Impaired endogenous fibrinolysis at high shear using a point-of-care test in STEMI is associated with alterations in clot architecture

© The Author(s) 2019Impaired endogenous fibrinolysis is an adverse prognostic biomarker in acute coronary syndrome (ACS). Abnormally dense in vitro fibrin thrombi have been demonstrated in ACS patients and related to hypofibrinolysis using cumbersome, laboratory-based methods. We aimed to assess endogenous fibrinolysis using a point-of-care technique and relate this to clot architecture. From patients with ST-segment elevation myocardial infarction (STEMI), venous blood was drawn immediately on arrival to assess thrombotic status. Blood was assessed using the point-of-care Global Thrombosis Test which measures occlusive thrombus formation under high shear and subsequently endogenous fibrinolysis (lysis time, LT). Two samples per patient were run in parallel. In one channel, the measurement was allowed to proceed as normal. In the other, after occlusion, thrombus was extracted, washed, fixed in glutaraldehyde, dried, sputter-coated, and assessed using scanning electron microscope. Endogenous fibrinolysis was strongly associated fibrin fibre thickness (p = 0.0001). As LT increased (less efficient fibrinolysis), the fibrin network of the thrombus was significantly more compact and dense, with thinner fibrin fibres and smaller gaps. Fibrin fibre thickness correlated inversely with LT (r = - 0.89, p = 0.001). Adverse clot architecture in vitro is directly related to impaired endogenous fibrinolysis using a relatively new point-of-care technique in patients with STEMI. This may transform the relevance of fibrin clot architecture from an off-line laboratory association to being directly relevant to endogenous fibrinolysis at the patient bedside, which could be used as a near-patient test to guide prognosis and assess the effect of treatment.Peer reviewedFinal Published versio

Quantitative Flow Ratio and Virtual Percutaneous Coronary Intervention for Serial Coronary Stenoses: Attractive Technology, But Still Crawling.

Objectives To evaluate the clinical care provided to cancer patients hospitalized for acute pulmonary embolism (PE), as well as the association between type of cancer, in-hospital care, and clinical outcomes. Methods This study examined the in-hospital care (systemic thrombolysis, catheter-directed thrombolysis, and surgical thrombectomy/embolectomy) and clinical outcomes (mortality, major bleeding, and hemorrhagic stroke) among adults hospitalized due to acute PE between October 2015 to December 2018 using the National Inpatient Sample (NIS). Multivariable logistic regression analysis was used to determine adjusted odds ratios (aOR) with 95% confidence interval (95% CI). Results Of 1,090,130 hospital records included in the analysis, 216,825 (19.9%) had current cancer diagnoses, including lung (4.7%), hematological (2.5%), colorectal (1.6%), breast (1.3%), prostate (0.8%), and ‘other’ cancer (9.0%). Cancer patients had lower adjusted odds of receiving systemic thrombolysis, catheter-directed therapy, and surgical thrombectomy/embolectomy compared with their non-cancer counterparts (P < 0.001), except for systemic thrombolysis (aOR 0.96, 95% CI 0.85–1.09, P = 0.553) and catheter-directed therapy (aOR 0.82, 95% CI 0.67–1.00, P = 0.053) for prostate cancer. Cancer patients had greater odds of mortality (P < 0.05). Lung cancer patients had the highest odds of mortality (aOR 2.68, 95% CI 2.61–2.76, P < 0.001) and hemorrhagic stroke (aOR 1.75, 95% CI 1.61–1.90, P < 0.001), while colorectal cancer patients had the greatest odds of bleeding (aOR 2.04, 95% CI 1.94–2.15, P < 0.001). Conclusion Among those hospitalized for PE, cancer diagnoses were associated with lower odds of invasive management and poorer in-hospital outcomes, with metastatic status being an especially important determinant. Appropriateness of care could not be assessed in this study

Dual Antiplatelet or Dual Antithrombotic Therapy for Secondary Prevention in High-Risk Patients with Stable Coronary Artery Disease?

