Panretinal photocoagulation (PRP) has been the gold standard treatment for proliferative diabetic retinopathy (PDR) for more than 4 decades.^1,2 In 1994, vascular endothelial factor (VEGF) was identified as a key mediator of neovascularization in ocular disease, ushering in an era of anti-VEGF therapeutics.³ Results from the 2015 Diabetic Retinopathy Clinical Research Network (DRCR Retina Network) Protocol S study demonstrated that ranibizumab was noninferior to PRP for PDR with respect to visual acuity outcomes and regression of neovascularization.⁴ Patients treated with ranibizumab initially experienced less visual field sensitivity loss, fewer vitrectomies, and a lower likelihood of center-involving diabetic macular edema (DME). However, concerns remained surrounding the practicality of anti-VEGF treatment for PDR outside of clinical trial settings. Adherence, cost, and feasibility of long-term anti-VEGF treatments continue to drive debate about optimal practice in a real-world setting.

This article describes results of a study undertaken by the authors to characterize the impact of the 2015 publication of DRCR Retina Network Protocol S on the utilization of intravitreal anti-VEGF injections as an alternative to PRP for the treatment of PDR.⁴ This included a stratified analysis of patients with and without DME.

METHODS

For this study, 568,387 patients with an incident diagnosis of PDR between January 1, 2012, and September 30, 2019 were identified from a large national insurance provider database. This timeframe was chosen to include the period before and after the publication of the Protocol S publication in 2015. Patients with ocular comorbidities, a prior diagnosis of PDR, treatment with PRP or anti-VEGF agents before the index of diagnosis of PDR, less than 1 year of follow-up after their index diagnosis, or treatment with observation only were excluded. Finally, 2,588 patients with known laterality of all treatments were included in the final analytic sample.

OVERALL FINDINGS

In the 8-year study period, 63.6% of PDR treatments were anti-VEGF compared with 36.4% that were PRP. Among anti-VEGF treatments, 58.0% were bevacizumab, 25.4% were aflibercept and 16.6% were ranibizumab. The proportion of anti-VEGF treatments for all PDR patients increased from 52.8% to 73.7% from 2012 to 2019. Conversely, from 2012 to 2019, the proportion of PRP claims fell from 47.2% to 26.3% and the rate PRP declined from 784 to 566 per 1,000 treated eyes.

FULL PROLIFERATIVE DR FINDINGS

Prior to the Protocol S study, PRP rates had declined from 784 per 1,000 treated eyes in 2012 to 746 per 1,000 eyes in 2015. After Protocol S, treatment rates decreased further to 566 per 1,000 treated eyes. Concurrently, anti-VEGF use increased significantly from before to after Protocol S (β=-48 vs 161, respectively; P=.001) which was mostly driven by bevacizumab use (Figure 1).

PROLIFERATIVE DR WITH DIABETIC MACULAR EDEMA FINDINGS

For PDR-treated eyes with DME, anti-VEGF use increased to 2,096 per 1,000 treated eyes in 2019 after Protocol S was published (β=-57 vs 187, respectively; P=.043). Use of all 3 agents (bevacizumab [Avastin; Genentech], aflibercept [Eylea; Regeneron], and ranibizumab [Lucentis; Genentech]) increased after Protocol S, but only bevacizumab demonstrated a significant difference in use between time periods. Interestingly, we did not observe a significant difference in PRP use between the periods before and after Protocol S (β=-9 vs -58, respectively; P=.091) (Figure 2). This demonstrates that PRP remains a crucial treatment for PDR. Physician utilization of anti-VEGF even before Protocol S publication for DME may explain the nonsignificant PRP change before and after the Protocol S study.

PROLIFERATIVE DR WITHOUT DME FINDINGS

For eyes with PDR without DME, PRP rates declined from 1,017 per 1,000 treatment eyes in 2012 to 977 per 1,000 treatment eyes before Protocol S. After Protocol S, the rate declined further to 707 per 1,000 eyes in 2019. The anti-VEGF rate increased significantly to 1,226 per 1,000 eyes in 2019 from 390 per 1,000 in 2015 (Figure 3). This increase was statistically significant for aflibercept and bevacizumab. Thus, in PDR eyes without DME, a significant change was observed for both PRP and anti-VEGF use after Protocol S publication. Panretinal photocoagulation rates decreased more rapidly in the period after Protocol S, whereas trends in anti-VEGF use reversed and increased after 2015. Of note, during the study period, PRP was the most commonly used treatment for eyes with PDR without DME, although its use is decreasing.

DIFFERENCES BETWEEN GROUPS WITH AND WITHOUT DME

This study found intravitreal anti-VEGF injections increased among all PDR eyes and PDR eyes without DME, while PRP use decreased since the publication of DRCR Retina Network Protocol S. Interestingly, for PDR eyes with DME, anti-VEGF agents were increasingly utilized, largely attributable to increases in bevacizumab use, but we did not observe a statistically significant rate of change in PRP before and after publication of Protocol S. These results suggest that a randomized controlled trial impacted clinical practice patterns for PDR patients and that the primary, driving anti-VEGF agents utilized were aflibercept and bevacizumab, not ranibizumab. Further, it also shows that PRP is still a mainstay of PDR treatment.

BARRIERS TO ADOPTION

The authors posit that the reason PDR with DME eyes did not have a significant change in PRP rates before and after the publication of Protocol S was that clinicians were already choosing to inject these patients for DME and that PRP still plays a major role in PDR treatment. Therefore, despite its decrease, PRP is still not totally abandoned. Further support for anti-VEGF treatment was provided by the CLARITY trial, which compared intravitreal aflibercept and PRP. The CLARITY trial demonstrated that on average only 4 total injections were needed at 1 year to treat PDR and that visual acuity benefits were present as well.⁵ Of course, concerns of patient adherence to frequent injection visits, the shorter acting effect of anti-VEGF vs PRP, and cost are all real-world issues that may limit the practicality of anti-VEGF monotherapy for PDR.

DIFFERENCES ACROSS AGENTS

Bevacizumab remains the most popular anti-VEGF agent, likely due to its lower cost and comparable efficacy in various clinical trials, despite not being studied specifically in randomized clinical trials for PDR management. Bevacizumab utilization is likely higher than other agents due to its lower cost, potential insurance coverage, and potentially lower financial burden on patients.⁶ Aflibercept use may also be influenced by the publication of the DRCR Protocol T study, which demonstrated improved visual acuity for DME patients with 20/50 or worse vision at 1 year compared to ranibizumab and at 1 and 2 years to bevacizumab.

CONCLUSION

This study demonstrates how clinical trial results may influence real-world clinical practice. For nearly 50 years, PRP was the standard of care to prevent severe vision loss in PDR. The authors found that intravitreal anti-VEGF injections for the treatment of PDR increased whereas PRP use decreased since DRCR Retina Network Protocol S publication. These same trends were observed in PDR eyes without DME, whereas in PDR eyes with DME, only anti-VEGF use significantly increased after Protocol S and PRP use remained stable. These results suggest that clinical trial results from Protocol S have influenced practice patterns, but that PRP remains a mainstay of PDR management in real-world practice. RP

REFERENCES

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