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Efficacy and Treatment Burden of Intravitreal Aflibercept Versus Intravitreal Ranibizumab Treat-and-Extend Regimens at 2 Years: Network Meta-Analysis Incorporating Individual Patient Data Meta-Regression and Matching-Adjusted Indirect Comparison.
Ohji, M, Lanzetta, P, Korobelnik, JF, Wojciechowski, P, Taieb, V, Deschaseaux, C, Janer, D, Tuckmantel, C
Advances in therapy. 2020;(5):2184-2198
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Abstract
PURPOSE To compare visual outcomes and treatment burden between intravitreally administered aflibercept (IVT-AFL) and ranibizumab (RBZ) treat-and-extend (T&E) regimens in patients with wet age-related macular degeneration (wAMD) at 2 years. METHODS A systematic literature review was carried out in Medline, EMBASE, and CENTRAL in October 2018. Matching-adjusted indirect comparison (MAIC) and/or individual patient data meta-regression was used to connect ALTAIR (assessing IVT-AFL T&E) with other studies, adjusting for between-trial differences in baseline visual acuity and age or baseline visual acuity, age, and polypoidal choroidal vasculopathy (PCV) status. Sensitivity analyses were conducted to test the robustness of the results, including direct MAIC between IVT-AFL T&E (ALTAIR) and RBZ T&E (CANTREAT and TREX-AMD trials). RESULTS Six randomized controlled trials (RCTs) (ALTAIR, VIEW 1 and 2, CATT, CANTREAT, and TREX) were included in the analysis. IVT-AFL T&E was assessed in one study, ALTAIR (n = 255), while RBZ T&E was assessed in two trials (n = 327). At 2 years, the median difference (95% credibility interval) between IVT-AFL T&E and RBZ T&E regarding the numbers of Early Treatment Diabetic Retinopathy Study (ETDRS) letters gained was not significant (M1: - 2.29 [- 8.10, 3.58]; M2: - 0.55 [- 6.34, 5.29]). IVT-AFL T&E was associated with significantly fewer injections than RBZ-T&E (M1: - 6.12 [- 7.60, - 4.65]; M2: - 5.93 [- 7.42, - 4.45]). Results of the sensitivity analyses were consistent with the main scenarios. CONCLUSION Patients with wAMD receiving an IVT-AFL T&E regimen achieved and maintained improvement in visual acuity with fewer injections over 2 years compared with RBZ T&E. IVT-AFL T&E may therefore serve as the optimal therapy for wAMD, as it was associated with clinical efficacy and minimized treatment burden.
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Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study).
Glassman, AR, Wells, JA, Josic, K, Maguire, MG, Antoszyk, AN, Baker, C, Beaulieu, WT, Elman, MJ, Jampol, LM, Sun, JK
Ophthalmology. 2020;(9):1201-1210
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Abstract
PURPOSE Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. DESIGN Multicenter cohort study. PARTICIPANTS Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). METHODS Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. MAIN OUTCOME MEASURES Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). RESULTS Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0-12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline but 4.8 letters (95% CI, 2.5-7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142-166) and was stable between 2 and 5 years (-1 μm; 95% CI, -12 to 9). CONCLUSIONS Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.
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Randomized Trial of Monthly Versus As-Needed Intravitreal Ranibizumab for Radiation Retinopathy-Related Macular Edema: 1-Year Outcomes.
