Defining Strategies of Modulation of Antiplatelet Therapy in Patients With Coronary Artery Disease: A Consensus Document from the Academic Research Consortium.

Antiplatelet therapy is the mainstay of pharmacologic treatment to prevent thrombotic or ischemic events in patients with coronary artery disease treated with percutaneous coronary intervention and those treated medically for an acute coronary syndrome. The use of antiplatelet therapy comes at the expense of an increased risk of bleeding complications. Defining the optimal intensity of platelet inhibition according to the clinical presentation of atherosclerotic cardiovascular disease and individual patient factors is a clinical challenge. Modulation of antiplatelet therapy is a medical action that is frequently performed to balance the risk of thrombotic or ischemic events and the risk of bleeding. This aim may be achieved by reducing (ie, de-escalation) or increasing (ie, escalation) the intensity of platelet inhibition by changing the type, dose, or number of antiplatelet drugs. Because de-escalation or escalation can be achieved in different ways, with a number of emerging approaches, confusion arises with terminologies that are often used interchangeably. To address this issue, this Academic Research Consortium collaboration provides an overview and definitions of different strategies of antiplatelet therapy modulation for patients with coronary artery disease, including but not limited to those undergoing percutaneous coronary intervention, and consensus statements on standardized definitions.

Design and Rationale of the CLEAR SYNERGY (OASIS 9) Trial: A 2x2 Factorial Randomized Controlled Trial of Colchicine versus placebo and Spironolactone versus placebo in Patients with Myocardial Infarction.

BACKGROUND: Patients experiencing myocardial infarction (MI) remain at high risk of future major adverse cardiovascular events (MACE). While low-dose colchicine and spironolactone have been shown to decrease post-MI MACE, more data are required to confirm their safety and efficacy in an unselected post-MI population. Therefore, we initiated the CLEAR SYNERGY (OASIS 9) trial to address these uncertainties. METHODS: The CLEAR SYNERGY trial is a 2 × 2 factorial randomized controlled trial of low-dose colchicine 0.5 mg daily versus placebo and spironolactone 25 mg daily versus placebo in 7,062 post-MI participants who were within 72 hours of the index percutaneous coronary intervention (PCI). We blinded participants, healthcare providers, research personnel, and outcome adjudicators to treatment allocation. The primary outcome for colchicine is the first occurrence of the composite of cardiovascular death, recurrent MI, stroke, or unplanned ischemia-driven revascularization. The co-primary outcomes for spironolactone are (1) the composite of the total numbers of cardiovascular death or new or worsening heart failure and (2) the first occurrence of the composite of cardiovascular death, new or worsening heart failure, recurrent MI or stroke. We finished recruitment with 7,062 participants from 104 centers in 14 countries on November 8, 2022, and plan to present the results in the fall of 2024. CONCLUSIONS: CLEAR SYNERGY is a large international randomized controlled trial that will inform the effects of low-dose colchicine and spironolactone in largely unselected post-MI patients who undergo PCI. (ClinicalTrials.gov Identifier: NCT03048825).

Effects of complete revascularization according to age in patients with ST-segment elevation myocardial infarction and multivessel disease (COMPLETE-AGE).

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI), complete revascularization with percutaneous coronary intervention (PCI) reduces major cardiovascular events compared with culprit-lesion-only PCI. Whether age influences these results remains unknown. METHODS: COMPLETE was a multinational, randomized trial evaluating a strategy of staged complete revascularization, consisting of angiography-guided PCI of all suitable nonculprit lesions, versus a strategy of culprit-lesion-only PCI. In this prespecified subgroup analysis, treatment effect according to age (≥65 years vs <65 years) was determined for the first coprimary outcome of cardiovascular (CV) death or new myocardial infarction (MI) and the second coprimary outcome of CV death, new MI, or ischemia-driven revascularization (IDR). Median follow-up was 35.8 months (interquartile range [IQR]: 27.6-44.3 months). RESULTS: Of 4,041 patients randomized in COMPLETE, 1,613 were aged ≥ 65 years (39.9%). Higher event rates were observed for both coprimary outcomes in patients aged ≥ 65 years comparted with those aged < 65 years (11.2% vs 7.9%, HR 1.49, 95% CI 1.22-1.83; 14.4% vs 11.8%, HR 1.28, 95% CI 1.07-1.52, respectively). Complete revascularization reduced the first coprimary outcome in patients ≥ 65 years (9.7% vs 12.5%, HR 0.77; 95% CI, 0.58-1.04) and < 65 years (6.7% vs 9.1%, HR 0.72; 95% CI, 0.54-0.96)(interaction P = .74). The second coprimary outcome was reduced in those ≥ 65 years (HR 0.56, 95% CI, 0.43-0.74) and < 65 years (HR 0.48, 95% CI, 0.37-0.61 (interaction P = .37). A sensitivity analysis was performed with consistent results demonstrated using a 75-year threshold (albeit attenuated). CONCLUSIONS: In patients with STEMI and multivessel CAD, complete revascularization compared with culprit-lesion-only PCI reduced major cardiovascular events regardless of patient age and could be considered as a revascularization strategy in older adults.

Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

OBJECTIVES: Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. METHODS: We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. RESULTS: The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. CONCLUSIONS: Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Intraoperative haemoadsorption for antithrombotic drug removal during cardiac surgery: initial report of the international safe and timely antithrombotic removal (STAR) registry.

Intraoperative antithrombotic drug removal by haemoadsorption is a novel strategy to reduce perioperative bleeding in patients on antithrombotic drugs undergoing cardiac surgery. The international STAR registry reports real-world clinical outcomes associated with this application. All patients underwent cardiac surgery before completing the recommended washout period. The haemoadsorption device was incorporated into the cardiopulmonary bypass (CPB) circuit. Patients on P2Y12 inhibitors comprised group 1, and patients on direct-acting oral anticoagulants (DOAC) group 2. Outcome measurements included bleeding events according to standardised definitions and 24-hour chest-tube-drainage (CTD). 165 patients were included from 8 institutions in Austria, Germany, Sweden, and the UK. Group 1 included 114 patients (62.9 ± 11.6years, 81% male) operated at a mean time of 33.2 h from the last P2Y12 inhibitor dose with a mean CPB duration of 117.1 ± 62.0 min. Group 2 included 51 patients (68.4 ± 9.4years, 53% male), operated at a mean time of 44.6 h after the last DOAC dose, with a CPB duration of 128.6 ± 48.4 min. In Group 1, 15 patients experienced a BARC-4 bleeding event (13%), including 3 reoperations (2.6%). The mean 24-hour CTD was 651 ± 407mL. In Group 2, 8 patients experienced a BARC-4 bleeding event (16%) including 4 reoperations (7.8%). The mean CTD was 675 ± 363mL. This initial report of the ongoing STAR registry shows that the intraoperative use of a haemoadsorption device is simple and safe, and may potentially mitigate the expected high bleeding risk of patients on antithrombotic drugs undergoing cardiac surgery before completion of the recommended washout period.Clinical registration number: ClinicalTrials.gov identifier: NCT05077124.

Non-vitamin-K-antagonist oral anticoagulants (NOACs) after acute myocardial infarction: a network meta-analysis.

