A Survey and Ontology of Blockchain Consensus Algorithms for Resource-Constrained IoT Systems.

The basic properties of blockchain, such as decentralization, security, and immutability, show promising potential for IoT applications. The main feature-decentralization of blockchain technology-depends on the consensus. However, consensus algorithms are mostly designed to work in extensive computational and communication environments for network security and immutability, which is not desirable for resource-restricted IoT applications. Many solutions are proposed to address this issue with modified consensus algorithms based on the legacy consensus, such as the PoW, PoS, and BFT, and new non-linear data structures, such as DAG. A systematic classification and analysis of various techniques in the field will be beneficial for both researchers and industrial practitioners. Most existing relevant surveys provide classifications intuitively based on the domain knowledge, which are infeasible to reveal the intrinsic and complicated relationships among the relevant basic concepts and techniques. In this paper, a powerful tool of systematic knowledge classification and explanation is introduced to structure the survey on blockchain consensus algorithms for resource-constrained IoT systems. More specifically, an ontology was developed for a consensus algorithm apropos of IoT adaptability. The developed ontology is subdivided into two parts-CONB and CONIoT-representing the classification of generic consensus algorithms and the ones that are particularly proposed for IoT, respectively. Guided by this ontology, an in depth discussion and analysis are provided on the major consensus algorithms and their IoT compliance based on design and implementation targets. Open research challenges and future research directions are provided.

Colchicine in Patients With Chronic Coronary Disease in Relation to Prior Acute Coronary Syndrome.

BACKGROUND: Colchicine reduces risk of cardiovascular events in patients post-myocardial infarction and in patients with chronic coronary disease. It remains unclear whether this effect is related to the time of onset of treatment following an acute coronary syndrome (ACS). OBJECTIVES: This study investigates risk for major adverse cardiovascular events in relation to history and timing of prior ACS, to determine whether the benefits of colchicine are consistent independent of prior ACS status. METHODS: The LoDoCo2 (Low-Dose Colchicine 2) trial randomly allocated patients with chronic coronary disease to colchicine 0.5 mg once daily or placebo. The rate of the composite of cardiovascular death, spontaneous myocardial infarction, ischemic stroke, or ischemia-driven coronary revascularization was compared between patients with no prior, recent (6-24 months), remote (2-7 years), or very remote (>7 years) ACS; interaction between ACS status and colchicine treatment effect was assessed. RESULTS: In 5,522 randomized patients, risk of the primary endpoint was independent of prior ACS status. Colchicine consistently reduced the primary endpoint in patients with no prior ACS (incidence: 2.8 vs 3.4 events per 100 person-years; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.52-1.27), recent ACS (incidence: 2.4 vs 3.3 events per 100 person-years; HR: 0.75; 95% CI: 0.51-1.10), remote ACS (incidence: 1.8 vs 3.2 events per 100 person-years, HR: 0.55; 95% CI: 0.37-0.82), and very remote ACS (incidence: 3.0 vs 4.3 events per 100 person-years, HR: 0.70; 95% CI: 0.51-0.96) (P for interaction = 0.59). CONCLUSIONS: The benefits of colchicine are consistent irrespective of history and timing of prior ACS. (The LoDoCo2 Trial: Low Dose Colchicine for secondary prevention of cardiovascular disease [LoDoCo2] ACTRN12614000093684).

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients.

BACKGROUND: Patients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. METHODS: Patients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). RESULTS: A total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77-1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66-1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62-1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. CONCLUSION: In ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial.

