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Vision-Related Quality of Life in Patients with Diabetic Macular Edema Treated with Intravitreal Aflibercept: The AQUA Study.
Garweg, JG, Stefanickova, J, Hoyng, C, Schmelter, T, Niesen, T, Sowade, O, Sivaprasad, S, ,
Ophthalmology. Retina. 2019;(7):567-575
Abstract
PURPOSE To examine vision-related quality of life in patients with diabetic macular edema (DME) treated with intravitreal aflibercept (EYLEA, Regeneron Pharmaceuticals, Inc, Tarrytown, NY). DESIGN AQUA was a multicenter, open-label, single-arm, phase 4 study. PARTICIPANTS Adults 18 years of age or older with type 1 or 2 diabetes mellitus and DME. METHODS Patients received intravitreal aflibercept 2 mg every 8 weeks for 52 weeks, after 5 initial doses every 4 weeks. MAIN OUTCOME MEASURES The primary outcome was the change in 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) total score from baseline to week 52. Secondary outcomes included the change in NEI VFQ-25 near and distant activities subscale scores, best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study [ETDRS] letters), and central retinal thickness (CRT) from baseline to week 52. Change in NEI VFQ-25 score at week 52 for better-seeing eyes (BSEs) and worse-seeing eyes (WSEs) also was evaluated. RESULTS A total of 553 patients comprised the full analysis set, and 560 patients comprised the safety analysis set. At baseline, the mean NEI VFQ-25 total score was 70.12, mean BCVA was 61.5 ETDRS letters, and mean CRT was 464.81 μm. A mean of 8.8 injections were administered over 52 weeks. At week 52, the mean improvement from baseline in the NEI VFQ-25 total score was +6.11 (standard deviation [SD], 11.46); the corresponding improvements in near and distant activities were +11.37 (SD, 18.01) and +7.33 (SD, 17.32), respectively. Similarly, improvements in patients whose BSE and WSE were treated were 7.74 (SD, 13.59) and 5.48 (SD, 9.70), respectively. At week 52, mean change in BCVA was +10.0 ETDRS letters (SD, 8.0 ETDRS letters), and mean change in CRT was -175.38 μm (SD, 132.62 μm). Overall, 53.6% of patients reported treatment-emergent adverse events (TEAEs), of whom 26.8% experienced an ocular TEAE in the study eye. The most common serious ocular TEAE was endophthalmitis (0.5% [n = 3]). Five deaths (0.9%) were reported, but were not considered treatment related. CONCLUSIONS Intravitreal aflibercept was associated with clinically meaningful improvements in NEI VFQ-25 total score over 52 weeks in patients with DME; these were even more pronounced for near than for distant activities. Adverse events were consistent with the known safety profile of intravitreal aflibercept.
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HEMORRHAGIC VASCULITIS AND RETINOPATHY HERALDING AS AN EARLY SIGN OF BACTERIAL ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTION.
Conrady, CD, Feistmann, JA, Roller, AB, Boldt, HC, Shakoor, A
Retinal cases & brief reports. 2019;(4):329-332
Abstract
PURPOSE To describe a case series of postintravitreal injection, bacterial endophthalmitis heralded by hemorrhagic retinal vasculitis. METHODS Observational case series of three patients with a history of intravitreal injections for age-related macular degeneration at a tertiary referral center who presented with vision changes and eye pain that were eventually found to have bacterial endophthalmitis. Clinical course was then followed. RESULTS All patients developed bacterial endophthalmitis and hemorrhagic retinal vasculitis. CONCLUSION These three cases highlight the importance of hemorrhagic retinal vasculitis as the presenting fundus finding of bacterial endophthalmitis and that this finding in a postinjection patient should be treated as endophthalmitis until proven otherwise.
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Correlation of Macular Thickness and Visual Acuity in DME Treated by Two Doses of Intravitreal Ziv-Aflibercept Versus Bevacizumab: Analysis of a Randomized, Three-Armed Clinical Trial.