BACKGROUND: Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The potential of non-vitamin K antagonist oral anticoagulants (NOACs) to prevent ischaemic cardiovascular events is promising, but the evidence remains limited. OBJECTIVES: To evaluate the efficacy and safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in addition to background antiplatelet therapy, compared with placebo, antiplatelet therapy, or both, after acute myocardial infarction (AMI) in people without an indication for anticoagulation (i.e. atrial fibrillation or venous thromboembolism). SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, the Conference Proceedings Citation Index - Science, and two clinical trial registers in September 2022 with no language restrictions. We checked the reference lists of included studies for any additional trials. SELECTION CRITERIA: We searched for randomised controlled trials (RCTs) that evaluated NOACs plus antiplatelet therapy versus placebo, antiplatelet therapy, or both, in people without an indication for anticoagulation after an AMI. DATA COLLECTION AND ANALYSIS: Two review authors independently checked the results of searches to identify relevant studies, assessed each included study, and extracted study data. We conducted random-effects pairwise analyses using Review Manager Web, and network meta-analysis using the R package 'netmeta'. We ranked competing treatments by P scores, which are derived from the P values of all pairwise comparisons and allow ranking of treatments on a continuous 0-to-1 scale. MAIN RESULTS: We identified seven eligible RCTs, including an ongoing trial that we could not include in the analysis. Of the six RCTs involving 33,039 participants, three RCTs compared rivaroxaban with placebo, two RCTs compared apixaban with placebo, and one RCT compared dabigatran with placebo. All participants in the six RCTs received concomitant antiplatelet therapy. The available evidence suggests that rivaroxaban compared with placebo reduces the rate of all-cause mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.69 to 0.98; number needed to treat for an additional beneficial outcome (NNTB) 250; 3 studies, 21,870 participants; high certainty) and probably reduces cardiovascular mortality (RR 0.83, 95% CI 0.69 to 1.01; NNTB 250; 3 studies, 21,870 participants; moderate certainty). There is probably little or no difference between apixaban and placebo in all-cause mortality (RR 1.09, 95% CI 0.88 to 1.35; number needed to treat for an additional harmful outcome (NNTH) 334; 2 studies, 8638 participants; moderate certainty) and cardiovascular mortality (RR 0.99, 95% CI 0.77 to 1.27; number needed to treat not applicable; 2 studies, 8638 participants; moderate certainty). Dabigatran may reduce the rate of all-cause mortality compared with placebo (RR 0.57, 95% CI 0.31 to 1.06; NNTB 63; 1 study, 1861 participants; low certainty). Dabigatran compared with placebo may have little or no effect on cardiovascular mortality, although the point estimate suggests benefit (RR 0.72, 95% CI 0.34 to 1.52; NNTB 143; 1 study, 1861 participants; low certainty). Two of the investigated NOACs were associated with an increased risk of major bleeding compared to placebo: apixaban (RR 2.41, 95% CI 1.44 to 4.06; NNTH 143; 2 studies, 8544 participants; high certainty) and rivaroxaban (RR 3.31, 95% CI 1.12 to 9.77; NNTH 125; 3 studies, 21,870 participants; high certainty). There may be little or no difference between dabigatran and placebo in the risk of major bleeding (RR 1.74, 95% CI 0.22 to 14.12; NNTH 500; 1 study, 1861 participants; low certainty). The results of the network meta-analysis were inconclusive between the different NOACs at all individual doses for all primary outcomes. However, low-certainty evidence suggests that apixaban (combined dose) may be less effective than rivaroxaban and dabigatran for preventing all-cause mortality after AMI in people without an indication for anticoagulation. AUTHORS' CONCLUSIONS: Compared with placebo, rivaroxaban reduces all-cause mortality and probably reduces cardiovascular mortality after AMI in people without an indication for anticoagulation. Dabigatran may reduce the rate of all-cause mortality and may have little or no effect on cardiovascular mortality. There is probably no meaningful difference in the rate of all-cause mortality and cardiovascular mortality between apixaban and placebo. Moreover, we found no meaningful benefit in efficacy outcomes for specific therapy doses of any investigated NOACs following AMI in people without an indication for anticoagulation. Evidence from the included studies suggests that rivaroxaban and apixaban increase the risk of major bleeding compared with placebo. There may be little or no difference between dabigatran and placebo in the risk of major bleeding. Network meta-analysis did not show any superiority of one NOAC over another for our prespecified primary outcomes. Although the evidence suggests that NOACs reduce mortality, the effect size or impact is small; moreover, NOACs may increase major bleeding. Head-to-head trials, comparing NOACs against each other, are required to provide more solid evidence.

Reversal and removal of oral antithrombotic drugs in patients with active or perceived imminent bleeding.

Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.

Management of patients on antithrombotic therapy with severe infections: a joint clinical consensus statement of the ESC Working Group on Thrombosis, the ESC Working Group on Atherosclerosis and Vascular Biology, and the International Society on Thrombosis and Haemostasis.

Patients with severe infections and a pre-existing indication for antithrombotic therapy, i.e. antiplatelet agents, anticoagulant drugs, or their combinations, require integrated clinical counselling among coagulation, infectious disease, and cardiology specialists, due to sepsis-induced coagulopathy that frequently occurs. Bacterial and viral pathogens constitute an increasing threat to global public health, especially for patients with ongoing antithrombotic treatment who have a high risk of thrombotic recurrences and high susceptibility to severe infections with increased morbidity and mortality. Similarly, sepsis survivors are at increased risk for major vascular events. Coagulopathy, which often complicates severe infections, is associated with a high mortality and obligates clinicians to adjust antithrombotic drug type and dosing to avoid bleeding while preventing thrombotic complications. This clinical consensus statement reviews the best available evidence to provide expert opinion and statements on the management of patients hospitalized for severe bacterial or viral infections with a pre-existing indication for antithrombotic therapy (single or combined), in whom sepsis-induced coagulopathy is often observed. Balancing the risk of thrombosis and bleeding in these patients and preventing infections with vaccines, if available, are crucial to prevent events or improve outcomes and prognosis.

