Socio-economic inequalities and heart failure morbidity and mortality: A systematic review and data synthesis.

Socio-economic status (SES) has been associated with incident and prevalent heart failure (HF), as well as its morbidity and mortality. However, the precise nature of the relationship between SES and HF remains unclear due to inconsistent data. This study aims to provide a comprehensive assessment and data synthesis of the relationship between SES and HF morbidity and mortality. We performed a systematic search and data synthesis using six databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines. The included studies comprised observational studies that reported on HF incidence and prevalence, HF hospitalizations, worsening HF (WHF) and all-cause mortality, as well as treatment options (medical, device and advanced HF therapies). SES was measured on both individual and area levels, encompassing single (e.g., income, education, employment, social risk score, living conditions and housing characteristics) and composite indicators. Among the 4124 studies screened, 79 were included, with an additional 5 identified through cross-referencing. In the majority of studies, a low SES was associated with an increased HF incidence (72%) and prevalence (75%). For mortality, we demonstrated that low SES was associated with increased mortality in 45% of the studies, with 18% of the studies showing mixed results (depending on the indicator, gender or follow-up) and 38% showing non-significant results. Similar patterns were observed for the association between SES, WHF, medical therapy prescriptions and the utilization of devices and advanced HF therapies. There was no clear pattern in the used SES indicators and HF outcomes. This systematic review, using contemporary data, shows that while socio-economic disparity may influence HF incidence, management and subsequent adverse events, these associations are not uniformly predictive. Our review highlights that the impact of SES varies depending on the specific indicators used, reflecting the complexity of its influence on health disparities. Assessment and recognition of SES as an important risk factor can assist clinicians in early detection and customizing HF treatment, while also aiding policymakers in optimizing resource allocation.

Design and rationale of the Engage-HF study: the impact of a gamified engagement toolkit on participation and engagement in a heart failure registry.

Aims: Heart failure (HF) registries provide valuable insights into patient management and quality of care. However, healthcare professionals face challenges due to the administrative burden of participation in registries. This study aims to evaluate the impact of education through an engagement toolkit on HF nurse practitioners' participation rate and data completeness in a national registry: the Netherlands Heart Registration-Heart Failure (NHR-HF) registry. Methods and results: Engage-HF is an observational study (intervention at the HF nurse level) with a pretest-posttest design within the participating hospitals. Between December 2022 and April 2024, 28 HF nurse practitioners from 12 hospitals will participate in a 24-week educational programme using the Engage-HF engagement toolkit. The main interaction platform in this toolkit is a gamified smartphone-based educational application called BrightBirds. The complete toolkit includes this educational application with weekly challenges, interactive posters, pop-ups, and alert messages, and a follow-up call at Week 4. The primary endpoints are the NHR-HF participation rates and data completeness at 1 and 6 months after using the toolkit. Additionally, we will analyse the experience of participants with the toolkit concerning their HF registry and knowledge of ESC 2021 HF guidelines. Conclusion: The Engage-HF study is the first to explore the impact of education through a gamified engagement toolkit to boost participation rates in a HF registry (NHR-HF) and test participant knowledge of the ESC 2021 HF guidelines. This innovative approach addresses challenges in the rollout of healthcare registries and the implementation of guidelines by providing a contemporary support base and a time-efficient method for education.

Coronary computed tomography angiography improves assessment of patients with acute chest pain and inconclusively elevated high-sensitivity troponins.

