Simulation of bempedoic acid and ezetimibe in the lipid-lowering treatment pathway in Austria using the contemporary SANTORINI cohort of high and very high risk patients.

OBJECTIVE: The low-density lipoprotein cholesterol goals in the 2019 European Society of Cardiology/European Atherosclerosis Society dyslipidaemia guidelines necessitate greater use of combination therapies. We describe a real-world cohort of patients in Austria and simulate the addition of oral bempedoic acid and ezetimibe to estimate the proportion of patients reaching goals. METHODS: Patients at high or very high cardiovascular risk on lipid-lowering treatments (excluding proprotein convertase subtilisin/kexin type 9 inhibitors) from the Austrian cohort of the observational SANTORINI study were included using specific criteria. For patients not at their risk-based goals at baseline, addition of ezetimibe (if not already received) and subsequently bempedoic acid was simulated using a Monte Carlo simulation. RESULTS: A cohort of patients (N = 144) with a mean low-density lipoprotein cholesterol of 76.4 mg/dL, with 94% (n = 135) on statins and 24% (n = 35) on ezetimibe monotherapy or in combination, were used in the simulation. Only 36% of patients were at goal (n = 52). Sequential simulation of ezetimibe (where applicable) and bempedoic acid increased the proportion of patients at goal to 69% (n = 100), with a decrease in the mean low-density lipoprotein cholesterol from 76.4 mg/dL at baseline to 57.7 mg/dL overall. CONCLUSIONS: The SANTORINI real-world data in Austria suggest that a proportion of high and very high-risk patients remain below the guideline-recommended low-density lipoprotein cholesterol goals. Optimising use of oral ezetimibe and bempedoic acid after statins in the lipid-lowering pathway could result in substantially more patients attaining low-density lipoprotein cholesterol goals, likely with additional health benefits.

Treatment gaps in the implementation of LDL cholesterol control among high- and very high-risk patients in Europe between 2020 and 2021: the multinational observational SANTORINI study.

Background: European data pre-2019 suggest statin monotherapy is the most common approach to lipid management for preventing cardiovascular (CV) events, resulting in only one-fifth of high- and very high-risk patients achieving the 2019 ESC/EAS recommended low-density lipoprotein cholesterol (LDL-C) goals. Whether the treatment landscape has evolved, or gaps persist remains of interest. Methods: Baseline data are presented from SANTORINI, an observational, prospective study that documents the use of lipid-lowering therapies (LLTs) in patients ≥18 years at high or very high CV risk between 2020 and 2021 across primary and secondary care settings in 14 European countries. Findings: Of 9602 enrolled patients, 9044 with complete data were included (mean age: 65.3 ± 10.9 years; 72.6% male). Physicians reported using 2019 ESC/EAS guidelines as a basis for CV risk classification in 52.0% (4706/9044) of patients (overall: high risk 29.2%; very high risk 70.8%). However, centrally re-assessed CV risk based on 2019 ESC/EAS guidelines suggested 6.5% (308/4706) and 91.0% (4284/4706) were high- and very high-risk patients, respectively. Overall, 21.8% of patients had no documented LLTs, 54.2% were receiving monotherapy and 24.0% combination LLT. Median (interquartile range [IQR]) LDL-C was 2.1 (1.6, 3.0) mmol/L (82 [60, 117] mg/dL), with 20.1% of patients achieving risk-based LDL-C goals as per the 2019 ESC/EAS guidelines. Interpretation: At the time of study enrolment, 80% of high- and very high-risk patients failed to achieve 2019 ESC/EAS guidelines LDL-C goals. Contributory factors may include CV risk underestimation and underutilization of combination therapies. Further efforts are needed to achieve current guideline-recommended LDL-C goals. Trial registration: ClinicalTrials.gov Identifier: NCT04271280. Funding: This study is funded by Daiichi Sankyo Europe GmbH, Munich, Germany.

Potential Cardiovascular Events Avoided with Bempedoic Acid Plus Ezetimibe Fixed-Dose Combination Compared with Ezetimibe Alone in Patients with Atherosclerotic Cardiovascular Disease Taking Maximally Tolerated Statins.