Schefler, AC, Fuller, D, Anand, R, Fuller, T, Moore, C, Munoz, J, Kim, RS, ,
American journal of ophthalmology. 2020;:165-173
Abstract
PURPOSE To assess efficacy of intravitreal ranibizumab injections and targeted panretinal photocoagulation (TRP) for radiation retinopathy-related macular edema. DESIGN Phase IIb, prospective, randomized clinical trial. METHODS Setting: Multicenter. SUBJECTS Forty eyes in 40 treatment-naïve patients with radiation-induced macular edema and a resulting decrease in visual acuity ranging between 20/25 and 20/400 (Snellen equivalent). INTERVENTION Patients either received intravitreal 0.5 mg ranibizumab monthly, monthly ranibizumab with TRP, or 3 monthly ranibizumab (loading doses) followed by as-needed (PRN) injections and TRP. After week 52, all subjects entered a treat-and-extend protocol for ranibizumab. MainOutcomeMeasures: Mean Early Treatment Diabetic Maculopathy Study (ETDRS) BCVA change from baseline. RESULTS Mean patient age was 57 years (range, 22-80 years), ETDRS BCVA was 56.7 letters (20/74 Snellen equivalent), and central macular thickness (CMT) was 423 μm (range, 183-826 μm). Thirty-seven patients completed the month 12 visit (92.5%), at which time the change in mean BCVA was +4.0 letters, -1.9 letters, and +0.9 letters in the monthly, monthly plus laser, and PRN plus laser cohorts, respectively. There was a significant difference in mean BCVA at 1 year among all 3 cohorts (P < .001), as well as between cohorts in pairwise comparisons, with the most significant gains in the monthly group. A total of 82.5% of the patients retained visual acuity of 20/200 or better, and 20.0% improved 10 or more ETDRS letters. CONCLUSIONS Ranibizumab may improve vision and anatomy in patients with radiation retinopathy-related macular edema and prevent vision loss through 48 weeks of therapy. Monthly injections were more effective than as-needed approach, and the addition of TRP yielded no therapeutic benefits.
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PHOTOCOAGULATION VERSUS RANIBIZUMAB FOR PROLIFERATIVE DIABETIC RETINOPATHY: Should Baseline Characteristics Affect Choice of Treatment?
Bressler, SB, Beaulieu, WT, Glassman, AR, Gross, JG, Melia, M, Chen, E, Pavlica, MR, Jampol, LM, ,
Retina (Philadelphia, Pa.). 2019;(9):1646-1654
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PURPOSE Among eyes with proliferative diabetic retinopathy, identify whether baseline characteristics impact the benefit of ranibizumab over panretinal photocoagulation (PRP) in DRCR.net Protocol S. METHODS Participants had proliferative diabetic retinopathy, visual acuity of 20/320 or better, and no previous PRP. Eyes were randomized to PRP or intravitreous 0.5-mg ranibizumab. RESULTS Ranibizumab was superior to PRP for change in visual acuity and development of vision-impairing central-involved diabetic macular edema over 2 years (P < 0.001). Among 25 characteristics, there were none in which participants assigned to PRP had superior outcomes relative to ranibizumab-assigned participants. The relative benefit of ranibizumab over PRP for change in visual acuity seemed greater in participants with higher mean arterial pressure (P = 0.03), without previous focal/grid laser (P = 0.03), with neovascularization of the disk and elsewhere on clinical examination (P = 0.04), and with more advanced proliferative diabetic retinopathy on photographs (P = 0.02). For development of vision-impairing central-involved diabetic macular edema, the relative benefit of ranibizumab over PRP seemed greater among nonwhite participants (P = 0.01) and those with higher mean arterial pressure (P = 0.01). CONCLUSION There were no characteristics identified in which outcomes were superior with PRP compared with ranibizumab. These exploratory analyses provide additional support that ranibizumab may be a reasonable alternative to PRP for proliferative diabetic retinopathy over a 2-year period.
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Intravitreal ranibizumab injection at the end of vitrectomy for diabetic vitreous hemorrhage (Observational Study).