OBJECTIVES: To determine whether coronary computed tomography angiography (CCTA) can improve the diagnostic work-up of patients with acute chest pain and inconclusively high-sensitivity troponins (hs-troponin). METHODS: We conducted a prospective, blinded, observational, multicentre study. Patients aged 30-80 years presenting to the emergency department with acute chest pain and inconclusively elevated hs-troponins were included and underwent CCTA. The primary outcome was the diagnostic accuracy of ≥ 50% stenosis on CCTA to identify patients with type-1 non-ST-segment elevation acute coronary syndrome (NSTE-ACS). RESULTS: A total of 106 patients (mean age 65 ± 10, 29% women) were enrolled of whom 20 patients (19%) had an adjudicated diagnosis of type-1 NSTE-ACS. In 45 patients, CCTA revealed non-obstructive coronary artery disease (CAD) or no CAD. Sensitivity, specificity, negative predictive value (NPV), positive predictive value and area-under-the-curve (AUC) of ≥ 50% stenosis on CCTA to identify patients with type 1 NSTE-ACS, was 95% (95% confidence interval: 74-100), 56% (45-68), 98% (87-100), 35% (29-41) and 0.83 (0.73-0.94), respectively. When only coronary segments with a diameter ≥ 2 mm were considered for the adjudication of type 1 NSTE-ACS, the sensitivity and NPV increased to 100%. In 8 patients, CCTA enabled the detection of clinically relevant non-coronary findings. CONCLUSION: The absence of ≥ 50% coronary artery stenosis on CCTA can be used to rule out type 1 NSTE-ACS in acute chest pain patients with inconclusively elevated hs-troponins. Additionally, CCTA can help improve the diagnostic work-up by detecting other relevant conditions that cause acute chest pain and inconclusively elevated hs-troponins. CLINICAL RELEVANCE STATEMENT: Coronary CTA (CCTA) can safely rule out type 1 non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in patients presenting to the ED with acute chest pain and inconclusively elevated hs-troponins, while also detecting other relevant non-coronary conditions. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03129659). Registered on 26 April 2017 KEY POINTS: Acute chest discomfort is a common presenting complaint in the emergency department. CCTA achieved very high negative predictive values for type 1 NSTE-ACS in this population. CCTA can serve as an adjunct for evaluating equivocal ACS and evaluates for other pathology.

Efficacy and safety of low-dose digoxin in patients with heart failure. Rationale and design of the DECISION trial.

AIMS: Digoxin is the oldest drug in cardiovascular (CV) medicine, and one trial conducted >25 years ago showed a reduction in heart failure (HF) hospitalizations but no effect on mortality. However, later studies suggested that the dose of digoxin used in that trial (and other studies) may have been too high. The DECISION (Digoxin Evaluation in Chronic heart failure: Investigational Study In Outpatients in the Netherlands) trial will examine the efficacy and safety of low-dose digoxin in HF patients with reduced or mildly reduced left ventricular ejection fraction (LVEF) with a background of contemporary HF treatment. METHODS: The DECISION trial is a randomized, double-blind, parallel-group, placebo-controlled event-driven outcome trial which will investigate the efficacy and safety of low-dose digoxin in patients with chronic HF and LVEF <50%. Both patients with sinus rhythm and atrial fibrillation will be enrolled and will be randomized (1:1) to low-dose digoxin or matching placebo. To maintain a target serum digoxin concentration of 0.5-0.9 ng/ml, dose adjustments are made throughout follow-up based on serum digoxin measurements with dummy values for the placebo group. The primary endpoint is a composite of CV mortality and total HF hospitalizations or total urgent hospital visits for worsening HF, and all endpoints are adjudicated blindly by a Clinical Event Committee. The estimated sample size was 982 patients who will be followed for a median of 3 years, and in December 2023 enrolment was completed after 1002 patients. CONCLUSIONS: The DECISION trial will provide important evidence regarding the effect of (low-dose) digoxin on CV mortality and total HF hospitalizations and urgent hospital visits when added to contemporary HF treatment of patients with reduced or mildly reduced LVEF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03783429.

An asymptotic description of a basic FcRn-regulated clearance mechanism and its implications for PBPK modelling of large antibodies.

