In the first and second parts of this series, we discussed the growing body of evidence showing that several therapies, including excellent glycemic control, intravitreal anti-VEGF, and intravitreal steroid, can halt and reverse the progression of diabetic retinopathy. The third and final installment of this series will focus on the clinical relevance of these findings, specifically in relation to anti-VEGF therapy, the new standard of care for patients with diabetic macular edema. Additional discussion is devoted to the economic impact of intravitreal anti-VEGF therapy for the treatment of diabetic retinal disease.

CLINICAL RELEVANCE

As discussed in part 2 of this series, several large clinical trials have conclusively shown the improvement that anti-VEGF therapy confers on DR severity score (DRSS).^1-3 Perhaps more surprisingly, long-term follow-up of patients in the RIDE/RISE studies found this treatment response to be durable even in cases of decreasing treatment frequency.⁴ While the improvement in DR severity has been impressive, its clinical relevance is less clear. The predominant factors used to assess treatment response in daily practice are BCVA and central retinal thickness (CRT) as assessed by optical coherence tomography (OCT). Not surprisingly, most clinical trials have focused on these metrics. However, several trials also included pre- and posttreatment 7-field fundus photographs and had secondary analysis devoted to DRSS changes. Post-hoc analysis of these data is the basis for our recent understanding of the changes that anti-VEGF and steroid treatment confer on the degree of DR. Several groups are currently investigating factors that may predict improvements in DRSS, with one group specifically analyzing the clinical relevance of these changes.^5-7

Recent Multicenter Trial Data

The VIVID and VISTA studies were phase 3 studies comparing aflibercept at 2 different dosing schedules to macular laser for the treatment of DME. As summarized in part 1 of this series, patients receiving aflibercept had a ≥2-step DRSS improvement approximately 3 times as often as patients receiving macular laser.² Singh reported data from a post-hoc analysis of VIVID/VISTA data, specifically investigating what pretreatment factors were predictive of ≥2-step DRSS improvement in this cohort.⁵ He reported that only pretreatment DRSS score correlated with the finding of DRSS reversal, and specifically found no correlation between other clinically useful metrics, including baseline CRT and vision. The clinical relevance of these data was not directly assessed in this presentation, but it is worth noting that changes in DRSS were not compared to changes in vision and CRT.

The RIDE and RISE studies compared ranibizumab (0.3 mg or 0.5 mg) to sham injections with rescue laser. Lalwani and colleagues carried out post-hoc analysis looking only at patients with the highest risk nonproliferative diabetic retinopathy (NPDR), which corresponded to an early treatment diabetic retinopathy study (ETDRS) DRSS of 47/53.⁶ They focused on macular nonperfusion (MNP) outcomes and baseline factors that predict DR improvement. In this subgroup, at 24 months more than 75% of patients with high-risk NPDR manifested ≥2-step DRSS improvement compared to only 12% in the sham treatment group. Only 3% of ranibizumab-treated eyes had ≥2-step DRSS worsening compared to 10% of the eyes in the sham treatment groups.

Macular nonperfusion remained relatively stable over time in the ranibizumab treated eyes, while it worsened significantly in the eyes receiving sham treatment. Baseline BCVA, CRT, and duration of diabetes were not predictive of response to ranibizumab treatment. It can be argued that the reduction in spread of MNP in these patients has clinical relevance, given the correlation between vision loss and extent of MNP. The authors concluded that vision-related quality of life is negatively affected by DR progression, and their data showed that progression is frequently reversed by treatment with ranibizumab.⁶

Ip et al carried out post-hoc analysis of the phase 3 RIDE/RISE studies of ranibizumab for the treatment of DME.⁷ Twenty-four-month follow-up data from these studies showed that 57% of treated eyes had at least a 1-step DRSS improvement, while 40% maintained their DRSS score, and only 3% had worsening. To evaluate the clinical relevance of these changes, Ip et al examined the BCVA data segregated based on DRSS scores. They found that eyes with stable or improving DRSS had greater improvements in BCVA than those with DRSS worsening. A BCVA gain of ≥15 letters was more likely in patients with a 2- to 3-step DRSS improvement. Not surprisingly, a ≥15 letter loss was more common in the patients with DRSS worsening. There was also a correlation between DRSS improvement and decrease in CRT, with 84.2%, 87.7%, and 92.3% of patients with 1-, 2-, and 3-step DRSS improvement, respectively, achieving less than or equal to 250-micron CRT on OCT.

