Does the induction immunotherapy (basiliximab) influence the early acute cellular rejection index after orthotopic heart transplantation?- Preliminary assessment report.

The study aimed to determine the influence of induction therapy on the acute cellular rejection (ACR) index in adult heart transplant recipients during the one-year observation. The study population consisted of 256 consecutive adult patients (pts), aged 51.5 (±11.9) years, 199 (77%) men treated with orthotopic heart transplantation (OHT) in the period between 2015 and 2020 in a single high-volume heart transplant center. The endomyocardial biopsies (EMBs) were performed according to the protocol consisting of 7 protocolary EMBs for up to 3 months and 10 EMBs for up to one year after OHT. The rejection index (ACRI) was calculated as the number of scheduled EMBs with the ACR ≥ 2 divided by the total number of protocolary EMBs. The study population was divided into two groups according to the application of basiliximab. The total number of pts. who received basiliximab was 10 (3.9%). The main indications for the usage of the induction therapy were heart retransplantation, mechanical circulatory support (MCS), severe renal insufficiency (eGFR <30 mL/min/1.73 m2), and a panel of reactive antibody (PRA) > 10%. In the group with induction, the mean age was 49 (±14) years; 3 (30%) patients had the MCS prior to OHT, and 3 (30%) patients had heart retransplantation. Four (40%) patients had diabetes mellitus, and 4 (40%) patients had severe renal insufficiency. As maintenance therapy during the observation period, tacrolimus was given to 10 (100%) patients, everolimus to 2 (20%) patients, and MPA to 9 (90%) patients. In the group with no induction, the mean age was 51.8 (±12) years, MCS was used in 56 (23%) patients, 2 (0.8%) patients were retransplanted; 10 (4%) patients had eGFR <30 mL/min/1.73 m2 and 58 (24%) patients had diabetes. Tacrolimus was administered to 243 (99%) patients, cyclosporine to 3 (1%), everolimus to 40 (16%), and mycophenolate to 245 (99.6%) heart recipients. The median one-year ACRI was 0.0, IQR:0.0-0.08 in the group with induction vs. 0.077, IQR: 0.0-0.154 with no induction; p = 0.11. ACRI up to three months was significantly higher in the entire cohort in comparison to up to one year (P < 0.01). The multivariate analysis showed that only everolimus implementation and younger age at the time of transplant influenced patients' mortality rate (P < 0.01). Significant graft rejections (≥ 2R ISHLT) are most common in the first three months after OHT. Patients who are initially at high risk of significant cellular rejection may benefit from induction therapy.

Cost-Utility Comparison of Bevacizumab and Aflibercept in the Treatment of Central or Hemiretinal Vein Occlusion in the SCORE2 Trial.

Importance: Retinal vein occlusion is the second most common retinal vascular disease. Bevacizumab was demonstrated in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) to be noninferior to aflibercept with respect to visual acuity in study participants with macular edema due to central retinal vein occlusion (CRVO) or hemiretinal vein occlusion (HRVO) following 6 months of therapy. In this study, the cost-utility of bevacizumab vs aflibercept for treatment of CRVO is evaluated. Objective: To investigate the relative cost-effectiveness of bevacizumab vs aflibercept for treatment of macular edema associated with CRVO or HRVO. Design, Setting, and Participants: This economic evaluation study used a microsimulation cohort of patients with clinical and demographic characteristics similar to those of SCORE2 participants and a Markov process. Parameters were estimated and validated using a split-sample approach of the SCORE2 population. The simulated cohort included 5000 patients who were evaluated 100 times, each with a different set of characteristics randomly selected based on the SCORE2 trial. SCORE2 data were collected from September 2014 October 2019, and data were analyzed from October 2019 to July 2021. Interventions: Bevacizumab (followed by aflibercept among patients with a protocol-defined poor or marginal response to bevacizumab at month 6) vs aflibercept (followed by a dexamethasone implant among patients with a protocol-defined poor or marginal response to aflibercept at month 6). Main Outcomes and Measures: Incremental cost-utility ratio. Results: The simulation demonstrated that patients treated with aflibercept will have an expected cost $18 127 greater than those treated with bevacizumab in the year following initiation. When coupled with the lack of clinical superiority over bevacizumab (ie, patients treated with bevacizumab had a gain over aflibercept in visual acuity letter score of 4 in the treated eye and 2 in the fellow eye), these results demonstrate that first-line treatment with bevacizumab dominated aflibercept in the simulated cohort of SCORE2 participants. At current price levels, aflibercept would be considered the preferred cost-effective option only if treatment restored the patient to nearly perfect health. Conclusions and Relevance: While there will be some patients with CRVO-associated or HRVO-associated macular edema who will benefit from first-line treatment with aflibercept rather than bevacizumab, given the minimal differences in visual acuity outcomes and large cost differences for bevacizumab vs aflibercept, first-line treatment with bevacizumab is cost-effective for this condition.

