Impact of very low dose rivaroxaban in addition to dual antiplatelet therapy on endogenous fibrinolysis in acute coronary syndrome: The VaLiDate-R study.

BACKGROUND: Impaired endogenous fibrinolysis is adverse cardiovascular risk factor in acute coronary syndrome (ACS) patients. Addition of very low dose rivaroxaban (VLDR) to dual antiplatelet therapy (DAPT) reduces cardiovascular events but increases bleeding. OBJECTIVE: We aimed to assess whether addition of VLDR to DAPT can enhance endogenous fibrinolysis. METHODS: In a prospective, open-label trial, we assessed endogenous fibrinolysis in whole blood, in 549 patients with ACS using the Global Thrombosis Test (GTT) and Thromboelastography (TEG). Patients (n = 180) who demonstrated impaired endogenous fibrinolysis (lysis time [LT] >2000s with the GTT) were randomised 1:1:1 to (i) clopidogrel 75 mg daily; (ii) clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily; or (iii) ticagrelor 90 mg twice daily, for 30 days, in addition to aspirin. Fibrinolytic status was assessed at 0, 2, 4 and 8 weeks. The primary outcome was the change in LT from admission to week 4. We also measured thrombotic occlusion time (OT) at high shear, and rivaroxaban level. RESULTS: There was no difference between the groups with respect to LT or clot lysis with TEG, and no change in these parameters compared to baseline during study drug allocation. In the rivaroxaban plus clopidogrel group, OT was prolonged compared to the other groups, although rivaroxaban levels were low, suggesting non-compliance. CONCLUSION: Addition of rivaroxaban 2.5 mg twice daily to DAPT does not affect endogenous fibrinolysis of thrombus formed at either high or low shear. Further studies are needed to determine whether higher doses of rivaroxaban can favourably modulate fibrinolysis. CONDENSED ABSTRACT: Impaired endogenous fibrinolysis is a strong risk factor in ACS. We aimed to assess whether adding very low dose rivaroxaban (VLDR) to DAPT can enhance fibrinolysis. Fibrin and clot lysis were assessed in whole blood. ACS patients with impaired fibrinolysis were randomised 1:1:1 to clopidogrel 75 mg daily; clopidogrel 75 mg plus VLDR; or ticagrelor 90 mg twice daily, in addition to aspirin. At 30-days, there was no difference in lysis time between the groups, nor change from baseline. VLDR does not improve fibrinolysis at high or low shear. Further studies are needed to determine whether alternative antithrombotic regimens can enhance endogenous fibrinolysis.

Ethnic Differences in Thrombotic Profiles of Acute Coronary Syndrome Patients and Relationship to Cardiovascular Outcomes: A Comparison of East Asian and White subjects.

BACKGROUND: East Asians (EAs), compared to white Caucasians (W), have a lower risk of ischemic heart disease and a higher risk of bleeding with antithrombotic medications. The underlying mechanisms are incompletely understood. OBJECTIVES: We sought to compare thrombotic profiles of EA and W patients with myocardial infarction (MI) and relate these to cardiovascular outcomes. METHODS: In a prospective study in the United Kingdom and Korea, blood samples from patients (n = 515) with ST- or non-ST-elevation MI (STEMI and NSTEMI) were assessed using the Global Thrombosis Test, measuring thrombotic occlusion (OT) and endogenous fibrinolysis (lysis time [LT]). Patients were followed for 1 year for major adverse cardiovascular events (MACE) and bleeding. RESULTS: EA patients showed reduced OT (longer OT) compared to W (646 seconds [470-818] vs. 436 seconds [320-580], p < 0.001), with similar LT. In STEMI, OT (588 seconds [440-759] vs. 361 seconds [274-462], p < 0.001) and LT (1,854 seconds [1,389-2,729] vs. 1,338 seconds [1,104-1,788], p < 0.001) were longer in EA than W. In NSTEMI, OT was longer (OT: 734 seconds [541-866] vs. 580 seconds [474-712], p < 0.001) and LT shorter (1519 seconds [1,058-2,508] vs. 1,898 seconds [1,614-2,806], p = 0.004) in EA than W patients. MACE was more frequent in W than EA (6.3 vs. 1.9%, p = 0.014) and bleeding infrequent. While OT was unrelated, LT was a strong independent predictor of MACE event after adjustment for risk factors (hazard ratio: 3.70, 95% confidence interval: 1.43-9.57, p = 0.007), predominantly in W patients, and more so in STEMI than NSTEMI patients. CONCLUSION: EA patients exhibit different global thrombotic profiles to W, associated with a lower rate of cardiovascular events.

