[Pharmacoeconomic analysis of anti-angiogenic drugs for diabetic macular edema]. / Farmakoekonomicheskii analiz primeneniya antiangiogennykh preparatov pri diabeticheskom makulyarnom oteke.

Diabetic macular edema (DME) is a degenerative disease of the macular area in diabetes mellitus and can lead to vision loss, disability, and significantly reduced quality of life. Faricimab is the only bispecific antibody for DME therapy that targets two pathogenic pathways (Ang-2 and VEGF-A). PURPOSE: This study comparatively evaluates the clinical and economic feasibility of faricimab and other angiogenesis inhibitors in patients with DME. MATERIAL AND METHODS: This article analyzed literature on the efficacy and safety of intravitreal injections (IVI) of ranibizumab 0.5 mg, aflibercept 2 mg, and faricimab 6 mg. A model of medical care was developed for patients with DME receiving anti-angiogenic therapy. Pharmacoeconomic analysis was performed using cost minimization and budget impact analysis (BIA) methods. Modeling time horizon was 2 years. The research was performed from the perspective of the healthcare system of the Russian Federation. RESULTS: The efficacy and safety of faricimab in a personalized regimen (up to one IVI in 16 weeks) are comparable to those of aflibercept and ranibizumab, administered in various regimens. The use of faricimab is associated with the lowest number of IVIs. Over 2 years, the maximum costs of drug therapy were associated with the use of ranibizumab (about 914 thousand rubles), while the minimum costs were associated with the use of faricimab (614 thousand rubles). The reduction in inpatient care costs with faricimab therapy was 36% compared to aflibercept (216 and 201 thousand rubles in inpatient and day hospitals, respectively) and 82% compared to ranibizumab (486 and 451 thousand rubles in inpatient and day hospitals, respectively). BIA demonstrated that the use of faricimab will reduce the economic burden on the healthcare system by 11.3 billion rubles (9.8%) over 2 years. CONCLUSION: The use of faricimab is a cost-effective approach to treatment of adult patients with DME in Russia.

[Application of optical coherence tomography in the assessment of the posterior lens capsule during anti-angiogenic therapy]. / Primenenie opticheskoi kogerentnoi tomografii v otsenke zadnei kapsuly khrustalika na fone provedeniya antiangiogennoi terapii.

Intravitreal injection (IVI) of anti-angiogenic drugs is one of the most common therapeutic procedures in ophthalmology. In recent years, a new non-contact study method has been developed - anterior segment optical coherence tomography (AS-OCT), which allows the formation of three-dimensional images of the lens and provides more detailed information about its structure and morphology. PURPOSE: This study uses optical coherence tomography method to analyze the risks of developing changes in the posterior lens capsule in patients after IVI of an anti-angiogenic drug. MATERIAL AND METHODS: The study involved 100 people (14 men and 86 women) with a natural lens and neovascular age-related macular degeneration (nAMD). The average age was 70.57±7.98 years. During the study (12 months), all patients underwent IVI of an anti-angiogenic drug aflibercept in the treat-and-extend (T&E) mode. All subjects were divided into 2 groups: with a total number of IVI less than 10 - group 1 (50 patients), and more than 10 IVI - group 2 (50 patients, of which 49 were included in the study). All patients underwent OCT using the Optopol REVO NX device (Poland) with the Anterior B-scan Wide protocol before inclusion in the study, as well as after 3, 6 and 12 months. RESULTS: It was found that the risk of developing a posterior lens capsule rupture, visualized using OCT, depends on the total number of IVI (correlation coefficient 0.473 p=0.001): the more IVI, the higher the probability that damage to the posterior capsule will occur after the next IVI, and after the 15th injection the risk of developing damage to the posterior capsule increases sharply. CONCLUSION: The astudy analyzed the risk factors for the development of posterior lens capsule damage that can be detected using OCT, and presented three risk groups for the development of rupture (or damage) of the posterior lens capsule depending on the number of intravitreal injections performed.

Diabetic macular edema and proliferative diabetic retinopathy treated with anti-vascular endothelial growth factor under the reimbursement policy in Taiwan.