A basic FcRn-regulated clearance mechanism is investigated using the method of matched asymptotic expansions. The broader aim of the work is to obtain further insight on the mechanism, thereby providing theoretical support for future pharmacologically-based pharmacokinetic modelling efforts. The corresponding governing equations are first non-dimensionalised and the order of magnitudes of the model parameters are assessed based on their values reported in the literature. Under the assumption of high FcRn-binding affinity, analytical approximations are derived that are valid over the characteristic phases of the problem. Additionally, relatively simple equations relating clearance and AUC to physiological model parameters are derived, which are valid over the longest characteristic time scale of the problem. For lower to moderate doses clearance is effectively linear, whereas for higher doses it is nonlinear. It is shown that for all doses sufficiently high the leading-order approximation for the IgG concentration in plasma, over the longest characteristic time scale, is independent of the initial dose. This is because IgG that is in 'excess' of FcRn is eliminated over a time scale much shorter than that of the terminal phase. In conclusion, analytical approximations of the basic FcRn mechanism have been derived using matched asymptotic expansions, leading to a simple equation relating clearance to FcRn binding affinity, the ratio of degradation and FcRn concentration, and the volumes of the system.

Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

To rule-in, or not to falsely rule-out, that is the question: evaluation of hs-cTnT EQA performance in light of the ESC-2020 guideline.

OBJECTIVES: To accurately evaluate non-ST-elevated acute cardiac syndrome (NSTE-ACS), the quality of high-sensitive cardiac troponin (hs-cTn) assays is of vital importance. The 2020 revision of the NSTE-ACS guideline includes clinical decision-limits (CDL's) to both rule-in and rule-out NSTE-ACS for most commercially available platforms, providing both 0/1 h and 0/2 h delta limits. Our study evaluated whether laboratories are able to meet the analytical performance specifications for imprecision (APS) for hs-cTnT. METHODS: Results from external quality assurance (EQA) in commutable samples were used to evaluate the current and historic performance of analyzers. The performance of analyzers that either passed or failed to comply with 0/1 h-APS were used on a real-world dataset of first hs-cTnT-values to simulate 10.000 samples of t=0, t=1 and t=2 h values with multiple delta's for all relevant CDL's. We compared the simulated values to the input values to obtain the percentage of aberrant results simulated. RESULTS: The majority of analyzers complies with APS for rule-in in 2022 (0/1 h: 90.4 % and 0/2 h: 100 %), compliance for the 0/1 h rule-out is still far from optimal (0/1 h: 30.7 %, 0/2 h: 75.4 %), with improving compliance over the past years (rule-in p=<0.0001, rule-out p=0.011, χ2). Whilst 0/1 h-APS-passing analyzers have a minute risk to falsely rule-out patients whom should be ruled-in (0.0001 %), failing performance increases this risk to 2.1 % upon using 0/1 h CDL's. Here, adopting 0/2 h CDL's is favorable (0.01 %). CONCLUSIONS: Laboratories that fail to meet hs-cTnT 0/1 h-APS should improve their performance to the required and achievable level. Until performance is reached clinics should adopt the 0/2 h CDL's.

Embedding routine health care data in clinical trials: with great power comes great responsibility.

Randomised clinical trials (RCTs) are vital for medical progress. Unfortunately, 'traditional' RCTs are expensive and inherently slow. Moreover, their generalisability has been questioned. There is considerable overlap in routine health care data (RHCD) and trial-specific data. Therefore, integration of RHCD in an RCT has great potential, as it would reduce the effort and costs required to collect data, thereby overcoming some of the major downsides of a traditional RCT. However, use of RHCD comes with other challenges, such as privacy issues, as well as technical and practical barriers. Here, we give a current overview of related initiatives on national cardiovascular registries (Netherlands Heart Registration, Heart4Data), showcasing the interrelationships between and the relevance of the different registries for the practicing physician. We then discuss the benefits and limitations of RHCD use in the setting of a pragmatic RCT from a cardiovascular perspective, illustrated by a case study in heart failure.

RELEASE-HF study: a protocol for an observational, registry-based study on the effectiveness of telemedicine in heart failure in the Netherlands.

