Ranibizumab Biosimilars in Treating Retinal Disorders: A Cost-Effective Revolution?

Ranibizumab, is a humanized, monoclonal antibody fragment that binds and inactivates vascular endothelial growth factor-A (VEGF-A) and VEGF-B. One of the main indications for an intravitreal treatment with ranibizumab is age-related macular degeneration (AMD), which is a retinal disease with a high worldwide socioeconomic impact. Biosimilars constitute biological products that demonstrate similar pharmacodynamic and pharmacokinetic characteristics with a reference product, as well as comparable clinical efficacy, safety and immunogenicity. Since the approval of the first biosimilar Razumab, there has been a variety of new biosimilars available on the market. They offer the advantage of the same good clinical and safety results at a better price. All Ranibizumab biosimilars that have gained approval were tested in double masked Phase 3 clinical studies. The use of Ranibizumab biosimilars in neovascular AMD is well reported in the bibliography. Nevertheless, over the last few years, there is a tendency of using biosimilars in other retinal diseases like retinopathy of prematurity (ROP), diabetic macular edema (DME) or polypoidal choroidal vasculopathy (PCV). In conclusion, ranibizumab biosimilars offer a promising avenue for the management of retinal diseases, especially in countries with lower socioeconomic status, where there is lack of availability of innovator ranibizumab. However, further research is required to fully explore their efficacy, safety, and long-term outcomes in a plethora of retinal diseases.

Retinal changes after fluocinolone acetonide implant (ILUVIEN®) for DME: SD-OCT imaging assessment using ESASO classification.

INTRODUCTION: A detailed understanding of the anatomical and structural changes occurring in the retina following intravitreal fluocinolone acetonide implantation may help improve the management and prognosis of persistent or recurrent diabetic macular edema (DME). METHODS: Overall, 45 eyes (from 35 patients) with refractory center-involved DME received an intravitreal fluocinolone acetonide implant. They were monitored at baseline and at 6, 12, 24, and 36 months for best-corrected visual acuity (BCVA), central foveal thickness (CFT), and the seven retinal parameters used in the classification of diabetic maculopathy recently developed at the European School for Advanced Studies in Ophthalmology (ESASO). RESULTS: Within 6 months of implantation, significant improvements were evident in BCVA, CFT, maculopathy stage, and the percentage of eyes with: intraretinal cysts; CFT > 30% above the upper normal value; and disrupted or absent ellipsoid zone (EZ) and/or external limiting membrane (ELM). Significant improvements were still maintained at 36 months post-implantation. At month 36, early treatment with the implant (i.e., after < 6 previous intravitreal injections for DME) trended toward being more effective than later treatment in improving BCVA, CFT, maculopathy stage, and the percentage of eyes with CFT > 30% above the upper normal value. However, statistical significance was not achieved. CONCLUSION: In persistent or recurrent DME, fluocinolone acetonide implantation can be effective in improving maculopathy stage and reducing the percentage of eyes with: intraretinal cysts; CFT > 30% above the upper normal value; and disrupted or absent EZ and/or ELM. It can also increase BCVA and reduce CFT.

SGLT2 inhibitors and diabetic retinopathy progression.

PURPOSE: To evaluate whether sodium-glucose co-transporter 2 (SGLT2) inhibitors affect progression of non-proliferative diabetic retinopathy (NPDR) compared to standard of care. METHODS: A retrospective cohort study compared subjects enrolled in a commercial and Medicare Advantage medical claims database who filled a prescription for a SGLT2 inhibitor between 2013 and 2020 to unexposed controls, matched up to a 1:3 ratio. Patients were excluded if they were enrolled for less than 2 years in the plan, had no prior ophthalmologic exam, had no diagnosis of NPDR, had a diagnosis of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), had received treatment for vision-threatening diabetic retinopathy (VTDR), or were younger than 18 years. To balance covariates of interest between the cohorts, an inverse probability treatment weighting (IPTW) propensity score for SGLT2 inhibitor exposure was used. Multivariate Cox proportional hazard regression modeling was employed to assess the hazard ratio (HR) for VTDR, PDR, or DME relative to SGLT2 exposure. RESULTS: A total of 6065 patients who initiated an SGLT2 inhibitor were matched to 12,890 controls. There were 734 (12%), 657 (10.8%), and 72 (1.18%) cases of VTDR, DME, and PDR, respectively, in the SGLT2 inhibitor cohort. Conversely, there were 1479 (11.4%), 1331 (10.3%), and 128 (0.99%) cases of VTDR, DME, and PDR, respectively, among controls. After IPTW, Cox regression analysis showed no difference in hazard for VTDR, PDR, or DME in the SGLT2 inhibitor-exposed cohort relative to the unexposed group [HR = 1.04, 95% CI 0.94 to 1.15 for VTDR; HR = 1.03, 95% CI 0.93 to 1.14 for DME; HR = 1.22, 95% CI 0.89 to 1.67 for PDR]. CONCLUSION: Exposure to SGLT2 inhibitor therapy was not associated with progression of NPDR compared to patients receiving other diabetic therapies.

Subthreshold micropulse laser versus standard laser for the treatment of central-involving diabetic macular oedema with central retinal thickness of <400µ: a cost-effectiveness analysis from the DIAMONDS trial.