Complete revascularization in elderly patients with myocardial infarction-a safe, effective, and necessary strategy?

The FIRE trial compared culprit-only revascularization to physiology-guided complete revascularization strategy in elderly patients presenting with myocardial infarction. The study has shown that it is a safe approach and may confer additional prognostic benefit in patients with NSTEMI.

Meta-analysis Comparing Long-Term Clinical Outcomes of Percutaneous Coronary Intervention versus no Intervention in Patients with Chronic Total Occlusion.

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) has substantially improved due to increasing operator experience and advancements in equipment, techniques, and management algorithms. However, the overall benefit of CTO PCI remains controversial, particularly since only a few randomized trials have been reported to date. Methods: We performed a meta-analysis to evaluate the efficacy of CTO PCI. The study outcomes were the occurrence of all-cause mortality, myocardial infarction, repeat revascularization, stroke, or freedom from angina at the longest documented follow-up period. Results: In five trials including 1790 patients, the mean age was 63 ± 10 years, 17% were female, with a median follow-up of 2.9 years. The procedural success rate ranged from 73% to 97% and the right coronary artery was the most involved artery (52%). There was no significant difference between CTO PCI and no intervention regarding all-cause mortality (odds ratio [OR]: 1.10, 95% confidence interval [CI]: 0.49-2.47, P = 0.82), myocardial infarction (OR: 1.20, 95% CI: 0.81-1.77, P = 0.36), repeat revascularization (OR: 0.67, 95% CI: 0.40-1.14, P = 0.14), or stroke (OR: 0.60, 95% CI: 0.26-1.36, P = 0.22). In two trials including 686 patients, significantly more patients were free of angina at 1 year, defined as the Canadian Cardiovascular Society grading of angina pectoris Grade 0, in the CTO PCI group compared to the no intervention group (OR: 0.52, 95% CI: 0.35-0.76, P < 0.001). Meta-regression analyses based on various trial-level covariates (gender, diabetes, previous myocardial infarction, PCI or coronary artery bypass graft, SYNTAX or J-CTO scores, and CTO-related artery percentages) did not suggest any statistically significant relationships. Conclusions: CTO PCI appears to have a similar efficacy profile compared to no intervention at long-term follow-up, but with a significant improvement of angina favoring PCI-treated patients. Further adequately powered and long-term trials are required to identify the best management strategy for patients with coronary CTO.