INTRODUCTION: Meta-analyses show postive effects of telemedicine in heart failure (HF) management on hospitalisation, mortality and costs. However, these effects are heterogeneous due to variation in the included HF population, the telemedicine components and the quality of the comparator usual care. Still, telemedicine is gaining acceptance in HF management. The current nationwide study aims to identify (1) in which subgroup(s) of patients with HF telemedicine is (cost-)effective and (2) which components of telemedicine are most (cost-)effective. METHODS AND ANALYSIS: The RELEASE-HF ('REsponsible roLl-out of E-heAlth through Systematic Evaluation - Heart Failure') study is a multicentre, observational, registry-based cohort study that plans to enrol 6480 patients with HF using data from the HF registry facilitated by the Netherlands Heart Registration. Collected data include patient characteristics, treatment information and clinical outcomes, and are measured at HF diagnosis and at 6 and 12 months afterwards. The components of telemedicine are described at the hospital level based on closed-ended interviews with clinicians and at the patient level based on additional data extracted from electronic health records and telemedicine-generated data. The costs of telemedicine are calculated using registration data and interviews with clinicians and finance department staff. To overcome missing data, additional national databases will be linked to the HF registry if feasible. Heterogeneity of the effects of offering telemedicine compared with not offering on days alive without unplanned hospitalisations in 1 year is assessed across predefined patient characteristics using exploratory stratified analyses. The effects of telemedicine components are assessed by fitting separate models for component contrasts. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee 2021 of the University Medical Center Utrecht (the Netherlands). Results will be published in peer-reviewed journals and presented at (inter)national conferences. Effective telemedicine scenarios will be proposed among hospitals throughout the country and abroad, if applicable and feasible. TRIAL REGISTRATION NUMBER: NCT05654961.

The different risk of new-onset, chronic, worsening, and advanced heart failure: A systematic review and meta-regression analysis.

AIMS: Heart failure (HF) is a chronic and progressive syndrome associated with a poor prognosis. While it may seem intuitive that the risk of adverse outcomes varies across the different stages of HF, an overview of these risks is lacking. This study aims to determine the risk of all-cause mortality and HF hospitalizations associated with new-onset HF, chronic HF (CHF), worsening HF (WHF), and advanced HF. METHODS AND RESULTS: We performed a systematic review of observational studies from 2012 to 2022 using five different databases. The primary outcomes were 30-day and 1-year all-cause mortality, as well as 1-year HF hospitalization. Studies were pooled using random effects meta-analysis, and mixed-effects meta-regression was used to compare the different HF groups. Among the 15 759 studies screened, 66 were included representing 862 046 HF patients. Pooled 30-day mortality rates did not reveal a significant distinction between hospital-admitted patients, with rates of 10.13% for new-onset HF and 8.11% for WHF (p = 0.10). However, the 1-year mortality risk differed and increased stepwise from CHF to advanced HF, with a rate of 8.47% (95% confidence interval [CI] 7.24-9.89) for CHF, 21.15% (95% CI 17.78-24.95) for new-onset HF, 26.84% (95% CI 23.74-30.19) for WHF, and 29.74% (95% CI 24.15-36.10) for advanced HF. Readmission rates for HF at 1 year followed a similar trend. CONCLUSIONS: Our meta-analysis of observational studies confirms the different risk for adverse outcomes across the distinct HF stages. Moreover, it emphasizes the negative prognostic value of WHF as the first progressive stage from CHF towards advanced HF.

Guideline implementation, drug sequencing, and quality of care in heart failure: design and rationale of TITRATE-HF.