BACKGROUND: Patients with atherosclerotic cardiovascular disease who require additional low-density lipoprotein cholesterol (LDL-C) lowering despite maximally tolerated statins have a significant unmet medical need and are at increased risk of future cardiovascular events and a reduced quality of life. OBJECTIVE: We aimed to estimate the percentage of cardiovascular events avoided following treatment with a fixed-dose combination of bempedoic acid plus ezetimibe (BA+EZE FDC) versus ezetimibe (EZE) in patients with atherosclerotic cardiovascular disease receiving maximally tolerated statins across a range of baseline LDL-C levels. METHODS: A Markov cohort simulation model estimated major adverse cardiovascular events avoided over a lifetime horizon among patients with atherosclerotic cardiovascular disease and baseline LDL-C levels from 80 to >200 mg/dL. BA+EZE FDC was compared with EZE based on mean percent LDL-C reductions versus placebo reported in a phase III trial. Health outcomes for the average patient were extrapolated to a US population of 100,000 persons using evidence on contemporary LDL-C levels from the National Health and Nutrition Examination Survey. RESULTS: Among patients with atherosclerotic cardiovascular disease not at the LDL-C goal with maximally tolerated statins, the addition of BA+EZE FDC compared with the addition of EZE was predicted to provide incremental absolute reductions in major adverse cardiovascular events dependent on baseline LDL-C levels at the population level. For those with baseline LDL-C of 101-110 mg/dL (n = 15,237), there were 4.9% (744) fewer events predicted, while for patients with baseline LDL-C of > 200 mg/dL (n = 1689), 10.9% (184) fewer events were predicted through the addition of BA+EZE FDC versus EZE. CONCLUSIONS: Further LDL-C reductions through the addition of BA+EZE FDC to maximally tolerated statins are predicted to reduce major adverse cardiovascular events compared with the addition of EZE. Benefits are potentially greater among those with higher starting LDL-C.

Treatment and low-density lipoprotein cholesterol levels in patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular risk: a population-based cross-sectional study in the Netherlands.

OBJECTIVE: To describe treatment patterns, low-density lipoprotein cholesterol (LDL-C) levels and healthcare resource utilization (HCRU) in the Netherlands in 2018 of patients with hypercholesterolaemia or mixed dyslipidaemia at high or very high cardiovascular (CV) risk. METHODS: From the PHARMO Database Network adult patients with a diagnosis or receiving lipid lowering therapy (LLT) between 2009 and 2018 were selected. Patients at high or very high CV risk according to 2016 ESC/EAS guidelines with recorded LDL-C levels who were treated with LLT or were characterized as statin intolerant in 2018 were included. LLT treatment patterns, LDL-C levels and HCRU (General Practitioner [GP] consultations and hospitalizations) were assessed. RESULTS: The study population included 54,346 patients, of which 70% were at very high CV risk and 30% at high CV risk. The majority (93%) received statin monotherapy, mostly of moderate (73%) or high (15%) intensity. Only 3% received a combination of statin and ezetimibe. Statin intolerance, based on a treatment algorithm, was estimated at 3%. Average LDL-C decreased with LLT intensity. Overall, 74% reached LDL-C < 2.5 mmol/l and 34% <1.8 mmol/l with their current treatment, and 46% reached their LDL-C goal according to 2016 ESC/EAS guidelines. The highest rates of hospitalizations and GP consultations, including home visits, were recorded in patients with peripheral artery disease or polyvascular disease. CONCLUSION: The treatment of hypercholesterolaemia and mixed dyslipidaemia in patients at high or very high CV risk in the Netherlands was suboptimal in 2018. To further lower CV risk alternative treatment strategies using add-on therapies are needed.

Simulation study on LDL cholesterol target attainment, treatment costs, and ASCVD events with bempedoic acid in patients at high and very-high cardiovascular risk.