Liang, X, Zhang, Y, Wang, JX, Wang, LF, Huang, WR, Tang, X
Medicine. 2019;(20):e15735
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To evaluate the outcomes and complications of intravitreal injections of ranibizumab in patients during pars plana vitrectomy for treatment of diabetic vitreous hemorrhage. This retrospective, observational, comparative study included 103 patients (103 eyes) who underwent pars plana vitrectomy for treatment of diabetic vitreous hemorrhage. Sixty-six patients received an intravitreal injection of 0.05 mg (0.05 cc) of ranibizumab at the end of surgery. Main outcome measures were the occurrence of recurrent early vitreous hemorrhage, reoperation, intraocular pressure, best corrected visual acuity. Mean follow-up time was 6 months. The rate of rebleeding in the intravitreal ranibizumab (IVR) group was 6.1% (4 eyes), which is significantly lower than the control group (24.3%, 9 eyes, P < .01). The incidence of postoperative diabetic vitreous hemorrhage (PDVH) was significantly lower in the IVR group than the control group, OR=0.26, 95% CI= (0.06, 0.95). Visual acuity 6 months after operation was better in IVR group (P<.01) There was no difference in mean intraocular pressure between the 2 groups (P=.56). The present clinical study suggests that intravitreal injection of ranibizumab is effective in the prevention of postoperative diabetic vitreous hemorrhage in eyes undergoing pars plana vitrectomy for the treatment of diabetic vitreous hemorrhage.
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Canadian Treat-and-Extend Analysis Trial with Ranibizumab in Patients with Neovascular Age-Related Macular Disease: One-Year Results of the Randomized Canadian Treat-and-Extend Analysis Trial with Ranibizumab Study.
Kertes, PJ, Galic, IJ, Greve, M, Williams, RG, Rampakakis, E, Scarino, A, Sheidow, T
Ophthalmology. 2019;(6):841-848
Abstract
PURPOSE To compare the efficacy of ranibizumab using a treat-and-extend (T&E) regimen with monthly dosing in treatment-naive patients with neovascular age-related macular degeneration (nAMD). DESIGN Prospective, randomized, open-label, multicenter, noninferiority, postauthorization study. PARTICIPANTS Treatment-naive patients with choroidal neovascularization secondary to AMD. METHODS Patients with nAMD were randomized 1:1 to receive intravitreal ranibizumab at a dose of 0.5 mg in either a T&E or monthly dosing regimen. The noninferiority of T&E compared with the monthly dosing regimen was to be shown using a margin of 5 letters in best-corrected visual acuity (BCVA) improvement. MAIN OUTCOME MEASURES Mean change in BCVA in Early Treatment Diabetic Retinopathy Study letters from baseline to month 12. RESULTS Baseline and 12-month visual acuity data are available for 526 patients (T&E, n = 268; monthly, n = 258). At baseline, mean age was 78.8 years (standard deviation [SD], 7.8 years), 60.3% were women, and 94.3% were white. No significant between-group baseline differences were observed. The primary outcome of noninferiority regarding visual acuity was met with mean BCVA improvement of 8.4 letters (SD, 11.9 letters) and 6.0 letters (SD, 11.9 letters; P = 0.017) in the T&E and monthly regimens, respectively, with a between-group mean difference of 2.38 letters (95% confidence interval, 0.32-4.45 letters). Per protocol, a secondary analysis was performed to test for superiority of number of injections received up to month 12. This analysis demonstrated significantly fewer injections with T&E versus monthly dosing (9.4 and 11.8 injections, respectively), with a mean difference of -2.46 injections (95% confidence interval, -2.68 to -2.23 injections). CONCLUSIONS The 12-month results of this 2-year study demonstrated that regarding visual outcomes, the T&E regimen was noninferior to a monthly dosing regimen. Similar visual outcomes in the T&E group as in the monthly dosing group were achieved with significantly fewer injections.
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A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema.
Gale, JD, Berger, B, Gilbert, S, Popa, S, Sultan, MB, Schachar, RA, Girgenti, D, Perros-Huguet, C
Investigative ophthalmology & visual science. 2018;(6):2659-2669
Abstract
PURPOSE Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME. METHODS In this phase II, randomized, placebo-controlled, double-masked study, eligible subjects (≥18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score ≤ 78), and up to 20/320 or better (≥24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm. RESULTS A total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was -2.41 letters (80% CI: -3.91, -0.91; P = 0.04) compared with ranibizumab. PF-04634817 was well tolerated. CONCLUSIONS Treatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.