Biomarkers of Thrombotic Status Predict Spontaneous Reperfusion in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Spontaneous reperfusion, seen in ∼20% of patients with ST-segment elevation myocardial infarction (STEMI), manifests as normal epicardial flow in the infarct-related artery, with or without ST-segment resolution, before percutaneous coronary intervention (PCI). The drivers mediating this are unknown. OBJECTIVES: The authors sought to relate spontaneous reperfusion to the thrombotic profile. METHODS: In a prospective study, blood from STEMI patients (n = 801) was tested pre-PCI to assess in vitro, point-of-care, occlusion times (OT) and endogenous lysis times (LT). Spontaneous reperfusion was defined as infarct-related artery Thrombolysis In Myocardial Infarction flow grade 3 before PCI. Patients were followed for major cardiovascular events (death, myocardial infarction, or stroke). RESULTS: Spontaneous reperfusion was associated with a longer OT (435 seconds vs 366 seconds; P < 0.001) and a shorter LT (1,257 seconds vs 1,616 seconds; P < 0.001), lower troponin, and better left ventricular function. LT was superior to OT for predicting spontaneous reperfusion (area under the curve for LT: 0.707; 95% CI: 0.661-0.753; area under the curve for OT: 0.629; 95% CI: 0.581-0.677). Among patients with spontaneous reperfusion, those with complete, vs partial ST-segment resolution, had a longer OT (P = 0.002) and a shorter LT (P < 0.001). Spontaneous reperfusion was unrelated to clinical characteristics or pain-to-angiography times. Over 4 years, patients with spontaneous reperfusion experienced fewer major adverse cardiovascular events than those without (4.1% vs 10.6%; P = 0.013), especially in those with both spontaneous reperfusion and complete ST-segment resolution (1.5% vs 10.1%; P = 0.029). CONCLUSIONS: We demonstrate a novel hematological signature in STEMI patients with spontaneous reperfusion, namely, decreased platelet reactivity and faster endogenous fibrinolysis, relating to smaller infarcts and improved survival. This finding indicates a role for modulating thrombotic status early after STEMI onset, to facilitate spontaneous reperfusion and improve outcomes.

Spontaneous Reperfusion in Patients with Transient ST-Elevation Myocardial Infarction-Prevalence, Importance and Approaches to Management.

Patients with transient ST-elevation myocardial infarction (STEMI) or spontaneous resolution (SpR) of the ST-segment elevation on electrocardiogram could potentially represent a unique group of patients posing a therapeutic management dilemma. In this review, we discuss the potential mechanisms underlying SpR, its relation to clinical outcomes and the proposed management options for patients with transient STEMI with a focus on immediate versus early percutaneous coronary intervention. We performed a structured literature search of PubMed and Cochrane Library databases from inception to December 2020. Studies focused on SpR in patients with acute coronary syndrome were selected. Available data suggest that deferral of angiography and revascularization within 24-48 h in these patients is reasonable and associated with similar or perhaps better outcomes than immediate angiography. Further randomized trials are needed to elucidate the best pharmacological and invasive strategies for this cohort.

Assessment and Mitigation of Bleeding Risk in Atrial Fibrillation and Venous Thromboembolism: Executive Summary of a European and Asia-Pacific Expert Consensus Paper.

While there is a clear clinical benefit of oral anticoagulation in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision for initiating and continuing anticoagulation is often based on a careful assessment of both thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug-drug and food-drug interactions. Bleeding risk is also not a static "one-off" assessment based on baseline factors but is dynamic, being influenced by aging, incident comorbidities, and drug therapies. In this executive summary of a European and Asia-Pacific Expert Consensus Paper, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with a view to summarizing "best practice" when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, and review established bleeding risk factors and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism, are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice.

Assessment and mitigation of bleeding risk in atrial fibrillation and venous thromboembolism: A Position Paper from the ESC Working Group on Thrombosis, in collaboration with the European Heart Rhythm Association, the Association for Acute CardioVascular Care and the Asia-Pacific Heart Rhythm Society.

