The intravitreal injection: Variations in regulations, cost and reimbursement in Europe

Zusammenfassung: HINTERGRUND: Grosse prospektive, randomisierte, kontrollierte klinische Studien haben für den intravitrealen Einsatz von Inhibitoren des vaskulären endothelialen Wachstumsfaktors (VEGF) klare Behandlungsvorgaben mit höchstem Evidenzniveau gegeben. Dies gilt für die häufigsten exsudativen Makulaerkrankungen (neovaskuläre, altersbezogene Makuladegeneration, Makulaödem im Rahmen eines Diabetes oder eines venösen, retinalen Gefässverschlusses). Aufgrund zahlreicher Faktoren ist jedoch die Umsetzung einer optimalen, Evidenz basierten intravitrealen Therapie in kaum einem europäischen Land möglich. MATERIAL UND METHODE: Die folgende Übersicht zeigt die wesentlichsten Einflussfaktoren und deren grosse Variabilität innerhalb von Europa, die eine adäquate Patientenbehandlung in ganz Europa erschweren. Um die Unterschiede zwischen einzelnen europäischen Ländern aufzuzeigen, wurden u. a. Fragebogen an Retinologen in Europa verschickt. Zu den wesentlichsten limitierenden Faktoren gehören das in der Europäischen Union (EU) geltende Behandlungslabel für Ranibizumab und die national und teilweise regional geltenden Vorgaben für die Durchführung und Kostenerstattung der intravitrealen Therapie. Hinzu kommen teilweise regionale oder institutionelle Einschränkungen, die die Anzahl der intravitrealen Injektionen reglementieren. Die Ergebnisse zeigen, dass es innerhalb von Europa Unterschiede gibt. RESULTATE: Zu den wichtigen Unterschieden gehört die Dauer des nationalen Entscheidungsprozesses zur gesetzlichen Regelung der Kostenerstattung. Dieser Prozess kann in einzelnen Ländern mehrere Jahre in Anspruch nehmen. Eine weitere Einschränkung besteht in vielen Ländern in Hinblick darauf, welche Personen/Institutionen intravitreale Injektionen durchführen darf und erstattet bekommt. Dies ist in den meisten Ländern an die Kostenerstattung durch das Gesundheitssystem gebunden. Besonders in osteuropäischen Ländern sind die Institutionen, denen intravitreale Injektionen erstattet werden, Budgets unterworfen, die adäquate evidenzbasierte Versorgung der Patienten weiter deutlich erschweren. Erhebliche Unterschiede sind zudem bei den jeweils vorhandenen räumlichen Anforderungen und Auflagen an den Raum in dem die Injektion durchgeführt wird - von lediglich designiertem Injektionsraum bis zu vollwertigem Operationssaal - feststellbar. Hier zeigt sich innerhalb Europas eine deutliche Ost-West-Verteilung. Dieser Aspekt hat u. a. einen möglichen Einfluss auf die Sicherheit, aber auch auf die anfallenden Kosten und die Effizienz der Abläufe. Zum Teil sind die erheblichen Unterschiede in der Kostenerstattung für eine intravitreale Injektion innerhalb Europas durch die Vorgaben für den Injektionsraum erklärbar. Der Preis für die Durchführung einer intravitrealen Injektion an Institutionen mit Kostenerstattung durch das Gesundheitssystem variiert innerhalb Europa von etwa 80 bis etwa 600 €. Jedoch variiert die Kostenerstattung für die intravitreale Injektion mitunter sogar regional oder in Abhängigkeit vom Versicherungssystem. Fast ubiquitär zeigt sich jedoch ein Mangel an finanziellen und personellen Ressourcen, um die Untersuchungs- und Behandlungsabläufe der Ära der intravitrealen Injektionen anzupassen. Dies ist von erheblichen Nachteil für die betroffenen Patienten aber auch für viele behandelnde Ärzte. SCHLUSSFOLGERUNG: Mit einer zunehmenden Anzahl betroffener und mit intravitrealen Injektionen behandelbarer Patienten wird der Druck für einen verbesserten Behandlungszugang steigen. Einheitlichere Vorgaben für die Durchführung und Kostenerstattung intravitrealer Injektionen innerhalb Europas oder zumindest auf nationaler Ebene wären wünschenswert. Leider ist ein Trend zur weiteren Regionalisierung feststellba