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Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study).
Figueira, J, Fletcher, E, Massin, P, Silva, R, Bandello, F, Midena, E, Varano, M, Sivaprasad, S, Eleftheriadis, H, Menon, G, et al
Ophthalmology. 2018;(5):691-700
Abstract
PURPOSE Comparison of the efficacy of ranibizumab (RBZ) 0.5 mg intravitreal injections plus panretinal photocoagulation (PRP) versus PRP alone in the regression of the neovascularization (NV) area in subjects with high-risk proliferative diabetic retinopathy (HR-PDR) over a 12-month period. DESIGN Prospective, randomized, multicenter, open-label, phase II/III study. PARTICIPANTS Eighty-seven participants (aged ≥18 years) with type 1/2 diabetes and HR-PDR (mean age, 55.2 years; 37% were female). METHODS Participants were randomized (1:1) to receive RBZ+PRP (n = 41) or PRP monotherapy (n = 46). The RBZ+PRP group received 3 monthly RBZ injections along with standard PRP. The PRP monotherapy group received standard PRP between day 1 and month 2; thereafter, re-treatments in both groups were at the investigators' discretion. MAIN OUTCOME MEASURES The primary outcome was regression of NV total, on the disc (NVD) plus elsewhere (NVE), defined as any decrease in the area of NV from the baseline to month 12. Secondary outcomes included best-corrected visual acuity (BCVA) changes from baseline to month 12, time to complete NV regression, recurrence of NV, macular retinal thickness changes from baseline to month 12, need for treatment for diabetic macular edema, need for vitrectomy because of occurrence of vitreous hemorrhage, tractional retinal detachment or other complications of DR, and adverse events (AEs) related to treatments. RESULTS Seventy-seven participants (88.5%) completed the study. Overall baseline demographics were similar for both groups, except for age. At month 12, 92.7% of participants in the RBZ+PRP group presented NV total reduction versus 70.5% of the PRP monotherapy participants (P = 0.009). The number of participants with NVD and NVE reductions was higher with RBZ+PRP (93.3% and 91.4%, respectively) versus PRP (68.8% and 73.7%, respectively), significant only for NVE (P = 0.048). Complete NV total regression was observed in 43.9% in the RBZ+PRP group versus 25.0% in the PRP monotherapy group (P = 0.066). At month 12, the mean BCVA was 75.2 letters (20/32) in the RBZ+PRP group versus 69.2 letters (20/40) in the PRP monotherapy group (P = 0.104). In the RBZ+PRP group, the mean number of PRP treatments over month 12 was 3.5±1.3, whereas in the PRP monotherapy group, it was 4.6±1.5 (P = 0.001). No deaths or unexpected AEs were reported. CONCLUSIONS Treatment with RBZ+PRP was more effective than PRP monotherapy for NV regression in HR-PDR participants over 12 months.
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Panretinal Photocoagulation Versus Ranibizumab for Proliferative Diabetic Retinopathy: Factors Associated with Vision and Edema Outcomes.