Whilst there is a clear clinical benefit of oral anticoagulation (OAC) in patients with atrial fibrillation (AF) and venous thromboembolism (VTE) in reducing the risks of thromboembolism, major bleeding events (especially intracranial bleeds) may still occur and be devastating. The decision to initiate and continue anticoagulation is often based on a careful assessment of both the thromboembolism and bleeding risk. The more common and validated bleeding risk factors have been used to formulate bleeding risk stratification scores, but thromboembolism and bleeding risk factors often overlap. Also, many factors that increase bleeding risk are transient and modifiable, such as variable international normalized ratio values, surgical procedures, vascular procedures, or drug-drug and food-drug interactions. Bleeding risk is also not a static 'one off' assessment based on baseline factors but is dynamic, being influenced by ageing, incident comorbidities, and drug therapies. In this Consensus Document, we comprehensively review the published evidence and propose a consensus on bleeding risk assessments in patients with AF and VTE, with the view to summarizing 'best practice' when approaching antithrombotic therapy in these patients. We address the epidemiology and size of the problem of bleeding risk in AF and VTE, review established bleeding risk factors, and summarize definitions of bleeding. Patient values and preferences, balancing the risk of bleeding against thromboembolism are reviewed, and the prognostic implications of bleeding are discussed. We propose consensus statements that may help to define evidence gaps and assist in everyday clinical practice.

Breast cancer and incident cardiovascular events: A systematic analysis at the nationwide level.

BACKGROUND: Breast cancer (BC) is one of the most common cancers worldwide, and the treatments are frequently cardiotoxic. Whether BC is associated with a higher risk of cardiovascular events is a matter of debate. We evaluated the associations among BC and incident cardiovascular events in a contemporary population. METHODS: All female patients discharged from French hospitals in 2013 with at least 5 years of follow-up and without a history of major adverse cardiovascular event (myocardial infarction [MI], heart failure [HF], ischaemic stroke or all-cause death, and MACE-HF, which includes cardiovascular death, MI, ischaemic stroke or HF) or cancer (except BC) were identified. After propensity score matching, patients with BC were matched 1:1 with patients with no BC. Hazard ratios (HRs) for cardiovascular events during follow-up were adjusted on age, sex and smoking status at baseline. RESULTS: 1,795,759 patients were included, among whom 64,480 (4.3%) had history of BC. During a mean follow-up of 5.1 years, matched female patients with BC had a higher risk of all-cause death (HR 3.55, 95% confidence interval [CI]: 3.47-3.64), new-onset HF (HR 1.08, 95% CI 1.04-1.11), major bleeding (HR 1.43, 95% CI 1.36-1.49), MACE-HF (HR 1.07, 95% CI 1.04-1.11) and net adverse clinical events (NACE) including all-cause death, MI, ischaemic stroke, HF or major bleeding (HR 2.53, 95% CI 2.48-2.58) compared with those with no BC. By contrast, risks were not higher for cardiovascular death (HR 0.94, 95% CI 0.88-1.00) and were lower for MI (HR 0.81, 95% CI 0.75-0.88) and ischaemic stroke (HR 0.85, 95% CI 0.79-1.11). CONCLUSIONS: In a large and contemporary analysis of female patients seen in French hospitals, women with history of breast cancer had a higher risk of all-cause mortality, new-onset heart failure and major bleeding compared to a matched cohort of women without breast cancer. In contrast, they have a reduced risk of cardiovascular mortality, MI and stroke.

Analysis of the ESC/EACTS 2020 Atrial Fibrillation Guidelines With Perioperative Implications.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia worldwide, with an individual lifetime risk of approximately 37% in the United States. Broadly defined as a supraventricular tachyarrhythmia with disorganized atrial activation, AF results in an increased risk of stroke, heart failure, valvular heart disease, and impaired quality of life, and confers a significant burden on the health of individuals and society. AF in the perioperative setting is common and a significant source of perioperative morbidity and mortality worldwide. The latest iteration of the European Society of Cardiology AF guidelines published in 2020 provide the clinician a valuable road map for the management of this arrythmia. This expert review will comprehensively analyze the 2020 European Society of Cardiology guidelines and provide perioperative management tools for the clinician.

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

Hypofibrinolysis is a recently-recognized risk factor for recurrent cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI), but the mechanistic determinants of this are not well understood. In patients with STEMI, we show that the effectiveness of endogenous fibrinolysis in whole blood is determined in part by fibrinogen level, high sensitivity C-reactive protein, and shear-induced platelet reactivity, the latter directly related to the speed of thrombin generation. Our findings strengthen the evidence for the role of cellular components and bidirectional crosstalk between coagulatory and inflammatory pathways as determinants of hypofibrinolysis.