Assessment of joint bleeding and target joints in patients with severe or moderately severe hemophilia B (factor IX ≤2%) receiving prophylaxis with rIX-FP in the PROLONG-9FP clinical trial program.

OBJECTIVE: To assess the impact of prophylaxis with rIX-FP, a fusion protein linking recombinant factor IX (FIX) with human albumin, on joint outcomes. METHODS: Joint outcomes were assessed in pediatric (<12 years) and adult/adolescent (≥12 years) patients receiving rIX-FP prophylaxis every 7, 10, or 14 days; patients (>18 years) well-controlled on a 14-day regimen could switch to a 21-day regimen. Target joints were defined as ≥3 spontaneous bleeds into a single joint within a 6-month period. RESULTS: For adult/adolescent (n = 63) and pediatric (n = 27) patients, median (Q1, Q3) annualized joint bleeding rate was 0.39 (0.00, 2.31), 0.80 (0.00, 2.85), 0.20 (0.00, 2.58), and 0.00 (0.00, 1.78) when treated with 7-, 10-, 14-, or 21-day prophylaxis. 50.0%, 38.9%, 45.5%, and 63.6% of adult/adolescent patients had no joint bleeds when treated with 7-, 10-, 14-, or 21-day prophylaxis, respectively, and 40.7%, 37.5%, and 37.5% of pediatric patients had no joint bleeds when treated with 7-, 10-, or 14-day prophylaxis. Ten adult and two pediatric patients developed target joints; all resolved by the end of the study. CONCLUSION: Prophylaxis with rIX-FP produced low joint bleeding rates and provided excellent hemostatic efficacy in the treatment of joint bleeds. All target joints reported resolved with rIX-FP prophylaxis.

The Biosimilar Paradox: How Anti-Vascular Endothelial Growth Factor Biosimilars Could Increase Patient and Overall Health Care Costs.

PURPOSE: Anti-vascular endothelial growth factor (VEGF) medications for intraocular use are a major and increasing cost, and biosimilars may be a means of reducing the high cost of many biologic medications. However, a bevacizumab biosimilar, which is currently pending Food and Drug Administration (FDA) approval (bevacizumab-vikg), paradoxically may increase the cost burden of intravitreal anti-VEGF agents, because off-label repackaged drugs may no longer be allowed per the Drug Quality and Security Act (DQSA). We aimed to investigate the potential impact of biosimilars on costs in the United States. DESIGN: Cost analysis of anti-VEGF medications. PARTICIPANTS: Medicare data from October 2022 and previously published market share data from 2019. METHODS: Average sales prices (ASPs) of ranibizumab, aflibercept, and bevacizumab were calculated from Medicare allowable payments. The ASPs of biosimilars were calculated from wholesale acquisition costs from a representative distributor. The cost of an intraocular bevacizumab formulation is modeled at $500/1.25-mg dose and $900/1.25-mg dose. MAIN OUTCOME MEASURES: Costs of anti-VEGF drugs to Medicare Part B and patients. RESULTS: If an intraocular bevacizumab biosimilar were to be priced at $500, costs to Medicare would increase by $457 million from $3.01 billion to $3.47 billion (15.2% increase). Patient responsibility would increase by $117 million from $768 million to $884 million. Similarly, if intraocular bevacizumab were priced at $900, Medicare costs would increase by $897 million to $3.91 billion (29.8% increase), and patient responsibility would increase by $229 million to $997 million. If bevacizumab were $500/dose, switching all patients currently receiving ranibizumab or aflibercept to respective biosimilars would compensate for only 28.8% of the increased cost. Current prices of ranibizumab and aflibercept biosimilars would have to decrease by an aggregate of 15.7% to $616.80/injection, $1027.97/injection, and $1436.88/injection for ranibizumab 0.3 mg, ranibizumab 0.5 mg, and aflibercept, respectively. CONCLUSIONS: An FDA-approved bevacizumab biosimilar for ophthalmic use could increase costs to the health care system and patients, raising concerns for access. This increase would not be offset by ranibizumab and aflibercept biosimilar use at current prices. These data support the need for an exemption of section 503B of the DQSA and continued use of repackaged off-label bevacizumab. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Post hoc longitudinal assessment of the efficacy and safety of recombinant factor IX Fc fusion protein in hemophilia B.