BACKGROUND AND AIMS: The LDL cholesterol (LDL-C) treatment goals recommended by the 2019 ESC/EAS guidelines are only achieved in a minority of patients. The study objective was to estimate the impact of bempedoic acid treatment on LDL-C target attainment, drug costs, and atherosclerotic cardiovascular disease (ASCVD) events. The simulation used a Monte Carlo approach in a representative cohort of German outpatients at high or very-high cardiovascular risk. Additionally to statins, consecutive treatment with ezetimibe, bempedoic acid, and a PCSK9 inhibitor was simulated in patients not achieving their LDL-C goal. Considered were scenarios without and with bempedoic acid (where bempedoic acid was replaced by a PCSK9 inhibitor when LDL-C was not controlled). RESULTS: The simulation cohort consisted of 105,577 patients, of whom 76,900 had very-high and 28,677 high cardiovascular risk. At baseline, 11.2% of patients achieved their risk-based LDL-C target. Sequential addition of ezetimibe and bempedoic acid resulted in target LDL-C in 33.1% and 61.9%, respectively. Treatment with bempedoic acid reduced the need for a PCSK9 inhibitor from 66.6% to 37.8% and reduced drug costs by 35.9% per year on stable lipid-lowering medication. Compared to using only statins and ezetimibe, this approach is projected to prevent additional 6,148 ASCVD events annually per 1 million patients, whereas PCSK9 inhibition alone would prevent 7,939 additional ASCVD events annually. CONCLUSIONS: A considerably larger proportion of cardiovascular high- and very-high-risk patients can achieve guideline-recommended LDL-C goals with escalated lipid-lowering medication. Bempedoic acid is projected to substantially decrease the need for PCSK9 inhibitor treatment to achieve LDL-C targets, associated with reduced drug costs albeit with fewer prevented events.

Prevalence and Patient Outcomes of Adult Primary Hypercholesterolemia and Dyslipidemia in the UK: Longitudinal Retrospective Study Using a Primary Care Dataset from 2009 to 2019.

Background: Guidelines for the management of dyslipidemias recommend intensive low-density lipoprotein (LDL-C) control through lifestyle advice and lipid-lowering drugs to reduce the risk of cardiovascular disease (CVD). Objective: This retrospective study aimed to characterize the adult primary care population with primary hypercholesterolemia (PH)/mixed dyslipidemia (MD). Methods: Data on adults with PH/MD between 1 January 2009 and 31 December 2019 in the UK were extracted from linked primary Clinical Practice Research Datalink (CPRD) and secondary care (Hospital Episode Statistics) datasets and analyzed. Results: A total of 279,221 patients met the inclusion criteria. Mean follow-up was 8.6 years. Crude prevalence of PH/MD increased from 13.5% in 2009 to 23.5% by 2019. The incidence decreased from 176 to 49 per 100,000 population. Mean age of the cohort was 58 years, baseline LDL-C was 4.32 mmol/L, 19.6% had atherosclerotic CVD, 30.1% diabetes, and 8.5% heterozygous familial hypercholesterolemia. Estimated LDL-C reductions of 40% and 50% were achieved in 2.6% and 2.3% of patients, respectively. Most received moderate-intensity statins as monotherapy (62.4%); high-intensity statins were used less frequently (24.3% as initial treatment). Less than 10% of patients received ezetimibe plus statins of different intensities. Conclusion: The prevalence of dyslipidemia doubled between 2009 and 2019, likely due to more systematic identification of PH/MD. A large proportion of patients with PH/MD are of high and very high CV risk, remain suboptimally treated in terms of lipid lowering, and may experience CV events with associated non-negligible clinical and economic sequelae. Despite intensive LDL-C-lowering recommendations, these do not translate in clinical practice to the wider population.

Evaluation of contemporary treatment of high- and very high-risk patients for the prevention of cardiovascular events in Europe - Methodology and rationale for the multinational observational SANTORINI study.