Lebensqualität aus der Sicht darmkrebserkrankter Frauen und Männer: Rekonstruierte Lebens- und Krankengeschichten und ihre Bedeutungen für eine patienten- und patientinnenorientierte Versorgung

Background of the problem: In contrast to an increasing incidence of colorectal cancer, the mortality of affected men and women is constantly decreasing (GEKID 2010). Typically cancer of the colon proceeds in a chronic course, leading to the necessity of maintaining or improving quality of life of the patients by ensuring the best possible patient care. The task of health care research is, particularly with regard to an effective and patient-oriented health care, to analyze and characterize the determinants of quality of life under disease conditions (Pfaff 2003; SVR 2000/2001, 2003). Concerning that goal also gender-specific differences must be taken into account (Kuhlmann/Kolip 2005). Current state of research on subjective quality of life of patients suffering from colorectal cancer is regarding gender aspects considered to be insufficient, due to mainly relying on objectifying measuring methods. Goal of this work: What are the expectations of men and women suffering from colorectal cancer concerning their quality of life and what s the significance of these expectations in respect of a patient- or gender-oriented health care? Theoretical framework: In the present study, the trajectory framework for management of chronic illness of Corbin and Strauss (1988, 2004) was chosen as a theoretical frame of reference. With respect to empirical studies, this framework primarily served as a heuristic model, leading to the development of new questions and theories, respectively. Methods: The empirical studies of the present work are based on the scientific approach of the grounded theory (Glaser & Strauss 1968). Ten narrative-biographical interviews with men and women suffering from colorectal cancer were conducted (Schütze 1977). Six of these interviews (3 with affected females, 3 with affected males) were evaluated in terms of the method of biographic case reconstructions by Gabriele Rosenthal (1995). Results: Due to their medical history, one of the central ideas of quality of life of both sexes is reflected by the chances and possibilities to participate in everyday life (i.e. work, relationships). The genesis of this idea, the experience of participatory action strategies and the way of narrative representation, partly appear to be gender-specific, though. An improved participation represents the central aim of colorectal cancer patients, also concerning a direct interaction with health professionals. In the present study, this need for interaction, appearing as a part of the efforts to cope with disease- and everyday-life related work (Corbin/Strauss 2004) was categorized as a reference. The affected men and women often don t pronounce their subjective requirements from health professionals clearly. The main reason for that is that health professionals often address the patients with a lack of empathy, especially at the beginning of personal contact and treatment. Conclusions: Quality of life from the perspective of individuals suffering from colorectal cancer is not simply explainable as a deterministic condition, but as a process that s influenced by the biography of the patients and sometimes even gender-specificity as well as the manner of interaction. Objectives for the further development of quality of life-oriented concepts of health care for persons affected by colorectal cancer include in particular: 1) Improvement of the interaction between health care professionals and patients based on empiric, gender-sensitive research, taking also theoretical approaches of communication and findings of emotion-psychological studies in account. 2) The intensified focus on gender-specificity in tertiary prevention and health promotion, also considering psychosocial pressures and the competence of participation of the patients

Phonological awareness in German-speaking preschool children with cochlear implants – 3 case examples