Jabbarpoor Bonyadi, MH, Baghi, A, Ramezani, A, Yaseri, M, Soheilian, M
Ophthalmic surgery, lasers & imaging retina. 2019;(11):684-690
Abstract
BACKGROUND AND OBJECTIVE To report the correlation of central macular thickness (CMT) and best-corrected visual acuity (BCVA) after 1-year treatment by two doses (2.5 mg or 1.25 mg) of intravitreal ziv-aflibercept (IVZ) versus bevacizumab (IVB) in eyes with diabetic macular edema (DME). PATIENTS AND METHODS In this study, the correlation of CMT and BCVA changes of the eyes enrolled in a previous clinical trial of 123 eyes were re-evaluated. The correlation of BCVA and CMT changes at each visit was evaluated in the three study arms individually. Then, the eyes in each of the arms were classified at each follow-up visit into three subgroups based on their CMT changes related to the baseline CMT: CMT decrease of 30% or more of baseline CMT, between 10% to 29% of baseline CMT, and less than 9% of baseline CMT or CMT increase. RESULTS BCVA and CMT changes were correlated significantly (P < .05) in all and in half of the follow-up visits, respectively, in the eyes treated by IVZ 1.25 mg and IVB (r = 0.554 and r = 0.617 at 1 year, respectively). Nevertheless, such a significant correlation was not detected in the eyes treated by IVZ 2.5 mg in any of the follow-up visits (r = 0.202 at 1 year; P = .259). In the IVZ 2.5 mg group, BCVA improvement was observed in all subgroups with each level of CMT reductions. CONCLUSION Ziv-aflibercept 2.5 mg might have a beneficial effect on DME beyond thickness reduction. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:684-690.].
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Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.
Ehlers, JP, Uchida, A, Hu, M, Figueiredo, N, Kaiser, PK, Heier, JS, Brown, DM, Boyer, DS, Do, DV, Gibson, A, et al
Ophthalmology. Retina. 2019;(12):1056-1066
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Abstract
PURPOSE To investigate retinal fluid features and ellipsoid zone (EZ) integrity dynamics on spectral-domain OCT (SD-OCT) in eyes with diabetic macular edema (DME) treated with intravitreal aflibercept injection (IAI) in the VISTA-DME study. DESIGN A post hoc subanalysis of a phase III, prospective clinical trial. PARTICIPANTS Eyes received either IAI 2 mg every 4 weeks (2q4) or every 8 weeks after 5 initial monthly doses (2q8). METHODS All eyes from the VISTA Phase III study in the IAI groups imaged with the Cirrus HD-OCT system (Zeiss, Oberkochen, Germany) were included. The OCT macular cube datasets were evaluated using a novel software platform to generate retinal layer and fluid boundary lines that were manually corrected for assessment of change in EZ parameters and volumetric fluid parameters from baseline. The retinal fluid index (i.e., proportion of the retinal volume consisting of cystic fluid) was also calculated at each time point. MAIN OUTCOME MEASURES The feasibility of volumetric assessment of higher-order OCT-based retinal parameters and its correlation with best-corrected visual acuity (BCVA). RESULTS Overall, 106 eyes of 106 patients were included. Specifically, 52 eyes of 52 patients were included in the IAI 2q4 arm, and 54 eyes of 54 patients were included in the IAI 2q8 arm. Ellipsoid zone integrity metrics significantly improved from baseline to week 100, including central macular mean EZ to retinal pigment epithelium (RPE) thickness (2q4: 26.6 μm to 31.6 μm, P < 0.001; 2q8: 25.2 μm to 31.4 μm, P < 0.001). At week 100, central macular intraretinal fluid volume was reduced by >65% (P < 0.001) and central macular subretinal fluid volume was reduced by >99% in both arms (P < 0.001). Central macular retinal fluid index (RFI) significantly improved in both arms (2q4: 17.9% to 7.2%, P < 0.001; 2q8: 19.8% to 4.2%, P < 0.001). Central macular mean EZ-RPE thickness (i.e., a surrogate for photoreceptor outer segment length) and central RFI were independently correlated with BCVA at multiple follow-up visits. CONCLUSIONS Intravitreal aflibercept injection resulted in significant improvement in EZ integrity and quantitative fluid metrics in both 2q4 and 2q8 arms and correlated with visual function.
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Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial.