Background and aims: Clinical practice before 2019 suggests a substantial proportion of high and very high CV risk patients taking lipid-lowering therapy (LLT) would not achieve the new LDL-C goals recommended in the 2019 ESC/EAS guidelines (<70 and < 55 mg/dL, respectively). To what extent practice has changed since the last ESC/EAS guideline update is uncertain, and quantification of remaining implementation gaps may inform health policy. Methods: The SANTORINI study is a multinational, multicentre, prospective, observational, non-interventional study documenting patient data at baseline (enrolment) and at 12-month follow-up. The study recruited 9606 patients ≥18 years of age with high and very high CV risk (as assigned by the investigators) requiring LLT, with no formal patient or comparator groups. The primary objective is to document, in the real-world setting, the effectiveness of current treatment modalities in managing plasma levels of LDL-C in high- and very high-risk patients requiring LLT. Key secondary effectiveness objectives include documenting the relationship between LLT and levels of other plasma lipids, high-sensitivity C-reactive protein (hsCRP) and overall predicted CV risk over one year. Health economics and patient-relevant parameters will also be assessed. Conclusions: The SANTORINI study, which commenced after the 2019 ESC/EAS guidelines were published, is ideally placed to provide important contemporary insights into the evolving management of LLT in Europe and highlight factors contributing to the low levels of LDL-C goal achievement among high and very high CV risk patients. It is hoped the findings will help enhance patient management and reduce the burden of ASCVD in Europe.

Validated Instruments of Quality of Life (QOL) in Patients With Acute Myeloid Leukemia (AML) and Other Cancers.

INTRODUCTION: Acute myeloid leukemia (AML) can negatively impact quality of life (QOL). Few QOL instruments are specific to and have been validated in AML. This review aims to identify QOL instruments that have been validated in patients with AML and other cancers and summarize their psychometric properties reported in published literature. A literature review search was performed using PubMed and OVID (Biosis, Embase, MEDLINE) databases through June 25, 2020. Search terms included: QOL, health-related QOL, patient-reported outcomes and validity, reliability, validated, tools, instruments, test-retest, and leukemia myeloid acute, leukemia, myeloid, acute, acute myeloid leukemia. Articles were included if they focused on cancer and reported psychometric properties that could be extracted. Abstracts and their references were reviewed for inclusion. RESULTS: Twelve evaluating ten instruments were included. Functional Assessment of Cancer Therapy Leukemia (FACT-Leu) showed internal consistency (IC) of α = 0.86 to >0.9, correlation with EQ-5D-3L of r > 0.50, correlation with European Organisation for Research and Treatment of Cancer (EORTC) QLQ-Leu of ρ = 0.29-0.63, test-retest reliability of κ = 0.861. FACT-F showed correlations with EORTC QLQ-C30 of r = 0.40-0.83. Hematological Malignancy Patient-Reported Outcome (HM-PRO) showed intraclass correlation coefficient (ICC) of 0.94-0.98. EORTC-8D and EQ-5D-3L showed ICC = 0.595, correlations with each other of ρ = 0.137-0.634 and with EORTC QLQ-C30 of r = 0.651-0.917. EORTC QLQ-C30 showed person separation reliability of 0.47 to 0.90 and patient-observer agreement of 0.85. Life Ingredient Profile (LIP) showed IC of α = 0.29-0.77 and test-retest reliability of κ = 0.42-1.0. QOL-E showed correlation with FACT-general of R = 0.71, internal validity of α = 0.7, and test-retest reliability of standardized Cronbach's α = 0.7-0.92. EORTC QLQ-Leu showed IC of α = 0.6-0.79. The Acute Myeloid Leukemia-Quality of Life (AML-QOL) instrument showed IC of α = 0.72, correlations with EORTC QLQ-30 of magnitudes ρ = 0.59-0.72, and test-retest reliability of ICC = 0.52-0.91. CONCLUSION: Although several QOL instruments have been validated, more research is needed to determine the most clinically useful instruments in patients with AML.

Burden of Migraine in Europe Using Self-Reported Digital Diary Data from the Migraine Buddy© Application.

