Introduction
Diabetic macular edema (DME) generally manifests as slowly progressive vision loss. Signs of DME include blurred vision, retinal hemorrhages, retinal detachment, colours appearing “washed out” or faded, changes in contrast sensitivity, impaired colour vision, gaps in vision (scotomas), and potentially permanent vision loss. Persistent elevation of blood glucose, characteristic of diabetes mellitus, can cause damage to blood vessels on a microvascular level such as those in the eye resulting in diabetic retinopathy (DR). Some patients with diabetic retinopathy (DR) and continued poorly managed blood glucose may then experience DME.1 The prevalence of diabetes in Canada is 9.2%, and it is estimated that there are 528,524 patients with DME across Canada, 13,530 of whom experienced vision impairment.2,3 Overall, more than 50% of patients with DME experiencing vision loss were older than 60 years and more than 22% of patients with DME experiencing vision loss are patients within the First Nation communities.2 Furthermore, some patients with DME are pseudophakic (natural lens surgically replaced with an artificial lens) and would therefore comprise a subset of the overall DME population.
Macular laser photocoagulation therapy for DME was the standard of care for more than 25 years before the introduction of anti-vascular endothelial growth factor (VEGF) drugs, and is still widely used following anti-VEGF therapy.4 Recently, clinical studies have shown robust efficacy and safety for frequent (monthly or bimonthly) anti-VEGF injections for the treatment of DME patients.5–8 However, there is limited evidence of benefit and risk of continuous anti-VEGF injections among patients who did not respond well to prior anti-VEGF therapy.9 Canadian evidence based guidelines and clinical treatment algorithms recommend anti-VEGF injections as therapy for most patients with clinically significant DME involving central vision. If there is no response after six months treatment, patients should switch to intravitreal steroids, vitrectomy, or laser.10,11
Dexamethasone is a synthetic glucocorticoid receptor agonist, analogue to the naturally occurring glucocorticoids hydrocortisone and cortisone, and is administered into the vitreous on an as-needed basis to mitigate the effects of DME.12 Corticosteroids target multiple mediators in DME, possessing anti-inflammatory, anti-vascular permeability, and anti-angiogenic properties.13 These drugs act by decreasing the production of mediators such as interleukin-6 and VEGF, and may also directly stabilize the blood-retinal barrier.14 In contrast to anti-VEGF drugs, which inhibit the actions of synthesized VEGF, corticosteroids act to directly decrease the synthesis of VEGF.15 Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular edema.16–18 In general, treatment with dexamethasone is associated with elevated intraocular pressure and secondary cataract, which is consistent with the adverse events (AEs) profile of intravitreal steroid therapies.12,19
Dexamethasone (Ozurdex) has a Health Canada–approved indication for the treatment of macular edema following central retinal vein occlusion, the treatment of noninfectious uveitis affecting the posterior segment of the eye, and for the treatment of adult patients with DME who are pseudophakic. The objective of this review is to perform a systematic review of the beneficial and harmful effects of dexamethasone 700 mcg intravitreal injection for the treatment of adults with DME who are pseudophakic.
Results and Interpretation
Included Studies
No trials were identified that exclusively enrolled the patient population of interest for this review (i.e., adults with DME who are pseudophakic). Rather, the evidence for this review as it pertains to the use of dexamethasone 700 mcg intravitreal injection was derived from subgroups of adult patients with DME who were pseudophakic from two similarly designed masked phase III multi-centre, multinational and sham-controlled pivotal randomized controlled trials (RCTs). MEAD-010 (N = 494) and MEAD-011 (N = 554) randomized DME patients to a 1:1:1 ratio of dexamethasone 700 mcg, dexamethasone 350 mcg (not of a Health Canada–approved dose) or sham treatment. Overall, only a subset of the enrolled population (a pre-specified subgroup of adult patients with DME who are pseudophakic [MEAD-010, n = 94; MEAD-011, n = 93] derived from the intent-to-treat population (ITT) and the safety population) met the Health Canada–approved indication. The primary efficacy outcome was the average best-corrected visual acuity (BCVA) mean change from baseline evaluated after three years of follow-up based on Early Treatment for Diabetic Retinopathy Study (ETDRS) charts using an area-under-the-curve (AUC) approach. The MEAD trials were not initially designed to assess the average BCVA mean change from baseline as the primary end point. Rather, the original end point was the proportion of patients who achieved at least a 15-letter improvement by end of study. Subsequent to a protocol amendment was the primary end point changed to include the average BCVA mean change from baseline. Secondary outcomes included other BCVA end points, retinal thickness, health-related quality of life, and vision-related quality of life.