Long-term efficacy and safety of the extended half-life recombinant factor IX Fc fusion protein (rFIXFc) has been established among previously treated patients with severe hemophilia B in 2 phase 3 trials (B-LONG [#NCT01027364] and Kids B-LONG [#NCT01440946]) and a long-term extension study (B-YOND [#NCT01425723]). In this study, we report post hoc analyses of pooled longitudinal data for up to 6.5 years for rFIXFc prophylaxis. In the B-LONG study, subjects ≥12 years received weekly dose-adjusted prophylaxis (WP; starting dose, 50 IU/kg), individualized interval-adjusted prophylaxis (IP; initially, 100 IU/kg every 10 days), or on-demand dosing. In the Kids B-LONG study, subjects <12 years received 50 to 60 IU/kg every 7 days, adjusted as needed. In the B-YOND study, subjects received WP (20-100 IU/kg every 7 days), IP (100 IU/kg every 8-16 days), modified prophylaxis, or on-demand dosing; switching between treatment groups was permitted. A total of 123 subjects from B-LONG and 30 from Kids B-LONG study were included, of whom 93 and 27, respectively, enrolled in the B-YOND study. The median cumulative duration of treatment was 3.63 years (range, 0.003-6.48 years) in B-LONG/B-YOND and 2.88 years (range, 0.30-4.80 years) in Kids B-LONG/B-YOND group. Annualized bleed rates (ABRs) remained low, annualized factor consumption remained stable, and adherence remained high throughout treatment. Low ABRs were also maintained in subjects with dosing intervals ≥14 days or with target joints at baseline. Complete resolution of evaluable target joints and no recurrence in 90.2% of baseline target joints during follow-up were observed. rFIXFc prophylaxis was associated with sustained clinical benefits, including long-term bleed prevention and target joint resolution, for severe hemophilia B.

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.

IDEAL study: A real-world assessment of pattern of use and clinical outcomes with recombinant coagulation factor IX albumin fusion protein (rIX-FP) in patients with haemophilia B in Italy.

INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.

Cost-effectiveness of recombinant factor VIII Fc versus emicizumab for prophylaxis in adults and adolescents with haemophilia A without inhibitors in the UK.

INTRODUCTION: The economic and clinical burden of haemophilia A is high. Primary prophylaxis with factor VIII replacement therapy is the recognised standard of care, but the emergence of non-factor therapies, such as emicizumab, is extending treatment options for people with haemophilia A. AIM: There are currently no direct comparisons of efficacy or cost between recombinant factor FVIII Fc-fusion protein efmoroctocog alfa (a recombinant factor FVIII Fc-fusion protein referred to herein as rFVIIIFc) and emicizumab; therefore, a cost-effectiveness model was developed to compare prophylactic treatment with rFVIIIFc versus emicizumab in patients with haemophilia A without inhibitors in the UK. METHODS: The cost-effectiveness model was based on a matching-adjusted indirect comparison and included male patients, aged ≥12 years, with haemophilia A without inhibitors. The model was designed as a Markov process with a flexible lifelong time horizon, and cost-effectiveness was presented as an incremental cost-effectiveness ratio. Base-case analysis and sensitivity analyses (including scenario analyses, one-way deterministic sensitivity analysis [DSA] and probability sensitivity analysis [PSA]) were performed using the following treatment strategies: individualised prophylaxis with rFVIIIFc and prophylaxis with emicizumab administered once weekly (scenario analyses used regimens of once every 2 weeks or once every 4 weeks). RESULTS: Base-case analysis, DSA and PSA indicated that, compared with emicizumab administered once weekly, rFVIIIFc individualised prophylaxis was the dominant treatment strategy, with lower costs, a greater number of quality-adjusted life years, and a lower number of bleeds. CONCLUSIONS: rFVIIIFc has proven efficacy and is cost-effective compared with emicizumab, providing clinicians with a viable treatment option to improve the health outcomes for adults and adolescents with haemophilia A in the UK.

