Subthreshold laser may reduce intravitreal injections for DME

March 3, 2020

Used as an adjunct, ST laser may reduce the treatment burden for patients while maintaining visual acuity

Used as an adjunct, ST laser may reduce the treatment burden for patients while maintaining visual acuity

Special to Ophthalmology Times®Diabetic macular edema (DME) is a significant cause of vision loss in patients with diabetes.

In the 1980s, the Early Treatment Diabetic Retinopathy Study (ETDRS) established focal laser photocoagulation as the standard of care for eyes with clinically significant macular edema (CSME).1

Though laser treatment decreased the risk of moderate vision loss by 50%, the rate of visual gain following focal laser treatment is low.

Over the past decade, ETDRS focal laser treatment for CSME has been largely replaced by anti-vascular endothelial growth factor therapy (VEGF) injections.2,3

Related: The ABCs of VEGF treatment for diabetic macular edema

Anti-VEGF injections are more likely to result in visual gain than conventional focal laser treatment. However, regular ongoing injections are required and can carry risks, including endophthalmitis and uveitis. Systemic risks are low, but also a consideration in diabetics.

From a practical standpoint, monthly visits are a significant burden for patients, and not all patients respond completely to anti-VEGF injections3

Intravitreal steroid injections are also available for DME and may extend the treatment interval from several months (Ozurdex, Allergan)4 to three years (Iluvien, Alimera Sciences).5

In addition to a risk for endophthalmitis, intraocular steroid injections pose significant risks of glaucoma and cataract progression. Researchers have continued their effort to develop effective treatment for DME with a more advantageous risk profile.
 

Related: Seeking the holy grail treatmtent for endophthalmitis 

 

ST laser development 
Conventional ETDRS focal laser treatment uses a continuous wave (CW) laser, where the clinical endpoint is a visible retinal burn6

The mechanism of action involves absorption of the laser radiation primarily by melanin in the retinal pigment epithelium (RPE) and choroid, where it is converted into heat. This heat may spread to adjacent tissues, increasing the risk of causing collateral thermal damage.7 The size of the laser scars increases over time.8

If such laser burns are placed too close to the fovea, risk of central vision loss may increase. Even with properly performed CW focal laser treatment, there can be loss of contrast sensitivity and/or visual field.

With the development of subthreshold (ST) laser treatment-which breaks the laser exposure into a train of brief subpulses-thermal injury is reduced while still inducing the outer retinal metabolism. 9

There is also evidence that this approach decreases the collateral damage.10

Related: Why you should consider laser therapy in young diabetic patients 

Research
In 2009, a study comparing ST micropulse laser treatments with CW focal laser for CSME showed the ST treatment to be equally effective with less retinal scarring.11

In 2011, a randomized, controlled study of 123 patients showed greater improvement in functional and anatomical outcome measures with high-density ST micropulse laser treatment compared with modified ETDRS focal/grid laser.12

Based on these results, ST laser treatment may provide an adjunctive treatment option for CSME, with a safer risk profile compared with standard ETDRS CW focal laser treatment or anti-VEGF or steroid injections alone.

For CSME treatment, my colleagues and I have been offering the addition of ST laser combined with CW focal laser where indicated, in hopes of reducing the number of intravitreal injections patients may need while maintaining excellent visual and anatomic outcomes.

Related: Laser therapy maintains position as key DME treatment option 
 

Study: adjunctive treatmtent with ST laser
With institutional review board (IRB) approval, we performed a retrospective chart review of patients with at least 6 months follow-up after adjunctive treatment with the ST laser.

Endpoints included best-corrected visual acuity (BCVA) (in logMAR), central foveal thickness (CFT), and macular volume (MV). Values were reported at baseline and at a 6-month follow-up.

In addition, the number of intravitreal injections during the 6 months before baseline was compared with the number of treatments (intravitreal injections and/or additional lasers) during the 6 months after baseline. All statistics were performed with a spreadsheet program (Microsoft Excel). Means before and after baseline were compared with paired t-tests.