Acute, periprocedural and longterm antithrombotic therapy in older adults: 2022 Update by the ESC Working Group on Thrombosis

The first international guidance on antithrombotic therapy in the elderly came from the European Society of Cardiology Working Group on Thrombosis in 2015. This same group has updated its previous report on antiplatelet and anticoagulant drugs for older patients with acute or chronic coronary syndromes, atrial fibrillation, or undergoing surgery or procedures typical of the elderly (transcatheter aortic valve implantation and left atrial appendage closure). The aim is to provide a succinct but comprehensive tool for readers to understand the bases of antithrombotic therapy in older patients, despite the complexities of comorbidities, comedications and uncertain ischaemic- vs. bleeding-risk balance. Fourteen updated consensus statements integrate recent trial data and other evidence, with a focus on high bleeding risk. Guideline recommendations, when present, are highlighted, as well as gaps in evidence. Key consensus points include efforts to improve medical adherence through deprescribing and polypill use; adoption of universal risk definitions for bleeding, myocardial infarction, stroke and cause-specific death; multiple bleeding-avoidance strategies, ranging from gastroprotection with aspirin use to selection of antithrombotic-drug composition, dosing and duration tailored to multiple variables (setting, history, overall risk, age, weight, renal function, comedications, procedures) that need special consideration when managing older adults.

Clinical decision aids and computed tomography coronary angiography in patients with suspected acute coronary syndrome.

BACKGROUND: The HEART score, the T-MACS model and the GRACE score support early decision-making for acute chest pain, which could be complemented by CT coronary angiography (CTCA). However, their performance has not been directly compared. METHODS: In this secondary analysis of a multicentre randomised controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, C-statistics and performance metrics (using the predefined cut-offs) of clinical decision aids and CTCA, alone and then in combination, for the index hospital diagnosis of acute coronary syndrome and for 30-day coronary revascularisation were assessed in those who underwent CTCA and had complete data. RESULTS: Among 699 patients, 358 (51%) had an index hospital diagnosis of acute coronary syndrome, for which the C-statistic was higher for CTCA (0.80), followed by the T-MACS model (0.78), the HEART score (0.74) and the GRACE score (0.60). The negative predictive value was higher for the absence of coronary artery disease on CTCA (0.90) or a T-MACS estimate of <0.05 (0.83) than a HEART score of <4 (0.81) and a GRACE score of <109 (0.55). For 30-day coronary revascularisation, CTCA had the greatest C-statistic (0.80) with a negative predictive value of 0.96 and 0.92 in the absence of coronary artery disease and obstructive coronary artery disease, respectively. The combination of the T-MACS estimates and the CTCA findings was most discriminative for the index hospital diagnosis of acute coronary syndrome (C-statistic, 0.88) and predictive of 30-day coronary revascularisation (C-statistic, 0.85). No patients with a T-MACS estimate of <0.05 and normal coronary arteries had acute coronary syndrome during index hospitalisation or underwent coronary revascularisation within 30 days. CONCLUSIONS: In intermediate-risk patients with suspected acute coronary syndrome, the T-MACS model combined with CTCA improved discrimination of the index hospital diagnosis of acute coronary syndrome and prediction of 30-day coronary revascularisation. TRIAL REGISTRATION NUMBER: NCT02284191.

Rationale and design of the DAPA-MI trial: Dapagliflozin in patients without diabetes mellitus with acute myocardial infarction.