OBJECTIVES: To estimate the economic costs, health-related quality-of-life outcomes and cost-effectiveness of subthreshold micropulse laser (SML) versus standard laser (SL) for the treatment of diabetic macular oedema (DMO) with central retinal thickness (CRT) of <400µ. DESIGN: An economic evaluation was conducted within a pragmatic, multicentre, randomised clinical trial, DIAbetic Macular Oedema aNd Diode Subthreshold. SETTING: 18 UK Hospital Eye Services. PARTICIPANTS: Adults with diabetes and centre involving DMO with CRT<400µ. INTERVENTIONS: Participants (n=266) were randomised 1:1 to receive SML or SL. METHODS: The base-case used an intention-to-treat approach conducted from a UK National Health Service (NHS) and personal social services (PSS) perspective. Costs (2019-2020 prices) were collected prospectively over the 2-year follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained and the incremental net monetary benefit of SML in comparison to SL. Sensitivity analyses explored uncertainty and heterogeneity in cost-effectiveness estimates. RESULTS: One participant in the SL arm withdrew consent for data to be used; data from the remaining 265 participants were included in analyses. Mean (SE) NHS and PSS costs over 24 months were £735.09 (£111.85) in the SML arm vs £1099.70 (£195.40) in the SL arm (p=0.107). Mean (SE) QALY estimates were 1.493 (0.024) vs 1.485 (0.020), respectively (p=0.780), giving an insignificant difference of 0.008 QALYs. The probability SML is cost-effective at a threshold of £20 000 per QALY was 76%. CONCLUSIONS: There were no statistically significant differences in EQ-5D-5L scores or costs between SML and SL. Given these findings and the fact that SML does not burn the retina, unlike SL and has equivalent efficacy to SL, it may be preferred for the treatment of people with DMO with CRT<400µ. TRIAL REGISTRATION NUMBERS: ISRCTN17742985; NCT03690050.

Implante biodegradável de dexametasona para o tratamento do edema macular diabético em maiores de 18 anos, conforme Protocolo Clínico do Ministério da Saúde / Biodegradable dexamethasone implant for the treatment of diabetic macular edema in people over 18 years of age, according to the Clinical Protocol of the Ministry of Health