There are no randomised data on which antiplatelet agent to use in elderly patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and an indication for oral anticoagulation (OAC). The randomised POPular Age trial, in patients of 70 years or older with NSTE-ACS, showed a reduction in bleeding without increasing thrombotic events in patients using clopidogrel as compared to ticagrelor. In this sub-analysis of the POPular AGE trial, we compare clopidogrel with ticagrelor in patients with a need for oral anticoagulation. The follow-up duration was one year. The primary bleeding outcome was Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding. The primary thrombotic outcome consisted of cardiovascular death, myocardial infarction and stroke. The primary net clinical benefit outcome was a composite of all-cause death, myocardial infarction, stroke, and PLATO major and minor bleeding. A total of 184/1011 (18.2%) patients on OAC were included in this subanalysis; 83 were randomized to clopidogrel and 101 to ticagrelor. The primary bleeding outcome was lower in the clopidogrel group (17/83, 20.9%) compared to the ticagrelor group (33/101, 33.5%; p = 0.051), as was the thrombotic outcome (7/83, 8.4% vs. 19/101, 19.2%; p = 0.035) and the primary net clinical benefit outcome (23/83, 27.7% vs. 49/101, 48.5%; p = 0.003). In this subgroup of patients using OAC, clopidogrel reduced PLATO major and minor bleeding compared to ticagrelor without increasing thrombotic risk. This analysis therefore suggests that, in line with the POPular Age trial, clopidogrel is a better option than ticagrelor in NSTE-ACS patients ≥70 years using OAC.

Design and rationale of DUTCH-AF: a prospective nationwide registry programme and observational study on long-term oral antithrombotic treatment in patients with atrial fibrillation.

INTRODUCTION: Anticoagulation therapy is pivotal in the management of stroke prevention in atrial fibrillation (AF). Prospective registries, containing longitudinal data are lacking with detailed information on anticoagulant therapy, treatment adherence and AF-related adverse events in practice-based patient cohorts, in particular for non-vitamin K oral anticoagulants (NOAC). With the creation of DUTCH-AF, a nationwide longitudinal AF registry, we aim to provide clinical data and answer questions on the (anticoagulant) management over time and of the clinical course of patients with newly diagnosed AF in routine clinical care. Within DUTCH-AF, our current aim is to assess the effect of non-adherence and non-persistence of anticoagulation therapy on clinical adverse events (eg, bleeding and stroke), to determine predictors for such inadequate anticoagulant treatment, and to validate and refine bleeding prediction models. With DUTCH-AF, we provide the basis for a continuing nationwide AF registry, which will facilitate subsequent research, including future registry-based clinical trials. METHODS AND ANALYSIS: The DUTCH-AF registry is a nationwide, prospective registry of patients with newly diagnosed 'non-valvular' AF. Patients will be enrolled from primary, secondary and tertiary care practices across the Netherlands. A target of 6000 patients for this initial cohort will be followed for at least 2 years. Data on thromboembolic and bleeding events, changes in antithrombotic therapy and hospital admissions will be registered. Pharmacy-dispensing data will be obtained to calculate parameters of adherence and persistence to anticoagulant treatment, which will be linked to AF-related outcomes such as ischaemic stroke and major bleeding. In a subset of patients, anticoagulation adherence and beliefs about drugs will be assessed by questionnaire. ETHICS AND DISSEMINATION: This study protocol was approved as exempt for formal review according to Dutch law by the Medical Ethics Committee of the Leiden University Medical Centre, Leiden, the Netherlands. Results will be disseminated by publications in peer-reviewed journals and presentations at scientific congresses. TRIAL REGISTRATION NUMBER: Trial NL7467, NTR7706 (https://www.trialregister.nl/trial/7464).

Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial.

BACKGROUND: Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS: Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION: In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk. FUNDING: ZonMw.

Effect of Using the HEART Score in Patients With Chest Pain in the Emergency Department: A Stepped-Wedge, Cluster Randomized Trial.

