Article

Anti-VEGF Medications for Proliferative Diabetic Retinopathy

VEGF blockade might be better as an adjunct to, rather than a replacement for, laser.

PEER REVIEWED

Anti-VEGF Medications for Proliferative Diabetic Retinopathy

VEGF blockade might be better as an adjunct to, rather than a replacement for, laser.

ARTHI VENKAT, MS, MD • RISHI P. SINGH, MD

The Diabetic Retinopathy Study (DRS)1 established the standard of care for the treatment of proliferative diabetic retinopathy as laser photocoagulation. However, the advent of anti-VEGF medications for the treatment of diabetic macular edema has markedly changed the management of diabetic eye disease.

Studies have demonstrated a decrease in the progression of nonproliferative diabetic retinopathy (NPDR) to PDR and even regression from PDR to NPDR with the use of anti-VEGF medications, raising the question of whether these medications should be considered as the first line in the management of DR (Figures 1 and 2).

Figure 1. Ultrawidefield fluorescein angiogram of the right eye with proliferative diabetic retinopathy.

Figure 2. Fundus photograph of an eye following scatter laser for diabetic retinopathy.

THE RANGE OF EVIDENCE

Multiple studies (Table) have evaluated whether anti-VEGF therapy in patients with DME demonstrated an effect on the progression of retinopathy. The RISE and RIDE studies,2 which evaluated the use of ranibizumab for DME, investigated the progression of retinopathy in these cases. These studies showed a significantly lower incidence of vitreous hemorrhage in the treatment group, as well as less progression to PDR.

Table. Comparative Data of Trials of Different Anti-VEGF Drugs in DME
DRUG STUDY COMPARED WITH (VS) DURATION OF THE STUDY (YEARS) RESULTS COMMENTS
MEAN VISION CHANGE (LETTERS) MEAN CMT CHANGE (MICRONS)
BVZ BOLT Laser 2 +8.6 vs -0.5 -146 vs -118 Median number of treatments: 13 for BVZ and 4 for laser; VA benefit was maintained through 2 years
RBZ RIDE/RISE Sham injection 3 -11.8 vs +4.5 -258 vs -126 Efficacy equivalent between 0.3- and 0.5-mg doses; FDA approved 0.3-mg dose
RESOLVE Sham injection 1 -10.3 vs -1.4 -194 vs -48 VA improvement 3-fold higher in RBZ group
READ-2 Laser and laser + RBZ 3 -10.3 vs -1.6 vs +2.0 -70 vs -36 vs -24 Resolution of edema more common in RBZ group
DRCR I Laser 5 +7.2 (prompt) vs +9.8 (deferred) -167 (prompt) vs -165 (deferred) Focal/grid laser at initiation of RBZ therapy is no better than deferring laser for 24 weeks
RESTORE Laser 3 +8.0 (RBZ) vs +6.7 (RBZ+ laser) vs +6.0 (laser) -142 vs -146 Efficacy with progressively declining number of injections of PRN dosing
AFB DA VINCI Laser 1 +11 vs -1.3 -189 vs -58 Benefit in the 2-mg q8 weeks treatment schedule, which could reduce the number of visits by half
VISTA/VIVID Laser 2 +11.5 vs +0.8 -193 vs -85 Similar efficacy of AFB in q4 weeks and q8 weeks dosing
BVZ = BEVACIZUMAB; RBZ = RANIBIZUMAB; AFB = AFLIBERCEPT; CMT = CENTRAL MACULAR THICKNESS
TABLE APPEARS COURTESY OF WOLTERS KLUWER

However, per protocol patients had to receive monthly injections, unlike what is done in routine clinical practice, with only 13% demonstrating three-step improvement and 38% demonstrating two-step improvement.

Similarly, VIVID and VISTA compared aflibercept (Eylea, Regeneron, Tarrytown, NY) with macular laser for DME,3 and they demonstrated the superiority of anti-VEGF to laser for vision improvement and anatomic improvement as measured by optical coherence tomography. However, the endpoint of the Diabetic Retinopathy Severity Scale (DRSS) did not reflect significant regression of retinopathy with the use of anti-VEGF alone.

Arthi Venkat, MS, MD, is a retina fellow at the George Washington University in Washington, DC. Rishi P. Singh, MD, is a staff physician at the Cole Eye Institute of the Cleveland Clinic in Ohio. Neither author reports any financial interests in any products mentioned in this article. Dr. Venkat can be reached via e-mail at arthi.venkat@gmail.com..