INTRODUÇÃO: A retinopatia diabética, a principal causa de cegueira em pessoas em idade laboral, é uma manifestação do diabetes na forma de lesão de órgãos-alvo. Clinicamente, as primeiras lesões são anormalidades vasculares como microaneurismas, hemorragias e exsudatos. O aumento da vasopermeabilidade resulta em espessamento da retina e/ou depósitos lipídicos. Quando esses eventos ocorrem na mácula, instala-se o edema macular diabético (EMD), levando ao risco de perda visual central. Dois mecanismos fundamentais estão envolvidos no EMD: angiogênese e inflamação. A angiogênese é secundária ao aumento da expressão de VEGF, principal molécula envolvida na perda da ruptura da barreira hemato-retiniana, que por sua vez causa a exsudação e espessamento macular. A inflamação pode ser causa ou consequência da angiogênese, atualmente considerada fator interdependente. Citocinas encontram-se elevadas em pacientes com retinopatia diabética e EMD, tendo correlação positiva com a severidade da doença ocular. O PCDT atual de retinopatia diabética, publicado pelo Ministério da Saúde, inclui os antiVEGFs ranibizumabe e aflibercepte para pacientes sem tratamento medicamentoso prévio, associado ou não à fotocoagulação a laser, para o EMD, mas não contempla a corticoterapia para o bloqueio da produção dos mediadores inflamatórios e barreira vascular endotelial. Por este motivo ainda existem necessidades não atendidas no cenário de tratamento das retinopatias diabéticas, especialmente relacionadas ao EMD. De acordo com a literatura, pacientes vitrectomizados, pacientes com eventos tromboembólicos recentes ou que não apresentaram resposta satisfatória ao tratamento com os antiangiogênicos, por exemplo, se encontram desassistidos pelo PCDT, além das dificuldades relacionadas ao regime de aplicações dos anti-VEGFs (injeções frequentes com deslocamentos aos serviços em saúde), complicando o atendimento no SUS. Ainda, relacionado às complicações da retinopatia diabética e qualidade de vida dos pacientes, a falta de tratamento ou tratamento subotimo pode levar à cegueira, além de outras complicações. BREVE HISTÓRICO: Em 2020 a tecnologia foi submetida e teve recomendação desfavorável devido as incertezas frente à ineficácia terapêutica, ausência de evidências robustas e falta de informação sobre delimitação e escopo para uso no SUS. PERGUNTA: O uso do implante intravítreo de dexametasona é seguro e efetivo no tratamento tratamento de adultos com edema macular diabético , como opção terapêutica no SUS? EVIDÊNCIAS CLÍNICAS: As evidências de eficácia e segurança do implante intravítreo de dexametasona são baseadas no estudo pivotal do implante intravítreo de dexametasona e em três estudos de comparação direta com os antiVEGFs, já incorporados ao SUS. O estudo pivotal que comparou o implante de dexametasona ao placebo, utilizando adicionalmente ou não a fotocoagulação a laser, demonstrou melhora da acuidade visual maior ou igual a 15 letras da linha de base do estudo, em ambos os braços de tratamento (DEXi 0,7 e 0,35 mg) em relação ao grupo placebo tratado apenas com fotocoagulação a laser. A melhora significativa no BCVA (do inglês, Best Corrected Visual Acuity) ocorreu independentemente do status do cristalino na linha de base do estudo. Os resultados do primeiro estudo de comparação direta são de não-inferioridade da dexametasona em relação ao ranibizumabe e redução do número de injeções realizadas, com perfil de segurança aceitável. O segundo estudo demonstrou equivalência da dexametasona ao tratamento com aflibercepte, uma vez que a diferença em BCVA não foi clinicamente significativa. O terceiro ECR de comparação direta incluído aponta para a segurança e eficácia em melhorar a BCVA e diminuir a espessura da mácula central, em pacientes com EMD, por ambos os implantes intravítreos (dexametasona vs ranibizumabe). A avaliação da qualidade metodológica dos ECRs foi realizada e os riscos de vieses foram descritos sendo de baixo risco, em sua maioria. AVALIAÇÃO ECONÔMICA: O presente dossiê demonstrou que Ozurdex se configura como uma tecnologia poupadora de recursos para o sistema de saúde, através de apresentação de uma análise de custo-minimização abrangente, que incluiu custos de medicação, custos de administração e custos relativos a potenciais eventos adversos. Através de uma análise de cenários que variou os principais parâmetros tais como horizonte temporal (1 ou 3 anos), e custo de aquisição dos comparadores (anti-VEGFs), valor de APAC (forma de financiamento dos antiangiogênicos) ou custo do frasco-ampola proposto pelos fabricantes em suas solicitações de incorporação, foi possível demonstrar que o tratamento com Ozurdex pode proporcionar economia de recursos que varia de R$ 1.533,21 até R$ 15.651,77 por paciente, em comparação aos anti-VEGFs. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Na análise de impacto orçamentário, foram avaliados sete cenários com combinações de diferentes valores para os comparadores (APAC e custo frasco-ampola), estimativas populacionais (epidemiológica ou demanda aferida) e dois possíveis comportamentos de market shares. A economia projetada foi de pelo menos R$ 8 milhões, avaliando o cenário mais conservador. Nos demais cenários as economias projetadas foram de R$ 16 e R$ 39 milhões, e entre R$ 148 e R$ 716 milhões em estimativa de usuários consideravelmente maior. Os montantes apresentados podem contribuir para a otimização dos recursos no manejo dos pacientes com RD. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas 3 tecnologias para compor o esquema terapêutico do edema macular diabético em adultos. São 3 anticorpos monoclonais inibidores do crescimento do endotélio vascular (VEGF): brolucizumabe, faricimabe e tarcocimabe tedromer, sendo que o segundo apresenta também ação anti-angiopoietina 2 (Ang-2). O brolucizumabe e faricimabe estão registrados na FDA e EMA desde 2022. O tarcocimabe está em fase 3 e pode apresentar resultados dos ensaios a partir de 2023. CONSIDERAÇÕES FINAIS: Adicionalmente às evidências clínicas de qualidade, a avaliação de custo-minimização possui e a análise de impacto orçamentário possuem incertezas em relação à definição de custos e cenários de comparação, mas que sugerem dominância do Implante biodegradável de dexametasona para tratamento do edema macular diabético sob a perspectiva do Sistema Único de Saúde. PERSPECTIVA DO PACIENTE: Foi aberta a Chamada Pública nº 09/2022 de 13 a 26 de fevereiro 2022 e duas pessoas se inscreveram, ambas representantes de associações de pacientes. A definição dos representantes titular e suplente foi determinada por decisão consensual entre o grupo de inscritos. A representante leu três relatos de pacientes que possuem edema macular diabético e recorrem ao DEXi. Os três pacientes iniciaram o tratamento com um antiangiogênico e, após o uso do DEXi, apresentaram melhora dos sintomas e o alcance de maior qualidade de vida. Nenhum deles manifestou eventos adversos após o uso do implante. RECOMENDAÇÃO PRELIMINAR: Os membros do plenário, presentes na 118ª Reunião ordinária da Conitec, no dia 03 de maio de 2023, deliberaram por unanimidade encaminhar para a consulta pública com recomendação favorável a incorporação do implante biodegradável de dexametasona para o tratamento do edema macular diabético (EMD) em maiores de 18 anos no SUS. CONSULTA PÚBLICA: Realizada no período de 03 de julho a 24 de julho do presente ano, teve 62 contribuições de caráter técnico-científico e 146 respostas tidas como de experiência ou opinião. As contribuições recebidas na consulta pública sobre o relatório que avalia a proposta de incorporação do Implante biodegradável de dexametasona para o tratamento do edema macular diabético (EMD) em maiores de 18 anos no SUS foram majoritariamente favoráveis a recomendação preliminar da Conitec, de incorporação. Não foram adicionadas na consulta pública, referências que alterassem a análise da evidência apresentada no relatório, apenas atualização pelo demandante. RECOMENDAÇÃO FINAL: Os membros do plenário, presentes na 121ª Reunião ordinária da Conitec, no dia 02 de agosto de 2023, deliberaram por unanimidade recomendar a incorporação do implante biodegradável de dexametasona para o tratamento do edema macular diabético (EMD) em maiores de 18 anos conforme Protocolo Clínico do Ministério da Saúde, sob registro de deliberação 840/2023. Para tal recomendação, levou-se em consideração, entre outros fatores, que há economia de recursos em todos os cenários analisados e que os estudos demostraram que o benefício clínico do implante de dexametasona é maximizado para algumas populações, que atualmente encontram-se desassistidas ou subtratadas devido à ausência de uma opção de corticoterapia no âmbito do SUS. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, o implante biodegradável de dexametasona para o tratamento do edema macular diabético em maiores de 18 anos, conforme Protocolo Clínico do Ministério da Saúde, publicada no Diário Oficial da União nº 193, seção 1, página 143, em 9 de outubro de 2023.

