Effect of less aggressive treatment on diabetic retinopathy severity scale scores: analyses of the RIDE and RISE open-label extension

Introduction

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes. In 2010, more than 7 million Americans were estimated to have DR; this prevalence is projected to more than double to 15 million by 2050.1 Vascular endothelial growth factor (VEGF)-A is upregulated in patients with DR, and intravitreal injections of VEGF inhibitors have been shown to reduce DR severity.2 However, the durability of such improvement is not well understood. The RIDE/RISE trials of ranibizumab in patients with DR and diabetic macular oedema (DME), together with the open-label extension (OLE) study of these trials, offer up to 5 years of follow-up in patients receiving anti-VEGF therapy. Furthermore, there is a switch at year 3 from monthly treatments to a less-intensive pro re nata (PRN) regimen. This trial design offers a unique opportunity to investigate what happens with DR improvements achieved with intensive VEGF suppression once monthly treatment is reduced. Here, we report the findings of post hoc analyses of RIDE/RISE OLE data, which aim to characterise the changes in Diabetic Retinopathy Severity Scale (DRSS) score after induction therapy ends and identify factors that may be associated with changes in DRSS outcomes with intermittent ranibizumab treatment over time.

Methods

Results

Relationship between OLE baseline BCVA and CFT and DRSS outcomes

Patients who improved or maintained their DRSS score during the OLE (months 36–48) had a similar mean BCVA at RIDE/RISE baseline and OLE baseline compared with patients who had a worsened DRSS score. At OLE baseline, mean BCVA was higher (ie, better) than at RIDE/RISE baseline in both DRSS score subgroups (figure 1A).

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Figure 1

Relationship between (A) mean best-corrected visual acuity (BCVA) and (B) mean central foveal thickness (CFT) and improvement/maintenance or worsening of Diabetic Retinopathy Severity Scale (DRSS) scores at RIDE/RISE baseline and open-label extension (OLE) baseline (month 36). ETDRS, Early Treatment Diabetic Retinopathy Scale.

Patients who had an improved or maintained DRSS score during the OLE had a similar mean CFT at RIDE/RISE baseline and OLE baseline compared with patients who had a worsened DRSS score. Mean CFT was lower at OLE baseline than at RIDE/RISE baseline in both DRSS score subgroups (figure 1B). At both RIDE/RISE and OLE baseline, mean CFT was significantly lower in patients who had a worsened DRSS score compared with patients who had an improved or maintained DRSS score (both p<0.01)

DRSS outcomes in native versus induced mild-to-moderate NPDR subgroups

The native mild-to-moderate NPDR subgroup included 62 patients and the induced mild-to-moderate NPDR subgroup included 90 patients who had complete DRSS data at OLE baseline and month 48. Patients with induced mild-to-moderate NPDR showed significant worsening (p<0.0001) in DRSS scores from OLE baseline to month 48, with a mean (95% CI) increase of 1.0 (0.7 to 1.4) during this 12-month period, compared with a mean (95% CI) increase of 0.1 (–0.1 to 0.4) in the native mild-to-moderate NPDR group between RIDE/RISE baseline and month 12 (figure 2).

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Figure 2

Changes in Diabetic Retinopathy Severity Scale (DRSS) scores in patients with induced and native mild-to-moderate non-proliferative diabetic retinopathy (DRSS score ≤43). Among eyes with induced DRSS score ≤43 (white column), changes were evaluated from open-label extension (OLE) baseline (month 36) to month 48. Among sham-treated eyes with native DRSS score ≤43 (grey column), changes were evaluated from RIDE/RISE baseline to month 12. A positive change in DRSS score indicates worsening of diabetic retinopathy, whereas a negative change in DRSS score indicates DR improvement.

Examination of individual patient profiles revealed that patients in the native mild-to-moderate NPDR subgroup had more stable DRSS scores than patients in the induced mild-to-moderate NPDR subgroup because more patients in the latter subgroup showed worsening in DRSS score over the 12 months of follow-up (figure 3).

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Figure 3

Changes in Diabetic Retinopathy Severity Scale (DRSS) scores in patients with (A) native mild-to-moderate non-proliferative diabetic retinopathy (NPDR; DRSS score ≤43) from RIDE/RISE baseline to month 12 and (B) with induced mild-to-moderate NPDR from open-label extension baseline (month 36) to month 48. Each bar represents the change in DRSS score for an individual patient. Patients are ordered from left to right by the magnitude of DRSS score change.