The purpose of this retrospective interventional case series is to compare the functional and anatomical outcomes in eyes with diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) treated intravitreally with aflibercept or ranibizumab under the Taiwan National Insurance Bureau reimbursement policy. 84 eyes were collected and all eyes were imaged with spectral-domain optical coherence tomography (SD-OCT), color fundus photographs (CFPs), and fluorescein angiography (FA). At 24 months after therapy initiation, the logMAR BCVA improved from 0.58 ± 0.33 to 0.47 ± 0.38 (p < 0.01), the CRT decreased from 423.92 ± 135.84 to 316.36 ± 90.02 (p < 0.01), and the number of microaneurysms decreased from 142.14 ± 57.23 to 75.32 ± 43.86 (p < 0.01). The mean injection count was 11.74 ± 5.44. There was no intergroup difference in logMAR BCVA (p = 0.96), CRT (p = 0.69), or injection count (p = 0.81). However, the mean number of microaneurysms was marginally reduced (p = 0.06) in eyes treated with aflibercept at the end of the follow-up, and the incidence rates of supplementary panretinal photocoagulation (PRP) (p = 0.04) and subthreshold micropulse laser (SMPL) therapy sessions (p = 0.01) were also reduced. Multivariate analysis revealed that only initial logMAR BCVA influenced the final VA improvements (odds ratio (OR) 0.49, 95% confidence interval (CI) 0.21 ~ 0.93, p < 0.01); in contrast, age (OR - 0.38, 95% CI - 6.97 ~ - 1.85, p < 0.01) and initial CRT (OR 0.56, 95% CI 0.34 ~ 0.84, p < 0.01) both influenced the final CRT reduction at 24 months. To sum up, both aflibercept and ranibizumab are effective in managing DME with PDR in terms of VA, CRT and MA count. Eyes receiving aflibercept required less supplementary PRP and SMPL treatment than those receiving ranibizumab. The initial VA influenced the final VA improvements at 24 months, while age and initial CRT were prognostic predictors of 24-month CRT reduction.

ASSESSMENT OF EARLY CHANGES IN SPECTRAL DOMAIN-OPTICAL COHERENCE TOMOGRAPHY AFTER INITIATION OF TREATMENT WITH INTRAVITREAL AFLIBERCEPT (EYLEA) OVER A 12-WEEK PERIOD FOR PATIENTS WITH NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Multicenter French Study (START).

PURPOSE: To assess early changes in spectral-domain optical coherence tomography during the loading phase with intravitreal aflibercept therapy in patients with neovascular age-related macular degeneration. METHODS: In this prospective, open-label, single-arm, multicenter study, patients with neovascular age-related macular degeneration, who were antivascular endothelial growth factor treatment-naïve, received three monthly initial doses of intravitreal aflibercept 2 mg. The primary outcome was the proportion of patients with dry spectral-domain optical coherence tomography at 12 weeks, defined as an absence of intraretinal edema, intraretinal cysts, subretinal fluid, and subretinal pigment epithelium fluid. RESULTS: Fifty eyes of 50 patients were investigated. At 12 weeks, 34.0% (17/50) had dry spectral-domain optical coherence tomography. Marked reductions were observed for all other spectral-domain optical coherence tomography parameters. The mean macular central thickness fell significantly from 463.2 ± 184.3 µm at baseline to 288.9 ± 76.8 µm at Week 12 (P < 0.0001). The mean best-corrected visual acuity also improved significantly from 61.0 ± 16.0 letters at baseline to 66.6 ± 19.0 letters at Week 12 (P = 0.0006). CONCLUSION: The anatomic and functional outcomes improved over the 12-week study period. All outcome variables peaked after the third aflibercept injection, confirming the benefit of three initial doses.

Longitudinal Assessment of Ellipsoid Zone Integrity, Subretinal Hyperreflective Material, and Subretinal Pigment Epithelium Disease in Neovascular Age-Related Macular Degeneration.

PURPOSE: To assess longitudinally the effect of anti-vascular endothelial growth factor (VEGF) treatment on ellipsoid zone (EZ) integrity, subretinal hyperreflective material (SHRM), and the sub-retinal pigment epithelium (sub-RPE) compartment in eyes with neovascular age-related macular degeneration (nAMD). DESIGN: Post hoc analysis of the OSPREY clinical trial, a prospective, double-masked, phase 2 study comparing brolucizumab 6 mg with aflibercept 2 mg over 56 weeks. PARTICIPANTS: Participants with treatment-naïve nAMD at the initiation of the trial were included in the analysis. METHODS: Eyes were evaluated with spectral-domain OCT at 4-week intervals in the OSPREY trial (n = 81). Spectral-domain OCT scans collected from each visit were segmented automatically using a proprietary, machine learning-enabled higher-order feature-extraction platform for retinal layer, SHRM, and sub-RPE boundary lines, which were evaluated and corrected as needed by masked trained graders. The current analysis focused only on patients evaluated with the Cirrus (Zeiss) platform (n = 28). MAIN OUTCOME MEASURES: Outcome measures included change from baseline in EZ-RPE (i.e., photoreceptor outer segment) volume, EZ-RPE central subfield thickness (CST), total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume. The correlation between each of these measures and best-corrected visual acuity (BCVA) at each visit was evaluated. RESULTS: EZ-RPE volume and EZ-RPE CST showed significant increases, and total EZ attenuation, SHRM volume, SHRM CST, and total sub-RPE volume showed significant decreases from baseline at each visit from weeks 4 through 56 (P < 0.05 at each visit). Ellipsoid zone integrity measures and SHRM volume correlated significantly with BCVA at most visits (P < 0.05). No significant correlation was found between total sub-RPE volume and BCVA. CONCLUSIONS: EZ integrity, SHRM, and sub-RPE disease features in eyes with nAMD showed improvement as early as week 4 of anti-VEGF treatment. EZ integrity measures and SHRM volume were predictors of visual acuity over the first year of treatment.

