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In this trial, bedside platelet-function monitoring to adjust antiplatelet therapy after coronary stent implantation did not reduce the rate of subsequent cardiovascular events, a finding that calls into question the clinical value of this type of testing. Clopidogrel and aspirin play a central role in the treatment of patients undergoing percutaneous coronary intervention. 1 Up to one third of patients have inadequate platelet inhibition, with an increased risk of events. 2 – 5 Platelet-function testing can determine the degree of platelet reactivity during treatment at the bedside and potentially identify patients in whom adjustment of antiplatelet therapy is warranted to minimize the risks of both ischemic and bleeding complications. 6 Cohort studies and meta-analyses have largely shown the prognostic value of high platelet reactivity during antiplatelet therapy in patients undergoing coronary stenting. 7 , 8 Randomized clinical trials have also shown that stronger . . .

In patients with manifestations of cardiovascular disease, acetylsalicylic acid (popularly known as aspirin) has been the mainstay of treatment for decades owing to its capacity to reduce the risk of ischaemic events. Accordingly, novel antithrombotic therapies have been traditionally tested on a background of acetylsalicylic acid therapy. Although the adjunctive use of such antithrombotic therapies can potentially further reduce the risk of ischaemic events, these agents are also inevitably associated with an increased risk of bleeding. However, acetylsalicylic acid also increases the risk of bleeding, challenging the paradigm that this agent should remain the cornerstone of antiplatelet treatment when alternative antithrombotic agents are also used. Many antithrombotic compounds are characterized by increased potency and consistent efficacy, which might lessen the need for concomitant acetylsalicylic acid. Accordingly, numerous investigations are testing the hypothesis that acetylsalicylic acid-sparing regimens based on newer antithrombotic agents might have an increased net benefit for individual patients owing to the reduction in bleeding risk, without a trade-off in efficacy. This Review summarizes the state of the art relating to antithrombotic approaches with and without acetylsalicylic acid for the prevention of cardiovascular disease and cardioembolic stroke. Discussion of the scientific rationale, from bench to bedside, for ongoing studies of acetylsalicylic acid-free pharmacological strategies is included.

Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computer-generated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6–18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00827411. Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC-Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15–18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1·17 [95% CI 0·68–2·03]; p=0·58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0·5%] patient; HR 0·15 [0·02–1·20]; p=0·073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0·26 [0·07–0·91]; p=0·04). Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. Allies in Cardiovascular Trials Initiatives and Organized Networks (ACTION Study Group), Fondation de France, Sanofi-Aventis, Cordis, Medtronic, Boston Scientific, Fondation SGAM.

Clopidogrel and low-dose aspirin have become the mainstay oral antiplatelet regimen to prevent recurrent ischaemic events after acute coronary syndromes or stent placement. The frequent genetic functional variant 681 G>A (*2) of cytochrome P450 2C19 ( CYP2C19) is an important contributor to the wide variability between individuals of the antiplatelet effect of clopidogrel. We assessed whether the CYP2C19*2 polymorphism affected long-term prognosis of patients who were chronically treated with clopidogrel. Between April 1, 1996, and April 1, 2008, 259 young patients (aged <45 years) who survived a first myocardial infarction and were exposed to clopidogrel treatment for at least a month, were enrolled in a multicentre registry and underwent CYP2C19*2 determination. The primary endpoint was a composite of death, myocardial infarction, and urgent coronary revascularisation occurring during exposure to clopidogrel. Follow-up was every 6 months. The key secondary endpoint was stent thrombosis proven by angiography. Median clopidogrel exposure time was 1·07 years (IQR 0·28–3·0). Baseline characteristics were balanced between carriers (heterozygous *1/*2, n=64; homozygous *2/*2, n=9) and non-carriers (n=186) of CYP2C19*2 variant. The primary endpoint occurred more frequently in carriers than in non-carriers (15 vs 11 events; hazard ratio [HR] 3·69 [95% CI 1·69–8·05], p=0·0005), as did stent thrombosis (eight vs four events; HR 6·02 [1·81–20·04], p=0·0009). The detrimental effect of the CYP2C19*2 genetic variant persisted from 6 months after clopidogrel initiation up to the end of follow-up (HR 3·00 [1·27–7·10], p=0·009). After multivariable analysis, the CYP2C19*2 genetic variant was the only independent predictor of cardiovascular events (HR 4·04 [1·81–9·02], p=0·0006). The CYP2C19*2 genetic variant is a major determinant of prognosis in young patients who are receiving clopidogrel treatment after myocardial infarction. Délégation à la Recherche Clinique, Assistance Publique-Hôpitaux de Paris.