INTRODUCTION: Migraine is a neurological disease characterized by recurring attacks that can cause severe disabling pain. This study described the burden of migraine as reported by individuals with migraine in the real world using a mobile application. METHODS: A retrospective, cross-sectional analysis was conducted using data captured through the Migraine Buddy© smartphone application from adult, self-diagnosed individuals with migraine in 17 European countries. Data were analyzed descriptively for the most recent 28-day period reported by users (n = 3900) during the study period (June 2015-July 2016) who were randomly selected on the basis of data completeness (completion rates > 70%) and stratified by migraine headache days/month: 4-7 episodic migraine (EM; n = 1500), 8-14 EM (n = 1500), and chronic migraine (≥ 15; CM; n = 900). RESULTS: More than 95% of users reported that migraine negatively affected their daily activities during at least one migraine attack. Attacks affected 50.5% (184.4 days/year), 26.9% (98 days/year), and 14.5% (53 days/year) of the year among CM, 8-14 EM, and 4-7 EM groups, respectively. On average, 44.8% CM, 40.9% 8-14 EM, and 34.7% of 4-7 EM sufferers, respectively, reported anxiety and/or depression symptoms during migraine attacks. Social or home activities, productivity, and sleep were highly affected, regardless of migraine frequency. Employed respondents (n = 3106) reported an average of 2.3 workdays missed per month and that at least one in four migraines led to work absenteeism; these migraines were commonly reported to have at least moderate to severe levels of pain, corresponding to the inability of persons to perform some or even any activities. Triptans (68%), opioids (46%), and nonsteroidal anti-inflammatory drugs (45%) were self-reported as the most common medicines used. CONCLUSIONS: This study, leveraging patient-reported data collected through a mobile application, demonstrates the high burden and impact of migraine on health-related quality of life, work productivity, and overall well-being of individuals suffering from migraines. FUNDING: Novartis Pharma AG, Switzerland.

Patients' perspective on the burden of migraine in Europe: a cross-sectional analysis of survey data in France, Germany, Italy, Spain, and the United Kingdom.

BACKGROUND: Migraine is a distinct neurological disease that imposes a significant burden on patients, society, and the healthcare system. This study aimed to characterize the incremental burden of migraine in individuals who suffer from ≥4 monthly headache days (MHDs) by examining health-related quality of life (HRQoL), impairments to work productivity and daily activities, and healthcare resource utilization (HRU) in the EU5 (France, Germany, Italy, Spain, United Kingdom). METHODS: This retrospective cross-sectional study used data from the 2016 National Health and Wellness Survey (NHWS; N = 80,600). Short-Form 36-Item Health Survey, version 2 (SF-36v2) physical and mental component summary scores (PCS and MCS), Short-form-6D (SF-6D), and EuroQoL (EQ-5D), impairments to work productivity and daily activities (Work Productivity and Activity Impairment Questionnaire (WPAI), and HRU were compared between migraine respondents suffering from ≥4 MHDs (n = 218) and non-migraine controls (n = 218) by propensity score matching using sociodemographic characteristics. Chi-square, T-tests, and Mann-Whitney tests were performed to determine significant differences between the groups after propensity score matching. RESULTS: HRQoL was lower in migraine individuals suffering from ≥4 MHDs compared with non-migraine controls, with reduced SF-36v2 PCS (46.00 vs 50.51) and MCS (37.69 vs 44.82), SF-6D health state utility score (0.62 vs 0.71), and EQ-5D score (0.68 vs 0.81) (for all, p < 0.001). Respondents with migraine suffering from ≥4 MHDs also reported higher levels of absenteeism from work (14.43% vs 9.46%; p = 0.001), presenteeism (35.52% vs 20.97%), overall work impairment (38.70% vs 23.27%), and activity impairment (44.17% vs 27.75%) than non-migraine controls (for all, p < 0.001). Additionally, HRU was significantly higher for individuals with ≥4 MHDs compared to their matched controls. Consistently, migraine subgroups (4-7 MHDs, 8-14 MHDs and CM) had lower HRQoL, greater overall work and activity impairment, and higher HRU compared to non-migraine controls. CONCLUSIONS: Migraine of ≥4 MHDs was associated with poorer HRQoL, greater work productivity loss, and higher HRU compared with non-migraine controls. The findings of the study suggest that an unmet need exists among individuals suffering from ≥4 MHDs in the EU5 suggesting the need for effective prophylactic treatments to lessen the humanistic and economic burden of migraine.