In the induced mild-to-moderate NPDR subgroup at month 48, 51% (46/90) of patients had maintained the improvement in DRSS score that was achieved during RIDE/RISE (figure 4A). A further 34% (31/90) had originally improved to DRSS score ≥43 during RIDE/RISE but worsened by one to two steps between OLE baseline and month 48, resulting in a net stable DRSS score over the entire 48-month treatment period, with improvement during RIDE/RISE and worsening during the OLE. A total of 14% (13/90) of patients had an unstable DR phenotype, in that they showed some improvement during RIDE/RISE, but then worsened by at least three steps between months 36 and 48 (figure 4A). Among patients with an unstable phenotype, 46% (6/13) had PDR at RIDE/RISE baseline (figure 4B). In contrast, only 13% (4/31) of patients with stable DR and 9% (4/46) of patients who maintained DR improvement had PDR at baseline (figure 4B).

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Figure 4

Changes in Diabetic Retinopathy Severity Scale (DRSS) scores in patients with (A) induced mild-to-moderate non-proliferative diabetic retinopathy from RIDE/RISE baseline to month 36 and from open-label extension (OLE) baseline (month 36) to month 48, and the same plot (B) showing the distribution of patients who had been diagnosed with proliferative diabetic retinopathy (PDR) at RIDE/RISE baseline (hatched bars). Each bar represents the change in DRSS score for an individual patient. Patients are ordered from left to right by the magnitude of DRSS score change. Black bars (DRSS score change from RIDE/RISE baseline to month 36) and white bars (DRSS score change from OLE baseline to month 48) are overlaid.

Patients with PDR at RIDE/RISE baseline appeared to have the most unstable treatment responses during RIDE/RISE and the OLE compared with patients with mild-to-moderate or moderately severe-to-severe NPDR at RIDE/RISE baseline (figure 5). These patients showed the greatest improvements in DRSS score during RIDE/RISE, followed by some of the greatest deteriorations during the OLE (figure 5).

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Figure 5

Changes in Diabetic Retinopathy Severity Scale (DRSS) scores from RIDE/RISE baseline to month 36 and from open-label extension (OLE) baseline (month 36) to month 48, stratified by DRSS score (mild-to-moderate non-proliferative diabetic retinopathy (NPDR), moderately severe-to-severe NPDR, proliferative diabetic retinopathy) at RIDE/RISE baseline. This analysis included 167 patients from the OLE who were randomised to ranibizumab treatment during RIDE/RISE and who did not have a DRSS score ≤35 at RIDE/RISE baseline and had not undergone previous pan-retinal photocoagulation. Each bar represents the change in DRSS score for an individual patient. Patients are ordered from left to right by the magnitude of DRSS score change. Black bars (DRSS score change from RIDE/RISE baseline to month 36) and white bars (DRSS score change from OLE baseline to month 48) are overlaid.

Discussion

This post hoc analysis of the RIDE/RISE OLE evaluates not only the potential predictors of changes in DRSS outcomes over time with PRN ranibizumab after a period of monthly induction therapy, but also investigates how these changes may affect observed differences in patient responses, and whether the induced regression in DRSS score behaves similar to native NPDR of the same DRSS level. These are important analyses as we seek to better understand anti-VEGF–induced regression of DR.

OLE findings from months 36 to 48 showed that the majority of patients improved or maintained their DRSS score from the initial 3-year RIDE/RISE trial period, suggesting that ranibizumab was able to provide ongoing clinical benefit on a less frequent PRN schedule. Patients with an improved or maintained DRSS score during the OLE received a median of four injections from months 36 to 48, compared with a median of only one injection in the subgroup with worsened DRSS score during the OLE. This suggests that a minimum amount of PRN treatment may be necessary to maintain any gains in DRSS score achieved during induction therapy. Importantly, BCVA or CFT, either at baseline or after induction therapy, did not affect the likelihood of maintaining DRSS score gains achieved during RIDE/RISE during the OLE, despite re-treatment criteria during the OLE being based largely on visual acuity and OCT findings.

In the current analysis, patients who had induced mild-to-moderate NPDR during the RIDE/RISE trials were significantly more prone to DRSS score worsening over 12 months of follow-up when treated intermittently with PRN ranibizumab during the OLE than patients who had native mild-to-moderate NPDR at the start of RIDE/RISE and were randomised to sham injections. This suggests that the induced improvements in DRSS score may not be equivalent to true disease regression. Indeed, the eyes with induced mild-to-moderate NPDR were more unstable than their native counterparts, and likely require ongoing aggressive VEGF suppression to prevent backsliding. Data from a retrospective analysis that used medical claims data for patients with DR who had not received anti-VEGF therapy, laser photocoagulation, intravitreal steroid treatment or retinal surgery during the baseline period support the interpretation of our data for the native mild-to-moderate NPDR subgroup. The authors of this analysis reported that the risk of DR progression and DME over 5 years was highest among patients with an initial diagnosis of moderate and severe NPDR, respectively, and that patients with mild NPDR were the least likely to progress.8 A separate post hoc analysis of data from the OLE after RIDE/RISE showed that patients who required a higher number of PRN ranibizumab injections tended to have a longer duration of DME and greater retinal thickening than those who required fewer injections; they also received more focal macular laser surgery, which was indicative of chronic disease.9