All laser treatments were performed with a green laser (Smart532, Lumenis). In eyes with focal extrafoveal leakage on fluorescein angiography (FA), extrafoveal microaneurysms were treated in the CW mode, where the laser signal consisted of a single pulse with a duration of 50 to 100 msec.

The spot size was 50 to 100 μm. Power was titrated to obtain a light grey endpoint, usually between 90 to 140 mW.

Related: Imaging-reading accuracy increases with deep-learning DR algorithms 

Areas of leakage identified on FA and thickening on OCT were treated with ST laser, using the laser’s SmartPulse (SP) mode.

In this mode, each pulse consisted of a train of brief (100 ms) subpulses, delivered at a duty cycle of 5%. The spot size was 200 μm. A titration procedure was performed to determine the power.

Starting in the CW mode, a single spot was applied in an extrafoveal area, using an initial power of 80 mW and gradually increasing it until a grey response was obtained.

Related: Laser therapy may offer fast-acting option for CSR resolution 

Next, the laser was switched to SP mode, and the power was multiplied by 3 (up to a maximum of 400 mW). With these settings, the tissue reaction was subthreshold. A scanner was used to deliver 3 x 3 patterns with a spacing of 0.25 spot size. Patterns were overlapped to ensure contiguous treatment.

During the 6 months after baseline testing, eyes were evaluated to determine whether they were stable or improving or if further treatment was needed.
 

Additional treatment could be an intravitreal anti-VEGF or steroid injection or an additional ST laser treatment.
 

Outcomes suggest possible benefit of ST laser

Twenty eyes of 15 patients with DME had 6 months follow-up after ST laser treatment. (Table 1) Six eyes (30%) eyes had proliferative diabetic retinopathy, and 14 (70%) had non-proliferative diabetic retinopathy (NPDR).

In 18 eyes (90%), there was a history of prior intravitreal injections, and 12 eyes (60%) had received focal laser treatment.

In the 6 months prior to baseline, 15 eyes (75%) were treated with 3.07±0.96 (mean±SD; range: 1 to 4) anti-VEGF injections. Two eyes (10%) were treated with 1 steroid injection each. For the entire cohort of 20 eyes, the average number of intravitreal injections (anti-VEGF or steroids) was 2.4±1.64.

Related: Small changes can help beat endophthalmitis bug 

Outcome measures at baseline and final 6-month follow-up are shown in Table 2.  BCVA and CFT remained stable (p = 0.584 and p = 0.478, respectively), while MV decreased by 3% (p < 0.05).

The number of anti-VEGF injections decreased by 72%, from 2.3 to 0.65 (p < 0.001), and the total number of intravitreal injections decreased by a similar proportion, from 2.4 to 0.7 (p < 0.001). In two cases, additional ST laser treatments were given after the baseline.

For a fair comparison, we tallied any treatments given during these two periods, including both types of injections and ST laser. The number of treatments significantly decreased by 67%, from 2.4 to 0.8 (p < 0.001). No adverse events or complications were observed.

Figure 1 shows OCTs of a 56-year-old male with a history of stroke and NPDR/DME in his left eye, with a BCVA of 20/50 at presentation. CFT was 270 μm with intraretinal fluid. (Figure 1A)

In the 6 months before baseline, his eye was treated with 2 ranibizumab injections‎ (Lucentis, Genentech). At baseline, extrafoveal microaneurysms were treated focally with CW laser, and then the central DME was treated with ST laser.

With no additional injections, at the 6-month follow-up, BCVA improved to 20/40 and CFT decreased 15% to 229 μm. On OCT, the intraretinal fluid was essentially resolved. (Figure 1B)


Related: Determining DR progression: Much work still needs to be done 


Future outlook for ST laser

In this retrospective study of DME patients treated with the Lumenis Smart532, there was a good safety profile.