AIMS: Current heart failure (HF) guidelines recommend to prescribe four drug classes in patients with HF with reduced ejection fraction (HFrEF). A clear challenge exists to adequately implement guideline-directed medical therapy (GDMT) regarding the sequencing of drugs and timely reaching target dose. It is largely unknown how the paradigm shift from a serial and sequential approach for drug therapy to early parallel application of the four drug classes will be executed in daily clinical practice, as well as the reason clinicians may not adhere to new guidelines. We present the design and rationale for the real-world TITRATE-HF study, which aims to assess sequencing strategies for GDMT initiation, dose titration patterns (order and speed), intolerance for GDMT, barriers for implementation, and long-term outcomes in patients with de novo, chronic, and worsening HF. METHODS AND RESULTS: A total of 4000 patients with HFrEF, HF with mildly reduced ejection fraction, and HF with improved ejection fraction will be enrolled in >40 Dutch centres with a follow-up of at least 3 years. Data collection will include demographics, physical examination and vital parameters, electrocardiogram, laboratory measurements, echocardiogram, medication, and quality of life. Detailed information on titration steps will be collected for the four GDMT drug classes. Information will include date, primary reason for change, and potential intolerances. The primary clinical endpoints are HF-related hospitalizations, HF-related urgent visits with a need for intravenous diuretics, all-cause mortality, and cardiovascular mortality. CONCLUSIONS: TITRATE-HF is a real-world multicentre longitudinal registry that will provide unique information on contemporary GDMT implementation, sequencing strategies (order and speed), and prognosis in de novo, worsening, and chronic HF patients.

Using the LeiCNS-PK3.0 Physiologically-Based Pharmacokinetic Model to Predict Brain Extracellular Fluid Pharmacokinetics in Mice.

INTRODUCTION: The unbound brain extracelullar fluid (brainECF) to plasma steady state partition coefficient, Kp,uu,BBB, values provide steady-state information on the extent of blood-brain barrier (BBB) transport equilibration, but not on pharmacokinetic (PK) profiles seen by the brain targets. Mouse models are frequently used to study brain PK, but this information cannot directly be used to inform on human brain PK, given the different CNS physiology of mouse and human. Physiologically based PK (PBPK) models are useful to translate PK information across species. AIM: Use the LeiCNS-PK3.0 PBPK model, to predict brain extracellular fluid PK in mice. METHODS: Information on mouse brain physiology was collected from literature. All available connected data on unbound plasma, brainECF PK of 10 drugs (cyclophosphamide, quinidine, erlotonib, phenobarbital, colchicine, ribociclib, topotecan, cefradroxil, prexasertib, and methotrexate) from different mouse strains were used. Dosing regimen dependent plasma PK was modelled, and Kpuu,BBB values were estimated, and provided as input into the LeiCNS-PK3.0 model to result in prediction of PK profiles in brainECF. RESULTS: Overall, the model gave an adequate prediction of the brainECF PK profile for 7 out of the 10 drugs. For 7 drugs, the predicted versus observed brainECF data was within two-fold error limit and the other 2 drugs were within five-fold error limit. CONCLUSION: The current version of the mouse LeiCNS-PK3.0 model seems to reasonably predict available information on brainECF from healthy mice for most drugs. This brings the translation between mouse and human brain PK one step further.

The PBPK LeiCNS-PK3.0 framework predicts Nirmatrelvir (but not Remdesivir or Molnupiravir) to achieve effective concentrations against SARS-CoV-2 in human brain cells.

SARS-CoV-2 was shown to infect and persist in the human brain cells for up to 230 days, highlighting the need to treat the brain viral load. The CNS disposition of the antiCOVID-19 drugs: Remdesivir, Molnupiravir, and Nirmatrelvir, remains, however, unexplored. Here, we assessed the human brain pharmacokinetic profile (PK) against the EC90 values of the antiCOVID-19 drugs to predict drugs with favorable brain PK against the delta and the omicron variants. We also evaluated the intracellular PK of GS443902 and EIDD2061, the active metabolites of Remdesivir and Molnupiravir, respectively. Towards this, we applied LeiCNS-PK3.0, the physiologically based pharmacokinetic framework with demonstrated adequate predictions of human CNS PK. Under the recommended dosing regimens, the predicted brain extracellular fluid PK of only Nirmatrelvir was above the variants' EC90. The intracellular levels of GS443902 and EIDD2061 were below the intracellular EC90. Summarizing, our model recommends Nirmatrelvir as the promising candidate for (pre)clinical studies investigating the CNS efficacy of antiCOVID-19 drugs.