Value of Anti-Vascular Endothelial Growth Factor Gene Therapy for Neovascular Age-Related Macular Degeneration.

PURPOSE: To use discounted cash flow (DCF) analysis to estimate the value creation associated with anti-vascular endothelial growth factor (VEGF) genetic therapy for neovascular age-related macular degeneration (nAMD). DESIGN: Economic analysis. PARTICIPANTS: Adults undergoing serial intravitreal anti-VEGF injections in 1 eye for nAMD. METHODS: Discounted cash flow modeling with scenario analysis was used to derive a present value for a 1-time alternative treatment to lifelong anti-VEGF treatment for nAMD. Multiple sensitivity analyses were performed on the basis of patient age at time of first injection and frequency interval of intravitreal injection. MAIN OUTCOME MEASURES: Present values of DCF and scenario analyses. RESULTS: Discounted cash flow analysis of intravitreal anti-VEGF treatment for nAMD resulted in a base-case valuation of $208 420.61, $219 093.31, and $17 379.41 for a 1-time alternative treatment to aflibercept, ranibizumab, and bevacizumab, respectively. This figure covaried significantly with anti-VEGF agent according to the patient age at first injection ($78 323.19-$292 449.87) and frequency of injections ($148 422.91-$388 096.81). In addition, for bevacizumab, variability was driven by the hypothetical degree of clinical superiority of 1-time therapy to repeated intravitreal injections due to reduction in adverse events ($17 379.41-$18 250.79) or reduction in direct or indirect costs associated with age-related macular degeneration ($17 379.41-$657 406.55). CONCLUSIONS: Anti-VEGF gene therapy approaches can create significantly different value propositions based on the agent modeled, patient age at first injection, frequency of injections, and clinical profile of the medication. Although the use of aflibercept or ranibizumab as a comparative cost metric is logical from a bioequivalence perspective, the disparity in medication costs should not be the primary value driver in applied models. Instead, bevacizumab should be the base case ($17 379.41), with additional value driven from an improvement in quality of life through clinical superiority. A reduction in direct and indirect costs can be used to approximate the value from maintained visual acuity, which is elaborated in the DCF analysis approach described in this article. This model can serve as a basis for assessing the price ceiling of myriad gene therapy approaches. Given the high present values for these therapeutics, innovative costing and reimbursement mechanisms should be further explored, with contingencies for sustained efficacy.

Twenty-Four-Month OCTA Assessment in Diabetic Patients Undergoing Fixed-Interval Intravitreal Aflibercept Therapy.

BACKGROUND AND OBJECTIVE: Evaluate capillary perfusion density (CPD) in patients with diabetic macular edema (DME) undergoing fixed intravit-real aflibercept injections (IAI) through 24 months. PATIENTS AND METHODS: Prospective, interventional, single-arm study enrolling 20 patients with persistent DME. Patients received IAI every 4 weeks until DME resolution followed by extension to every 8 weeks. Optical coherence tomography angiography was obtained at baseline, 6, 12, and 24 months. RESULTS: Sixteen of 20 eyes completed the study. Baseline mean central subfield thickness was 420 µm, which improved to 251 µm (P < .001). The mean best-corrected visual acuity (BCVA) improved by 5.5 letters (P = .042). The whole superficial CPD decreased by 5.3% (P = .001) and the deep CPD decreased by 4.4% (P = .009). Better BCVA correlated with less CPD loss within the superficial parafovea (r = +0.66 [0.23, 0.88]; P = .006) and whole (r = +0.60 [0.12, 0.85]; P = .017) areas. CONCLUSION: Superficial and deep CPD decreased despite fixed IAI through 24 months. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:448-455.].

