Clinical Updates — Clinical Updates
Trial Shows Beneficial Effects of Intravitreal Triamcinolone in DME Patients Nonresponsive to Bevacizumab
In February, Retina published a report by Jeon, et al on a prospective, nonrandomized interventional trial showing that intravitreal triamcinolone has beneficial effects in diabetic macular edema (DME) that persist after at least 3 monthly intravitreal bevacizumab injections. Their finding of efficacy correlates to the detection of interleukin 8 (IL-8) in aqueous samples obtained at the time of the injection as an independent factor for anatomic response.
DME has been proposed to be a multifactorial disease,[2-6] with inflammatory factors and VEGF playing a significant role in driving pathologic permeability, thus allowing intravascular fluid to accumulate in the intraretinal space. There has been bountiful evidence for corticosteroid injection as treatment for DME refractory to laser since the early 2000s through DRCR.net, as cited in Jeon’s paper.
This article is significant, as it is informative on a relatively new class of refractory DME: patients who are nonresponsive to anti-VEGF injections and non-candidates for laser treatment. With the profound visual success (vs laser) of anti-VEGF primary therapy for center-involving DME, it is important to have a “plan B” for patients who underperform compared with the mean and the clinician’s appropriately high level of expectation.
Jeon’s paper shows a visual benefit of 4.0 mg/1.0 ml of intravitreal triamcinolone for patients whose central subfield thickness (CST) fails to improve by at least 11% after a series of an average of more than 4 (and at least 3) bevacizumab injections. The paper acknowledges that this trial’s methodology is not proposed as a uniform definition of nonresponsiveness, but as one reasonable way to consider that state.
The trial results speak to the difficulties in treating an underperforming population, perhaps more than to the relative efficacy of intravitreal triamcinolone. Study patients who showed a reduction greater than the 11% “cut-off” for poor response to the initial bevacizumab therapy after being treated with intravitreal steroid were only 12/20 at 1 month and 10/20 at 2 months; they showed a significant reduction in mean CST from 465.5 μm at baseline to 380.5 μm and 402.1 μm at 1 and 2 months, respectively. Patients also had a visual gain of about 6 and 5 letters, respectively, with treatment effect statistically insignificant at month 3.
These results show a reasonable improvement, but there is poor treatment durability for the triamcinolone injection. The response is also less profound than one would expect in a typical population mostly responsive to any primary intravitreal therapy.
The probable reason for the somewhat underwhelming response to the steroid injection in the study population is that patients who fail any initial intravitreal therapy are probably relatively severe cases that would be resistant to any treatment. Because many retinal surgeons initially treat with 1 of 2 (perhaps soon, 3) effective anti-VEGF injectables, it is instructive that at least a majority of the small number of patients who may not improve to a satisfactory level with anti-VEGF treatment may respond better with a steroid adjuvant.
It is also instructive that there was an inflammatory factor (IL-8) to triamcinolone associated with the better responders. The presence of IL-8 supports the assumption that patients who respond poorly to anti-VEGF seem to have a preponderance of inflammatory disease in their DME. Of special interest, the aqueous VEGF levels of the patients in the study were low at the time of triamcinolone injection, implying that there was biologic effect of the prior bevacizumab, but their DME was still severe enough to meet the inclusion criteria.
There is likely a continuum of more VEGF- and inflammatory-mediated disease in the diabetic population. We see it all as the same clinical diagnosis: DME. Suppressing either the VEGF or inflammatory component is likely to effectively treat the majority of patients; the good anatomic and visual results are demonstrated in many studies (eg, DRCR.net Protocol I).
I do not believe that the paper's results advocate that we need to routinely check the intraocular inflammatory factors of patients responding poorly to anti-VEGF therapy. Rather, the presence of IL-8 in this study as an independent correlate to triamcinolone response demonstrates there is a plausible explanation as to why a small but significant patient population needs something more than anti-VEGF monotherapy. Conversely, the presence of interleukins in this study also validly explains why intravitreal steroid monotherapy works well in many patients.
As in many common disease states such as hypertension, a combination approach with several different classes of drugs with varying mechanisms of action may be the best approach for more severe cases. It is important for the retinal community to develop protocols and best practices for these challenging patients.
It will be more difficult to decide what is “best” when we start combining therapies, as it will be difficult to design large trials standardizing nonresponsive patients and looking at the various agents and dosing frequencies. I think we will become more dependent on smaller studies, such as this paper, to inform us regarding the definitions of nonresponse and help determine a treatment regimen once that has been determined.
Jeon et al report a low incidence of adverse events with adjuvant intravitreal triamcinolone. The sample size is too small to make any generalizations, but it is encouraging to see an absence of uncontrollable intraocular pressure (IOP) in this small population.
As reasonably expected, 25% of the subjects developed IOP >21 mmHg, but all could be controlled on drops. There is a remote possibility that patients who respond poorly to anti-VEGF may not have as high a rate of profound or uncontrollable steroid response, but that is not a generalization we can make based on this small population.
Therapeutic options for the most challenging DME patients are valuable to the clinician. It will take time and experience for the retinal community to grasp which combinations are most appropriate at various points in this multifaceted disease process.
1. Jeon S, Lee WK. Effect of intravitreal triamcinolone in diabetic macular edema unresponsive to intravitreal bevacizumab [published online February 18, 2014]. Retina. doi:10.1097/IAE.0000000000000109.
2. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmol. 2009;116(1):73-79. doi:10.1016/j.ophtha.2008.09.037.
3. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmol. 2002;109(5):920–927.
4. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial [published online July 6, 2006]. Ophthalmol. 2006;113(9):1533–1538. doi:10.1016/j.ophtha.2006.02.065.
5. Gillies MC, McAllister IL, Zhu M, et al. Intravitreal triamcinolone prior to laser treatment of diabetic macular edema: 24-month results of a randomized controlled trial [published online January 12, 2011]. Ophthalmol. 2011;118(5):866-872. doi:10.1016/j.ophtha.2010.09.029.
6. Elman MJ, Bressler NM, Qin H, et al; Diabetic Retinopathy Clinical Research Network, Writing Committee. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmol. 2011;118(4):609-614. doi:10.1016/j.ophtha.2010.12.033.
Published April 2014
Dr. Eichenbaum - ALLERGAN, INC: Consultant, Honoraria; GENENTECH, INC: Advisory Board, Consultant, Speaker, Grants, Honoraria; HEMERA BIOSCIENCES, INC: Stockholder, Stock; UNITED STATES RETINA, LLC: Stockholder, Stock.
Dr. Albini - ALLERGAN, INC: Consultant, Honoraria; BAUSCH + LOMB, INC: Consultant, Honoraria; GENENTECH, INC: Grants, Other; THROMBOGENICS, INC: Consultant, Honoraria.