In comparing ranibizumab (Lucentis, Genentech, South San Francisco, CA) plus prompt or deferred laser for DME, Protocol I of the DRCRnet also failed to show significant improvement in retinopathy by ranibizumab, despite its benefit as an adjunct to macular laser for DME.4

An article from JAMA Ophthalmology in 2013 demonstrated that patients without PDR at baseline who received ranibizumab showed a 7% to 18% probability of progression to PDR, while those with PDR at baseline showed an 18% to 21% probability of progression.5

In contrast, laser photocoagulation has demonstrated long-term durability in the regression of retinopathy. A follow-up study to the Early Treatment of Diabetic Retinopathy Study (ETDRS) explored the long-term effects of panretinal photocoagulation.6

In this study, after patients received laser treatment 15 years earlier, the visual acuity outcomes demonstrated at least 20/20 VA in almost half of patients and at least 20/40 in more than 80%. PRP was shown to reduce the risk of severe vision loss from 30% to 15% in the DRS.7

THE SIGNIFICANCE OF PROTOCOL S

Arguably, the most revealing recent study with regard to the treatment of PDR is the DRCRnet’s Protocol S, which compared the efficacy of prompt PRP to 0.5-mg ranibizumab with deferred PRP.8

The primary outcome of the study was VA change at two years, with secondary outcomes of vision throughout follow-up (area under the curve), peripheral visual field loss, incidence of vitrectomy, development of DME, and retinal neovascularization. In the first year, patients receiving prompt PRP were seen every 16 weeks, while those receiving ranibizumab initially were seen every four weeks.

The ranibizumab group received injections for neovascularization at the first six visits; injections were withheld if no neovascularization was found. Starting at six months, the ranibizumab patients received injections if neovascularization improved compared to any previous three consecutive visits when an injection was given, and injections were withheld if neovascularization was stable over the previous three consecutive injections. Injections were resumed if neovascularization worsened.

The PRP group initially received one to three sessions of laser within eight weeks of randomization, with standard initial laser being 1,200 to 1,600 burns and automated pattern laser being 1,800 to 2,400 burns. Between years 1 and 2, the PRP follow-up interval remained the same, while the ranibizumab patients were seen every four to 16 weeks, with extension of the interval if injections for PDR and DME were deferred.

Protocol S demonstrated that the VA outcomes at two years were at least equivalent in both groups, with the mean change in VA in the ranibizumab group demonstrating noninferiority, and area under the curve analysis demonstrating superiority of the ranibizumab group over PRP. Decreased incidence of vitrectomy was also seen in the ranibizumab group.

Although Protocol S demonstrated noninferiority between the PRP and ranibizumab groups with regard to the regression of PDR, the cost of multiple injections was estimated to be approximately $20,000, while two sessions of PRP cost $3,750.

This price difference raises the question of whether the significantly higher cost of the ranibizumab with deferred laser option is adequately balanced by its equivalent efficacy outcome to laser alone.

In addition, anti-VEGF therapy carries a more significant side effect profile than laser. Although some of the ocular side effects of anti-VEGF, such as worsening vitreomacular traction leading to retinal detachment and intraocular inflammation, are shared with PRP, the existence of systemic side effects with anti-VEGF therapy presents a clear disadvantage as compared to PRP.

Side effects such as proteinuria, stroke, and myocardial infarction are life-threatening, and they limit our ability to use anti-VEGF in more systemically ill patients, who often comprise the patient population with severe diabetic disease.9

CONCLUSION

Although anti-VEGF therapy carries promise in the treatment of PDR, the cost-benefit analysis and safety profile of monthly treatments likely indicate its role as an adjunct, rather than the sole therapy. PRP is an effective long-term treatment for PDR with a relatively low side effect profile, as well as significant cost efficacy in comparison to anti-VEGF therapy.

Future considerations for the use of anti-VEGF in this arena would include further study of longer-term VA and retinopathy outcomes to five years. Additionally, more cost-effective anti-VEGF therapies, such as bevacizumab (Avastin, Genentech), could be evaluated for efficacy in regressing PDR. RP

REFERENCES

1. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol. 1976;81:383-396.

2. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE 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. 2012;119:789-801.

3. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122:2044-2052.

4. Diabetic Retinopathy Clinical Research Network. 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.

5. Bressler SB, Qin H, Melia M, et al; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013;131:1033-1040.

6. Chew EY, Ferris FL 3rd, Csaky KG, et al. The long-term effects of laser photocoagulation in patients with diabetic retinopathy. Ophthalmology. 2003;110:1683-1689.

7. Photocoagulation treatment of proliferative diabetic retinopathy: The second report from the Diabetic Retinopathy Study. Ophthalmology. 1978;85:82-106.

8. Writing Committee for the Diabetic Retinopathy Clinical Research Network; Gross JG, Glassman AR, Jampol LM, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial. JAMA. 2015;314:2137-2146.

9. Avery RL. What is the evidence for systemic effects of intravitreal anti-VEGF agents, and should we be concerned? Br J Ophthalmol. 2014;98(Suppl 1):i7-i10.