressure rises in 11 of the patients were managed with topical medications. The authors reported a sustained visual acuity improvement after the procedure over 6 months, and that in 45% of treated patients, anti-VEGF injections were discontinued.

SUMMARY
It is clear that there will be no magic bullet for our patients who require intervention for these complex disease states. The promise of combination therapy with corticosteroids for AMD and DME and other retinal vascular disease remains largely unrealized at this time with respect to level one clinical trial evidence although some series report on potential efficacy. In light of the number of patients who still do not respond to current therapies for exudative AMD and DME, it is reasonable to pursue randomized clinical trials employing corticosteroid therapy. Further study is required to determine how medical, laser, and surgical interventions complement one another and to ensure that we are offering the safest, least burdensome treatments for our patients while achieving efficacious outcomes.

Allen C. Ho, MD, is a Professor of Ophthalmology at Thomas Jefferson University Retina Service and Wills Eye Hospital in Philadelphia. Dr. Ho is the Chief Medical Editor of Retina Today. Dr. Ho can be reached at acho@att.net.

  1. Spaide RF. Rationale for combination therapies for choroidal neovascularization. Am J Ophthalmol. 2006;141:149–156.
  2. Spaide RF. Combination therapies for choroidal neovascularization. In: Holz FG, Spaide RF, eds. Medical Retina (Essentials in Ophthalmology). Heidelberg: Springer; 2007:90–104.
  3. Rhen T, Cidlowski JA. Anti-inflammatory action of glucocorticoids: new mechanisms for old drugs. N Engl J Med. 2005;353:1711–1723.
  4. Spaide RF, Sorenson J, Maranan L. Photodynamic therapy with verteporfin combined with intravitreal injection of triamcinolone acetonide for choroidal neovascularization. Ophthalmology. 2005;112:301–304.
  5. Augustin AJ, Schmidt- Erfurth U. Verteporfin therapy combined with intravitreal triamcinolone in all types of choroidal neovascularization due to age-related macular degeneration. Ophthalmology. 2006;113:14–22.
  6. Augustin AJ, Schmidt- Erfurth U. Verteporfin and intravitreal triamcinolone acetonide combination therapy for occult choroidal neovascularization in age-related macular degeneration. Am J Ophthalmol. 2006;141:638–645.
  7. Frimpong-Boateng A, Bunse A, Rüfer F, Roider J. Photodynamic therapy with intravitreal application of triamcinolone acetonide in age-related macular degeneration: functional results in 54 patients. Acta Ophthalmol. 2009;87(2):183–187. Epub 2008 Jun 11.
  8. Rouvas AA, Papakostas TD, Vavvas D, et al. Intravitreal ranibizumab, intravitreal ranibizumab with PDT, and intravitreal triamcinolone with PDT for the treatment of retinal angiomatous proliferation: a prospective study. Retina. 2009;29(4):536–544.
  9. Chaudhary V, Mao A, Hooper PL, Sheidow TG. Triamcinolone acetonide as adjunctive treatment to verteporfin in neovascular age-related macular degeneration: a prospective randomized trial. Ophthalmology. 2007;114(12):2183–2189.
  10. Piermarocchi S, Sartore M, Lo Giudice G, Maritan V, Midena E, Segato T. Combination of photodynamic therapy and intraocular triamcinolone for exudative age-related macular degeneration and long-term chorioretinal macular atrophy. Arch Ophthalmol. 2008;126(10):1367–1374.
  11. Neovascular Age-Related Macular Degeneration, Periocular Corticosteroids, and Photodynamic Therapy (NAPP) Trial Research Group; Gilson MM, Bressler NM, Jabs DA, Solomon SD, Thorne JE, Wilson DJ. Periocular triamcinolone and photodynamic therapy for subfoveal choroidal neovascularization in age-related macular degeneration. Ophthalmology. 2007;114(9):1713–1721.
  12. Soheilian M, Ramezani A, Bijanzadeh B, et al. Intravitreal bevacizumab (avastin) injection alone or combined with triamcinolone versus macular photocoagulation as primary treatment of diabetic macular edema. Retina. 2007;27(9):1187–1195.
  13. Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 2009;116(6):1142–1150. Epub 2009 Apr 19.
  14. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol. 2008;246(4):483–489. Epub 2007 Oct 5.
  15. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep;115(9):1447–9, 1449.e1–10
  16. Shimura M, Nakazawa T, Yasuda K, Shiono T, Nishida K. Pretreatment of posterior subtenon injection of triamcinolone acetonide has beneficial effects for grid pattern photocoagulation against diffuse diabetic macular oedema. Br J Ophthalmol. 2007;91(4):449–454.
  17. Chung EJ, Freeman WR, Azen SP, Lee H, Koh HJ. Comparison of combination posterior subtenon triamcinolone and modified grid laser treatment with intravitreal triamcinolone treatment in patients with diffuse diabetic macular edema. Yonsei Med J. 2008 Dec 31;49(6):955–964.
  18. Unoki N, Nishijima K, Kita M, et al. Randomized controlled trial of posterior sub-Tenon triamcinolone as adjunct to panretinal photocoagulation for treatment of diabetic retinopathy. Br J Ophthalmol. 2009;93(6):765–770. Epub 2009 Feb 12.
  19. Lam DS, Chan CK, Mohamed S, et al. Intravitreal triamcinolone plus sequential grid laser versus triamcinolone or laser alone for treating diabetic macular edema: six-month outcomes. Ophthalmology. 2007;114(12):2162–2167.
  20. Liggett PE, Colina J, Chaudhry NA, Tom D, Haffner G. Triple therapy of intravitreal triamcinolone, photodynamic therapy, and pegaptanib sodium for choroidal neovascularization. Am J Ophthalmol. 2006;142(6):1072–1074.
  21. Augustin AJ, Puls S, Offermann I. Triple therapy for choroidal neovascularization due to agerelated macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27:133–140.
  22. Bakri SJ, Couch SM, McCannel CA, Edwards AO. Same-day triple therapy with photodynamic therapy, intravitreal dexamethasone, and bevacizumab in wet age-related macular degeneration. Retina. 2009;29(5):573–578.
  23. Yip PP, Woo CF, Tang HH, Ho CK. Triple therapy for neovascular age-related macular degeneration using single-session photodynamic therapy combined with intravitreal bevacizumab and triamcinolone. Br J Ophthalmol. 2009;93(6):754–758. Epub 2009 Mar 8.
  24. Koss MJ, Scholtz S, Haeussler-Sinangin Y, Singh P, Koch FH. Combined Intravitreal Pharmacosurgery in Patients with Occult Choroidal Neovascularization Secondary to Wet Age- Related Macular Degeneration. Ophthalmologica. 2009 Aug 26;224(2):72-78. [Epub ahead of print]