Thrombopoietin receptor agonist discontinuation rates and reasons among patients with immune thrombocytopenia: a study of administrative claims linked with medical chart review.

Administrative claims provide a rich data source for retrospective studies of real-world clinical practice, yet some important data may be inconsistent or unavailable. This study explored factors influencing discontinuation of thrombopoietin receptor agonists (TPO-RAs) among patients with immune thrombocytopenia (ITP), by adding medical chart abstraction for additional details. Adult (≥ 18 years) patients with continuous commercial or Medicare Advantage with Part D health insurance coverage were included. Inclusion criteria were ≥ 1 claim for eltrombopag or romiplostim and ≥ 2 diagnoses of ITP between December 31, 2017, and January 1, 2020. Providers were asked to provide access to medical charts for abstraction. The analyses included only patients who discontinued TPO-RA and described patient characteristics, treatment patterns, platelet values, and reasons for discontinuation. Among 207 ITP patients treated with a TPO-RA, 137 (66%) discontinued treatment during the observation period. The mean TPO-RA treatment duration was 185 days. Mean platelet count at the time of discontinuation was 197 × 109/L. The most common reason for discontinuation was improvement of the patient's condition (42%). Other reasons included worsening of ITP/lack of response (12%), adverse events (12%), and cost-related or social reasons (23%). No reason was reported for 10%. Notably 26% of patients who discontinued remained off all ITP therapy for the remainder of the study, with a mean treatment-free period of 262 days. These results emphasize that some patients with ITP are able to discontinue TPO-RA therapy and achieve durable treatment-free periods.

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 choriocapillaris/Sattler and Haller layer changes after intravitreal injection in eyes with neovascular age-related macular degeneration: aflibercept vs ranibizumab.

PURPOSE: To evaluate the changes in choriocapillaris (CC)/Sattler and Haller layer thicknesses in eyes with neovascular age-related macular degeneration (nAMD) after aflibercept or ranibizumab injections. STUDY DESIGN: Retrospective. METHODS: A total of 70 eyes of 70 patients with treatment-naïve exudative nAMD were treated with 3 consecutive injections of aflibercept (IVA) or ranibizumab (IVR). CC/Sattler and Haller layer thicknesses were measured at the nasal and temporal regions 1000 µm from the center of the fovea by enhanced-depth imaging optical coherence tomography at baseline and after the 3 monthly intravitreal injections. In addition, the hyperfluorescence region (HF) was measured as the largest horizontal diameter of the hyperfluorescence area on the early-middle phase fluorescein angiographic images at baseline and after the 3 loading doses. RESULTS: After the 3 consecutive injections, the mean reductions in the nasal/temporal CC/Sattler layer thicknesses in the IVR and IVA groups were - 10.1 ± 2.3/ - 8.5 ± 1.8 and - 25.2 ± 15.2/ - 19.4 ± 12.8 µm, respectively. Also, the mean reductions in the nasal/temporal Haller layer thicknesses in the IVR and IVA groups were - 6.5 ± 3.6/ - 7.2 ± 7.9 and - 9.5 ± 8.0/ - 7.0 ± 6.2 µm, respectively. The changes in the CC/Sattler layer thicknesses of the IVA group were greater than those of the IVR group (P < .001); however, the changes in the Haller layer thickness were similar between the groups (P > .05). The mean decrease in the HF size of the IVA group was greater than that of the IVR group (P < .001). CONCLUSIONS: Aflibercept treatment has a more pronounced effect on the CC/Sattler layer. Such results may indicate that aflibercept treatment influences choroidal neovascularization, possibly by reducing the capillary permeability associated with active neovascularization in the CC layer.