Contrast sensitivity was an additional functional outcome measured in this study, and improvements in contrast sensitivity were also positively correlated with improvements in DRSS. Patients with DRSS improvement showed a trend toward larger reductions in leakage on fluorescein angiography (FA), although this did not achieve statistical significance.⁷ These preliminary data suggest that DRSS correlates with functional and anatomic improvements in DR, and warrants additional investigation in clinical trials.

DRSS in Clinical Practice

Post-hoc analysis of RIDE/RISE provides support for the merit of using DRSS to assess outcomes in DR. While we await a similar analysis of data from VIVID/VISTA and several other large, multicenter trials, it is likely safe to assume that a similar correlation will be observed in patients receiving aflibercept and bevacizumab. However, the practical application of these findings is not entirely clear.

In light of the overwhelming burden of diabetic eye disease, most clinical practices are set up to maximize patient throughput while still delivering excellent patient care. While clinical examination can be used to grade DR at multiple clinical visits, it remains a more subjective outcome measure. To assess the accuracy of clinical DR grading, Gangaputra et al reported data on the correlation between clinical examination and image grading at a reading center for the classification of DR and DME.⁸ They found exact agreement in only 70% of patients in 2 large multicenter trials and concluded that clinical examination is most useful for defining broad DR categories, but is less helpful for documenting small to moderate changes of DR over time.

The DRSS was designed as a tool for multicenter clinical trials, and its use requires imaging, including 7 standard stereoscopic field fundus photographs and clinical reading centers. However, obtaining photography at multiple patient visits is both time intensive and invasive, and the use of reading centers is not feasible for everyday patient care.

DRSS Response as a Guide for Long-Term PRN Dosing Schedules

Data from several large clinical trials have definitively shown that anti-VEGF treatment confers a treatment benefit that persists after treatment is de-escalated.^4,9 However, this long-term treatment response is varied, with some patients requiring very few injections annually and others requiring more frequent maintenance treatment.

Having metrics in place to appropriately select patients for different treatment regimens would be of great clinical value, potentially reducing the burden of frequent patient assessments by placing patients into well-defined treatment protocols. Several authors have investigated criteria that will help predict patient outcomes following initial monthly anti-VEGF treatment.

Wykoff et al carried out post-hoc analysis of data from the open-label extension of RIDE/RISE, investigating factors that predict patients’ long-term treatment frequencies.¹⁰ In this report, 500 patients completed the treatment extension protocol. Of these patients, 121 required no additional injections annually, 132 required 0 to ≤3 injections annually, 159 required 4 to ≤7 injections annually, and 88 required >7 injections annually. Patients receiving 0 vs >7 annual injections were more likely to have had a ≥2 step DRSS improvement at months 24 and 36 (21.5% and 33.9%, respectively) vs patients requiring >7 injections annually (12.5% and 17.0%, respectively). This suggests that improvements in DRSS following initial intensive treatment foreshadows reduced long-term treatment needs. The presence of NPDR vs PDR at baseline was also a significant variable. Other factors correlated with needing 0 injections included shorter duration of DME and decreased proportion of patients with PDR. Patients requiring 0 injections also had thinner CRT, less FA leakage, and fewer rescue laser treatments. These data may have relevance, not only in beginning to define appropriate PRN dosing regimens, but also in investigating patients that should be treated with alternative therapies, including long-term release steroid depots, at an earlier stage. The data have perhaps the greatest clinical relevance in terms of the value of DRSS changes in clinical practice.