Bressler, SB, Beaulieu, WT, Glassman, AR, Gross, JG, Melia, M, Chen, E, Pavlica, MR, Jampol, LM, ,
Ophthalmology. 2018;(11):1776-1783
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PURPOSE To identify baseline factors associated with change in visual acuity or development of vision-impairing central-involved diabetic macular edema (DME) over 2 years when treating proliferative diabetic retinopathy (PDR) with ranibizumab or panretinal photocoagulation (PRP). DESIGN Post hoc analyses of randomized, multicenter clinical trial data. PARTICIPANTS Eyes completing the 2-year visit (n = 328) or without vision-impairing central-involved DME at baseline (n = 302) in Diabetic Retinopathy Clinical Research Network Protocol S. METHODS Intravitreous ranibizumab (0.5 mg/0.05 ml) or PRP. MAIN OUTCOME MEASURES Change in visual acuity (area under the curve) and development of vision-impairing (20/32 or worse) central-involved DME over 2 years. RESULTS After multivariable model selection with adjustment for baseline visual acuity and central subfield thickness, no factors were identified as associated with change in visual acuity or development of vision-impairing central-involved DME within the ranibizumab group. In the PRP group, worse change in visual acuity was more likely with higher hemoglobin A1c level (-0.6 letters per 1% increase; 95% confidence interval [CI], -1.2 to -0.1 letters; continuous P = 0.03), more severe diabetic retinopathy (difference between high-risk PDR or worse vs. moderate PDR or better, -2.8 letters [95% CI, -5.5 to -0.2 letters]; continuous P = 0.003), and higher mean arterial pressure (difference between ≥100 mmHg vs. <100 mmHg, -2.0 letters [95% CI, -4.6 to 0.5 letters]; continuous P = 0.009). Development of vision-impairing central-involved DME was more likely with higher hemoglobin A1c level (hazard ratio [HR] per 1% increase, 1.31 [95% CI, 1.13-1.52]; continuous P < 0.001), more severe diabetic retinopathy (HR for high-risk PDR or worse vs. moderate PDR or better, 1.46 [95% CI, 0.73-2.92]; continuous P = 0.03), and the presence of cystoid abnormalities within 500 μm of the macula center (HR, 2.90 [95% CI, 1.35-6.24]; P = 0.006). CONCLUSIONS For eyes managed with PRP, higher hemoglobin A1c level and more severe diabetic retinopathy were associated with less vision improvement and an increased risk of vision-impairing central-involved DME developing. When managing PDR with ranibizumab, eyes gained vision, on average, with no baseline characteristics identified as associated with visual acuity or central-involved DME outcomes.
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Analysis of retinal layer thickness in diabetic macular oedema treated with ranibizumab or triamcinolone.
Prager, SG, Lammer, J, Mitsch, C, Hafner, J, Pemp, B, Scholda, C, Kundi, M, Schmidt-Erfurth, U, Kriechbaum, K
Acta ophthalmologica. 2018;(2):e195-e200
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Abstract
PURPOSE To evaluate detailed changes in retinal layer thickness in spectral-domain optical coherence tomography (SD-OCT) images during a 1-year follow-up of patients treated for diabetic macula oedema (DME). METHODS Post hoc analysis of retinal layer thickness changes applying the automated layer segmentation of SD-OCT images in eyes with DME that were randomly assigned to receive pro re nata (PRN) treatment with either 0.5 mg ranibizumab or 8 mg triamcinolone. In each patient, seven retinal layers were segmented in 49 scans covering a 20° × 20° area of the macula at baseline and after 1 year of treatment. Changes in individual layer thickness were correlated with visual acuity (VA) and compared between treatment arms. RESULTS Twenty-five patients (seven female, 60.2 ± 15.1 years) were evaluated. Thickness decrease of retinal nerve fibre layer (RNFL) was associated with a gain in VA over 12 months (r > 0.54; p < 0.05). Decrease in ganglion cell layer (GCL) and GCL+IPL thickness pooled for nasal Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields correlated with VA as follows: ranibizumab r = 0.74 (GCL) and r = 0.63 (GCL+IPL); and triamcinolone r = 0.45 (GCL) and r = 0.46 (GCL+IPL). CONCLUSION In DME therapy, reduction in RNFL thickness may have a considerable impact on retinal function, unrelated to the type of pharmacological treatment. Precise morphologic quantification of neurosensory layers by SD OCT offers new insight into disease pathology and therapeutic targets.