Disease burden of neovascular age-related macular degeneration and diabetic macular edema.

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) are the leading causes of vision impairment in elderly patients and people living with diabetes, respectively. Common features of nAMD and DME include increased vascular permeability, inflammation, and neovascularization. Intravitreal administration of vascular endothelial growth factor (VEGF) inhibitors has been the gold standard for treating retinal diseases, and numerous studies have demonstrated their ability to stabilize disease progression and improve visual acuity. However, many patients struggle with the burden of frequent injections, experience a suboptimal treatment response, or lose vision over time. For these reasons, the outcomes of anti-VEGF treatment are often worse in the real-world compared with clinical trials.

Treatment approaches for neovascular age-related macular degeneration and diabetic macular edema.

Neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) can cause substantial disease burden for patients. Several organizations have published clinical guidelines on appropriate diagnosis and treatment recommendations to alleviate this burden. Treatment approaches include both nonpharmacologic methods and pharmacologic therapies, with anti-vascular endothelial growth factor (VEGF) therapy being the standard of care. Anti-VEGF therapy is an effective treatment option for both nAMD and DME; however, long-term patient compliance may be reduced due to the burden of costs, monthly intravitreal injections, and repeat clinic visits to assess clinical response parameters. Emerging treatments and dosing strategies aim to decrease treatment burden and increase patient safety. Retina specialists can play a key role in improving the management of both nAMD and DME by incorporating patient-specific treatment strategies tailored to improve clinical outcomes. Enhanced knowledge of retinal disease therapies will allow clinicians to optimize evidence-based treatment strategies to improve clinical outcomes for their patients.

The role of managed care professionals in the management of neovascular age-related macular degeneration and diabetic macular edema.

Managed care professionals play a significant role in the management of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) through formulary management and drug utilization strategies. These strategies are designed to improve access to affordable care and minimize medical costs to both patients and payers. Preserving vision in patients with nAMD and DME is key to improving clinical outcomes and reducing the risk of comorbid conditions, such as depression. With the approval of new intravitreal treatment options, managed care professionals must stay up to date with evidence-based guidelines as well as the addition of cost-effective treatments to drug formularies to better manage health care resources and improve patient outcomes.

Cost-Effectiveness of Dexamethasone Intravitreal Implant in Naïve and Previously Treated Patients with Diabetic Macular Edema.

PURPOSE: To compare the direct costs associated with the dexamethasone intravitreal implant (DEX-i) in treatment-naïve and previously treated eyes with diabetic macular edema (DME) in a real clinical setting. METHODS: Retrospective and single-center study conducted in a real clinical scenario. Consecutive DME patients, either naïve or previously treated with vascular endothelial growth factor inhibitors (anti-VEGF), who received treatment with one or more DEX-i between May 2015 and December 2020, and who were followed-up for a minimum of 12 months, were included in the study. The cost analysis was performed from the perspective of the Andalusian Regional Healthcare Service. The primary effectiveness endpoint was the probability of achieving an improvement in best-corrected visual acuity (BCVA) ≥ 15 ETDRS letters after 1 year of treatment. The incremental cost-effectiveness ratio (ICER) of different improvements in BCVA was calculated. RESULTS: Forty-nine eyes, twenty-eight (57.1%) eyes from the treatment-naïve group and twenty-one (42.9%) from the previously treated group, were included in the analysis. The total cost of one year of treatment was significantly lower in the treatment-naïve eyes than in the previously treated eyes [Hodges-Lehmann median difference: EUR 819.1; 95% confidence interval (CI): EUR 786.9 to EUR 1572.8; p < 0.0001]. The probability of achieving a BCVA improvement of ≥15 letters at month 12 was significantly greater in the treatment-naïve group than in the previously treated group (rate difference: 0.321; 95% CI: 0.066 to 0.709; p = 0.0272). The Cochran-Mantel-Haenszel Odds Ratio of achieving a BCVA improvement of ≥15 letters at month 12 was 3.55 (95% CI: 1.09 to 11.58; p = 0.0309). In terms of ICER, the treatment-naïve group showed cost savings of EUR 7704.2 and EUR 5994.2 for achieving an improvement in BCVA ≥ 15 letters at month 12 and at any of the measured time points, respectively. CONCLUSIONS: DEX-i was found to be more cost-effective in treatment-naïve eyes than in those previously treated with anti-VEGF. Further studies are needed to determine the most cost-effective treatment based on patient profile.

Cost-effectiveness of Aflibercept Monotherapy vs Bevacizumab First Followed by Aflibercept If Needed for Diabetic Macular Edema.