Possible Clinical Solutions

At a minimum, to impact patient care, a modified DRSS would need to be designed with clinical practice in mind. Utilizing widefield fundus photography, practices could obtain baseline images, with repeated photographs obtained following a set number of injections. The response to anti-VEGF could then be quantified, with patients stratified into different treatment regimens based on initial response. Automated imaging software may have particular utility in this regard. Optical coherence tomography and OCTA may also play important roles in a new clinical treatment response algorithm. More work is needed in this area.

ECONOMIC IMPACT OF IMPROVEMENTS IN DIABETIC RETINOPATHY SEVERITY

In the face of rising health care costs, the specter of endless monthly injections adds a significant burden to the health care system and society at large. Direct cost analysis in light of DRSS changes has not currently been published. However, extrapolating from the work of Ip et al, we can make a few generalizations about the costs associated with DRSS improvement, which was shown to correlate with improvements in CRT and BCVA.⁷

In 2016, Ross et al published cost-effectiveness data from their post-hoc analysis of the DRCR network comparative effectiveness trial of aflibercept, bevacizumab, and ranibizumab.¹¹ The authors reported the incremental cost-effectiveness data (ICERs), defined as the ratio of each agent’s incremental cost (in 2015 US dollars) to its incremental benefit in quality-adjusted life years (QALY). Participants’ visual acuity levels were used to calculate QALYs using data from a previous study by Brown et al, who used VA in a patient’s better-seeing eye to estimate QALY.¹² Adverse events were used to deduct QALY. Costs consisted of the wholesale price of anti-VEGF agents and the Medicare physician injection fee, and mathematical modeling was used to assess cost-effectiveness data beyond 1 year.¹¹

The study found that the costs of aflibercept and ranibizumab would need to be reduced approximately 69% and 80%, respectively, to reach a commonly agreed-upon cost-effectiveness metric compared to bevacizumab. Results were similar when analyzing patients with worse vision at study initiation. Perhaps more surprisingly, aflibercept was not cost effective compared to ranibizumab (0.3mg dose).¹¹ The authors concluded that from a societal standpoint, using bevacizumab as the first line agent for DME confers the greatest value. Given the known correlation between improvements in DRSS, BCVA, and CRT, it is not unreasonable to assume that a similar result would occur if the outcome measure for the 3 anti-VEGF agents was improvement in DRSS.

Panretinal photocoagulation (PRP) has been the standard of care for the treatment of PDR for more than 30 years.¹³ Recently, ranibizumab has been shown to be noninferior to PRP for the treatment of PDR.¹⁴ While anti-VEGF therapy does not result in tissue destruction and also concurrently treats DME, its cost is significantly higher than PRP considering the ongoing need for intravitreal treatment.

Lin et al estimated a full life expectancy QALY differential increase of 85% to 90% for ranibizumab compared to PRP.¹⁵ An alternative strategy would be to use bevacizumab off label, which would result in a much more favorable lifetime cost comparison to PRP. However, the effect of bevacizumab was not directly compared to PRP in this study, which limits the ability to make this comparison.

FUTURE DIRECTIONS

Anti-VEGF therapy has heralded a new era in the treatment of blinding retinal diseases, including DR. Its ability to slow, halt, and in many cases reverse DR severity has transformed the treatment landscape of this disease. The clinical relevance of DRSS reversal is tied to the correlations between DRSS, BCVA, and CRT. Developing a clinically relevant DRSS substitute could play an important role in identification of treatment response, with corresponding early treatment stratification. The cost of anti-VEGF therapy is an important societal issue, especially considering the aging population and increasing rates of diabetes.

The continued use of bevacizumab for appropriate patients and the development of biosimilars may help alleviate some of the cost burden of these treatments. The possibility of extended-release anti-VEGF formulations in the future adds another interesting dynamic to this topic. However, developing a long-lasting biologic drug is difficult, and questions remain regarding the impact these drugs would have on retinal health. Cost-benefit analysis will depend in large part on the cost of these medications. The role of anti-VEGF agents to treat PDR is an evolving area of research, and decisions to use this therapy should be made with consideration for the unique challenges of treating some of the patients with PDR, including difficulties with compliance. RP

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