Treatment regimens for administration of anti-vascular endothelial growth factor agents for neovascular age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD) is one of the leading causes of permanent blindness worldwide. The current mainstay of treatment for neovascular AMD (nAMD) is intravitreal injection of anti-vascular endothelial growth factor (anti-VEGF) agents: aflibercept, ranibizumab, and off-label bevacizumab. Injections can be given monthly, every two or three months ('extended-fixed'), or as needed (pro re nata (PRN)). A variant of PRN is 'treat-and-extend' whereby injections are resumed if recurrence is detected and then delivered with increasing intervals. Currently, injection frequency varies among practitioners, which underscores the need to characterize an optimized approach to nAMD management. OBJECTIVES: To investigate the effects of monthly versus non-monthly intravitreous injection of an anti-VEGF agent in people with newly diagnosed nAMD. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers from 2004 to October 2019; checked references; handsearched conference abstracts; and contacted pharmaceutical companies to identify additional studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared different treatment regimens for anti-VEGF agents in people with newly diagnosed nAMD. We considered standard doses only (ranibizumab 0.5 mg, bevacizumab 1.25 mg, aflibercept 2.0 mg, or a combination of these). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for trial selection, data extraction, and analysis. MAIN RESULTS: We included 15 RCTs. The total number of participants was 7732, ranging from 37 to 2457 in each trial. The trials were conducted worldwide. Of these, six trials exclusively took place in the US, and three included centers from more than one country. Eight trials were at high risk of bias for at least one domain and all trials had at least one domain at unclear risk of bias. Seven trials (3525 participants) compared a PRN regimen with a monthly injection regimen, of which five trials delivered four to eight injections using standard PRN and three delivered nine or 10 injections using a treat-and-extend regimen in the first year. The overall mean change in best-corrected visual acuity (BCVA) at one year was +8.8 letters in the monthly injection group. Compared to the monthly injection, there was moderate-certainty evidence that the mean difference (MD) in BCVA change at one year for the standard PRN subgroup was -1.7 letters (95% confidence interval (CI) -2.8 to -0.6; 4 trials, 2299 participants), favoring monthly injections. There was low-certainty evidence of a similar BCVA change with the treat-and-extend subgroup (0.5 letters, 95% CI -3.1 to 4.2; 3 trials, 1226 participants). Compared to monthly injection, there was low-certainty evidence that fewer participants gained 15 or more lines of vision with standard PRN treatment at one year (risk ratio (RR) 0.87, 95% CI 0.76 to 0.99; 4 trials, 2299 participants) and low-certainty evidence of a similar gain with treat-and-extend versus monthly regimens (RR 1.11, 95% CI 0.91 to 1.36; 3 trials, 1169 participants). The mean change in central retinal thickness was a decrease of -166 µm in the monthly injection group; the MD compared with standard PRN was 21 µm (95% CI 6 to 32; 4 trials, 2215 participants; moderate-certainty evidence) and with treat-and extend was 22 µm (95% CI 37 to -81 µm; 2 trials, 635 participants; low-certainty evidence), in favor of monthly injection. Only one trial (498 participants) measured quality of life and reported no evidence of a difference between regimens, but data could not be extracted (low-certainty evidence). Both PRN regimens (standard and 'treat-and-extend') used fewer injections than monthly regimens (standard PRN: MD -4.6 injections, 95% CI -5.4 to -3.8; 4 trials, 2336 participants; treat-and-extend: -2.4 injections, 95% CI -2.7 to -2.1 injections; moderate-certainty evidence for both comparisons). Two trials provided cost data (1105 participants, trials conducted in the US and the UK). They found that cost differences between regimens were reduced if bevacizumab rather than aflibercept or ranibizumab were used, since bevacizumab was less costly (low-certainty evidence). PRN regimens were associated with a reduced risk of endophthalmitis compared with monthly injections (Peto odds ratio (OR) 0.13, 95% CI 0.04 to 0.46; 6 RCTs, 3175 participants; moderate-certainty evidence). Using data from all trials included in this review, we estimated the risk of endophthalmitis with monthly injections to be 8 in every 1000 people per year. The corresponding risk for people receiving PRN regimens was 1 in every 1000 people per year (95% CI 0 to 4). Three trials (1439 participants) compared an extended-fixed regimen (number of injections reported in only one large trial: 7.5 in one year) with monthly injections. There was moderate-certainty evidence that BCVA at one year was similar for extended-fixed and monthly injections (MD in BCVA change compared to extended-fixed group: -1.3 letters, 95% CI -3.9 to 1.3; RR of gaining 15 letters or more: 0.94, 95% CI 0.80 to 1.10). The change in central retinal thickness was a decrease of 137 µm in the monthly group; the MD with the extended-fixed group was 8 µm (95% CI -11 to 27; low-certainty evidence). The frequency of endophthalmitis was lower in the extended-fixed regimen compared to the monthly group, but this estimate was imprecise (RR 0.19, 95% CI 0.03 to 1.11; low-certainty evidence). If we assumed a risk of 8 cases of endophthalmitis in 1000 people receiving monthly injections over one year, then the corresponding risk with extended-fixed regimen was 2 in 1000 people (95% CI 0 to 9). Other evidence comparing different extended-fixed or PRN regimens yielded inconclusive results. AUTHORS' CONCLUSIONS: We found that, at one year, monthly regimens are probably more effective than PRN regimens using seven or eight injections in the first year, but the difference is small and clinically insignificant. Endophthalmitis is probably more common with monthly injections and differences in costs between regimens are higher if aflibercept or ranibizumab are used compared to bevacizumab. This evidence only applies to settings in which regimens are implemented as described in the trials, whereas undertreatment is likely to be common in real-world settings. There are no data from RCTs on long-term effects of different treatment regimens.

Real-World Injection Frequency and Cost of Ranibizumab and Aflibercept for the Treatment of Neovascular Age-Related Macular Degeneration and Diabetic Macular Edema.

BACKGROUND: Ranibizumab and aflibercept are FDA-approved treatments for patients with neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Although these agents differ in cost and labeled dosing, it is unclear whether these differences are reflected in clinical practice. OBJECTIVE: To compare the real-world frequency and cost of ranibizumab and aflibercept injections among treatment-naive and previously treated patients with nAMD and DME. METHODS: Claims data from MarketScan Research Databases were retrospectively reviewed to identify treatment-naive patients with nAMD who initiated intravitreal ranibizumab or aflibercept between January 1, 2014, and January 1, 2016, and treatment-naive patients with DME who initiated intravitreal ranibizumab or aflibercept between July 29, 2014, and July 1, 2016. Patients who switched to subsequent-line aflibercept or ranibizumab during the study period were eligible to enter previously treated subgroups. Multivariable regression models were derived to compare the per-patient frequency and cost of injections between ranibizumab- and aflibercept-treated patients with nAMD over 12 months (treatment-naive: n = 1,087 and n = 1,578; previously treated: n = 221 and n = 751) and 24 months (treatment-naive: n = 454 and n = 568; previously treated: n = 93 and n = 284) and in patients with DME over 6 months (treatment-naive: n = 507 and n = 681; previously treated: n = 53 and n = 223) and 12 months (treatment-naive: n = 326 and n = 382; previously treated: n = 24 and n = 122). RESULTS: After adjusting for patient demographics and clinical characteristics, per-patient injection frequency and cost were not significantly different between treatment-naive patients with nAMD who received ranibizumab versus aflibercept over 12 months (5.62 vs. 5.54; P = 0.52, and $11,351 vs. $10,702; P = 0.06, respectively) and 24 months (7.86 vs. 8.37; P = 0.16, and $16,286 vs. $16,666; P = 0.69, respectively). In previously treated patients with nAMD, injection frequency was significantly lower among ranibizumab- versus aflibercept-treated patients over 24 months (7.98 vs. 9.63; P = 0.03), whereas treatment costs were comparable over 12 months ($11,512 vs. $12,050; P = 0.44) and 24 months ($16,303 vs. $19,361; P = 0.13). In treatment-naive patients with DME, ranibizumab was associated with significantly fewer injections and lower costs than aflibercept over 6 months (2.60 vs. 2.92 and $3,379 vs. $5,925, respectively; both P < 0.001) and 12 months (3.33 vs. 3.87 and $4,136 vs. $7,656, respectively; both P < 0.001). Similar cost savings were observed among previously treated patients with DME who received ranibizumab over 6 months ($3,834 vs. $6,775 for aflibercept; P = 0.0001) and 12 months ($4,606 vs. $9,190; P = 0.02), despite nonsignificant differences in injection frequency during follow-up. CONCLUSIONS: Although the frequency and cost of ranibizumab and aflibercept injections were generally comparable among patients treated for nAMD, ranibizumab was associated with estimated per-patient-per-year cost savings of $3,500-$4,500 in those treated for DME. Most patients received fewer injections than any FDA-indicated dosing schedule, suggesting potential undertreatment that may result in suboptimal vision outcomes. DISCLOSURES: Study funding was provided by Genentech, a member of the Roche Group. The sponsor participated in the design of the study; collection, analysis, and interpretation of the data; preparation of the manuscript; and the decision to submit the article for publication. Kiss has been a consultant for and received honoraria from Alcon, Alimera, Allergan, BioMarin, Novartis, and Spark; has been on the advisory board for, a consultant for, received honoraria from, and held stock options in Adverum and Regenxbio; has been a consultant for, received honoraria from, and held stock/stock options in Fortress; has been on the advisory board for, a consultant and investigator for, and received grants and honoraria from Genentech and Regeneron; and has been on the advisory board for, a consultant for, and received grants and honoraria from Optos. Malangone-Monaco, Wilson, Varker, Stetsovsky, and Smith are employees of IBM Watson Health, which received funding from Genentech to undertake this study. Garmo is an employee of Genentech. Data reported in this manuscript were presented in part at the Academy of Managed Care Pharmacy (AMCP) Managed Care and Specialty Pharmacy Annual Meeting; April 23-26, 2018; Boston, MA.

Cardiovascular assessment after treatment for retinopathy of prematurity: a comparative study between anti-VEGF agent (aflibercept) and laser.