Drug Distribution in Brain and Cerebrospinal Fluids in Relation to IC50 Values in Aging and Alzheimer's Disease, Using the Physiologically Based LeiCNS-PK3.0 Model.

BACKGROUND: Very little knowledge exists on the impact of Alzheimer's disease on the CNS target site pharmacokinetics (PK). AIM: To predict the CNS PK of cognitively healthy young and elderly and of Alzheimer's patients using the physiologically based LeiCNS-PK3.0 model. METHODS: LeiCNS-PK3.0 was used to predict the PK profiles in brain extracellular (brainECF) and intracellular (brainICF) fluids and cerebrospinal fluid of the subarachnoid space (CSFSAS) of donepezil, galantamine, memantine, rivastigmine, and semagacestat in young, elderly, and Alzheimer's patients. The physiological parameters of LeiCNS-PK3.0 were adapted for aging and Alzheimer's based on an extensive literature search. The CNS PK profiles at plateau for clinical dose regimens were related to in vitro IC50 values of acetylcholinesterase, butyrylcholinesterase, N-methyl-D-aspartate, or gamma-secretase. RESULTS: The PK profiles of all drugs differed between the CNS compartments regarding plateau levels and fluctuation. BrainECF, brainICF and CSFSAS PK profile relationships were different between the drugs. Aging and Alzheimer's had little to no impact on CNS PK. Rivastigmine acetylcholinesterase IC50 values were not reached. Semagacestat brain PK plateau levels were below the IC50 of gamma-secretase for half of the interdose interval, unlike CSFSAS PK profiles that were consistently above IC50. CONCLUSION: This study provides insights into the relations between CNS compartments PK profiles, including target sites. CSFSAS PK appears to be an unreliable predictor of brain PK. Also, despite extensive changes in blood-brain barrier and brain properties in Alzheimer's, this study shows that the impact of aging and Alzheimer's pathology on CNS distribution of the five drugs is insignificant.

Coronary CT angiography for improved assessment of patients with acute chest pain and low-range positive high-sensitivity troponins: study protocol for a prospective, observational, multicentre study (COURSE trial).

INTRODUCTION: Current evaluation of patients suspected of a non-ST-elevation acute coronary syndrome (NSTE-ACS) involves the use of algorithms that incorporate clinical information, electrocardiogram (ECG) and high-sensitivity cardiac troponins (hs-troponins). While primarily designed to rule out NSTE-ACS safely, these algorithms can also be used for rule in of NSTE-ACS in some patients. Still, in a substantial number of patients, these algorithms do not provide a conclusive work-up. These patients often present with an atypical clinical profile and low-range positive hs-troponin values without a characteristic rise or fall pattern. They represent a heterogeneous group of patients with various underlying conditions; only a fraction (30%-40%) will eventually be diagnosed with a myocardial infarction. Uncertainty exists about the optimal diagnostic strategy and their management depends on the clinical perspective of the treating physician ranging from direct discharge to admission for invasive coronary angiography. Coronary CT angiography (CCTA) is a non-invasive test that has been shown to be safe, fast and reliable in the evaluation of coronary artery disease. In this study, we will determine the usefulness of CCTA in patients with acute chest pain and low-range positive hs-troponin values. METHODS AND ANALYSIS: A prospective, double-blind, observational, multicentre study conducted in the Netherlands. Patients aged 30-80 years presenting to the emergency department with acute chest pain and a suspicion of NSTE-ACS, a normal or non-diagnostic ECG and low-range positive hs-troponins will be scheduled to undergo CCTA. The primary outcome is the diagnostic accuracy of CCTA for the diagnosis of NSTE-ACS at discharge, in terms of sensitivity and negative predictive value. ETHICS AND DISSEMINATION: This study was approved by the Medical Research Ethics Committee of Erasmus Medical Center in Rotterdam, the Netherlands (registration number MEC-2017-506). Written informed consent to participate will be obtained from all participants. This study's findings will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov (NCT03129659).