A previous post hoc analysis of RIDE/RISE demonstrated that greater treatment benefit (DRSS score improvement) over 36 months was attained with monthly ranibizumab in patients with moderate-to-severe NPDR at baseline compared with mild NPDR.10 Our post hoc analysis revealed that more severe DR at baseline was also associated with some of the greatest DR improvements during the initial RIDE/RISE trial period; however, this subgroup appeared to have less stable DR, manifested by greater worsening when monthly treatment was switched to PRN. This finding was most pronounced in patients with baseline PDR, for whom the largest fluctuations in DRSS score were observed between RIDE/RISE baseline and month 36, and OLE baseline and month 48. Of patients who exhibited some improvement in DRSS score but then worsened by three or more steps between months 36 and 48, almost half had PDR at RIDE/RISE baseline. This suggests that the significant gains acquired from monthly ranibizumab over the first 3 years of treatment might be more difficult to maintain beyond this time point with a PRN regimen if the patient has PDR to begin with, and that the patient is at high risk of worsening in the long term. Interestingly, patients in the induced mild-to-moderate NPDR subgroup received a similar number of PRN injections (four to five), irrespective of baseline DRSS score. It is possible that patients in the PDR subgroup might have benefited from an increased number of PRN injections; however, investigators did not deem this necessary at the time based on the OLE re-treatment criteria. Alternatively, our findings suggest that a period of intense treatment followed by PRN treatment may not be the best approach for patients with PDR. Other treatment approaches could be considered for these patients, including sustained VEGF suppression or scatter photocoagulation for PDR combined with ranibizumab injections for DME. The pathologic anatomical changes typical of moderate or moderate-to-severe NPDR, such as intraretinal haemorrhages or microvascular abnormalities, retinal exudates and venous beading, are more easily reversible than PDR-related neovascular changes, and the stabilisation of VEGF levels through intravitreal ranibizumab therapy may help to restore normal vascular permeability and endothelial integrity.10 Additionally, studies using OCT angiography have shown regression of neovascularisation with VEGF inhibition, and subsequent return of flow through those pathological vessels post-treatment.11 Therefore, one of the goals of anti-VEGF treatment may be to prevent progression to PDR, because this more volatile phenotype is associated with vision-threatening complications, such as vitreous haemorrhage or tractional detachment.12

Limitations of our post hoc analyses include the absence of prespecified end points or formal statistical comparisons. The original RIDE/RISE and OLE trials were not designed with inclusion and exclusion criteria to select patients and collect data that may have best addressed our hypotheses because these trials were focused on the treatment of DME, not DR. In addition, no power analyses were conducted to ensure a sufficient sample size to evaluate the data. Approximately two-thirds (500/759) of patients in RIDE/RISE continued in the OLE, but only 367 patients with evaluable DR images and non-missing data for OLE baseline and month 48 were included in the analyses. This resulted in a number of the subgroups in this analysis having relatively small numbers of patients. The main reason for missing images and data for month 48 was early discontinuation of patients after US Food and Drug Administration approval of ranibizumab for the treatment of DR. The strengths of our analyses include the detailed analysis of factors affecting the response to PRN ranibizumab treatment in the OLE and generation of hypotheses/data concerning the optimal frequency of PRN injections and the characteristics of eyes most likely to procure benefit.

In conclusion, the majority of ranibizumab-treated patients had improved or maintained DRSS scores with less-than-monthly PRN treatment. Some minimum treatment may be necessary to maintain earlier DRSS score improvement. More severe DR at baseline was associated with greater clinical benefit from monthly ranibizumab treatment during RIDE/RISE, but was also indicative of risk of DRSS score instability with intermittent dosing in the OLE. Over 12 months of follow-up, patients with induced mild-to-moderate NPDR were more likely to have worsened DRSS scores than patients with native mild-to-moderate NPDR; this may be a reflection of more severe disease at baseline and a longer time since DME diagnosis in the induced mild-to-moderate NPDR subgroup. Nonetheless, our results suggest that continuous long-term monitoring and treatment may be necessary to maintain DRSS score improvements achieved with induction therapy. Therefore, one goal of treatment of advanced NPDR may be to prevent the progression to PDR and a more unstable phenotype.