BACKGROUND: Therapies that could further prevent the development of heart failure (HF) and other cardiovascular and metabolic events in patients with recent myocardial infarction (MI) represent a large and unmet medical need. METHODS: DAPA-MI is a multicenter, parallel-group, registry-based, randomized, double-blind, placebo-controlled phase 3 trial in patients without known diabetes or established HF, presenting with MI and impaired left ventricular systolic function or Q-wave MI. The trial evaluated the effect of dapagliflozin 10 mg vs placebo, given once daily in addition to standard of care therapy, on death, hospitalization for HF (HHF), and other cardiometabolic outcomes. The primary objective of the trial was to determine, using the win-ratio method, if dapagliflozin is superior to placebo by comparing the hierarchical composite outcome of death, HHF, nonfatal MI, atrial fibrillation/flutter, new onset of type 2 diabetes mellitus, HF symptoms as measured by New York Heart Association Functional Classification at last visit, and body weight decrease ≥5% at last visit. Assuming a true win-ratio of 1.20 between dapagliflozin and placebo, 4,000 patients provide a statistical power of 80% for the test of the primary composite outcome. A registry-based randomized controlled trial framework allowed for recruitment, randomization, blinding, and pragmatic data collection of baseline demographics, medications, and clinical outcomes using existing national clinical registries (in Sweden and the UK) integrated with the trial database. CONCLUSIONS: The trial explores opportunities to improve further the outcome of patients with impaired LV function after MI. The innovative trial design of DAPA-MI, incorporating national clinical registry data, has facilitated efficient patient recruitment as well as outcome ascertainment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04564742.

Early computed tomography coronary angiography and preventative treatment in patients with suspected acute coronary syndrome: A secondary analysis of the RAPID-CTCA trial.

BACKGROUND: Computed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome. METHODS: In this secondary analysis of a multicenter randomized controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin-angiotensin system blocker, and beta-blocker therapies from randomization to discharge were compared within then between those randomized to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined. RESULTS: In 1,743 patients (874 randomized to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapies increased more in the early CTCA group (between-group difference: 4.6% [95% confidence interval, 0.3-8.9], 4.5% [95% confidence interval, 0.2-8.7], and 4.3% [95% confidence interval, 0.2-8.5], respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Among patients randomized to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries. CONCLUSIONS: Prescription patterns of preventative treatment varied during index hospitalization in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualization of these therapies based on the extent of coronary artery disease.

Treatment inequity in antiplatelet therapy for ischaemic heart disease in patients with advanced chronic kidney disease: releasing the evidence vacuum.

Chronic kidney disease (CKD) is a global health problem and an independent risk factor for cardiovascular morbidity and mortality. Despite evidence-based therapies significantly improving cardiovascular mortality outcomes in the general population and those with non-dialysis-dependent CKD, this risk reduction has not translated to patients with end-stage kidney disease (ESKD). Absent from all major antiplatelet trials, this has led to insufficient safety data for P2Y12 inhibitor prescriptions and treatment inequity in this subpopulation. This review article presents an overview of the progression of research in understanding antiplatelet therapy for ischaemic heart disease in patients with advanced CKD (defined as eGFR <30 mL/min/1.73 m2). Beyond trial recruitment strategies, new approaches should focus on registry documentation by CKD stage, risk stratification with biomarkers associated with inflammation and haemorrhage and building a knowledge base on optimal duration of dual and single antiplatelet therapies.

What is the context? Patients with kidney disease are more likely to experience a heart attack than those without.Those with advanced kidney disease have a higher risk of death following a heart attack.Over the past two decades, advances in treatment following a heart attack have reduced the risk of death, however this has not translated to those with advanced kidney disease.Progression of kidney disease influences antiplatelet (e.g. clopidogrel) treatment efficacy.What is new?This contemporary review analyses registry and trial data to highlight some of the issues surrounding treatment inequity in patients with advanced kidney disease.This article describes potential mechanisms by which progression of kidney disease can influence clotting, bleeding and antiplatelet treatments.What is the impact?Further research into antiplatelet therapy for patients with advanced kidney disease is required.Registry and trial data can improve upon classification of kidney disease for future research.Future trials in antiplatelet therapy for advanced kidney disease are anticipated.

A Proteomics-Based Assessment of Inflammation Signatures in Endotoxemia.

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.

Patient selection for long-term secondary prevention with ticagrelor: insights from PEGASUS-TIMI 54.

AIM: In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting patients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor. METHODS AND RESULTS: PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety outcome was TIMI major bleeding; differences in Kaplan-Meier event rates at 3 years are presented. Post-hoc subgroups based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0-1 ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI -2.4 to 2.5). In patients at low bleeding risk, the ARDs in the primary efficacy endpoint with ticagrelor were -0.5% (-2.2, 1.3), -1.5% (-3.1, 0.02), and -2.6% (-5.0, -0.24, P = 0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant trends for greater absolute risk reductions for cardiovascular death (P-trend 0.018), all-cause mortality (P-trend 0.027), and net outcomes (P-trend 0.037) with ticagrelor across these risk groups. CONCLUSION: In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for those with prior MI with multiple IRFs at low bleeding risk. CLINICAL TRIAL REGISTRATION: NCT01225562 ClinicalTrials.gov.