Intravitreal Pharmacotherapies for Diabetic Macular Edema: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the evidence on the safety and efficacy of current anti-vascular endothelial growth factor (VEGF) and intravitreal corticosteroid pharmacotherapies for the treatment of diabetic macular edema (DME). METHODS: Literature searches were last conducted on May 13, 2020, in the PubMed database with no date restrictions and limited to articles published in English. The combined searches yielded 230 citations, of which 108 were reviewed in full text. Of these, 31 were deemed appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. RESULTS: Only the 21 articles with level I evidence were included in this assessment. Seventeen articles provided level I evidence for 1 or more anti-VEGF pharmacotherapies, including ranibizumab (14), aflibercept (5), and bevacizumab (2) alone or in combination with other treatments for DME. Level I evidence was identified in 7 articles on intravitreal corticosteroid therapy for treatment of DME: triamcinolone (1), dexamethasone (4), and fluocinolone acetonide (2). CONCLUSIONS: Review of the available literature indicates that intravitreal injections of anti-VEGF agents and corticosteroids are efficacious treatments for DME. Elevated intraocular pressure and cataract progression are important potential complications of corticosteroid therapy. Further evidence is required to assess the comparative efficacy of these therapies. Given the limited high-quality comparative efficacy data, choice of therapy must be individualized for each patient and broad therapeutic access for patients is critical to maximize outcomes.

Costs comparison of treating diabetic macular edema with aflibercept, ranibizumab or dexamethasone at 1 year in France (INVICOST study).

PURPOSE: INVICOST, a medico-economic analysis, compared costs of managing treatment-naive patients with diabetic macular edema (DME) receiving intravitreal injections (IVIs) of aflibercept (AFL), dexamethasone implant (DXI) or ranibizumab (RAN) over 1 year. METHODS: Healthcare resource use and associated costs were estimated using individual patient data from INVICTUS, a prospective, open-label, monocentric study. Healthcare costs comprised direct medical costs such as drug acquisition and administration, consultations and ophthalmological procedures. Costs were assessed from the French National Health Insurance perspective using published national tariffs expressed in 2019 euros. RESULTS: Of the 60 treated eyes, 48 had no treatment switch; 14 received AFL, 19 received DXI and 15 received RAN. AFL-treated eyes received an average of 6.5 IVIs, DXI-treated patients received 2 IVIs and RAN-treated received 6.8 IVIs. All treated eyes received an initial prescription for adjunctive ocular medications and 349 follow-up procedures were performed including an average of 3.9 optical coherence tomography and 3.2 retinography procedures per eye. Average total direct cost of per-eye treatment was €4516 (€1128-€8257). Average cost was €5782 for eyes treated with AFL, €2779 with DXI and €5536 with RAN. Drug therapy was the cost driver: €4394 (76%) for AFL, €1915 for DXI (69%) and €4268 (77%) for RAN. CONCLUSION: The difference in total treatment cost is largely explained by the significantly lower frequency of IVI and annual cost of therapy with DXI, compared with AFL and RAN. INVICOST is the first study comparing treatment costs with AFL, DXI and RAN in France in current clinical practice.

Cost-minimisation analysis of a treat-and-extend regimen with anti-VEGFs in patients with neovascular age-related macular degeneration.