Importance: The DRCR Retina Network Protocol AC showed no significant difference in visual acuity outcomes over 2 years between treatment with aflibercept monotherapy and bevacizumab first with switching to aflibercept for suboptimal response in treating diabetic macular edema (DME). Understanding the estimated cost and cost-effectiveness of these approaches is important. Objective: To evaluate the cost and cost-effectiveness of aflibercept monotherapy vs bevacizumab-first strategies for DME treatment. Design, Setting, and Participants: This economic evaluation was a preplanned secondary analysis of a US randomized clinical trial of participants aged 18 years or older with center-involved DME and best-corrected visual acuity of 20/50 to 20/320 enrolled from December 15, 2017, through November 25, 2019. Interventions: Aflibercept monotherapy or bevacizumab first, switching to aflibercept in eyes with protocol-defined suboptimal response. Main Outcomes and Measures: Between February and July 2022, the incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-year (QALY) over 2 years was assessed. Efficacy and resource utilization data from the randomized clinical trial were used with health utility mapping from the literature and Medicare unit costs. Results: This study included 228 participants (median age, 62 [range, 34-91 years; 116 [51%] female and 112 [49%] male; 44 [19%] Black or African American, 60 [26%] Hispanic or Latino, and 117 [51%] White) with 1 study eye. The aflibercept monotherapy group included 116 participants, and the bevacizumab-first group included 112, of whom 62.5% were eventually switched to aflibercept. Over 2 years, the cost of aflibercept monotherapy was $26 504 (95% CI, $24 796-$28 212) vs $13 929 (95% CI, $11 984-$15 874) for the bevacizumab-first group, a difference of $12 575 (95% CI, $9987-$15 163). The aflibercept monotherapy group gained 0.015 (95% CI, -0.011 to 0.041) QALYs using the better-seeing eye and had an ICER of $837 077 per QALY gained compared with the bevacizumab-first group. Aflibercept could be cost-effective with an ICER of $100 000 per QALY if the price per dose were $305 or less or the price of bevacizumab was $1307 per dose or more. Conclusions and Relevance: Variability in individual needs will influence clinician and patient decisions about how to treat specific eyes with DME. While the bevacizumab-first group costs still averaged approximately $14 000 over 2 years, this approach, as used in this study, may confer substantial cost savings on a societal level without sacrificing visual acuity gains over 2 years compared with aflibercept monotherapy.

Comparison of Snellen Visual Acuity Measurements in Retinal Clinical Practice to Electronic ETDRS Protocol Visual Acuity Assessment.

PURPOSE: Evaluate the differences between clinical visual acuity (VA) as recorded in medical records and electronic Early Treatment Diabetic Retinopathy Study (eETDRS) protocol VA measurements and factors affecting the size of the differences. DESIGN: Retrospective chart review. PARTICIPANTS: Study and fellow eyes of participants enrolled in DRCR Retina Network Protocols AC and AE (diabetic macular edema), and W (nonproliferative diabetic retinopathy) with clinical VA recorded within 3 months before the protocol visit. METHODS: Differences and their association with patient and ocular factors were evaluated using linear mixed models with random effects for correlations within sites and participants. MAIN OUTCOME MEASURE: Difference between VA letter scores measured by eETDRS during a study visit versus measured by Snellen during a regular clinical visit (Snellen fraction converted to eETDRS). RESULTS: Data from 1016 eyes (511 participants) across 74 sites were analyzed. The mean VA measurements were 68.6 letters (Snellen equivalent 20/50) at the clinical visit and 76.3 letters (Snellen equivalent 20/32) at the protocol visit, with a mean (standard deviation [SD]) of 26 (21) days between visits. Mean (SD) protocol VA was better than clinical VA by 7.6 (9.6) letters overall, 10.7 (12.6) letters in eyes with clinical VA ≤ 20/50 (n = 376), and 5.8 (6.6) letters in eyes with clinical VA ≥ 20/40 (n = 640). On average, the difference between clinical and protocol VA was 1.3 letters smaller for every 1-line (5 letters) increase in clinical VA (P < 0.001). Mean (SD) differences by clinical correction of refractive error were 3.9 (9.0) letters with refraction, 6.9 (9.2) letters with glasses/contact lenses, 7.9 (11.5) letters with pinhole, and 9.8 (9.3) letters without correction (P = 0.06). CONCLUSIONS: On average, clinical Snellen VA is 1 to 2 lines worse than eETDRS protocol refraction and VA testing, which may partly explain why clinical practice does not always replicate clinical trial results. Eyes with lower clinical measurements and eyes tested without clinical refraction tended to have larger differences. Considering the potential discrepancies between clinical and protocol VA measurements, refracting eyes in the clinic may benefit patients when determining treatment plans and study referrals based on vision. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Early-switch versus late-switch in patients with diabetic macular edema: a cost-effectiveness study.

BACKGROUND: To evaluate the cost-effectiveness of early- versus late-switch to the intravitreal-dexamethasone implant (DEX-i) in patients with diabetic macular edema (DME) who did not adequately respond to vascular endothelial growth factor inhibitors (anti-VEGF). METHODS: Retrospective analysis of a multicenter Clinical Data Registry. The registry included DME eyes who received 3 intravitreal anti-VEGF injections (early-switch) or > 3 intravitreal anti-VEGF injections (late-switch) before switching to DEX-i injections. The primary outcome was to estimate the incremental cost needed to obtain a best-corrected visual acuity (BCVA) improvement ≥ 0.1 or a central-retinal thickness CRT ≤ 250 µm. RESULTS: The analysis included 108 eyes, 32 (29.6%) and 76 (70.4%) in the early- and late-switch groups, respectively. Early-switch strategy was associated with a cost saving of €3,057.8; 95% CI: €2,406.4-3,928.4, p < 0.0001). Regarding incremental-cost-effectiveness ratio, late-switch group was associated with an incremental cost of €25,735.2 and €13,533.2 for achieving a BCVA improvement ≥ 0.1 at month 12 and at any of the time-point measured, respectively. At month 12, 38 (35.2%) eyes achieved a BCVA improvement ≥ 0.1. At month 12, 52 (48.1) eyes had achieved a CRT ≤ 250 micron. As compared to baseline, the mean (95% CI) CRT reduction was - 163.1 (- 212.5 to - 113.7) µm and - 161.6 (- 183.8 to - 139.3) µm in the early-switch and late-switch groups, respectively, p = 0.9463. CONCLUSIONS: In DME eyes, who did not adequately respond to anti-VEGF, switching to DEX-i at early stages (after the first 3-monthly injections) was found to be more cost-effective than extending the treatment to 6-monthly injections of anti-VEGF.