Objective The aim was to explore PA skills German-speaking preschool children with cochlea implants (CIs) and how these skills may be related to their speech and language skills. Methods Three monolingual German-speaking pre-school children aged 5;04–6;01 with bilateral CIs were tested. Their cognitive, speech and language skills were assessed. Six subtests of a standardized PA test battery were administered (i.e. rhyme identification, rhyme production; phoneme identification- input and -output; phoneme blending-input and -output). Results All three children showed distinctive PA profiles. One boy, who had no spoken language deficits, struggled to complete the rhyme tasks but performed well on three phoneme tasks. However, he showed a discrepancy between expressive and receptive phoneme blending skills, scoring poorly on the expressive subtest. The second boy, who displayed grammar comprehension and expressive vocabulary difficulties, showed a mixed profile, with a below average performance on rhyme production. The girl who had significant speech and language deficits scored below average on all six PA subtests. Conclusions PA profiles in children with CI vary considerably and PA testing should include a range of different PA tasks. The assumed link between spoken language deficits and PA difficulties shown in children with normal hearing could be confirmed

Effects of nintedanib in patients with idiopathic pulmonary fibrosis by GAP stage

We conducted a post hoc analysis to assess the potential impact of GAP (gender, age, physiology) stage on the treatment effect of nintedanib in patients with idiopathic pulmonary fibrosis. Outcomes were compared in patients at GAP stage I versus II/III at baseline in the INPULSIS\uae trials. At baseline, 500 patients were at GAP stage I (nintedanib 304, placebo 196), 489 were at GAP stage II (nintedanib 296, placebo 193) and 71 were at GAP stage III (nintedanib 38, placebo 33). In nintedanibtreated patients, the annual rate of decline in forced vital capacity (FVC) was similar in patients at GAP stage I and GAP stage II/III at baseline (-110.1 and -116.6 mL.year-1, respectively), and in both subgroups was lower than in placebo-treated patients (-218.5 and -227.6 mL.year-1, respectively) (treatment-by-time-by-subgroup interaction p=0.92). In the nintedanib group, the number of deaths was 43.8% of those predicted based on GAP stage (35 versus 79.9). In the placebo group, the number of deaths was 59.8% of those predicted based on GAP stage (33 versus 55.2). In conclusion, data from the INPULSIS\uae trials suggest that nintedanib has a similar beneficial effect on the rate of FVC decline in patients at GAP stage I versus II/III at baseline

Investigating the effects of nintedanib on biomarkers of extracellular matrix turnover in patients with IPF : design of the randomised placebo-controlled INMARK®trial

Introduction A feature of the pathogenesis of idiopathic pulmonary fibrosis (IPF) is the excess accumulation of extracellular matrix (ECM) in the lungs. Cleavage of the ECM by metalloproteinases (MMPs) generates freecirculating protein fragments known as neoepitopes. The PROFILE study suggested that changes in ECM turnover proteins may be of value as markers of disease progression in patients with IPF. Nintedanib is an approved treatment for IPF that slows disease progression by reducing decline in forced vital capacity (FVC). Methods and analysis The INMARK® trial is evaluating the effect of nintedanib on the rates of change of biomarkers of ECM turnover in patients with IPF, the value of changes in these biomarkers as predictors of disease progression and whether nintedanib affects the associations between changes in these biomarkers and disease progression. Following a screening period, 347 patients with IPF and FVC ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg two times a day or placebo for 12 weeks, followed by an open-label period in which all patients will receive nintedanib for 40 weeks. The primary endpoint is the rate of change in C reactive protein degraded by MMP-1/8 from baseline to week 12. Ethics and dissemination This trial is being conducted in compliance with the protocol, the ethical principles detailed in the Declaration of Helsinki and in accordance with the International Conference on Harmonisation Harmonised Tripartite Guideline for Good Clinical Practice. The results of the trial will be presented at national and international meetings and published in peer-reviewed journals. Trial registration number NCT0278847

KESTREL and KITE Phase 3 studies: 100-week results with brolucizumab in patients with diabetic macular edema.