Lumbar cerebrospinal fluid-to-brain extracellular fluid surrogacy is context-specific: insights from LeiCNS-PK3.0 simulations.

Predicting brain pharmacokinetics is critical for central nervous system (CNS) drug development yet difficult due to ethical restrictions of human brain sampling. CNS pharmacokinetic (PK) profiles are often altered in CNS diseases due to disease-specific pathophysiology. We previously published a comprehensive CNS physiologically-based PK (PBPK) model that predicted the PK profiles of small drugs at brain and cerebrospinal fluid compartments. Here, we improved this model with brain non-specific binding and pH effect on drug ionization and passive transport. We refer to this improved model as Leiden CNS PBPK predictor V3.0 (LeiCNS-PK3.0). LeiCNS-PK3.0 predicted the unbound drug concentrations of brain ECF and CSF compartments in rats and humans with less than two-fold error. We then applied LeiCNS-PK3.0 to study the effect of altered cerebrospinal fluid (CSF) dynamics, CSF volume and flow, on brain extracellular fluid (ECF) pharmacokinetics. The effect of altered CSF dynamics was simulated using LeiCNS-PK3.0 for six drugs and the resulting drug exposure at brain ECF and lumbar CSF were compared. Simulation results showed that altered CSF dynamics changed the CSF PK profiles, but not the brain ECF profiles, irrespective of the drug's physicochemical properties. Our analysis supports the notion that lumbar CSF drug concentration is not an accurate surrogate of brain ECF, particularly in CNS diseases. Systems approaches account for multiple levels of CNS complexity and are better suited to predict brain PK.

Undetectable High-Sensitivity Troponin T as a Gatekeeper for Coronary Computed Tomography Angiography in Patients Suspected of Acute Coronary Syndrome.

OBJECTIVES: The aim of this study was to characterize the safety and efficiency of a strategy employing the limit of detection (LoD) of high-sensitivity troponin T (hs-TnT) as a gatekeeper for coronary computed tomography angiography (CCTA) in suspected acute coronary syndrome (ACS) patients in the emergency department (ED). METHODS: We included suspected ACS patients who underwent CCTA and were evaluated with hs-TnT. Patients were categorized as below the LoD and at or above the LoD. The primary outcome was 30-day major adverse cardiac events (MACEs), defined as all-cause mortality, ACS, or coronary revascularization. RESULTS: The study population consisted of 177 patients (mean age 55 ± 10 years, 50.3% women), and 16 (9.0%) patients reached the primary outcome. None of the patients died, while 13 had an adjudicated diagnosis of ACS, and 3 underwent elective coronary revascularization. There were 77 patients (44%) with an hs-TnT value below the LoD (MACEs; n = 1 [1.3%]) and 100 (56%) with at or above the LoD levels (MACEs; n = 15 [15%]). None of 67 patients with an hs-TnT value below the LoD and <50% stenosis on CCTA experienced MACEs. Out of the 10 patients with an hs-TnT value below the LoD and ≥50% stenosis on CCTA, 1 patient underwent elective percutaneous coronary revascularization. In patients with an hs-TnT value at or above the LoD, 74 patients had <50% stenosis on CCTA, and 2 patients (3%) were diagnosed with myocardial infarction without obstructive coronary artery disease confirmed on invasive angiography. Thirteen (50%) patients with an hs-TnT value at or above the LoD and ≥50% stenosis on CCTA experienced MACEs (11 ACS and 2 elective percutaneous coronary revascularizations). CONCLUSION: Our findings support that implementing the LoD of hs-TnT as a gatekeeper may reduce the need for CCTA in suspected ACS patients in the ED.

Diagnostic performance and clinical implications for enhancing a hybrid quantitative flow ratio-FFR revascularization decision-making strategy.