Cost Effectiveness of Apixaban versus Warfarin or Aspirin for Stroke Prevention in Patients with Atrial Fibrillation: A Greek Perspective.

BACKGROUND: Strokes attributed to atrial fibrillation (AF) represent a major cause of adult disability and a great burden to society and healthcare systems. OBJECTIVES: Our objective was to assess the cost effectiveness of apixaban, a direct acting oral anticoagulant (DOAC), versus warfarin or aspirin for patients with AF in the Greek healthcare setting. METHODS: We used a previously published Markov model to simulate clinical events for patients with AF treated with apixaban, the vitamin K antagonist (VKA) warfarin, or aspirin. Clinical events (ischemic and hemorrhagic stroke, intracranial hemorrhage, other major bleed, clinically relevant non-major bleed, myocardial infarction, and cardiovascular [CV] hospitalizations) were modeled using efficacy data from the ARISTOTLE and AVERROES clinical trials. The cohort's baseline characteristics also sourced from these trials. Among VKA-suitable patients, 64.7% were men with a mean age of 70 years and average CHADS2 (cardiac failure, hypertension, age, diabetes, stroke2) score of 2.1, whereas 58.5% of VKA-unsuitable patients were men with a mean age of 70 years and a CHADS2 score of 2.0. A panel of experts (cardiologists and internists) provided information on the resource use associated with the management of AF. Cost calculations reflect the local clinical setting and a third-party payer perspective (€, discounted at 3%). RESULTS: Based on a simulation of 1000 VKA-suitable patients over a lifetime horizon, the use of apixaban versus warfarin resulted in 26 fewer strokes and systemic embolisms in total, 65 fewer bleeds, 41 fewer myocardial infarctions, and 29 fewer CV-related deaths, with an incremental cost-effectiveness ratio (ICER) of €14,478/quality-adjusted life-year (QALY). For VKA-unsuitable patients, apixaban versus aspirin resulted in 72 fewer strokes and systemic embolisms and 57 fewer CV-related deaths, with an ICER of €7104/QALY. Sensitivity analyses indicated that results were robust. CONCLUSIONS: Based on the present analysis, apixaban represents a cost-effective treatment option versus warfarin and aspirin for the prevention of stroke in patients with AF from a Greek healthcare payer perspective over a lifetime horizon.

Cost-effectiveness of eplerenone in NYHA class II chronic heart failure patients with reduced LVEF: an analysis for Greece.

OBJECTIVES: The aim of the study was to evaluate the cost-effectiveness (CE) of treatment with eplerenone versus standard care in adult patients with New York Heart Association class II chronic heart failure and reduced left ventricular ejection fraction from the perspective of the Greek national health care payer. METHODS: A discrete-event model simulating the clinical course and respective outcomes of eplerenone as an add-on to standard therapy versus standard therapy alone based on the pivotal Eplerenone in Mild Patients Hospitalization and SurvIval Study in Heart Failure (EMPHASIS-HF) trial was locally adapted for the Greek setting. Data on medications followed the resource use from eplerenone in mild patients hospitalization and survival study in heart failure and were estimated on a lifetime basis (or until discontinuation). Cost calculations were based on year 2014, event costs (cardiovascular hospitalizations, adverse events, and devices) were sourced from published diagnosis-related groups. A 3% discount rate was applied. In order to test the robustness of the model projections, a range of deterministic and probabilistic sensitivity analyses were carried out. RESULTS: Over a patient's lifetime, the addition of eplerenone to standard care compared to standard care alone led to an incremental gain of 1.33 quality-adjusted life-years (QALYs) (6.53 vs 5.20 QALYs, respectively) as well as an increase in the cost of treatment by €2,160; these outcomes produced an incremental CE ratio of €1,624/QALY for the Greek setting. On the basis of probabilistic sensitivity analysis, there was a 100% likelihood of eplerenone being cost-effective versus standard care at a threshold of €3,500/QALY. CONCLUSION: This analysis indicates that eplerenone may be a cost-effective option versus standard care accompanied by additional clinical benefits and an added incremental cost at an acceptable, if not low, CE ratio. The results are consistent with the previously published studies on the CE of eplerenone as an add-on therapy to standard care, such as those regarding the health care settings of Spain, the UK, and Australia.