Key limitations associated with the interpretation results of the subgroup of adult patients who are pseudophakic, as drawn from the MEAD trials, include lack of subgroup stratification leading to imbalances in patient characteristics and therefore concerns with randomization potentially leading to confounding; lack of adjustments for multiple statistical testing across end points, subgroups and sensitivity analyses; variability of treatment effect at different time points; imbalances in patient disposition and patient characteristics; and uncertain generalizability to the Canadian setting.
As there were no studies identified that compared dexamethasone against other active treatments for DME, according to the selection criteria outlined in Table 3, the results of the manufacturer’s indirect comparison (IDC) for the treatment of adult patients with DME were reviewed. In addition, three non-pivotal phase II trials comparing dexamethasone with other active treatments for DME were reviewed.
Efficacy
The efficacy results presented from the MEAD trials are for the Health Canada–approved dose of dexamethasone, as a 700 mcg intravitreal injection for the subgroup of patients that are pseudophakic.
The adjusted least squares mean differences in average BCVA mean change from baseline between dexamethasone 700 mcg and sham treatment as measured by ETDRS and using the AUC approach (the primary outcome) in the intention-to-treat (ITT) population were 5.9 letters ▬, P < 0.001 and 3.6 letters ▬, P = 0.018 in MEAD-010 and MEAD-011, respectively. Sensitivity analyses using a per-protocol (PP) population in both MEAD-010 and MEAD-011 were consistent with the primary analysis. According to the clinical expert consulted for this review, the degree of improvement reported in the MEAD trials may be considered clinically relevant, especially for patient with poor visual acuity. However, between-group differences did not exceed a 10-letter improvement. The difference in the proportion of patients achieving a ≥ 15-letter improvement versus sham was 18.1% (95% confidence interval [CI], 0.8 to 35.4; P = 0.043) and 6.0% (95% CI, −5.7 to 17.8; P = 0.461) in MEAD-010 and MEAD-011, respectively.
The adjusted least squares mean differences in average central retinal thickness (CRT), as measured by optical coherence tomography (OCT) using the AUC approach, were ▬▬▬▬▬ in MEAD-010 and MEAD-011, respectively. The changes from baseline in CRT as measured by OCT were also evaluated at the last study visit and in a sensitivity analysis using the PP population and were consistent with the AUC method.
The MEAD trials evaluated vision-related outcomes using the using the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25). Overall, no statistically significant differences were observed between treatment groups with adjusted average least squares mean differences for the overall composite score of ▬▬▬▬▬ in MEAD-010 and MEAD-011, respectively. Minimal clinically important differences for the NEI-VFQ-25 (among the general DME population) between 3.3 and 6.13 points in the overall composite score have been reported.20 No post-baseline data associated to health-related quality of life measures using the Short Form (36) Health Survey (SF-36) or the EuroQol 5-Dimensions Health Questionnaire (EQ-5D) were provided for the subgroup of patients who are pseudophakic in the MEAD trials.
No trials were identified that directly compared dexamethasone against other active treatments for DME according to the criteria outlined in the CADTH Common Drug Review protocol (Table 3). The manufacturer submitted an unpublished IDC to assess the comparative efficacy and safety of dexamethasone for use in the treatment of DME. The manufacturer–submitted IDC was originally prepared for the National Institute for Health and Care Excellence (NICE) in 2014. ▬▬▬▬▬
Three phase II studies (RAN study, BEVORDEX study and the COMB study) that evaluated the effects of dexamethasone compared with anti-VEGF therapies (ranibizumab, bevacizumab) for the treatment of adult patients with DME were also summarized in Appendix 7. The study findings suggested a similar change from baseline in the BCVA letters between treatment with dexamethasone and anti-VEGF therapy. However, these studies were designed to evaluate the effects of dexamethasone in the general DME population, not the pseudophakic subgroup of patients that is of interest for this review. Of the overall number of enrolled patients, 24% to 50% were pseudophakic. Some pseudophakic subgroup results were reported, however the lack of stratification at randomization based on this factor, as well as the absence of reporting on baseline characteristics for the pseudophakic population make it difficult to assess the comparative efficacy and harms between dexamethasone and anti-VEGF drugs (i.e., bevacizumab and ranibizumab). These studies were also likely underpowered to detect differences between treatments in the pseudophakic subgroup, there was no control for multiple statistical testing, study durations were short, and no Canadian sites were included.