OBJECTIVE: The aim of this study was to compare the cardiac effects and aortic arterial indices following intravitreal aflibercept treatment or diode laser photocoagulation for the treatment of retinopathy of prematurity (ROP) in infants. METHODS: This single-centre, retrospective study was conducted in infants who were administered laser photocoagulation (LPC) or intravitreal aflibercept (IVA) treatment as initial treatment and had completed at least one year of corrected age. The patients were evaluated in terms of aortic elastic parameters, right and left ventricular systolic and diastolic function using conventional, pulsed Doppler and tissue Doppler imaging (TDI) echocardiographic parameters. RESULTS: Fifteen infants were in the LPC group, 16 in the IVA group, and 20 in the control group. Although there were some statistically significant differences in terms of pulsed and TDI echocardiographic parameters between the treatment and control groups, these values could not clearly be adopted as a diastolic dysfunction and myocardial performance indices were not influenced. The aortic elastic parameters were impaired in both LPC and IVA groups compared to the control group. Consequently, we observed only minor differences between the treatment groups, which may suggest subtle changes due to the anti-angiogenic treatment. CONCLUSIONS: Although favourable and promising outcomes were obtained with intravitreal injection of anti-vascular endothelial growth factor agents for the treatment of ROP, concerns have been raised about potential systemic side effects, including potential cardiovascular side effects caused by these agents. The small reduction in right ventricular Doppler velocities could probably be explained by the use of anti-angiogenic or laser treatment in infants.

Cost-effectiveness analysis of intravitreal aflibercept in the treatment of diabetic macular edema in China.

Aim: To evaluate the cost-effectiveness of intravitreal aflibercept compared with macular laser photocoagulation and ranibizumab for diabetic macular edema (DME) in China. Methods: A Markov model was developed to reflect the vision changes in DME patients. Parameters were estimated from VIVID-EAST trial data, published literature and physician surveys. Results: In a 20-year horizon, intravitreal aflibercept was associated with 7.825 quality-adjusted life years (QALYs) and 217,841 Chinese Yuan Renminbi (CNY), laser photocoagulation was associated with 7.189 QALYs and 135,489 CNY, and ranibizumab was associated with 7.462 QALYs and 222,477 CNY. The incremental cost-effectiveness ratios were 129,397 CNY/QALY and -12,774 CNY/QALY for intravitreal aflibercept versus laser photocoagulation and ranibizumab, respectively. Conclusion: Intravitreal aflibercept was considered as a cost-effective strategy for DME when compared with laser photocoagulation; it was considered as a dominant strategy when compared with ranibizumab.

Evaluation of retinal function improvement in neovascular age-related macular degeneration after intravitreal aflibercept injections with the use of the assessment of retinal sensitivity: The use of the assessment of retinal sensitivity in anti-VEGF treatment - a STROBE-compliant observational study.

This study compares 2 methods of macular function evaluation: the microperimetric examination (mean central retinal sensitivity and fixation stability) and the distance best-corrected visual acuity (BCVA) examination, which is the most frequently used method of assessing macular function in patients with newly diagnosed wet age-related macular degeneration (AMD) who have been treated with anti-vascular endothelial growth factor (VEGF) drug (aflibercept).Prospective analysis was conducted on 44 eyes of 44 patients treated with intravitreal injection of anti-VEGF (aflibercept) because of newly diagnosed neovascular AMD. According to the research protocol, all patients had a 6-month follow-up. The response to treatment was monitored functionallybyMP-1 microperimetry, fixation, and distance BCVA assessment after injection. Improvement of retinal sensitivity and BCVA was found under aflibercept treatment. There was statistically significant improvement in retinal sensitivity in the MP-1 study 3 and 6 months from the beginning of anti-VEGF therapy. Moreover, a significant improvement in retinal sensitivity between 3 and 6 months of observation was demonstrated. At the same time, up to 3 months from the beginning of treatment, BCVA improved significantly compared to the baseline value. In the 6th month of the study BCVA remained stable without further significant improvement.Microperimetric examination with medium sensitivity and fixation stability assessment is a very valuable test determining the retinal function. It is clear that examining the macular morphology itself in modern diagnostics is not enough to assess retinal function. Microperimetry technique is a valuable tool for functional long-term evaluation of retinal function (also for a period of more than 3 months).

Healthcare resource use and costs of diabetic macular oedema for patients with antivascular endothelial growth factor versus a dexamethasone intravitreal implant in Korea: a population-based study.