Aflibercept Monotherapy versus Bevacizumab-First for Diabetic Macular Edema: A Cost Analysis Based on Diabetic Retinopathy Clinical Research Network Protocol AC Results.

PURPOSE: To calculate the costs of treatment for diabetic macular edema with bevacizumab-first (step therapy) compared with aflibercept monotherapy. DESIGN: Cost analysis of the treatment arms based on a published study. SUBJECTS: None. METHODS: Published results from the Diabetic Retinopathy Clinical Research Network protocol AC were used to assess costs. Data incorporated in the usage and outcome model included the frequency of injections, medication type, visits, and imaging. Costs were modeled based on the 2022 Medicare reimbursement data for both facility (hospital-based) and nonfacility settings in Miami. Outcomes were similar in protocol AC so were not differentially studied. Results were extrapolated so as to estimate lifetime (17 years for the age of the cohort). MAIN OUTCOME MEASURES: Cost of treatment options. RESULTS: Over the 2 years reported in the protocol AC, the cost required to treat in the facility (nonfacility setting) was $42 000 ($32 000) in the aflibercept monotherapy group and $29 000 ($22 000) in the bevacizumab-first group. Extrapolated modeled lifetime costs were $158 000 ($136 000) and $125 000 ($103 000), respectively. The total cost with bevacizumab-first was 33% lower at year 2 and 21% lower at year 17 compared with aflibercept monotherapy. Savings per year for the 2 years results were $6500 ($5000) in the facility (nonfacility) setting. For the extrapolated 17 years model, annual savings were $1900 ($1900) in the facility (nonfacility) setting. The professional fees accounted for a minority of overall costs; in contrast, medication costs accounted for 82% of the total costs for the aflibercept monotherapy and 73% in the bevacizumab-first group at 2 years. Our model predicted an additional 15% lifetime cumulative savings if patients still not meeting the threshold criteria after switching to aflibercept were placed back on bevacizumab, and a similar degree of improvement if those on not meeting threshold criteria on aflibercept monotherapy were switched to bevacizumab. CONCLUSIONS: Medication is the dominant driver of the total expenses associated with the treatment of diabetic macular edema. Although cost savings are realized with bevacizumab-first step therapy, the magnitude was not as much as might be intuited, probably because of the high (70%) incidence of patients switching to aflibercept within protocol AC. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Eficacia y seguridad del implante intravítreo de dexametasona de liberación prolongada sostenida para el tratamiento de pacientes adultos con edema macular secundario a oclusión venosa retiniana con disminución de la agudeza visual y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab / Efficacy and safety of intravitreal sustained-release dexamethasone implant for the treatment of adult patients with macular edema secondary to retinal vein occlusion with decreased visual acuity and/or increased or maintained macular thickness despite the use of three injections of bevacizumab

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N' 111-IETSI-ESSALUD-2021 se ha elaborado el presente dictamen. el cual expone la evaluación de la eficacia y seguridad del implante intravítreo de dexametasona de liberación prolongada sostenida para el tratamiento de pacientes adultos con edema macular secundario a oclusión venosa retiniana con disminución de la agudeza visual y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. Así. la médica Fiorella Norabuena Mautino. especialista en oftalmología del Servicio de Retina, a través del Comité Farmacoterapéutico del Hospital Nacional Edgardo Rebagliati Martins y siguiendo la Directiva N' 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de autorización de uso del producto farmacéutico dexametasona (implante intravítreo) no incluido en el Petitorio Farmacológico de EsSalud. ASPECTOS GENERALES: La oclusión venosa retiniana (OVR), una obstrucción parcial o completa del sistema venoso retinal, es considerada la segunda causa más común de trastorno vascular de la retina (Cugati et al., 2006; PAAO, 2019), y es una causa importante de pérdida de la visión en adultos a nivel mundial (Rogers et al., 2010: Song et al., 2019). En el 2015, se estimó que la prevalencia global de la OVR en personas de entre 30 y 89 años fue de 0.77 % (Song et al., 2019). Los dos tipos más comunes de OVR, son la oclusión de la rama venosa de la retina (ORVR), que ocurre en la vena retinal distal y ocasiona hemorragia en un vaso pequeño de la retina; y la oclusión de la vena central de la retina (OVCR), que ocurre en la vena retinal proximal y ocasiona hemorragia en toda la retina (Han & Ahmad, 2021). En un estudio realizado con datos de Europa, Asia, Australia y Estados Unidos se reporta que la prevalencia ajustada por edad y sexo de la ORVR es de 3.77 por 1000 personas, y de la OVCR es de 0.65 por 1000 personas. METODOLOGÍA: Se realizó una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad del uso de IIDLPS en el tratamiento de pacientes adultos con EM secundario a ORVR u OVCR con disminución de la AV y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library, LILACS y The Web of Science. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas. evaluaciones de tecnologías sanitarias y guías de práctica clínica. tales como The National Institute for Health and Care Excellence (NICE). RESULTADOS: De la búsqueda bibliográfica, se incluyó una GPC elaborada por The Royal College of Ophthalmologists (RCO) (The Royal College of Ophthalmologists. 2022). y tres estudios retrospectivos que evaluaron el cambio de bevacizumab a IIDLPS (Chiquet et al.. 2016: Lee et al.. 2017: Sharareh et al., 2013). Además se incluyeron dos GPC que fueron sugeridas por los especialistas de EsSalud, elaboradas por The European Society of Retina Specialists (EURETINA) (Schmidt-Erfurth et al., 2019) y la Sociedad Española de Retina y Vítreo (SERV) (SERV, 2015). No se identificaron RS con MA ni ETS que respondan a la pregunta PICO del presente dictamen. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación aprueba el uso de implante intravitreo de dexametasona de liberación prolongada sostenida (IIDLPS) para el tratamiento de pacientes adultos con edema macular (EM) secundario a oclusión de la vena central de la retina (OVCR) u oclusión de la rama venosa de la retina (ORVR) con disminución de la AV y/o incremento o mantenimiento del grosor macular a pesar del uso de tres inyecciones de bevacizumab. como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud. según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de 1 año a partir de la fecha de publicación. La continuación de dicha aprobación está sujeta a la evaluación de los resultados obtenidos y de nueva evidencia que pueda surgir en el tiempo.