Harms
Frequencies of AEs, serious adverse events (SAEs), withdrawal due to adverse events (WDAEs), and notable harms were provided for the individual MEAD trials; however, the most common AEs, SAEs, WDAEs, and notable harms were only reported based on a pooled analysis of the two MEAD trials.
A greater proportion of patients in the dexamethasone group experienced AEs compared with the sham group. AEs that occurred more frequently in the dexamethasone treatment groups compared with the sham groups were elevated intraocular pressure (IOP) and secondary cataracts, which is consistent with the adverse event profile of intravitreal steroid therapies.12,19. The frequency of blepharitis in the dexamethasone groups was lower than those observed in the sham groups. Similar frequencies of SAEs were reported in the dexamethasone groups compared with the sham groups. No data were provided for the subgroup of patients who are pseudophakic regarding the most common reasons for ocular SAEs. The overall WDAEs were similar between treatment groups, however; no data regarding the withdrawals due to ocular AEs were provided for the subgroup of adult patients with DME who are pseudophakic in the MEAD trials.
The occurrence of the remaining notable harms — specifically, eye inflammation, retinal detachment, arterial thrombotic event (ATE), dislocated implants, glaucoma, damage to optic nerve, conjunctival hemorrhage, and vitreous hemorrhage — was similar in both treatment groups across the MEAD trials. Endophthalmitis, eye infection, defects in visual acuity and visual field, and necrotizing retinitis were not reported in the MEAD trials.
Other Considerations
In consideration of the potential place in therapy for dexamethasone 700 mcg intravitreal injection (first- or second-line), the protocol for CADTH’s Common Drug Review included the examination of a subgroup of patients with DME who are pseudophakic and who are either unsuitable for anti-VEGF therapy or have had an inadequate response to prior anti-VEGF therapy. However, only between ▬ and ▬ of patients included in the MEAD trials had prior experience with anti-VEGF therapy; therefore, it is unclear if the results of the MEAD trials can be generalized to patients with prior experience or prior inadequate response to anti-VEGF therapy. Studies by Pacella et al. and Gonzalez et al. as well as a systematic review and meta-analysis conducted by Khan et al. evaluated the effects of dexamethasone in the general DME population who were refractory to anti-VEGF therapy; however results in patients with DME who are pseudophakic were not reported.9,21,22 Furthermore, the criteria for anti-VEGF therapy being unsuitable mostly remains unclear. The clinical expert consulted for this CDR review noted that there are different circumstances that may define a lack of suitability, such as history of glaucoma, allergies to anti-VEGF drugs and its components, pregnancy, phakic lens status with or without recent myocardial infarction, ischemic heart disease, or stroke. Similarly, patients may be considered unsuitable if they are unable to return for their regular monthly or bimonthly intraocular injection of anti-VEGF either due to transportation difficulties or work demands, which are especially common among younger patients who are actively employed.
Potential Place in Therapy1
The current standard of care for patients requiring treatment of center-involved DME is intraocular injection of anti-VEGF drugs. While the beneficial effects of anti-VEGF drugs typically only last between four and six weeks at the most, some patients may not adequately respond to treatment. Furthermore, treating DME with anti-VEGF drugs usually requires monthly or bimonthly injections which create barriers to adherence and therefore optimized treatment. In these cases, further improvement in BCVA is still possible; however, a switch to another anti-VEGF may not be effective or appropriate. According to the clinical expert consulted for this CDR review, all clinical studies associated to the treatment of DME with anti-VEGF therapy or intravitreal steroid therapy compared favourably to laser treatment. Therefore, currently preferred clinical practice for center-involved DME is either anti-VEGF or intravitreal steroid injections, with laser therapy being reserved for those with non–center-involved DME.