Antithrombotic treatment is a key component of secondary prevention following acute coronary syndromes (ACS). Although dual antiplatelet therapy is standard therapy post-ACS, duration of treatment is the subject of ongoing debate. Prolonged dual antiplatelet therapy in high-risk patients with history of myocardial infarction reduced the risk of recurrent myocardial infarction, stroke or cardiovascular death. Similarly, in patients with stable coronary artery disease, two-thirds of whom had a history of myocardial infarction, dual antithrombotic therapy with very-low-dose rivaroxaban and aspirin also resulted in improved ischaemic outcomes. In the absence of head-to-head comparison, choosing the most appropriate treatment strategy can be challenging, particularly when it comes to balancing the risks of ischaemia and bleeding. We aim to review the evidence for currently available antithrombotic treatments and provide a practical algorithm to aid the decision-making process

Prolonged enoxaparin therapy compared with standard-of-care antithrombotic therapy in opiate-treated patients undergoing primary percutaneous coronary intervention

A novel enoxaparin regimen consisting of intra-arterial bolus (0.75 mg/kg) followed by intravenous infusion (0.75 mg/kg/6 hours) has been developed as a possible solution to the delayed absorption of oral P2Y12 inhibitors in opiate-treated ST-elevation myocardial infarction (STEMI) patients undergoing primary angioplasty. We aimed to study the feasibility of this regimen as an alternative to standard-of-care treatment (SOC) with unfractionated heparin ± glycoprotein IIb/IIIa antagonist (GPI). One hundred opiate-treated patients presenting with STEMI and accepted for primary angioplasty were randomized (1:1) to either enoxaparin or SOC. Fifty patients were allocated enoxaparin (median age 61, 40% females) and 49 allocated SOC (median age 62, 22% females). One developed stroke before angiography and was withdrawn. One SOC patient had a gastrointestinal bleed resulting in 1 g drop in hemoglobin and early cessation of GPI infusion. Two enoxaparin patients had transient minor bleeding: one transient gingival bleed and one episode of coffee ground vomit with no hemoglobin drop or hemodynamic instability. Two SOC and no enoxaparin group patients had acute stent thrombosis. These preliminary data support further study of this novel 6-hour enoxaparin regimen in opiate-treated PPCI patients

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

Association of Epstein-Barr virus antibody titers with a human IL-10 promoter polymorphism in Japanese women

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Assessment of endogenous fibrinolysis in clinical using novel tests - Ready for clinical roll-out?

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The occurrence of thrombotic complications, which can result in excess mortality and morbidity, represent an imbalance between the pro-thrombotic and fibrinolytic equilibrium.The mainstay treatment of these complications involves the use of antithrombotic agents but despite advances in pharmacotherapy, there remains a significant proportion of patients who continue to remain at risk.Endogenous fibrinolysis is a physiological counter-measure against lasting thrombosis and may be measured using several techniques to identify higher risk patients who may benefit from more aggressive pharmacotherapy. However, the assessment of the fibrinolytic systemis not yet accepted into routine clinical practice.In this review, we will revisit the different methods of assessing endogenous fibrinolysis (factorial assays, turbidimetric lysis assays, viscoelastic and the global thrombosis tests), including the strengths, limitations, correlation to clinical outcomes of each method and howwe might integrate the assessment of endogenous fibrinolysis into clinical practice in the future.Peer reviewedFinal Published versio

Pharmacodynamic Effects of a 6-Hour Regimen of Enoxaparin in Patients Undergoing Primary Percutaneous Coronary Intervention (PENNY PCI Study)

Delayed onset of action of oral P2Y₁₂ inhibitors in ST-elevation myocardial infarction (STEMI) patients may increase the risk of acute stent thrombosis. Available parenteral anti-thrombotic strategies, to deal with this issue, are limited by added cost and increased risk of bleeding. We investigated the pharmacodynamic effects of a novel regimen of enoxaparin in STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Twenty patients were recruited to receive 0.75 mg/kg bolus of enoxaparin (pre-PPCI) followed by infusion of enoxaparin 0.75 mg/kg/6 h. At four time points (pre-anti-coagulation, end of PPCI, 2–3 hours into infusion and at the end of infusion), anti-Xa levels were determined using chromogenic assays, fibrin clots were assessed by turbidimetric analysis and platelet P2Y₁₂ inhibition was determined by VerifyNow P2Y₁₂ assay. Clinical outcomes were determined 14 hours after enoxaparin initiation. Nineteen of 20 patients completed the enoxaparin regimen; one patient, who developed no-reflow phenomenon, was switched to tirofiban after the enoxaparin bolus. All received ticagrelor 180 mg before angiography. Mean (± standard error of the mean) anti-Xa levels were sustained during enoxaparin infusion (1.17 ± 0.06 IU/mL at the end of PPCI and 1.003 ± 0.06 IU/mL at 6 hours), resulting in prolonged fibrin clot lag time and increased lysis potential. Onset of platelet P2Y₁₂ inhibition was delayed in opiate-treated patients. No patients had thrombotic or bleeding complications. In conclusion, enoxaparin 0.75 mg/kg bolus followed by 0.75 mg/kg/6 h provides sustained anti-Xa levels in PPCI patients. This may protect from acute stent thrombosis in opiate-treated PPCI patients who frequently have delayed onset of oral P2Y₁₂ inhibition