Baker, CW, Glassman, AR, Beaulieu, WT, Antoszyk, AN, Browning, DJ, Chalam, KV, Grover, S, Jampol, LM, Jhaveri, CD, Melia, M, et al
JAMA. 2019;(19):1880-1894
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Abstract
IMPORTANCE Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown. OBJECTIVE To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018. INTERVENTIONS Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits. MAIN OUTCOMES AND MEASURES The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported. RESULTS Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups. CONCLUSIONS AND RELEVANCE Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01909791.
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Evaluation of ranibizumab and aflibercept for the treatment of diabetic macular edema in daily clinical practice.
Plaza-Ramos, P, Borque, E, García-Layana, A
PloS one. 2019;(10):e0223793
Abstract
PURPOSE To evaluate the efficacy and safety of ranibizumab and aflibercept in the treatment of diabetic macular edema in a real world study, and to compare the two treatments with each other. METHODS Retrospective observational study of 213 eyes from 141 patients with diabetic macular edema was completed between June 2014 and June 2016. 122 were treated with ranibizumab intravitreal injection and 91 with aflibercept intravitreal injection, with a loading phase of 3 injections and a Pro Re Nata protocol. The drug was selected by the physician and fluorescein angiography was performed by physician`s criteria. Re-treatment was performed when a decline in BCVA, an increase of central macular thickness or an increase or persistence of intraretinal fluid in OCT was observed. The primary outcome was the mean change in best corrected visual acuity at 1 year, while central macular thickness, central macular volume, the number of injections and visits were evaluated as secondary outcomes. The correlation between BCVA at 4th month visit and BCVA at 12th month visit was also evaluated. RESULTS The mean baseline best corrected visual acuity for the eyes treated with ranibizumab was 0.55 (+/- 0.35) logMAR, and with aflibercept it was 0.48 (+/- 0.29) (P = 0.109). Best corrected visual acuity improved in both groups, and at the end of the follow-up was 0.40 (+/- 0.35) in the ranibizumab group and 0.40 (+/- 0.29) in the aflibercept group (P = 0.864). Best corrected visual acuity at 4th month visit is correlated at a high value (R = 0.789) with the one at the end of the study. No differences were found in central macular thickness, central macular volume and glycosylated hemoglobin when adjusting with baseline values. The overall number of injections was 5.77 (+/- 2.01), being 5.56 (+/- 2.0) in the ranibizumab group and 6.07 (+/- 1.99) in the aflibercept group (P = 0.069). The main outcome determining final best corrected visual acuity was the baseline best corrected visual acuity (P<0.001). CONCLUSION There are no differences in efficacy between ranibizumab and aflibercept in diabetic macular edema treatment in this real world study.
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Difference in Treatment Effect Between Intravitreal Aflibercept Injection and Laser by Baseline Factors in Diabetic Macular Edema.
Singh, RP, Silva, FQ, Gibson, A, Thompson, D, Vitti, R, Berliner, AJ, Saroj, N
Ophthalmic surgery, lasers & imaging retina. 2019;(3):167-173
Abstract
BACKGROUND AND OBJECTIVE To evaluate the effect of baseline factors on differences in vision gains with intravitreal aflibercept injection (IAI) versus laser control in patients with diabetic macular edema (DME). PATIENTS AND METHODS This was an integrated post-hoc subanalysis of two phase 3 trials (VISTA, VIVID) in patients with DME. Least square (LS) mean differences of patients treated with IAI compared to laser control in best-corrected visual acuity (BCVA) change from baseline at week 100 were evaluated for association with baseline demographics and baseline systemic disease characteristics. RESULTS At week 100, LS mean differences in BCVA change from baseline with IAI compared to laser control were not significant for association with baseline age, gender, and race or status of glycosylated hemoglobin, body mass index, renal impairment, hypertension, cerebrovascular disease, and ischemic heart disease. CONCLUSION Vision gains with IAI were significantly greater than laser control and were not influenced by demographics and systemic disease control at baseline. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:167-173.].
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Phase 2 study of vascular endothelial growth factor trap for the treatment of metastatic thyroid cancer.
Sherman, EJ, Dunn, LA, Schöder, H, Ho, AL, Baxi, SS, Ghossein, RA, Haque, SS, Sima, C, Tuttle, RM, Pfister, DG
Cancer. 2019;(17):2984-2990
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Abstract
BACKGROUND Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF. METHODS The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days. RESULTS A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months). CONCLUSIONS Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer.