PURPOSE: Although intraocular anti-vascular endothelial growth factors (anti-VEGFs) are effective as treatment of neovascular age-related macular degeneration (nAMD), the (economic) burden on the healthcare system is considerable. A treat-and-extend (T&E) regimen is associated with a lower number of injections without compromising the effectiveness and can therefore help optimise nAMD treatment. This study investigates the per-patient costs associated with nAMD treatment, when using aflibercept, bevacizumab, or ranibizumab with a T&E regimen. METHODS: In this cost-minimisation model, the per-patient costs in the Netherlands were modelled using a healthcare payers' perspective over a 3-year time horizon with the assumption that efficacy of treatments is similar. Additionally, the break-even price of the different anti-VEGFs was calculated relative to the cheapest option and injection frequency. RESULTS: The injection frequency varied from 14.2 for aflibercept to 27.4 for bevacizumab in 3 years. Nonetheless, bevacizumab remains the cheapest treatment option (€14,215), followed by aflibercept (€18,202) and ranibizumab (€31,048). The medication covers the majority of the per-patient costs for aflibercept and ranibizumab, while administration covers the majority of the per-patient costs for bevacizumab. The break-even prices of aflibercept and ranibizumab are respectively €507 and €60.58 per injection. Brolucizumab was included in the scenario analysis and was more expensive than aflibercept (€20,446). Brolucizumab should reduce to 13.8 injections over 3 years to be as costly as aflibercept. CONCLUSION: Bevacizumab is the cheapest anti-VEGF treatment. The list prices of all anti-VEGFs should reduce to be as costly as bevacizumab. Aflibercept is the second-choice treatment and so far brolucizumab is not.

Eficacia y seguridad de aflibercept para el tratamiento de pacientes con degeneración macular relacionada a la edad, de tipo neovascular, luego del tratamiento con bevacizumab / Efficacy and safety of aflibercept for the treatment of patients with neovascular age-related macular degeneration after treatment with bevacizumab

