Combination anti-VEGF, navigated laser for DME on a par with monotherapy

Take-home message: Data show that the combination of navigated laser and anti-vascular endothelial growth factor (VEGF) compares favorably with anti-VEGF monotherapy. 

By Marcus Kernt, MD, Special to Ophthalmology Times

Munich, Germany-With type 2 diabetes reaching epidemic proportions, the number of cases of diabetic macular edema (DME) is likely to increase. DME is already a leading cause of blindness in developed countries, and presents a significant burden to healthcare providers and payers, and society as a whole.^1,2

Findings from the Early Treatment Diabetic Retinopathy Study (ETDRS) established the clinical efficacy of laser photocoagulation in the treatment of DME. Perhaps unsurprisingly then, laser photocoagulation was the first-line DME treatment for many years. Unfortunately, although ETDRS data demonstrated that laser treatment reduced the risk of vision loss, its ability to improve visual acuity was limited.³

In contrast, intravitreal injection of anti-vascular endothelial growth factor (VEGF) inhibitors, such as ranibizumab (Lucentis, Genentech), has been shown to improve visual acuity (7 to 12 letters on average) within the first year of treatment.^4,5,6

Combining laser with anti-VEGF therapy

Although anti-VEGF therapy is highly effective and has largely replaced traditional laser photocoagulation as a first-line therapy for DME, seven to 12 injections are required during the first 12 months to achieve and maintain its effects. ^4,5,6

Consequently, anti-VEGF treatment it is associated with significant cost, patient burden, and real-world patient compliance issues. In addition, a significant number of patients only partially respond to anti-VEGF monotherapy, if at all.

In order to reduce treatment burden and make disease management more economical, it is necessary to reduce the number of injections without diminishing treatment benefits.

One strategy is to combine anti-VEGF therapy with laser photocoagulation. This approach has been investigated in clinical trials previously using conventional slit lamp-based laser application, but with little success in terms of either visual acuity gains or reductions in the injection burden-likely due to inadequate accuracy and completeness associated with conventional laser therapy.^4,5

However, the availability of a new computer-guided technology for navigated laser photocoagulation (Navilas Laser System, OD-OS GmbH) offers greater accuracy in laser spot application to areas of edema than traditional laser treatment.

The laser photocoagulator with retinal navigation integrates fundus imaging, including true color and FA with computer-based image-guided retinal laser therapy.⁷

Although navigated laser therapy is mainly used to treat DME and proliferative diabetic retinopathy, in terms of patient numbers, it has been used with good success in the treatment of retinal vein occlusions, polypoidal choroidal vasculopathy, idiopathic perifoveal teleangiectasia, central-serous chorioretinopathy, and choroidal neovascularisation.⁷

Navigated laser photocoagulation has also been shown to reduce the re-treatment rate (as compared with conventional laser therapy) by almost 50% in patients with DME.⁸

It was hypothesized, therefore, that using navigated laser treatment to effect earlier disease stabilization might lead to earlier stabilization of anti-VEGF visual gains, thereby reducing the anti-VEGF re-treatment rate and injection burden.⁹

One-year study highlights

To test a hypothesis, a 12-month, prospective, comparative cohort study of 66 patients with DME was conducted in which 34 patients were treated with combination therapy (ranibizumab plus navigated laser photocoagulation), and 32 patients were patients treated with ranibizumab alone. All patients received 3 monthly ranibizumab injections (loading phase) and additional injections pro re nata (PRN). Patients in the combination therapy arm also received navigated laser photocoagulation after the loading phase.

Findings showed that both navigated laser combination therapy and ranibizumab monotherapy provided similar improvements in mean best corrected visual acuity (BCVA) letter score (+8.41 versus  +6.31 letters, p = 0.258)-in trend better in the combined treatment arm.