Suprachoroidal Injection of Triamcinolone Acetonide Injectable Suspension for the Treatment of Macular Edema Associated With Uveitis in the United States: A Cost-Effectiveness Analysis.

OBJECTIVES: Suprachoroidal injection of triamcinolone acetonide is the first Food and Drug Administration-approved treatment for macular edema associated with uveitis. A cost-effectiveness analysis was performed comparing this treatment with best supportive care (BSC) for the management of this indication from US Medicare and commercial payer perspectives. METHODS: A patient-level simulation was developed per the patient characteristics and changes in best-corrected visual acuity letter scores observed in a phase III study of triamcinolone acetonide (PEACHTREE). The wholesale acquisition cost of triamcinolone acetonide was $1650/injection; suprachoroidal injection cost was assumed at $200/injection. Healthcare costs were informed by a US claims-based analysis. Mortality risk associated with severe vision loss and blindness was modeled by applying a hazard ratio to all-cause mortality rates of the US general population. Health-related quality of life weights, obtained from a regression model fitted to the Visual Function Questionnaire-25 data from PEACHTREE, were applied based on the best-corrected visual acuity scores of both eyes. Costs (2020 US dollar) and benefits were discounted at 3% annually. Incremental cost-effectiveness ratios were estimated over a 10-year horizon. RESULTS: In the base-case, the incremental cost-effectiveness ratio comparing triamcinolone acetonide with BSC was $28 479 per quality-adjusted life-year gained. The wholesale acquisition cost for triamcinolone acetonide for suprachoroidal use was ∼68%, ∼56%, and ∼27% below the willingness-to-pay thresholds of $150 000, $100 000, and $50 000 per quality-adjusted life-year gained, respectively. Results were robust in sensitivity and scenario analyses. CONCLUSIONS: Triamcinolone acetonide for suprachoroidal use is cost-effective compared with BSC for patients with macular edema associated with uveitis.

Economic Aspects in the Management of Diabetic Macular Edema in Italy.

Background: Diabetic Macular Edema (DME) is the most common cause of vision loss in diabetic patients. Currently, the Vascular Endothelial Growth Factor inhibitors (anti-VEGFs) are used as the first line of DME treatment and corticosteroid implants are usually used as a second-line treatment. These implants are a safe and effective therapeutic option that can improve the quality of life of DME patients by reducing the intravitreal injections number. We determined the economic impact related to DME, also from the social perspective, and the consequences of the increased use of the dexamethasone implant. Methods: The analysis compares two scenarios: the first based on the current rate of recourse to the therapeutic alternatives available in the Italian healthcare setting (as is) and the second based on the assumption of an increased recourse to dexamethasone implants (to be). The results are expressed both in terms of the resource absorption associated with the two scenarios and in terms of the cost differential yielded by their comparison. Results: The increased use of the dexamethasone implant allows considerable savings in terms of healthcare professionals' time, follow-up and productivity lost by patients/caregivers. These savings would reduce healthcare costs for the management of DME patients in Italy by €2,058,238 in 5 years. Conclusions: To optimize the healthcare resources allocation, it is necessary to implement treatments that yield not only cost reductions but also a clinical benefit for patients. The dexamethasone implant use is an example of DME management that generates value for patients, health system and society.

A Caveat About Financial Incentives for Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Retinopathy.