Evidence-based cardiac therapies are underutilized in elderly patients. We assessed differences in practice patterns, comorbidities, and in-hospital event rates, by age and type of acute coronary syndrome (ACS). We studied 24165 ACS patients in 102 hospitals in 14 countries stratified by age. Approximately two-thirds of patients were men, but this proportion decreased with age. In elderly patients (≥ 65 years), history of angina, transient ischemic attack/stroke, myocardial infarction(MI), congestive heart failure, coronary artery bypass graft (CABG) surgery, hypertension or atrial fibrillation were more common, and delay in seeking medical attention and non-ST-segment elevation MI were significantly higher. Aspirin, β-blockers, thrombolytic therapy, statins and glycoprotein IIb/IIIa inhibitors were prescribed less, while calcium antagonists and angiotensin-converting enzyme inhibitors were prescribed more often to elderly patients. Unfractionated heparin was prescribed more often in young patients, while low-molecular-weight heparins were similarly prescribed across all age groups. Coronary angiography and percutaneous intervention rates significantly decreased with age. The rate of CABG surgery was highest among patients aged 65–74 years (8.1%) and 55–64 years (7.7%), but reduced in the youngest (4.7%) and oldest (2.7%) groups. Major bleeding rates were 2–3% among patients aged < 65 years, and > 6% in those ≥ 85 years. Hospital-mortality rates, adjusted for baseline risk differences, increased with age (odds ratio: 15.7 in patients ≥ 85 years compared with those < 45 years). Many elderly ACS patients do not receive evidence-based therapies, highlighting the need for clinical trials targeted specifically at elderly cohorts, and quality-of-care programs that reinforce the use of such therapies among these individuals.

Abstract In 2019, the European Society of Cardiology and European Atherosclerosis Society released a new guideline document with substantial changes regarding the assessment of cardiovascular risk and treatments. The update of high-risk criteria and categories led to a better detection and primary prevention of patients at risk of a first cardiovascular event. Nonetheless, additional efforts are needed for a better inclusion of risk modifiers, especially specific to women, to improve risk stratification and direct primary prevention. Eventually, we discuss how these new guidelines implement PCSK9 inhibitors for very high-risk individuals and the evidence supporting new low-density lipoprotein cholesterol goals below, such as 55 and 40 mg/dL.

Oral antithrombotic (AT) drugs, which include antiplatelet and anticoagulant therapies, are widely implicated in serious preventable bleeding events. Avoiding inappropriate oral AT combinations is a major concern. Numerous practical guidelines have been released; a document to enhance prescriptions of oral AT combinations for adults would be of great help. To synthesize guidelines on the prescription of oral AT combinations in adults and to create a prescription support-tool for clinicians about chronic management (≥ one month) of oral AT combinations. A systematic review of guidelines published between January 2012 and April 2017, in English or in French, from Trip database, Guideline International Network and PubMed, dealing with the prescription of oral ATs in adults was conducted. In-hospital management of ATs, bridging therapy and switches of ATs were not considered. Some specific topics requiring specialized follow-up (cancer, auto-immune disease, haemophilia, HIV, paediatrics and pregnancy) were excluded. Last update was made in November 2018. A total of 885 guidelines were identified and 70 met the eligibility criteria. A prescription support-tool summarizing medical conditions requiring chronic management of oral AT combinations in adults with drug types, dosage and duration, on a double-sided page, was provided and tested by an external committee of physicians. The lack of specific guidelines for old people (age 75 years and older) is questioned considering the specific vulnerability of this age group to serious bleedings. Recommendations on prescriptions about chronic management of oral AT combinations in adults were mainly consensual but dispersed in numerous guidelines according to the medical indication. We provide a prescription support-tool for clinicians. Further studies are needed to assess the impact of this tool on appropriate prescribing and the prevention of serious adverse drug events.