BACKGROUND: The HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score is an easy-to-apply instrument to stratify patients with chest pain according to their short-term risk for major adverse cardiac events (MACEs), but its effect on daily practice is unknown. OBJECTIVE: To measure the effect of use of the HEART score on patient outcomes and use of health care resources. DESIGN: Stepped-wedge, cluster randomized trial. (ClinicalTrials.gov: NCT01756846). SETTING: Emergency departments in 9 Dutch hospitals. PATIENTS: Unselected patients with chest pain presenting at emergency departments in 2013 and 2014. INTERVENTION: All hospitals started with usual care. Every 6 weeks, 1 hospital was randomly assigned to switch to "HEART care," during which physicians calculated the HEART score to guide patient management. MEASUREMENTS: For safety, a noninferiority margin of a 3.0% absolute increase in MACEs within 6 weeks was set. Other outcomes included use of health care resources, quality of life, and cost-effectiveness. RESULTS: A total of 3648 patients were included (1827 receiving usual care and 1821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed. LIMITATION: Physicians were hesitant to refrain from admission and diagnostic tests in patients classified as low risk by the HEART score. CONCLUSION: Using the HEART score during initial assessment of patients with chest pain is safe, but the effect on health care resources is limited, possibly due to nonadherence to management recommendations. PRIMARY FUNDING SOURCE: Netherlands Organisation for Health Research and Development.

Statins for acute coronary syndrome.

BACKGROUND: The early period following the onset of acute coronary syndrome (ACS) represents a critical stage of coronary heart disease, with a high risk of recurrent events and deaths. The short-term effects of early treatment with statins on patient-relevant outcomes in patients suffering from ACS are unclear. This is an update of a review previously published in 2011. OBJECTIVES: To assess the effects, both harms and benefits, of early administered statins in patients with ACS, in terms of mortality and cardiovascular events. SEARCH METHODS: We updated the searches of CENTRAL (2013, Issue 3), MEDLINE (Ovid) (1946 to April Week 1 2013), EMBASE (Ovid) (1947 to 2013 Week 14), and CINAHL (EBSCO) (1938 to 2013) on 12 April 2013. We applied no language restrictions. We supplemented the search by contacting experts in the field, by reviewing the reference lists of reviews and editorials on the topic, and by searching trial registries. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing statins with placebo or usual care, with initiation of statin therapy within 14 days following the onset of ACS, follow-up of at least 30 days, and reporting at least one clinical outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed risk of bias and extracted data. We calculated risk ratios (RRs) for all outcomes in the treatment and control groups and pooled data using random-effects models. MAIN RESULTS: Eighteen studies (14,303 patients) compared early statin treatment versus placebo or no treatment in patients with ACS. The new search did not identify any new studies for inclusion. There were some concerns about risk of bias and imprecision of summary estimates. Based on moderate quality evidence, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction, and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) or four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up when compared to placebo or no treatment. There were no statistically significant risk reductions from statins for total death, total myocardial infarction, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month or at four months, although there were favorable trends related to statin use for each of these endpoints. Moderate quality evidence suggests that the incidence of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels more than 10 times the upper limit of normal) in statin-treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. AUTHORS' CONCLUSIONS: Based on moderate quality evidence, due to concerns about risk of bias and imprecision, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS. Serious side effects were rare.

Updated evidence on early statin therapy for acute coronary syndromes: meta-analysis of 18 randomized trials involving over 14,000 patients.

BACKGROUND: The short-term effects of early statin therapy in acute coronary syndromes (ACS) on clinical outcomes remain unclear. Our objective was to update the evidence on patient relevant outcomes from all randomized trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. METHODS: We performed a systematic review and meta-analysis of randomized trials that compared statins to control, initiated within 14 days after onset of ACS and with minimal follow-up of 30 days. Data were extracted in duplicate and analyzed by a random effects model. Investigators from individual trials contributed additional data where needed. RESULTS: A total of 18 trials involving 14,303 patients with ACS were included in the meta-analysis. We found no evidence for further trials on the topic. Risk ratios for the combined endpoint of death, myocardial infarction, and stroke of early statin therapy compared to control were 0.93 (95% confidence interval [CI], 0.80-1.08; P=0.34) at 1 month and 0.93 (95% CI, 0.81-1.06; P=0.27) at 4 months following ACS. There were favorable trends related to statin use for all individual secondary endpoints but there was no statistically significant risk reduction except for unstable angina with a risk ratio of 0.76 (95% CI, 0.59-0.96; P=0.02) at 4 months following ACS. CONCLUSIONS: Initiation of statin therapy within 14 days following ACS results in directionally favorable but non-significant reduction in death, myocardial infarction, or stroke up to 4 months, and significant reduction in the occurrence of unstable angina at 4 months following ACS.