For some patients, switching to treatment with an intravitreal steroid such as dexamethasone may be a reasonable alternative; however, the use of this medication class for many patients is currently limited due to elevated IOPs as well as the development and progression of cataracts. The clinical expert consulted for this CDR review highlighted potential issues in the prescribing of dexamethasone given that treatment is typically associated with increased frequency of elevated IOP, likely requiring IOP-lowering drugs, which may add to the treatment burden (number of concomitant treatments) and the overall cost of treatment. However, the expert noted that IOP-lowering treatments would mostly entail the use of topical medications, which should not be too bothersome. Furthermore, the development and progression of secondary cataracts as a result of intravitreal steroid injections would likely require further treatment to address the issue. For patients who have had complete removal of their natural lens, secondary cataracts will not form on the artificial lens. Generally, treatment regimens with intravitreal steroids are less frequent than those associated with anti-VEGF drugs (quarterly or biannual injections).
The clinical expert consulted for this CDR review noted that there are different circumstances where alternate therapies such as a dexamethasone implant should be considered, such as in patients who are allergic to anti-VEGF drugs and the components or in women during pregnancy given the teratogenicity of anti-VEGF therapies. In clinical practice, patients with DME who are pseudophakic without any history of glaucoma would be the best candidates to receive treatment with dexamethasone. The same clinical expert noted that intravitreal steroid injections should be particularly considered in those who are pseudophakic with or without recent myocardial infarction, ischemic heart disease, or stroke. Similarly, dexamethasone may also be considered in patients who are unable to return for their regular monthly or bimonthly anti-VEGF intraocular injection either due to transportation difficulties or work demands, which are especially common among younger patients who are actively employed. Patients who do not respond to the anti-VEGF treatment after 3 consecutive monthly intraocular injections or who have inadequate response to anti-VEGF therapy would also be considered for treatment with dexamethasone.
The clinical expert also highlighted that, overall, the effects of dexamethasone on BCVA reported in the MEAD trials (especially in MEAD-011) were found to be modest when compared with the change in BCVA that has been reported for anti-VEGF therapies. The same clinical expert noted that no specialized diagnostic test would be needed to identify patients in whom dexamethasone may be appropriate and that clinicians would likely base their decision on BCVA as well as OCT CRT, which would be routinely requested in this patient population.
Conclusions
The CDR systematic review included two masked, phase III, sham-controlled RCTs designed to assess the benefits and harms of dexamethasone in adult patients with DME. Given the Health Canada–approved indication for dexamethasone, the CDR review focused on the results of a subgroup of patients from the MEAD trials (i.e., adult patients with DME who are pseudophakic [MEAD-010 n = 94; MEAD-011 n = 93]).
Overall, dexamethasone was associated with a statistically significant improvement when compared with sham for the primary outcome (average BCVA mean change from baseline as measured by ETDRS based on the AUC approach) for patients with DME who are pseudophakic in both MEAD trials, while the proportion of patients achieving a ≥ 15 letter improvement was reported to be statistically significantly greater in the dexamethasone group in MEAD-010 only. However, between-group differences did not exceed a 10-letter improvement in either MEAD-010 or MEAD-011 (differences of 5.9 and 3.6 letters respectively) and were considered modest by the clinical expert consulted for this review. Further, the magnitude of improvement in visual acuity with dexamethasone compared with sham is uncertain, given the results are for a subgroup that was not subject to stratification at randomization and for which there was no adjustment for multiple testing. More patients in the dexamethasone group experienced AEs compared with the sham group in the MEAD trials. The most commonly reported AEs that occurred more frequently in the dexamethasone treatment groups compared with the sham groups were elevated IOP, which is consistent with the adverse event risk profile of intravitreal steroid therapies.
No data from the MEAD trials were available to assess the efficacy and safety of dexamethasone 700 mcg in adults with DME who are pseudophakic and who are either unsuitable for anti-VEGF therapy or have had an inadequate response to prior anti-VEGF therapy).
Due to the lack of direct evidence of dexamethasone versus other drugs in the MEAD trials, and the limitations with the supportive evidence including the manufacturer–submitted IDC, no definitive conclusions could be made regarding the comparative efficacy and safety of dexamethasone versus other drugs (including anti-VEGFs) for the treatment of patients with DME who are pseudophakic.
Summary of the Efficacy Results for the MEAD Trials (Pseudophakic Subgroup).
Summary of the Harms for the MEAD Trials (Pseudophakic subgroup).