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Safety of intravitreal ziv-aflibercept in choroido-retinal vascular diseases: A randomised double-blind intervention study.
Braimah, IZ, Kenu, E, Amissah-Arthur, KN, Akafo, S, Kwarteng, KO, Amoaku, WM
PloS one. 2019;(10):e0223944
Abstract
AIM: To evaluate the safety of 1.25mg and 2mg intravitreal ziv-aflibercept (IVZ) in Ghanaian eyes with choroido-retinal vascular diseases. DESIGN Prospective, randomised, double blind, interventional study. METHODS Twenty patients with centre involving macular oedema in diabetic retinopathy, retinal vein occlusion, and neovascular age-related macular degeneration were assigned to 2 groups receiving 3 doses of 1.25mg/0.05ml (group 1) and 2mg/0.08ml IVZ (Group 2) at 4 weekly intervals. Safety data was collected after 30 minutes, 1 and 7 days, and 4, 8 and 12 weeks after injection. Changes in continuous variables were compared using paired t-test and categorical variables were compared using chi-square test of proportions. Repeated-Measures ANOVA with nesting test was used to compare variations in continuous variables by IVZ dose over time. Primary outcome measures were ocular and systemic adverse events at 4 weeks. RESULTS Eleven females and nine males, with mean age of 63.2± 7.3 years were included. Ocular adverse events included subconjunctival haemorrhage in 1 eye, intraocular pressure (IOP) >21mmHg at 30 minutes in 6 eyes and mild pain in 3 eyes at 1-day. There was no significant difference in IOP rise between the 2 groups at 30 minutes (p = 0.21). No other ocular or systemic adverse events were observed. There was significant improvement in the best corrected visual acuity (LogMAR) from 0.95±0.6 to 0.6±0.4 (p<0.01) and 0.47±0.3 (p<0.01), reduction in central subfield foveal thickness from 405.9±140 um at baseline to 255.6±75 um (p<0.01) and 238±88 um (p<0.01) at 4 and 12 weeks respectively, although no difference was observed between the 2 groups (p = 0.34). CONCLUSION IVZ at 1.25mg and 2mg had similar safety profiles, and did not have any major unexpected adverse events. Further studies with larger cohorts are required to confirm efficacy.
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Ziv-aflibercept versus bevacizumab administration prior to diabetic vitrectomy: a randomised and controlled trial.
Aleman, I, Castillo Velazquez, J, Rush, SW, Rush, RB
The British journal of ophthalmology. 2019;(12):1740-1746
Abstract
PURPOSE To compare the effectiveness of intravitreal ziv-aflibercept (IVZ) to intravitreal bevacizumab (IVB) administered preoperatively to patients undergoing pars plana vitrectomy (PPV) for severe manifestations of proliferative diabetic retinopathy (PDR). DESIGN Randomised clinical trial (RCT). METHODS Two hundred and six patients with PDR-related complications requiring PPV were randomised into one of two treatment groups: Group A received IVZ (1.25 mg/0.05 mL) 1-10 days before PPV, while Group B received IVB (1.25 mg/0.05 mL) 1-10 days before PPV. The primary outcome was best-corrected visual acuity (BCVA) at 6 months follow-up. Secondary outcome measures were perioperative tractional retinal detachment (TRD) rates, surgical times, intraoperative and postoperative complications and incidence of unplanned PPV during the 6 month study interval. RESULTS One hundred and seventy three subjects underwent PPV and completed the 6-month follow-up interval. Group A subjects had better BCVA at 6 months (p=0.0035), shorter surgical times (p=0.0013) and were less likely to have a recurrence of vitreous haemorrhaging in the postoperative period (p=0.0101) when compared with subjects in Group B. There were no significant differences among the treatment groups with regards to baseline characteristics, perioperative TRD development, intraoperative complications and incidence of unplanned PPV during the 6 month study interval. CONCLUSIONS This RCT demonstrated better final visual outcomes, shorter operating times and less vitreous haemorrhage recurrences in the postoperative period when subjects received IVZ compared to IVB prior to PPV for the treatment of PDR-related complications.