Cost-effectiveness of apixaban vs. other new oral anticoagulants for the prevention of stroke: an analysis on patients with non-valvular atrial fibrillation in the Greek healthcare setting.

BACKGROUND AND OBJECTIVES: Three new oral anticoagulants (NOACs) are currently approved for stroke prevention and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). The objective of this analysis was to assess the cost effectiveness of apixaban against other NOACs for the prevention of stroke in patients with NVAF in Greece. METHODS: A Markov model that evaluated clinical events, quality-adjusted life expectancy, and costs for patients treated with apixaban or other NOACs formed the basis of the analysis. Clinical events were modeled for a lifetime horizon, based on clinical efficacy data from an indirect comparison, using the ARISTOTLE, ROCKET-AF, and RE-LY clinical trials. Resource use associated with patient monitoring was elicited via a panel of experts (cardiologists and internists). Cost calculations reflect the local clinical setting and followed a third-party payer perspective (Euros, discounted at 3 %). RESULTS: Apixaban was projected to reduce the occurrence of clinical events and increase quality-adjusted life expectancy and incremental costs of treatment compared with other NOACs. Taking into account costs of medications, patient monitoring, and management of events, the incremental cost-effectiveness ratios for apixaban 5 mg twice daily vs. dabigatran 110 mg twice daily, dabigatran 150 mg twice daily, and rivaroxaban 20 mg once daily were estimated at €9907/quality-adjusted life-year (QALY), €13,727/QALY, and €6936/QALY gained, respectively. Extensive sensitivity analyses indicated that results were robust over a wide range of inputs. CONCLUSIONS: Based on the results of this analysis, apixaban can be a cost-effective alternative to other NOACs for the prevention of stroke in patients with NVAF in Greece.

Spatial and temporal expressions of prune reveal a role in Müller gliogenesis during Xenopus retinal development.

The development of stratified retinal cell architecture is highly conserved in all vertebrates, implying that a common fundamental molecular mechanism is involved in the generation of the organized retina. However, the detailed molecular mechanisms of retinal development are not fully understood. Here we have identified the Xenopus ortholog of prune and show that it is expressed in both differentiating and differentiated retinal domains during development. Interestingly, these spatial and temporal expression patterns coincide with the expression of prune binding partners, the NM23 family members. Overexpression of prune in retinal precursor cells significantly increases the ratio of Müller glial cells as observed by modulation of NM23 activity (Mochizuki et al., 2009). However, a mutated form of prune that has replacement of four aspartate (D) residues (D'Angelo et al., 2004), essential for phosphodiesterase activity, does not exhibit gliogenic activity. Our observations suggest that Xenopus prune may regulate Müller gliogenesis through phosphodiesterase-mediated regulation of NM23 family members.

The role of cell cycle in retinal development: cyclin-dependent kinase inhibitors co-ordinate cell-cycle inhibition, cell-fate determination and differentiation in the developing retina.

The mature retina is formed through multi-step developmental processes, including eye field specification, optic vesicle evagination, and cell-fate determination. Co-ordination of these developmental events with cell-proliferative activity is essential to achieve formation of proper retinal structure and function. In particular, the molecular and cellular dynamics of the final cell cycle significantly influence the identity that a cell acquires, since cell fate is largely determined at the final cell cycle for the production of postmitotic cells. This review summarizes our current understanding of the cellular mechanisms that underlie the co-ordination of cell-cycle and cell-fate determination, and also describes a molecular role of cyclin-dependent kinase inhibitors (CDKIs) as co-ordinators of cell-cycle arrest, cell-fate determination and differentiation.