PURPOSE: To highlight the financial incentive to the physician of choosing an intravitreal anti-vascular endothelial growth factor (VEGF)-based strategy for treating non-proliferative and proliferative diabetic retinopathy, and its possible risks to the patient and costs to the health care system. DESIGN: Perspective with retrospective cost and profit analysis. METHODS: Review and synthesis of selected literature on the treatment of diabetic retinopathy, with interpretation of activity-based and time-based costing of an intravitreal aflibercept strategy for diabetic retinopathy. Data from the DRCR Retina Network Protocols W and AB and PANORAMA trial were used to illustrate the potential financial incentive underlying such a treatment strategy. RESULTS: Physician treatment algorithms for diabetic vitreous hemorrhage and non-proliferative diabetic retinopathy may be influenced by the substantial financial incentives that intravitreal aflibercept strategies present, despite functional equivalence with alternative and less profitable strategies. For example, pursuing an intravitreal aflibercept-based strategy for diabetic vitreous hemorrhage presents a 76% increased profit over pars plana vitrectomy with laser, with equivalent functional outcomes. For non-proliferative diabetic retinopathy, preventative aflibercept injections represent a potential 414% increase in profit over observation and an increased cost of $12,164 to $17,542 over 2 years per patient, with no improvement in visual function. These findings demonstrate that there may be misaligned financial incentives in the management of diabetic retinopathy. CONCLUSIONS: While anti-VEGF therapy is a useful tool in the management of proliferative diabetic retinopathy and diabetic macular edema, it is believed that physicians should avoid overreliance on anti-VEGF injections in the treatment of diabetic retinopathy. Retinal specialists should be cognizant of the limitations, costs, and risks of anti-VEGF monotherapy and prophylactic therapy, and of the imperative to avoid bias towards financially remunerative practice patterns when equally effective alternatives exist.

Assessment for Macular Thickness after Uncomplicated Phacoemulsification Using Optical Coherence Tomography.

PURPOSE: Macular edema including cystoid macular edema is one of the main causes of unfavorable visual outcomes after cataract surgery. The macular thickness and the occurrence of macular edema after uncomplicated cataract surgery was evaluated using optical coherence tomography (OCT) in this study. METHODS: Macular map images were taken by OCT before surgery and at 1 week, 1 month, and 2 months postsurgery. The subjects were classified into two groups (group 1, patients with no macular edema; group 2, patients with macular edema). Group 2 was defined as increase in central macular thickness (CMT) by 30% compared with that before surgery. The risk factors for macular edema were evaluated. Group 2 was divided into two subgroups: subclinical macular edema (group 2A) and cystoid macular edema (group 2B) and they were assessed in terms of the clinical course of best-corrected visual acuity and CMT. RESULTS: A total of 376 patients were enrolled in this study, of which 36 (9.57%, group 2) showed macular edema measured by OCT after the surgery. Univariate analysis for group 1 and 2 revealed that intracameral injection of epinephrine during phacoemulsification was associated with the development of macular edema. In group 2, five patients (1.33%) developed cystoid macular edema. Statistically significant differences in the clinical course of CMT were observed at 2 months (201.2 ± 23.1, 250.0 ± 29.8, and 371.0 ± 160.3 in group 1, group 2A, and group 2B, respectively; p < 0.001) and 1 month postoperatively (198.5 ± 23.6, 237.8 ± 40.9, and 314.0 ± 104.5 in group 1, group 2A, and group 2B, respectively; p < 0.001). Group 2B required additional treatment and eventually achieved best-corrected visual acuity of >0.2 with CMT in the normal range. CONCLUSIONS: The intracameral injection of epinephrine may cause macular edema after uncomplicated cataract surgery. Examination of CMT using OCT is recommended for the early detection of macular edema.

Healthcare expenditure of intravitreal anti-vascular endothelial growth factor inhibitors compared with dexamethasone implant for diabetic macular oedema.

PURPOSE: The aim of this study was to estimate the 1-year costs associated with treating diabetic macular oedema (DME) patients using current intravitreal anti-vascular endothelial growth factor (anti-VEGF) biologics compared with the dexamethasone implant. METHODS: We conducted a descriptive cost-evaluation analysis using data from Oslo University Hospital and literature to compare three different intravitreal drugs for DME: bevacizumab, aflibercept and dexamethasone. Stratification of patients into 'Naive' or 'Switch' group was based on treatment history. We estimated the costs from healthcare and 'extended' healthcare perspectives. Sensitivity analysis evaluated the impact of various parameters. RESULTS: The average injections per patient per year for the Naive group (bevacizumab), Switch group (aflibercept) and dexamethasone were 9.5, 9.1 and 3.0 respectively. From a healthcare perspective, the 1-year costs for the Naive group were 15% lower (bevacizumab, €3619), and for the Switch group, 23% higher (aflibercept, €5226) compared with dexamethasone (€4252). The 'extended' healthcare perspective showed the cost per patient per year for bevacizumab remained nominally lower in the Naive group, while dexamethasone remained lower for the Switch group (€5116 for dexamethasone, compared to €4987 for bevacizumab and €6537 for aflibercept). CONCLUSIONS: From a primary healthcare perspective, the dexamethasone as a first-line DME treatment may increase economic costs in settings where bevacizumab is used off-label. Treating resistant DMEwith dexamethasone may reduce the costs and treatment burden compared with switching to aflibercept.

Managed care opportunities and approaches to select treatment for sight preservation.

Anti-vascular endothelial growth factor therapies have become the mainstay of treatment for both diabetic macular edema and neovascular age-related macular degeneration. This treatment is imperative for vision preservation including visual acuity. However, treatment burdens include high costs, frequent injections, continued visual loss, and loss of ability to perform day-to-day functions. Although clinical trial data have provided insights to treatment options and protocols, real-world patient experiences and adherence to therapies do not often mimic clinical trials as patients cannot fully adhere to their treatment schedule, leading to poor disease outcomes. Payers may consider various strategies such as step therapies, fee schedule management, and driving utilization through specialty pharmacies to contain costs. However, it is important to recognize not all patients will respond to a one-size-fits-all approach to treatment, warranting a more personalized approach.