OBJECTIVES: To estimate the costs and healthcare resources of patients with diabetic macular oedema (DME) who received intravitreal antivascular endothelial growth factor (anti-VEGF) agents or a dexamethasone intravitreal implant (DEX-implant) in Korea. DESIGN: Retrospective cohort study. SETTING: The Korean National Health Insurance claim data from 1 January 2015 to 30 June 2017 were retrieved from the Health Insurance Review and Assessment Service. PARTICIPANTS: Adult patients with DME who were diagnosed with diabetic retinopathy or DME and received ranibizumab, aflibercept or a DEX-implant in conjunction with intravitreal injection were included. Patients whose primary diagnoses were age-related macular degeneration or retinal vein occlusion were excluded. MAIN OUTCOME MEASURES: Healthcare resource utilisation and costs related to DME in the 12-month postindex period. RESULTS: During the study period, 182 patients and 414 patients were identified in the anti-VEGF and DEX-implant groups, respectively, and there was no significant difference in the demographic characteristics between the two groups. The outpatient eye care-related medical costs were US$3002.33 for the anti-VEGF group vs US$2250.35 for the DEX-implant group (p<0.0001). After adjusting the relevant covariates based on the generalised linear model, the estimated outpatient eye care-related medical costs were 33% higher in the anti-VEGF group than in the DEX-implant group (p<0.0001, 95% CI 22% to 45%). The utilisation pattern of the two groups showed no significant difference except for the number of intravitreal injections, which was higher in the anti-VEGF group (2.69±2.29) than in the DEX-implant group (2.09±1.37, p<0.001). CONCLUSION: The average annual eye-related medical cost of the DEX-implant group was significantly lower than that of the anti-VEGF group during the study period, which was mainly due to decreased utilisation of eye care-related injections. Further long-term studies are needed.

Assessment of Patient Pain Experience During Intravitreal Ranibizumab and Aflibercept Injection.

PURPOSE: The aim of this study was to compare the pain scores of the patients during intravitreal injection of ranibizumab and aflibercept based on patient feedback. MATERIALS AND METHODS: Seventy-two eyes of 72 patients, who had not previously undergone any intravitreal injection procedures, were included in this study. Thirty-eight patients received ranibizumab, and 34 patients received aflibercept injections. The pain was measured by visual analog scale (VAS). Patients were asked to rate their pain experienced during the injection between 0 (no pain) and 10 (worst pain ever felt) on VAS just after the injection. RESULTS: VAS pain scores in ranibizumab and aflibercept groups were 3.28 ± 2.45 and 4.20 ± 2.30, respectively. There was a significant difference in average VAS pain scores between groups (P = 0.04). CONCLUSION: VAS pain scores in aflibercept group were found to be significantly higher than the scores in the ranibizumab group.

Higher-Order Assessment of OCT in Diabetic Macular Edema from the VISTA Study: Ellipsoid Zone Dynamics and the Retinal Fluid Index.

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.

Treatment compliance and adherence among patients with diabetic retinopathy and age-related macular degeneration treated by anti-vascular endothelial growth factor under universal health coverage.

PURPOSE: To analyze and compare loss to follow-up (LTFU) rates between patients with diabetic retinopathy (DR) and those with neovascular age-related macular degeneration (nAMD) in patients, receiving treatment with anti-vascular endothelial growth factor (VEGF), under universal health coverage. METHODS: We retrospectively analyzed the relevant data of 1264 patients receiving anti-VEGF therapy, in this cohort study. The observation period ranged from September 01, 2015 to December 31, 2018. Intervals between each procedure and the subsequent follow-up examination were measured. Demographic data, visual acuity (VA), the type of transport for treatment access, and distance between the residence and clinic were evaluated as risk factors for LTFU. RESULTS: We collected data for 841 patients with nAMD (age, 81.0 (± 8.1 years)) and 423 patients with DR (age, 67.7 (± 12.1 years)). The rate of LTFU, for at least 6 months, was 28.8% and 2.9% for patients with DR and nAMD, respectively (p < 0.001). In the DR group, 18.9% patients were lost to follow-up exceeding > 12 months. Multivariate regression analysis showed that advanced age, lack of mobility, and need for assisted transport, poor final VA despite treatment, and decrease in vision during the observational period were independent risk factors for LTFU exceeding 12 months (p < 0.05). CONCLUSIONS: We found a high long-term LTFU rate for patients with DR, despite treatment under universal health coverage. Considering the risk of disease progression, particularly in patients with chronic DR, strategies for better compliance and adherence to therapy should be considered for optimized patient care.

A Multinational Comparison of Anti-Vascular Endothelial Growth Factor Use: The United States, the United Kingdom, and Asia-Pacific.