Glycosylated apolipoprotein J in cardiac ischaemia: molecular processing and circulating levels in patients with acute ischaemic events.

AIM: Using proteomics, we previously found that serum levels of glycosylated (Glyc) forms of apolipoprotein J (ApoJ), a cytoprotective and anti-oxidant protein, decrease in the early phase of acute myocardial infarction (AMI). We aimed to investigate: (i) ApoJ-Glyc intracellular distribution and secretion during ischaemia; (ii) the early changes in circulating ApoJ-Glyc during AMI; and (iii) associations between ApoJ-Glyc and residual ischaemic risk post-AMI. METHODS AND RESULTS: Glycosylated apolipoprotein J was investigated in: (i) cells from different organ/tissue origin; (ii) a pig model of AMI; (iii) de novo AMI patients (n = 38) at admission within the first 6 h of chest pain onset and without troponin T elevation at presentation (early AMI); (iv) ST-elevation myocardial infarction patients (n = 212) who were followed up for 6 months; and (v) a control group without any overt cardiovascular disease (n = 144). Inducing simulated ischaemia in isolated cardiac cells resulted in an increased intracellular accumulation of non-glycosylated ApoJ forms. A significant decrease in ApoJ-Glyc circulating levels was seen 15 min after ischaemia onset in pigs. Glycosylated apolipoprotein J levels showed a 45% decrease in early AMI patients compared with non-ischaemic patients (P < 0.0001), discriminating the presence of the ischaemic event (area under the curve: 0.934; P < 0.0001). ST-elevation myocardial infarction patients with lower ApoJ-Glyc levels at admission showed a higher rate of recurrent ischaemic events and mortality after 6-month follow-up (P = 0.008). CONCLUSIONS: These results indicate that ischaemia induces an intracellular accumulation of non-glycosylated ApoJ and a reduction in ApoJ-Glyc secretion. Glycosylated apolipoprotein J circulating levels are reduced very early after ischaemia onset. Its continuous decrease indicates a worsening in the evolution of the cardiac event, likely identifying patients with sustained ischaemia after AMI.

Apixaban or Vitamin K Antagonists and Aspirin or Placebo According to Kidney Function in Patients With Atrial Fibrillation After Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the AUGUSTUS Trial.

BACKGROUND: In the AUGUSTUS trial (An Open-Label, 2×2 Factorial, Randomized Controlled, Clinical Trial to Evaluate the Safety of Apixaban Versus Vitamin K Antagonist and Aspirin Versus Aspirin Placebo in Patients With Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention), apixaban resulted in less bleeding and fewer hospitalizations than vitamin K antagonists, and aspirin caused more bleeding than placebo in patients with atrial fibrillation and acute coronary syndrome or percutaneous coronary intervention treated with a P2Y12 inhibitor. We evaluated the risk-benefit balance of antithrombotic therapy according to kidney function. METHODS: In 4456 patients, the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula was used to calculate baseline estimated glomerular filtration rate (eGFR). The effect of apixaban versus vitamin K antagonists and aspirin versus placebo was assessed across kidney function categories by using Cox models. The primary outcome was International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and ischemic events (death, stroke, myocardial infarction, stent thrombosis [definite or probable], or urgent revascularization). Creatinine clearance <30 mL/min was an exclusion criterion in the AUGUSTUS trial. RESULTS: Overall, 30%, 52%, and 19% had an eGFR of >80, >50 to 80, and 30 to 50 mL·min-1·1.73 m-2, respectively. At the 6-month follow-up, a total of 543 primary outcomes of bleeding, 1125 death or hospitalizations, and 282 ischemic events occurred. Compared with vitamin K antagonists, patients assigned apixaban had lower rates for all 3 outcomes across most eGFR categories without significant interaction. The absolute risk reduction with apixaban was most pronounced in those with an eGFR of 30 to 50 mL·min-1·1.73 m-2 for bleeding events with rates of 13.1% versus 21.3% (hazard ratio, 0.59; 95% CI, 0.41-0.84). Patients assigned aspirin had a higher risk of bleeding in all eGFR categories with an even greater increase among those with eGFR >80 mL·min-1·1.73 m-2: 16.6% versus 5.6% (hazard ratio, 3.22; 95% CI, 2.19-4.74; P for interaction=0.007). The risk of death or hospitalization and ischemic events were comparable to aspirin and placebo across eGFR categories with hazard ratios ranging from 0.97 (95% CI, 0.76-1.23) to 1.28 (95% CI, 1.02-1.59) and from 0.75 (95% CI, 0.48-1.17) to 1.34 (95% CI, 0.81-2.22), respectively. CONCLUSIONS: The safety and efficacy of apixaban was consistent irrespective of kidney function, compared with warfarin, and in accordance with the overall trial results. The risk of bleeding with aspirin was consistently higher across all kidney function categories. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02415400.