The NM23 family in development.

The NM23 (non-metastatic 23) family is almost universally conserved across all three domains of life: eubacteria, archaea and eucaryotes. Unicellular organisms possess one NM23 ortholog, whilst vertebrates possess several. Gene multiplication through evolution has been accompanied by structural and functional diversification. Many NM23 orthologs are nucleoside diphosphate kinases (NDP kinases), but some more recently evolved members lack NDP kinase activity and/or display other functions, for instance, acting as protein kinases or transcription factors. These members display overlapping but distinct expression patterns during vertebrate development. In this review, we describe the functional differences and similarities among various NM23 family members. Moreover, we establish orthologous relationships through a phylogenetic analysis of NM23 members across vertebrate species, including Xenopus laevis and zebrafish, primitive chordates and several phyla of invertebrates. Finally, we summarize the involvement of NM23 proteins in development, in particular neural development. Carcinogenesis is a process of misregulated development, and NM23 was initially implicated as a metastasis suppressor. A more detailed understanding of the evolution of the family and its role in vertebrate development will facilitate elucidation of the mechanism of NM23 involvement in human cancer.

Xenopus NM23-X4 regulates retinal gliogenesis through interaction with p27Xic1.

BACKGROUND: In Xenopus retinogenesis, p27Xic1, a Xenopus cyclin dependent kinase inhibitor, functions as a cell fate determinant in both gliogenesis and neurogenesis in a context dependent manner. This activity is essential for co-ordination of determination and cell cycle regulation. However, very little is known about the mechanism regulating the context dependent choice between gliogenesis versus neurogenesis. RESULTS: We have identified NM23-X4, a NM23 family member, as a binding partner of p27Xic1. NM23-X4 is expressed at the periphery of the ciliary marginal zone of the Xenopus retina and the expression overlaps with p27Xic1 at the central side. Our in vivo functional analysis in Xenopus retina has shown that knockdown of NM23-X4 activates gliogenesis. Furthermore, co-overexpression of NM23-X4 with p27Xic1 results in the inhibition of p27Xic1-mediated gliogenesis, through direct interaction of NM23-X4 with the amino-terminal side of p27Xic1. This inhibitory effect on gliogenesis requires serine-150 and histidine-148, which correspond to the important residues for the kinase activities of NM23 family members. CONCLUSION: This study demonstrates that NM23-X4 functions as an inhibitor of p27Xic1-mediated gliogenesis in Xenopus retina and suggests that this activity contributes to the proper spatio-temporal regulation of gliogenesis.

Transcriptional repressor erf determines extraembryonic ectoderm differentiation.

Extraembryonic ectoderm differentiation and chorioallantoic attachment are fibroblast growth factor (FGF)- and transforming growth factor beta-regulated processes that are the first steps in the development of the placenta labyrinth and the establishment of the fetal-maternal circulation in the developing embryo. Only a small number of genes have been demonstrated to be important in trophoblast stem cell differentiation. Erf is a ubiquitously expressed Erk-regulated, ets domain transcriptional repressor expressed throughout embryonic development and adulthood. However, in the developing placenta, after 7.5 days postcoitum (dpc) its expression is restricted to the extraembryonic ectoderm, and its expression is restricted after 9.5 dpc in a subpopulation of labyrinth cells. Homozygous deletion of Erf in mice leads to a block of chorionic cell differentiation before chorioallantoic attachment, resulting in a persisting chorion layer, a persisting ectoplacental cone cavity, failure of chorioallantoic attachment, and absence of labyrinth. These defects result in embryo death by 10.5 dpc. Trophoblast stem cell lines derived from Erf(dl1/dl1) knockout blastocysts exhibit delayed differentiation and decreased expression of spongiotrophoblast markers, consistent with the persisting chorion layer, the expanded giant cell layer, and the diminished spongiotrophoblast layer observed in vivo. Our data suggest that attenuation of FGF/Erk signaling and consecutive Erf nuclear localization and function is required for extraembryonic ectoderm differentiation, ectoplacental cone cavity closure, and chorioallantoic attachment.