PURPOSE: A comparison of anti-vascular endothelial growth factor (anti-VEGF) medication use across multiple countries. CLINICAL RELEVANCE: Anti-VEGF medication use is now considered first-line treatment for numerous retinal diseases globally. Exploring medication choices, costs within each healthcare system, policy challenges, emerging treatments, and patient access all provide insight into a newly recognized and major public health issue. METHODS: All data presented in this review are available through the published English literature in PubMed, non-peer-reviewed trade publications, and reported surveys. The following search terms were used: anti-VEGF OR bevacizumab OR ranibizumab OR aflibercept OR pegaptanib OR conbercept AND trends OR survey OR cost OR patterns OR preference. Countries with large populations and available data included the United States, United Kingdom, China, India, Korea, Singapore, and Australia. Population and economic statistics were obtained from published reports from the World Bank, World Health Organization, and Commonwealth Fund. RESULTS: Anti-VEGF medication use and costs are significant aspects of patient and healthcare system expenditures in each nation and may have an especially large potential economic burden in India and China. Bevacizumab use comprises the majority of anti-VEGF medication use in the United States and Singapore, although aflibercept use is growing rapidly. Paradoxically, data demonstrate that there is a significant trend in medication choice toward ranibizumab and aflibercept among practice settings outside of the United States, such as the United Kingdom, China, South Korea, and Australia. The price of anti-VEGF medications ranged from US $30 (ziv-aflibercept) to US $1950 (ranibizumab and aflibercept). Ranibizumab's price ranged from US $240 in India to US $1950 in the United States. Conbercept in China costs approximately US $1150 per dose. CONCLUSIONS: Outside of the United States, many nations are using a majority of more expensive anti-VEGF medications, which may lead to increased costs and decreased access. Increasing the availability of safely compounded anti-VEGF medications will likely improve access, create patient/provider choice, and decrease relative healthcare costs for the growing burden of retinal diseases globally.

Socio-economic status and outcomes for patients with age-related macular degeneration.

OBJECTIVES: To explore disparities in severity of baseline disease, treatment completion, and treatment outcomes among patients with wet age-related macular degeneration (AMD) receiving anti-vascular endothelial growth factor therapy by socio-economic status (SES) and distance from home to hospital. STUDY DESIGN: Retrospective cohort study. METHODS: Data from clinic records of 756 wet AMD patients receiving treatment for wet AMD with aflibercept between May 2013 and Jan 2017 were obtained. Area SES (using Index of Multiple Deprivation (IMD) 2015) and distance from hospital (dichotomized > = 10 vs. <10 km) were derived from anonymized postcodes. Univariate and multivariable logistic regression models were used to identify associations of area deprivation and distance from hospital at baseline-with visual acuity (VA) at baseline-treatment completion, and treatment outcome. RESULTS: Living in the most deprived compared with less deprived areas was associated with a significantly higher risk of presenting with severe reduction in VA (OR = 3.59; 95% CI = 1.39-9.27; P = .01). This association was maintained after adjustment for age, gender, and distance from hospital. On univariate analysis, delayed treatment completion was more likely in those living in most deprived areas (OR = 2.80; 95% CI = 1.21-6.47; P = .04), though this association was attenuated after adjustment for age, gender, and distance from hospital. No association was observed between SES and treatment outcomes or between distance from hospital and baseline VA, treatment completion or treatment outcome. CONCLUSION: This study found poorer baseline VA among people with wet AMD from more deprived areas. This work suggests a need for earlier identification of AMD among more deprived populations.

Evaluation of Physician Knowledge of the Key Safety Information for Aflibercept in Canada: Evaluation of Risk-Minimization Measures.

BACKGROUND: As part of the risk-management plan (RMP) for aflibercept, materials have been developed to educate physicians in Canada on the key safety information and safe use for aflibercept. OBJECTIVE: The objectives of this study were to assess whether physicians in Canada received and reviewed the aflibercept educational materials (i.e. vial preparation instruction card, intravitreal injection procedure video, and product monograph) and to evaluate their knowledge of key safety information. METHODS: Retinal specialists and ophthalmologists who prescribe and/or administer aflibercept were recruited to complete a survey. Physicians could complete and return a paper questionnaire by mail or complete the questionnaire online via a study website. RESULTS: Of the 308 physicians invited to participate in the survey, 95 (31%) completed the questionnaire. Nearly all physicians (98%) reported receiving at least one of the educational materials. The proportion of correct responses to individual questions on storage and preparation of aflibercept ranged from 54 to 98%. Physician knowledge was high on the recommended dose of aflibercept (91%), dose preparation (91-96% on individual items), and dosing guidelines (75-95% on individual items). Most physicians knew the contraindications for aflibercept (89%) and that aflibercept should not be used in pregnancy unless clearly indicated by medical need in which benefits outweigh risks (60%); 21% responded more conservatively that aflibercept should never be used in pregnancy. Knowledge was high for most questions about injection procedures (91-99% on individual items); however, fewer physicians (24%) correctly reported that the eye should be covered with a sterile drape. Knowledge was high for possible side effects (89-100% on individual items) and actions to take in relation to the potential for increased intraocular pressure (86-93% on individual items). CONCLUSION: Nearly all physicians (98%) reported having received the product monograph, and most (82%) reported having received the vial preparation instruction card; nearly half (46%) reported having received the intravitreal injection procedure video. Physicians' knowledge of the most important topics was high. Knowledge varied for topics that are less frequently encountered (e.g. use in women of childbearing potential) and for recommendations that are not standard medical practice in Canada (e.g. use of sterile drape).