Statins for acute coronary syndrome.

BACKGROUND: The early period following the onset of acute coronary syndromes (ACS) represents a critical stage of coronary heart disease with a high risk for recurrent events and deaths. The short-term effects of early treatment with statins in patients suffering from ACS on patient-relevant outcomes are unclear. OBJECTIVES: To assess the benefits and harms of early administered statins in patients with ACS from randomized controlled trials (RCTs). SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, and CINAHL (to 1 February 2010). No language restrictions were applied. We supplemented the search by contacting experts in the field, by reviewing reference lists of reviews and editorials on the topic, and by searching trial registries. SELECTION CRITERIA: RCTs comparing statins with placebo or usual care, initiation of statin therapy within 14 days following the onset of ACS, and follow-up of at least 30 days reporting at least one clinical outcome. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study quality and extracted data. We pooled treatment effects and calculated risk ratios (RRs) for all outcomes in the treatment and control groups using a random effects model. MAIN RESULTS: Eighteen studies (14,303 patients) compared early statin treatment versus placebo or usual care in patients with ACS. Compared to placebo or usual care, early statin therapy did not decrease the combined primary outcome of death, non-fatal myocardial infarction (MI), and stroke at one month (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.80 to 1.08) and four months (RR 0.93, 95% CI 0.81 to 1.06) of follow-up. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, revascularization procedures, and acute heart failure at one month and at four months, although there were favorable trends related to statin use for each of these endpoints. The incidence of episodes of unstable angina was significantly reduced at four months following ACS (RR 0.76, 95% CI 0.59 to 0.96). There were nine individuals with myopathy (elevated creatinine kinase levels > 10 times the upper limit of normal) in statin treated patients (0.13%) versus one (0.015%) in the control groups. Serious muscle toxicity was mostly limited to patients treated with simvastatin 80 mg. AUTHORS' CONCLUSIONS: Based on available evidence, initiation of statin therapy within 14 days following ACS does not reduce death, myocardial infarction, or stroke up to four months, but reduces the occurrence of unstable angina at four months following ACS.

Effects of early treatment with statins on short-term clinical outcomes in acute coronary syndromes: a meta-analysis of randomized controlled trials.

CONTEXT: The short-term effects of early treatment with statins in patients after the onset of acute coronary syndromes (ACS) for the outcomes of death, myocardial infarction (MI), and stroke are unclear. OBJECTIVE: To evaluate relevant outcomes of patients from randomized controlled trials comparing early statin therapy with placebo or usual care at 1 and 4 months following ACS. DATA SOURCES AND STUDY SELECTION: Systematic search of electronic databases (MEDLINE, EMBASE, PASCAL, Cochrane Central Register) from their inception to August 2005, which was supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of randomized controlled trials that compared treatment with statins with a control, were initiated within 14 days after onset of ACS, and had a minimal follow-up of 30 days. Trials with cerivastatin were only included in a sensitivity analysis. DATA EXTRACTION: Information on baseline characteristics of included trials and patients, reported methodological quality, lipid levels, and clinical outcome was independently extracted by 2 investigators. Investigators from each included trial contributed additional data if necessary. DATA SYNTHESIS: Twelve trials involving 13 024 patients with ACS were included in the meta-analysis. The risk ratios for the combined end point of death, MI, and stroke for patients treated with early statin therapy compared with control therapy were 0.93 (95% confidence interval [CI], 0.80-1.09; P = .39) at 1 month and 0.93 (95% CI, 0.81-1.07; P = .30) at 4 months following ACS. There were no statistically significant risk reductions from statins for total death, total MI, total stroke, cardiovascular death, fatal or nonfatal MI, or revascularization procedures (percutaneous coronary intervention or coronary artery bypass graft surgery). Sensitivity analyses with restriction to trials of high quality or with additional data from a large trial using cerivastatin indicated summary risk ratios even closer to 1. CONCLUSION: Based on available evidence, initiation of statin therapy within 14 days following onset of ACS does not reduce death, MI, or stroke up to 4 months.