Following treatment, the number of injections decreased by more than half, while visual acuity and central retinal thickness were maintained. This decrease in the treatment burden to the patients is encouraging.

Most studies of anti-VEGF treatment for CSME (e.g., RISE/RIDE,13 RESTORE,14 VISTA/VIVID,15 and PROTOCOL T of the DRCR network 16) excluded patients with very good vision and/or with mild macular edema.

Related: IRIS Registry Study: Overall anti-VEGF intervals for wet AMD stable after 1, 2 years 

Subthreshold laser is of particular interest in light of DRCR Protocol V. Patients with 20/25 or better vision and CSME treated with observation only, CW focal laser, or aflibercept (Eylea, Regeneron) showed no significant differences in visual acuity at 2 years, but there was a trend towards better vision with laser or aflibercept, compared to observation.17

Given the excellent safety profile of ST laser, this may be a reasonable treatment approach in such patients, either alone or in combination with CW focal laser.

It is encouraging to find that ST laser treatment may help reduce the treatment burden for patients with DME by decreasing the number of intravitreal injections needed, while maintaining visual acuity.

Randomized prospective studies are needed to further elucidate the merits of this approach.

Read more diabetic macular edema content 

Pauline T. Merrill, MD,is a partner at Illinois Retina Associates, as well as associate professor and section director for uveitis, Rush University, Chicago. She has received numerous honors, including the American Academy of Ophthalmology Achievement Award and the American Society of Retina Specialists Senior Honor Award.

Dr. Merrill reports research grants/funding from Gilead, Lumenis, the National Eye Institute, and Santen, and has served as a consultant with Alimera Sciences, Genentech, Graybug, Lumenis, and Santen.

Special acknowledgement to Yair Manor, PhD, clinical director, BU Vision, for his assistance with the study and statistical analysis.

 

References:

1.

Early treatment diabetic retinopathy study research group. Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol. 1985;103:1796-1806.

2.

Elman M, Ayala A, Bressler N, et al. Intravitreal Ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015 ;122:375-381.

3.

Wells J, Glassman A, Ayala A, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-1203.

4.

Singer M, Dugel P, Fine H, Capone AJ, Maltman J. Real-World Assessment of Dexamethasone Intravitreal Implant in DME: Findings of the Prospective, Multicenter REINFORCE Study. Ophthalmic Surg Lasers Imaging Retina. 2018;49:425-435.

5.

Augustin A, Bopp S, Fechner M, et al. Three-year results from the Retro-IDEAL study: Real-world data from diabetic macular edema (DME) patients treated with ILUVIEN (0.19 mg fluocinolone acetonide implant). Eur J Ophthalmol. 2019.

6.

Mainster M. Decreasing retinal photocoagulation damage: principles and techniques. Semin Ophthalmol. 1999;14:200-209.

7.

Desmettre T, Mordon S, Buzawa D, Mainster M. Micropulse and continuous wave diode retinal photocoagulation: visible and subvisible lesion parameters. Br J Opthalmol. 2006;90:709-712.

8.

Schatz H, Madeira D, McDonald H, Johnson R. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol. 1991;109:1549-1551.

9.

Yu A, Merrill K, Truong SFK, Morse LTD. The comparative histologic effects of subthreshold 532- and 810-nm diode micropulse laser on the retina. Invest Ophthalmol Vis Sci. 2013;54:2216-2224.

10.

Jain A, Blumenkranz M, Paulus Y, al e. Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol. 2008;126:78-85.

11.

Figueira J, Khan J, Nunes S, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol. 2009;93:1341-1344.

12.

Lavinsky D, Cardillo J, Melo LJ, Dare A, Farah M, Belfort RJ. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci. 2011;52:4314-4323.

13.

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.

14.

Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.

15.

Heier J, Korobelnik J, Brown D, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016;123:2376-2385.

16.

Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123:1351-1359.

17.

Diabetic Retinopathy Clinical Research Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019;321:1880-1894.