Invasive fractional flow reserve (FFR) adoption remains low mainly due to procedural and operator related factors as well as costs. Alternatively, quantitative flow ratio (QFR) achieves a high accuracy mainly outside the intermediate zone without the need for hyperaemia and wire-use. We aimed to determine the diagnostic performance of QFR and to evaluate a QFR-FFR hybrid strategy in which FFR is measured only in the intermediate zone. This retrospective study included 289 consecutive patients who underwent invasive coronary angiography and FFR. QFR was calculated for all vessels in which FFR was measured. The QFR-FFR hybrid approach was modelled using the intermediate zone of 0.77-0.87 in which FFR-measurements are recommended. The sensitivity, specificity, and accuracy on a per vessel-based analysis were 84.6%, 86.3% and 85.6% for QFR and 88.0%, 92.9% and 90.3% for the QFR-FFR hybrid approach. The diagnostic accuracy of QFR-FFR hybrid strategy with invasive FFR measurement was 93.4% and resulted in a 56.7% reduction in the need for FFR. QFR has a good correlation and agreement with invasive FFR. A hybrid QFR-FFR approach could extend the use of QFR and reduces the proportion of invasive FFR-measurements needed while improving accuracy.

Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study.

OBJECTIVE: This study aimed to validate trial patient eligibility screening and baseline data collection using text-mining in electronic healthcare records (EHRs), comparing the results to those of an international trial. STUDY DESIGN AND SETTING: In three medical centers with different EHR vendors, EHR-based text-mining was used to automatically screen patients for trial eligibility and extract baseline data on nineteen characteristics. First, the yield of screening with automated EHR text-mining search was compared with manual screening by research personnel. Second, the accuracy of extracted baseline data by EHR text mining was compared to manual data entry by research personnel. RESULTS: Of the 92,466 patients visiting the out-patient cardiology departments, 568 (0.6%) were enrolled in the trial during its recruitment period using manual screening methods. Automated EHR data screening of all patients showed that the number of patients needed to screen could be reduced by 73,863 (79.9%). The remaining 18,603 (20.1%) contained 458 of the actual participants (82.4% of participants). In trial participants, automated EHR text-mining missed a median of 2.8% (Interquartile range [IQR] across all variables 0.4-8.5%) of all data points compared to manually collected data. The overall accuracy of automatically extracted data was 88.0% (IQR 84.7-92.8%). CONCLUSION: Automatically extracting data from EHRs using text-mining can be used to identify trial participants and to collect baseline information.

Cardiac complications in patients hospitalised with COVID-19.

AIMS: To determine the frequency and pattern of cardiac complications in patients hospitalised with coronavirus disease (COVID-19). METHODS AND RESULTS: CAPACITY-COVID is an international patient registry established to determine the role of cardiovascular disease in the COVID-19 pandemic. In this registry, data generated during routine clinical practice are collected in a standardised manner for patients with a (highly suspected) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requiring hospitalisation. For the current analysis, consecutive patients with laboratory confirmed COVID-19 registered between 28 March and 3 July 2020 were included. Patients were followed for the occurrence of cardiac complications and pulmonary embolism from admission to discharge. In total, 3011 patients were included, of which 1890 (62.8%) were men. The median age was 67 years (interquartile range 56-76); 937 (31.0%) patients had a history of cardiac disease, with pre-existent coronary artery disease being most common (n=463, 15.4%). During hospitalisation, 595 (19.8%) patients died, including 16 patients (2.7%) with cardiac causes. Cardiac complications were diagnosed in 349 (11.6%) patients, with atrial fibrillation (n=142, 4.7%) being most common. The incidence of other cardiac complications was 1.8% for heart failure (n=55), 0.5% for acute coronary syndrome (n=15), 0.5% for ventricular arrhythmia (n=14), 0.1% for bacterial endocarditis (n=4) and myocarditis (n=3), respectively, and 0.03% for pericarditis (n=1). Pulmonary embolism was diagnosed in 198 (6.6%) patients. CONCLUSION: This large study among 3011 hospitalised patients with COVID-19 shows that the incidence of cardiac complications during hospital admission is low, despite a frequent history of cardiovascular disease. Long-term cardiac outcomes and the role of pre-existing cardiovascular disease in COVID-19 outcome warrants further investigation.