Cardiac manifestation in primary systemic vasculitides is associated with poor outcomes, leading to the use of immunosuppressive therapy. In contrast, the spectrum and the outcome of cardiac involvement in the setting of mixed cryoglobulinemia vasculitis (CryoVas) have never been evaluated. To describe the clinical presentation and to evaluate clinical outcomes of cardiac manifestations during hepatitis C virus (HCV)–related mixed CryoVas, the clinical records of 165 consecutive patients with HCV-related mixed CryoVas followed from January 1, 1993, to January 1, 2010, were reviewed. Of the 165 patients with HCV-related mixed CryoVas, 7 (4%) had cardiac manifestations. Thoracic pain and congestive heart failure manifestations were the main clinical manifestations (n = 4 [57%] each). Cardiac imaging showed dilated cardiomyopathy in 5 patients and hypertrophic cardiomyopathy in 1. In multivariate analysis, patients with cardiac manifestations had more frequent B-cell lymphoma (odds ratio 18.1, 95% confidence interval 2.8 to 116.7, p = 0.0023) and gastrointestinal involvement (odds ratio 14.6, 95% confidence interval 2.0 to 104.9, p = 0.0078). All cardiac manifestations were reversible early after the initiation of corticosteroids and aggressive immunosuppressive therapy. However, after a median follow-up period of 19 months, 3 patients (43%) had died. Respective 6-month, 1-year, and 2-year survival rates in patients with and without cardiac involvement were 86% and 99%, 71% and 96%, and 48% and 90% (hazard ratio 5.01, p = 0.003). In conclusion, cardiac damage is a rare manifestation of HCV-related mixed cryoglobulinemia vasculitis. Cardiac involvement is associated with B-cell lymphoma and life-threatening manifestations. Despite favorable early outcomes, patients with cardiac damage had poorer survival than those without.

A blood clot needs to have the right degree of stiffness and plasticity to stem the flow of blood and yet be digestable by lytic enzymes so as not to form a thrombus, causing heart attacks, strokes, or pulmonary emboli, but the origin of these mechanical properties is unknown. Clots are made up of a three-dimensional network of fibrin fibers stabilized through ligation with a transglutaminase, factor XIIIa. We developed methods to measure the elastic moduli of individual fibrin fibers in fibrin clots with or without ligation, using optical tweezers for trapping beads attached to the fibers that functioned as handles to flex or stretch a fiber. Here, we report direct measurements of the microscopic mechanical properties of such a polymer. Fibers were much stiffer for stretching than for flexion, as expected from their diameter and length. Elastic moduli for individual fibers in plasma clots were 1.7 ± 1.3 and 14.5 ± 3.5 MPa for unligated and ligated fibers, respectively. Similar values were obtained by other independent methods, including analysis of measurements of fluctuations in bead force as a result of Brownian motion. These results provide a basis for understanding the origin of clot elasticity.

Individual response to oral antiplatelet therapy is subject to variability, and bedside monitoring offers the opportunity of individualizing therapy for stent implantation. Time and consequence of discontinuation of thienopyridine after stenting is also an unsolved issue after drug eluting stent (DES) implantation. The ARCTIC trial is designed to demonstrate the superiority of a strategy of platelet function monitoring with dose adjustment in suboptimal responders as compared to a more conventional strategy without monitoring and without dose adjustment to reduce the primary end point evaluated 1 year after DES implantation. At the end of the 1-year follow-up, all patients will be randomized again to test the superiority of a strategy of pursuit of dual antiplatelet therapy beyond 1 year as compared to a strategy of interruption. ARCTIC is a multicenter, prospective, open-label study with parallel arms and a double randomization. Two thousand four hundred sixty-six patients with stable angina/ischemia or non–ST-elevation Acute Coronary Syndrome undergoing percutaneous coronary intervention (PCI) with DES implantation are being enrolled. The primary end point for the 2 tested hypotheses is the time to first occurrence of all-cause mortality, nonfatal myocardial infarction, definite/probable stent thrombosis, urgent revascularization, or nonfatal stroke. Platelet function analyses will be performed at the time of PCI and repeated 2 to 4 weeks after PCI. ARCTIC tests the hypothesis of personalized oral antiplatelet therapy at the time of and after DES implantation. It also examines the clinical impact of thienopyridine interruption 1 year after DES implantation.