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.

Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation.

BACKGROUND: Appropriate antithrombotic regimens for patients with atrial fibrillation who have an acute coronary syndrome or have undergone percutaneous coronary intervention (PCI) are unclear. METHODS: In an international trial with a two-by-two factorial design, we randomly assigned patients with atrial fibrillation who had an acute coronary syndrome or had undergone PCI and were planning to take a P2Y12 inhibitor to receive apixaban or a vitamin K antagonist and to receive aspirin or matching placebo for 6 months. The primary outcome was major or clinically relevant nonmajor bleeding. Secondary outcomes included death or hospitalization and a composite of ischemic events. RESULTS: Enrollment included 4614 patients from 33 countries. There were no significant interactions between the two randomization factors on the primary or secondary outcomes. Major or clinically relevant nonmajor bleeding was noted in 10.5% of the patients receiving apixaban, as compared with 14.7% of those receiving a vitamin K antagonist (hazard ratio, 0.69; 95% confidence interval [CI], 0.58 to 0.81; P<0.001 for both noninferiority and superiority), and in 16.1% of the patients receiving aspirin, as compared with 9.0% of those receiving placebo (hazard ratio, 1.89; 95% CI, 1.59 to 2.24; P<0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% vs. 27.4%; hazard ratio, 0.83; 95% CI, 0.74 to 0.93; P = 0.002) and a similar incidence of ischemic events. Patients in the aspirin group had an incidence of death or hospitalization and of ischemic events that was similar to that in the placebo group. CONCLUSIONS: In patients with atrial fibrillation and a recent acute coronary syndrome or PCI treated with a P2Y12 inhibitor, an antithrombotic regimen that included apixaban, without aspirin, resulted in less bleeding and fewer hospitalizations without significant differences in the incidence of ischemic events than regimens that included a vitamin K antagonist, aspirin, or both. (Funded by Bristol-Myers Squibb and Pfizer; AUGUSTUS ClinicalTrials.gov number, NCT02415400.).

Complete Revascularization with Multivessel PCI for Myocardial Infarction.

BACKGROUND: In patients with ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) of the culprit lesion reduces the risk of cardiovascular death or myocardial infarction. Whether PCI of nonculprit lesions further reduces the risk of such events is unclear. METHODS: We randomly assigned patients with STEMI and multivessel coronary artery disease who had undergone successful culprit-lesion PCI to a strategy of either complete revascularization with PCI of angiographically significant nonculprit lesions or no further revascularization. Randomization was stratified according to the intended timing of nonculprit-lesion PCI (either during or after the index hospitalization). The first coprimary outcome was the composite of cardiovascular death or myocardial infarction; the second coprimary outcome was the composite of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. RESULTS: At a median follow-up of 3 years, the first coprimary outcome had occurred in 158 of the 2016 patients (7.8%) in the complete-revascularization group as compared with 213 of the 2025 patients (10.5%) in the culprit-lesion-only PCI group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.91; P = 0.004). The second coprimary outcome had occurred in 179 patients (8.9%) in the complete-revascularization group as compared with 339 patients (16.7%) in the culprit-lesion-only PCI group (hazard ratio, 0.51; 95% CI, 0.43 to 0.61; P<0.001). For both coprimary outcomes, the benefit of complete revascularization was consistently observed regardless of the intended timing of nonculprit-lesion PCI (P = 0.62 and P = 0.27 for interaction for the first and second coprimary outcomes, respectively). CONCLUSIONS: Among patients with STEMI and multivessel coronary artery disease, complete revascularization was superior to culprit-lesion-only PCI in reducing the risk of cardiovascular death or myocardial infarction, as well as the risk of cardiovascular death, myocardial infarction, or ischemia-driven revascularization. (Funded by the Canadian Institutes of Health Research and others; COMPLETE ClinicalTrials.gov number, NCT01740479.).