Season of Birth and Cardiovascular Mortality in Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND: The fetal origins hypothesis have associated early life exposures with the development of adverse health outcomes in adulthood. Season of birth has been shown to be associated with overall and cardiovascular mortality. METHODS: We performed a retrospective database study to explore the association between season of birth and mortality in patients with atrial fibrillation. RESULTS: A total of 8962 patients with AF were identified in the database with 1253 deaths recorded. AF patients born in spring and summer had a higher mortality rate when compared to those born in autumn and winter (hazard ratio (HR) 1.13, 95% confidence interval (CI) 1.01-1.26, p = 0.03). This effect was consistent in the male subgroup (HR 1.25, 95% CI 1.03-1.51, p = 0.02 for males born in spring; HR 1.24, 95% CI 1.03-1.51, p = 0.03 for males born in summer when compared to winter as the reference) but not in females (HR 1.02, 95% CI 0.79-1.31, p = 0.88 for females born in spring; HR 1.11, 95% CI 0.87-1.42, p = 0.39 for females born in summer when compared to winter as the reference). Results persisted after adjustment for baseline characteristics and clinical risk profile. A similar pattern was observed with cardiovascular mortality. CONCLUSION: Birth in spring or summer is associated with a higher risk of cardiovascular mortality in male AF patients, but not in females. This could be related to the underlying differences in rates of major adverse clinical events between genders. Further studies should aim at clarifying the mechanisms behind this association, which may help us understand the higher level of risk in female patients with AF.

Fibrinolysis in Platelet Thrombi.

The extent and duration of occlusive thrombus formation following an arterial atherothrombotic plaque disruption may be determined by the effectiveness of endogenous fibrinolysis. The determinants of endogenous fibrinolysis are the subject of much research, and it is now broadly accepted that clot composition as well as the environment in which the thrombus was formed play a significant role. Thrombi with a high platelet content demonstrate significant resistance to fibrinolysis, and this may be attributable to an augmented ability for thrombin generation and the release of fibrinolysis inhibitors, resulting in a fibrin-dense, stable thrombus. Additional platelet activators may augment thrombin generation further, and in the case of coronary stenosis, high shear has been shown to strengthen the attachment of the thrombus to the vessel wall. Neutrophil extracellular traps contribute to fibrinolysis resistance. Additionally, platelet-mediated clot retraction, release of Factor XIII and resultant crosslinking with fibrinolysis inhibitors impart structural stability to the thrombus against dislodgment by flow. Further work is needed in this rapidly evolving field, and efforts to mimic the pathophysiological environment in vitro are essential to further elucidate the mechanism of fibrinolysis resistance and in providing models to assess the effects of pharmacotherapy.

Hypertension and atrial fibrillation: Closing a virtuous circle.

Ying Gue and Gregory Lip discuss the accompanying study by Ana-Catarina Pinho-Gomes and co-workers on blood pressure lowering treatment in patients with atrial fibrillation.

Precision Treatment in ACS-Role of Assessing Fibrinolysis.

Despite advancements in pharmacotherapy and interventional strategies, patients with acute coronary syndrome (ACS) remain at risk of recurrent thrombotic events. In addition to an enhanced tendency to thrombus formation, impairment in the ability to naturally dissolve or lyse a developing thrombus, namely impaired endogenous fibrinolysis, is responsible for a major part of this residual risk regardless of optimal antiplatelet medication. Global assessment of endogenous fibrinolysis, including a point-of-care assay, can identify patients with ACS at persistent high cardiovascular risk and might play an important role in allowing the personalisation of potent antithrombotic therapy to enhance fibrinolytic status, providing precision treatment of ACS to improve long-term outcome.