PURPOSE To report the 100-week outcomes from KESTREL and KITE. DESIGN Two phase 3, double-masked, active-controlled, randomized trials. METHODS Patients with diabetic macular edema (DME) were randomized 1:1:1 to brolucizumab 3 mg/6 mg (BRO3/BRO6) or aflibercept 2 mg (AFL) in KESTREL (N=566) or 1:1 to BRO6 or AFL in KITE (N=360). BRO3/BRO6 arms received 5 loading doses every 6 weeks (q6w) followed by q12w dosing, with an option to adjust to q8w at predefined disease activity assessment visits. In KITE, at Week 72, based on the disease stability assessment, treatment intervals could be extended by 4 weeks in the BRO6 arm. AFL arms received 5 monthly loading doses followed by fixed q8w dosing. RESULTS At Week 100, change from baseline in BCVA (letters) was +8.8 for BRO6 and +10.6 for AFL in KESTREL; +10.9 for BRO6 and +8.4 for AFL in KITE. In both studies, fewer BRO6 subjects had intraretinal fluid and/or subretinal fluid versus (vs) AFL. Results were achieved with 32.9% (KESTREL) and 47.5% (KITE) of BRO6 subjects maintained on q12w and q12w/q16w dosing, respectively. Intraocular inflammation rates for BRO6 vs AFL were 4.2% vs 1.1% (KESTREL) and 2.2% vs 1.7% (KITE) of which retinal vasculitis rates were 0.5% vs 0% in KESTREL, with no cases in KITE. Retinal vascular occlusion rates were 1.6% vs 0.5% (KESTREL) and 0.6% in both treatment arms in KITE. CONCLUSION Results show the long-term efficacy and durability of brolucizumab in improving visual and anatomical outcomes in DME; the overall safety profile of brolucizumab remained unchanged through Year 2

Cardiovascular safety of nintedanib in subgroups by cardiovascular risk at baseline in the TOMORROW and INPULSIS trials

Nintedanib is a tyrosine kinase inhibitor used to treat idiopathic pulmonary fibrosis (IPF). We investigated the cardiovascular safety of nintedanib using pooled data from the TOMORROW and INPULSIS trials.Cardiovascular events were assessed post hoc in patients with a history of atherosclerotic cardiovascular disease (CVD) and/or one or more cardiovascular risk factors at baseline ("higher cardiovascular risk") and patients with no history of atherosclerotic CVD and no cardiovascular risk factors at baseline ("lower cardiovascular risk").Incidence rates were calculated for 1231 patients (n=723 nintedanib and n=508 placebo), of whom 89.9% had higher cardiovascular risk. Incidence rates of major adverse cardiovascular events were similar in the nintedanib and placebo groups in patients with higher cardiovascular risk (3.88 (95% CI 2.58-5.84) and 3.49 (95% CI 2.10-5.79) per 100 patient-years, respectively) and lower cardiovascular risk (4.78 (95% CI 1.54-14.82) and 5.37 (95% CI 1.73-16.65) per 100 patient-years, respectively). Incidence rates of myocardial infarction in the nintedanib and placebo groups, respectively, were 3.03 (95% CI 1.91-4.81) and 1.16 (95% CI 0.48-2.79) per 100 patient-years in patients with higher cardiovascular risk and 1.59 (95% CI 0.22-11.29) and 1.78 (95% CI 0.25-12.64) per 100 patient-years in patients with lower cardiovascular risk. Incidence rates of other ischaemic heart disease in the nintedanib and placebo groups, respectively, were 1.85 (95% CI 1.02-3.34) and 3.28 (95% CI 1.94-5.54) per 100 patient-years in patients with higher cardiovascular risk and 0 and 1.80 (95% CI 0.25-12.78) per 100 patient-years in patients with lower cardiovascular risk.These data help to establish the cardiovascular safety profile of nintedanib in IPF

Retinal Vascular Occlusion after COVID-19 Vaccination : More Coincidence than Causal Relationship? Data from a Retrospective Multicentre Study

Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD). Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June–31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case– control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted. Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer (n = 221), followed by ChadOx1/AstraZeneca (n = 57), mRNA1273/Moderna (n = 21), and Ad26.COV2.S/Johnson & Johnson (n = 11; unknown n = 22). Our case–control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60–1.45, p = 0.75) in connection with a vaccination within a 4-week window. Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk