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.

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.

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.

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.

Colchicine in Patients with Chronic Coronary Disease.

BACKGROUND: Evidence from a recent trial has shown that the antiinflammatory effects of colchicine reduce the risk of cardiovascular events in patients with recent myocardial infarction, but evidence of such a risk reduction in patients with chronic coronary disease is limited. METHODS: In a randomized, controlled, double-blind trial, we assigned patients with chronic coronary disease to receive 0.5 mg of colchicine once daily or matching placebo. The primary end point was a composite of cardiovascular death, spontaneous (nonprocedural) myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization. The key secondary end point was a composite of cardiovascular death, spontaneous myocardial infarction, or ischemic stroke. RESULTS: A total of 5522 patients underwent randomization; 2762 were assigned to the colchicine group and 2760 to the placebo group. The median duration of follow-up was 28.6 months. A primary end-point event occurred in 187 patients (6.8%) in the colchicine group and in 264 patients (9.6%) in the placebo group (incidence, 2.5 vs. 3.6 events per 100 person-years; hazard ratio, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P<0.001). A key secondary end-point event occurred in 115 patients (4.2%) in the colchicine group and in 157 patients (5.7%) in the placebo group (incidence, 1.5 vs. 2.1 events per 100 person-years; hazard ratio, 0.72; 95% CI, 0.57 to 0.92; P = 0.007). The incidence rates of spontaneous myocardial infarction or ischemia-driven coronary revascularization (composite end point), cardiovascular death or spontaneous myocardial infarction (composite end point), ischemia-driven coronary revascularization, and spontaneous myocardial infarction were also significantly lower with colchicine than with placebo. The incidence of death from noncardiovascular causes was higher in the colchicine group than in the placebo group (incidence, 0.7 vs. 0.5 events per 100 person-years; hazard ratio, 1.51; 95% CI, 0.99 to 2.31). CONCLUSIONS: In a randomized trial involving patients with chronic coronary disease, the risk of cardiovascular events was significantly lower among those who received 0.5 mg of colchicine once daily than among those who received placebo. (Funded by the National Health Medical Research Council of Australia and others; LoDoCo2 Australian New Zealand Clinical Trials Registry number, ACTRN12614000093684.).

Variability in the Log Domain and Limitations to Its Approximation by the Normal Distribution.

Pharmacometric models using lognormal distributions have become commonplace in pharmacokinetic-pharmacodynamic investigations. The extent to which it can be interpreted by traditional description of variability through the normal distribution remains elusive. In this tutorial, the comparison is made using formal approximation methods. The quality of the resulting approximation was assessed by the similarity of prediction intervals (PIs) to true values, illustrated using 80% PIs. Approximated PIs were close to true values when lognormal standard deviation (omega) was smaller than about 0.25, depending mostly on the desired precision. With increasing omega values, the precision of approximation worsens and starts to deteriorate at omega values of about 1. With such high omega values, there is no resemblance between the lognormal and normal distribution anymore. To support dissemination and interpretation of these nonlinear properties, some additional statistics are discussed in the context of the three regions of behavior of the lognormal distribution.

ICD implantation for secondary prevention in patients with ventricular arrhythmia in the setting of acute cardiac ischemia and a history of myocardial infarction.

INTRODUCTION: In patients with a prior myocardial infarction (MI) but preserved left ventricular (LV) function, sustained ventricular arrhythmias (VAs) may arise in the setting of an acute coronary syndrome (ACS). It is unknown whether an implantable cardioverter-defibrillator (ICD) is mandatory in these patients as VA might be triggered by a reversible cause. The purpose of this study is to analyze the benefit of ICD therapy in this patient population. METHODS: We conducted a retrospective observational study in ICD recipients implanted from 2008 to 2011. The study group consisted of patients with sustained VA in the setting of an ACS, with a history of MI, but with left ventricular ejection fraction (LVEF) greater than 35 (group A). The two control groups consisted of patients admitted with VA with a history of MI, but without ACS at presentation, either with LVEF greater than 35% (group B) or ≤35% (group C). The primary endpoint was the number of patients with appropriate ICD therapy (antitachycardia pacing or shock). RESULTS: A total of 291 patients were included with a mean follow-up of 5.3 years. Appropriate ICD therapy occurred in 45.6% of the patients in group A vs 51.6% and 60.4% in groups B and C (P = .11). In group A, 31.1% received an appropriate ICD shock vs 34.7% and 44.3% in control groups B and C (P = .12). CONCLUSION: On the basis of these data, ICD implantation seems warranted in patients with history of MI presenting with VA in the setting of an ACS, despite preserved LV function and adequate revascularization. Further trials, preferably randomizes, should be performed to address these findings.

HEART score improves efficiency of coronary computed tomography angiography in patients suspected of acute coronary syndrome in the emergency department.

AIMS: Coronary computed tomography angiography is increasingly employed in the emergency department for suspected acute coronary syndrome patients. The HEART score has been proposed for initial risk stratification in these patients. The aim of this study was to investigate the diagnostic value and efficiency of the HEART score before coronary computed tomography angiography. METHODS AND RESULTS: We included patients suspected of acute coronary syndrome who underwent coronary computed tomography angiography in the emergency department. Based on the HEART score, patients were stratified as low-risk (HEART≤3), intermediate-risk (HEART4-6) and high-risk (HEART≥7). We assessed coronary computed tomography angiography for the presence of significant coronary artery disease (>50% stenosis). The primary outcome, the level of major adverse cardiac events, was a composite endpoint of all-cause mortality, acute coronary syndrome or coronary revascularisation within 30 days. The study population consisted of 340 patients (mean age: 55.6±10.1 years, 44.7% women), major adverse cardiac events occurred in 45 (13.2%) patients. The incidence of major adverse cardiac events in patients stratified as low-risk (35.0%), intermediate-risk (56.8%) and high-risk (8.2%) was 3.4%, 12.4% and 60.7%, respectively. All four low-risk patients with major adverse cardiac events had a HEART score of three. An algorithm where coronary computed tomography angiography is reserved for patients with HEART 3-6 resulted in a sensitivity of 97.8%, specificity of 84.1%, negative predictive value of 99.6% and positive predictive value of 48.4%, while reducing the need for coronary computed tomography angiography by 22% (n=75). CONCLUSION: The predictive value of coronary computed tomography angiography for 30-day major adverse cardiac events in suspected acute coronary syndrome patients is good, and reserving coronary computed tomography angiography for HEART score 3-6 patients reduces the number of needed coronary computed tomography angiograms without affecting diagnostic accuracy.

1-Year Outcomes of Delayed Versus Immediate Intervention in Patients With Transient ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: The aim of the present study was to determine the effect of a delayed versus an immediate invasive approach on final infarct size and clinical outcome up to 1 year. BACKGROUND: Up to 24% of patients with acute coronary syndromes present with ST-segment elevation myocardial infarction (STEMI) but show complete resolution of ST-segment elevation and symptoms before revascularization. Current guidelines do not clearly state whether these patients with transient STEMI should be treated with a STEMI-like or non-ST-segment elevation acute coronary syndrome-like intervention strategy. METHODS: In this multicenter trial, 142 patients with transient STEMI were randomized 1:1 to either delayed or immediate coronary intervention. Cardiac magnetic resonance imaging was performed at 4 days and at 4-month follow-up to assess infarct size and myocardial function. Clinical follow-up was performed at 4 and 12 months. RESULTS: In the delayed (22.7 h) and the immediate (0.4 h) invasive groups, final infarct size as a percentage of the left ventricle was very small (0.4% [interquartile range: 0.0% to 2.5%] vs. 0.4% [interquartile range: 0.0% to 3.5%]; p = 0.79), and left ventricular function was good (mean ejection fraction 59.3 ± 6.5% vs. 59.9 ± 5.4%; p = 0.63). In addition, the overall occurrence of major adverse cardiac events, consisting of death, recurrent infarction, and target lesion revascularization, up to 1 year was low and not different between both groups (5.7% vs. 4.4%, respectively; p = 1.00). CONCLUSIONS: At follow-up, patients with transient STEMI have limited infarction and well-preserved myocardial function in general, and delayed or immediate revascularization has no effect on functional outcome and clinical events up to 1 year.