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de aflibercept, comparado con bevacizumab, para el tratamiento de pacientes con DMRE de tipo neovascular con disminución de la agudeza visual y mantenimiento o incremento del grosor macular luego del tratamiento con bevacizumab. La degeneración macular relacionada a la edad (DMRE) se caracteriza por la angiogénesis en el espacio subretiniano. Esta genera microhemorragias y exudaciones que finalmente conducen a la ceguera del paciente. La DMRE puede ser de dos tipos: neovascular (también llamada exudativa o húmeda) y atrófica (también llamada no exudativa o seca). La DMRE neovascular es el tipo menos frecuente (10 % de los casos de DMRE a nivel mundial); pero es la responsable del 90 % de los casos de ceguera por DMRE. Actualmente, la DMRE neovascular no tiene cura, por lo que el objetivo del tratamiento es reducir la progresión de la enfermedad y evitar la disminución de la agudeza visual. El tratamiento estándar de la DMRE neovascular consiste en agentes anti-factor de crecimiento endotelial vascular (anti-VEGF, por sus siglas en inglés). En EsSalud, se cuenta con bevacizumab como tratamiento anti-VEGF de primera línea para dichos pacientes. No obstante, aproximadamente el 25 % de los pacientes con DMRE neovascular no responden a la terapia inicial. Los especialistas de la institución mencionan que, en dichos pacientes, bevacizumab sigue siendo administrado, ya que, a pesar de que no evita la progresión de la enfermedad, consideran que retirarlo podría ser contraproducente. Así, a la fecha, no existe otra alternativa de tratamiento para aquellos pacientes con DMRE que no responden a bevacizumab. Por este motivo, los especialistas solicitan la evaluación del uso de aflibercept como posible alternativa de tratamiento para estos pacientes. METODOLOGÍA: La búsqueda de la literatura se realizó con el objetivo de identificar la mejor evidencia disponible sobre la eficacia y seguridad de aflibercept, en comparación con bevacizumab, para el tratamiento de pacientes con DMRE de tipo neovascular, con disminución de la agudeza visual y mantenimiento o incremento del grosor macular, luego del tratamiento con bevacizumab. La búsqueda de la evidencia se realizó en las bases de datos bibliográficas: PubMed, LILACS y The Cochrane Library. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y GPC, tales como The National Institute for Health and Care Excellence (NICE), The Canadian Agency for Drugs and Technologies in Health (CADTH), Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Quality and Efficiency in Health Care (IQWiG), y Scottish Medicines Consortium (SMC). Adicionalmente, se realizó una búsqueda manual en las bases The Guidelines International Network (G-I-N), el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y en las páginas web de sociedades especializadas en DMRE como American Academy of Ophthalmology, The Royal College of Ophthalmologists, y Optometry Australia. Finalmente, se realizó una búsqueda manual en el portal ClinicalTrials.gov del National Institutes of Health (NIH) para identificar ensayos clínicos en desarrollo o cuyos resultados aún no hayan sido publicados en una revista científica. RESULTADOS: Se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES:  El objetivo del presente dictamen es evaluar la eficacia y seguridad de aflibercept, en comparación con bevacizumab, para el tratamiento de pacientes con DMRE neovascular, con disminución de la agudeza visual y mantenimiento o incremento del grosor macular, luego del tratamiento con bevacizumab. En la búsqueda de la literatura científica se identificaron tres GPC (NICE 2018; SERV 2014; Androudi et al. 2016), una ETS (CADTH 2016b), una RS con MA de estudios sin grupo control (Kimberly Spooner et al. 2017), y un ensayo clínico sin grupo control (K. Spooner et al. 2019). Las guías de NICE y SERV no consideran dentro de sus recomendaciones el uso de una segunda línea de tratamiento con otro anti-VEGF, luego de falla o no respuesta al tratamiento con un anti-VEGF y por su parte la GPC de conceso de Androudi et al. presenta un flujograma donde se considera el cambio de tratamiento a otro anti-VEGF en pacientes con sospecha de no respuesta luego de tratamiento con un anti-VEGF. No obstante, la evidencia que apoya el flujograma es de bajo nivel y contradictoria. La ETS de CADTH concluyó que aflibercept puede ser usado como tratamiento en pacientes con DMRE neovascular cuya AVMC no mejoró al menos 15 letras ETDRS luego de tres a seis meses de tratamiento con bevacizumab. No obstante, esta recomendación se basó en estudios que no analizaron pacientes que recibieron tratamiento con un anti-VEGF. La RS con MA de Spooner et al. reportó que los pacientes con DMRE neovascular y falla al tratamiento con anti-VEGF que cambiaron el tratamiento a aflibercept redujeron el grosor macular con un mantenimiento de la AVMC (hasta 12 meses después del cambio de tratamiento). Los resultados observados del ensayo sin grupo control publicado por Spooner et al. en el 2019 con un seguimiento de cuatro años van en línea con lo observado en la RS de Spooner et al. 2017. No obstante, las limitaciones de los estudios incluidos en el MA y del ensayo de Spooner et al. del 2019 impiden afirmar que los resultados observados en la AVMC y el grosor macular se deban al uso de aflibercept. El contexto de vacío terapéutico en una enfermedad que impacta fuertemente en la calidad de vida de los pacientes, y los resultados observados de manera consistente en la evidencia identificada, aunque de bajo nivel, generan una duda razonable sobre el posible rol del cambio a otro anti-VEGF, en pacientes no respondedores, en lograr el objetivo terapéutico de la DMRE neovascular (reducir la progresión de la enfermedad), al mantener la agudeza visual y reducir el grosor macular. Por lo expuesto, el IETSI aprueba el uso de aflibercept en pacientes con DMRE de tipo neovascular, con disminución de la agudeza visual y mantenimiento o incremento del grosor macular, luego del tratamiento con bevacizumab, según lo establecido en el Anexo N°1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Newborn screening for spinal muscular atrophy with disease-modifying therapies: a cost-effectiveness analysis.

OBJECTIVE: To assess cost-effectiveness of newborn screening (NBS) for spinal muscular atrophy (SMA) and early treatment with nusinersen or onasemnogene abeparvovec (gene therapy), compared with nusinersen without SMA screening. METHODS: Informed by an Australian state-wide SMA NBS programme, a decision analytical model nested with Markov models was constructed to evaluate costs and quality-adjusted life-years (QALYs) from a societal perspective with sensitivity analyses. RESULTS: By treating one presymptomatic SMA infant with nusinersen or gene therapy, an additional 9.93 QALYs were gained over 60 years compared with late treatment in clinically diagnosed SMA. The societal cost was $9.8 million for early nusinersen treatment, $4.4 million for early gene therapy and $4.8 million for late nusinersen treatment. Compared with late nusinersen treatment, early gene therapy would be dominant, gaining 9.93 QALYs while saving $360 000; whereas early nusinersen treatment would result in a discounted incremental cost-effectiveness ratio (ICER) of $507 000/QALY.At a population level, compared with no screening and late treatment with nusinersen, NBS and early gene therapy resulted in 0.00085 QALY gained over 60 years and saving $24 per infant screened (85 QALYs gained and $2.4 million saving per 100 000 infants screened). More than three quarters of simulated ICERs by probability sensitivity analyses showed NBS and gene therapy would be dominant or less than $50 000/QALY, compared with no screening and late nusinersen treatment. CONCLUSION: NBS coupled with gene therapy improves the quality and length of life for infants with SMA and would be considered value-for-money from an Australian clinical and policy context.