Study of two dose regimens of ticagrelor compared with clopidogrel in patients undergoing percutaneous coronary intervention for stable coronary artery disease

Background—Ticagrelor has superior efficacy to clopidogrel in the management of acute coronary syndromes but has not been assessed in patients undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD). We compared the pharmacodynamic effects of ticagrelor and clopidogrel in this stable population. Methods—180 aspirin-treated stable CAD patients, who were planned to undergo elective PCI in a single center, were randomized 1:1:1 to either a standard clopidogrel regimen or one of two regimens of ticagrelor, either 90mg (T90) or 60mg twice-daily (T60), both with 180mg loading dose. Cellular adenosine uptake was assessed, at the time of the procedure and pre- and post-dose at 1 month, by adding adenosine 1 μmol/L to aliquots of anticoagulated whole blood and mixing with a stop solution at 0, 15, 30 and 60 seconds then measuring residual plasma adenosine concentration by high-performance liquid chromatography. Systemic plasma adenosine concentration and platelet reactivity were assessed at the same timepoints. High-sensitivity troponin T (hsTnT) was measured pre- and 18-24 hours post-PCI. Results—174 patients underwent an invasive procedure, of which 162 patients received PCI (mean age 65 years, 18% female, 21% with diabetes mellitus). No effect on in vitro adenosine uptake was seen post-dose at 1 month for either ticagrelor dose compared with clopidogrel (residual adenosine at 15s, mean ± SD: clopidogrel 0.274 ± 0.101 μmol/L; T90 0.278 ± 0.134 μmol/L; T60 0.288 ± 0.149 μmol/L; P = 0.37). Similarly no effect of ticagrelor on in vitro adenosine uptake was seen at other timepoints, nor was plasma adenosine concentration affected (all P > 0.1). Both maintenance doses of ticagrelor achieved more potent and consistent platelet inhibition than clopidogrel (VerifyNow PRU, 1 month, mean ± SD: pre-dose, T60: 62 ± 47, T90: 40 ± 38, clopidogrel 181 ± 44; post-dose, T60: 34 ± 30, T90: 24 ± 21, clopidogrel 159 ± 57; all P 208, 1-month post-dose: 0%, 0% and 21%, respectively). Median (IQR) hsTnT increase was 16.9 (6.5-46.9) ng/l for clopidogrel, 22.4 (5.5-53.8) ng/L for T60 and 17.7 (8.1-43.5) ng/L for T90 (P = 0.95). There was a trend towards less dyspnea with T60 versus T90 (7.1% vs 19.0%; P = 0.09). Conclusions—Maintenance therapy with T60 or T90 had no detectable effect on cellular adenosine uptake at 1 month, nor was there any effect on systemic plasma adenosine levels. Both regimens of ticagrelor achieved greater and more consistent platelet inhibition than clopidogrel but did not appear to affect troponin release after percutaneous coronary interventio

Risk factors for peripartum hysterectomy among women with postpartum haemorrhage: analysis of data from the WOMAN trial.

BACKGROUND: Peripartum hysterectomy can cause significant morbidity and mortality. Most studies of peripartum hysterectomy are from high income countries. This cohort study examined risk factors for peripartum hysterectomy using data from Africa, Asia, Europe and the Americas. METHODS: We used data from the World Maternal Antifibrinolytic (WOMAN) trial carried out in 193 hospitals in 21 countries. Peripartum hysterectomy was defined as hysterectomy within 6 weeks of delivery as a complication of postpartum haemorrhage. Univariable and multivariable random effects logistic regression models were used to analyse risk factors. A hierarchical conceptual framework guided our multivariable analysis. RESULTS: Five percent of women had a hysterectomy (1020/20,017). Haemorrhage from placenta praevia/accreta carried a higher risk of hysterectomy (17%) than surgical trauma/tears (5%) and uterine atony (3%). The adjusted odds ratio (AOR) for hysterectomy in women with placenta praevia/accreta was 3.2 (95% CI: 2.7-3.8), compared to uterine atony. The risk of hysterectomy increased with maternal age. Caesarean section was associated with fourfold higher odds of hysterectomy than vaginal delivery (AOR 4.3, 95% CI: 3.6-5.0). Mothers in Asia had a higher hysterectomy incidence (7%) than mothers in Africa (5%) (AOR: 1.2, 95% CI: 0.9-1.7). CONCLUSIONS: Placenta praevia/accreta is associated with a higher risk of peripartum hysterectomy. Other risk factors for hysterectomy are advanced maternal age, caesarean section and giving birth in Asia