In the combination group, significantly less injections were required after the 3 injection loading phase (0.88 ± 1.23 versus 3.88 ± 2.32, p = 0.001). By month 12, 84% of patients in the monotherapy group required additional ranibizumab injections as compared with only 35% in the combination group ( p= 0.001).⁹

Our 12-month findings are similar to those of a 23-eye study conducted at the University of California, San Diego.¹⁰

Published in the British Journal of Ophthalmology in August 2014, the study showed that bevacizumab injections followed by navigated laser treatment for clinically significant DME produced significant visual gains (+10.6 ± 18) at month 12 from baseline. Fifty-seven percent of the eyes remained injection-free post-laser, while 43% needed additional injections of bevacizumab, corresponding to an average of 4.0 ± 1.2 injections by month 12 from baseline.

Two-year findings

The one-year data data demonstrate that navigated laser treatment helps to reduce the anti-VEGF re-treatment rate and injection burden. However, it was important to verify that patient benefits from navigated laser combination therapy can be maintained through year 2.

Consequently, 24 out of 34 patients previously treated with combination therapy for 12 months were followed for an additional 12-month period (total average follow-up, 27.7 months). The main outcome measures were mean number of injections in year 2 and change in BCVA from baseline to month 24.

Findings from the extension study showed that navigated laser combination therapy effected significant visual gains (on average, nine ETDRS letters or more), that were achieved with an average of 4.1 injections in year 1 and that could be maintained with an average of 2.1 injections through year 2 (Table 1).

Moreover, 50% of patients (n = 12) remained injection-free in year 2.

Overall, these data show that the combination of navigated laser and anti-VEGF compares favorably with anti-VEGF monotherapy in this study and major anti-VEGF trials-both in terms of injection numbers and re-treatment rates, and with equivalent or better visual outcomes.

As noted, previous conventional slit lamp-based laser/anti-VEGF combinations have previously failed in demonstrating such effects.

Finally, and perhaps most crucially, these data also serve to highlight that the treatment and economic burden reduction of fewer anti-VEGF injections during year 1 by the addition of navigated laser are maintained through year 2 and do not come at the price of losing vision in year 2 or an increased injection rate (“catch-up” effect).

In will be a topic for further study to determine if an even milder, microsecond-pulsed navigated laser therapy generates equivalent outcomes without tissue coagulation.

References

• Ciulla TA, Amador AG, Zinman B. Diabetic retinopathy and diabetic macular edema: pathophysiology, screening, and novel therapies. Diabetes Care. 2003;26:2653-2664.

• Ford JA, Lois N, Royle P, Clar C, Shyangdan D, Waugh N. Current treatments in diabetic macular oedema: systematic review and meta-analysis. BMJ Open. 2013;3.

• ETDRS Study Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:1796-1806.

• Michael J. Elman et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609-614.

• Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE Study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.

• Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, Schlottmann PG, Rundle AC, Zhang J, Rubio RG, Adamis AP, Ehrlich JS, Hopkins JJ; RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120:2013-2022.

• Kernt M, Ulbig M, Kampik A and Neubauer AS. Navigated laser therapy for diabetic macular oedema. European Ophthalmic Review. 2013;7:127–130.

• Neubauer AS, Langer J, Liegl R, et al., Navigated macular laser decreases retreatment rate for diabetic macular edema: a comparison with conventional macular laser. Clin Ophthalmol. 2013;7:121–128.

• Liegl R, Langer J, Seidensticker F, et al. Comparative evaluation of combined navigated laser photocoagulation and intravitreal ranibizumab in the treatment of diabetic macular edema.  PLoS One 2014;26;9:e113981.

• Barteselli G, Kozak I, El-Emam S, Chhablani J, Cortes MA, et al. 12-month results of the standardised combination therapy for diabetic macular oedema: intravitreal bevacizumab and navigated retinal photocoagulation. Br J Ophthalmol. 2014; 98:1036-1041.

Marcus Kernt, MD

E:marcus.kernt@med.uni-muenchen.de

Dr. Kernt is a consultant and retina specialist, Department of Ophthalmology, Ludwig-Maximilians-University of Munich, Germany. Dr. Kernt is a medical advisor of OD-OS GmbH.