Economic burden of age-related macular degeneration in routine clinical practice: the RAMDEBURS study.

PURPOSE: To describe and evaluate the main direct health costs, in routine clinical practice, of age-related macular degeneration (AMD) patients, from hospital perspective, in Spain. METHODS: Retrospective, multicenter, and observational study conducted on five third-level Spanish hospitals, between December 2018 and December 2019. The study included patients who were diagnosed of AMD before December 2018. Direct healthcare costs were obtained from a Spanish database. Study variables included demographic and clinical variables, and resources, such as treatment, diagnostic tests, medical examination, and surgery. Among the 1414 screened AMD patients, 1164 patients were included. In the overall study patients, the total cost was €5,386,511.0, with a mean cost per patient of €4627.6 ± 2383.9. The largest cost items were diagnostic examinations (€2.832.902,0) and vascular endothelial growth factor inhibitors (anti-VEGF) treatment (€2.038.257,2). Bevacizumab was administered to 325 (27.9%) patients, ranibizumab to 328 (28.2%), and aflibercept to 626 (53.8%); 115 (10.7%) patients received two anti-VEGF treatments, while 90 (7.7%) did not receive any. Over the course of the study, a total of 6,057 anti-VEGF injections were administered, with a mean (95% confidence interval) of 4.8 (4.4-5.2) injections per patient. Regarding safety, 29 patients experience injection-related adverse events, among them 12 patients had cataract and 11 ones elevated intraocular pressure (IOP). The incidence of endophthalmitis was 0.5% (6/1164). CONCLUSIONS: AMD was associated with considerable healthcare costs for regional healthcare systems. Diagnostic examinations, particularly OCT examinations, and anti-VEGF treatment represented the largest cost items.

Early Cost-Effectiveness of Onasemnogene Abeparvovec-xioi (Zolgensma) and Nusinersen (Spinraza) Treatment for Spinal Muscular Atrophy I in The Netherlands With Relapse Scenarios.

OBJECTIVES: Onasemnogene Abeparvovec-xioi (AVXS-101) is a gene therapy intended for curative treatment of spinal muscular atrophy (SMA) with an expected price of around €2 000 000. The goal of this study is to perform a cost-effectiveness analysis of treatment of SMA I patients with AVXS-101 in The Netherlands including relapse scenarios. METHODS: An individual-based state-transition model was used to model treatment effect and survival of SMA I patients treated with AVXS-101, nusinersen and best supportive care (BSC). The model included five health states: three health states according to SMA types, one for permanent ventilation and one for death. Deterministic and probabilistic sensitivity analyses were performed. Effects of relapsing to lower health states in the years following treatment was explored. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) for AVXS-101 versus BSC is €138 875/QALY, and €53 447/QALY for AVXS-101 versus nusinersen. If patients relapse within 10 years after treatment with AVXS-101, the ICER can increase up to 6-fold, with effects diminishing thereafter. Only relapses occurring later than 50 years after treatment have a negligible effect on the ICER. To comply with Dutch willingness-to-pay reference values, the price of AVXS-101 must decrease to €680 000. CONCLUSIONS: Based on this model, treatment with AVXS-101 is unlikely to be cost-effective under Dutch willingness-to-pay reference values. Uncertainty regarding the long-term curative properties of AVXS-101 can result in multiplication of the ICER. Decision-makers are advised to appropriately balance these uncertainties against the price they are willing to pay now.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.