rivaroxaban and Coronary-Thrombosis

Patients with acute coronary syndrome (ACS) usually receive acetylsalicylic acid plus an adenosine diphosphate (ADP) receptor inhibitor to reduce the long-term risk of recurrent events. However, patients receiving standard antiplatelet prophylaxis still face a substantial risk of recurrent events. Strategies involving 3 antithrombotic agents with different modes of action have now been tested. In Thrombin Receptor Antagonists for Clinical Event Reduction (TRA-CER), compared with standard care alone, bleeding complications including intracranial hemorrhage (ICH) were increased with the addition of vorapaxar, without efficacy benefit. In Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA 2°P-TIMI 50), the addition of vorapaxar reduced recurrent events compared with standard care in stable patients with prior myocardial infarction. This study was terminated early in patients with prior stroke owing to excess ICH, though an increased risk of ICH or fatal bleeding was not detected in patients with prior myocardial infarction. The Apixaban for Prevention of Acute Ischemic and Safety Events 2 (APPRAISE-2) trial of standard-dose apixaban added to standard care in patients with ACS was also stopped early owing to excess serious bleeding. However, in Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes (ATLAS ACS 2 TIMI 51), fatal bleeding or fatal ICH did not increase with low-dose rivaroxaban added to low-dose acetylsalicylic acid-based standard care compared with standard care alone. In that trial, a significant reduction of recurrent vascular events was shown with 3 antithrombotic regimens compared with standard care. Therefore, depending on drug dose and patient population, further reductions in recurrent vascular events after ACS may be possible in future clinical practice, with a favorable benefit-risk profile.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Coronary Thrombosis; Dabigatran; Hemorrhage; Humans; Imines; Lactones; Morpholines; Platelet Activation; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Thrombin

Patients with coronary artery disease (CAD), peripheral artery disease (PAD), or both remain at risk of cardiovascular events (including peripheral ischemic events), even when they receive the current guideline-recommended treatment. The phase III COMPASS trial demonstrated that treatment with rivaroxaban vascular dose 2.5 mg twice daily plus aspirin (dual pathway inhibition [DPI] regimen) significantly reduced the risk of major adverse cardiovascular events (including peripheral ischemic events) and increased the risk of major bleeding, but not fatal bleeding or intracranial hemorrhage, versus aspirin alone in patients with CAD, PAD, or both. The results of the COMPASS trial supported the regulatory approval of the DPI regimen in several geographic regions. However, it is unclear whether the patients selected for treatment with the DPI regimen in clinical practice will have a similar risk profile and event rates compared with the COMPASS trial population. The prospective post-approval XATOA registry study aims to assess treatment patterns, as well as ischemic and bleeding outcomes in patients with CAD, PAD, or both, who receive DPI therapy in routine clinical practice. Up to 10,000 patients from at least 400 centers in 22 countries will be enrolled and followed up for a minimum of 12 months, and all treatment will be at the discretion of the prescribing physician. The primary objective of the XATOA study will be to describe early treatment patterns, while ischemic and bleeding outcomes will be described as a secondary objective. TRIAL REGISTRATION NUMBER: NCT03746275.

Topics: Aspirin; Atherosclerosis; Coronary Thrombosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Registries; Rivaroxaban; Treatment Outcome

As part of its Single Technology Appraisal process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures rivaroxaban (Xarelto, Bayer) to submit evidence of the clinical and cost effectiveness of rivaroxaban for the prevention of adverse outcomes in patients after the acute management of acute coronary syndrome (ACS). The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology, based upon the company's submission to NICE. The evidence was derived mainly from a randomised, double-blind, phase III, placebo-controlled trial of rivaroxaban (either 2.5 or 5 mg twice daily) in patients with recent ACS [unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI)]. In addition, all patients received antiplatelet therapy [aspirin alone or aspirin and a thienopyridine either as clopidogrel (approximately 99 %) or ticlopidine (approximately 1 %) according to national or local guidelines]. The higher dose of rivaroxaban (5 mg twice daily) did not form part of the marketing authorisation. A post hoc subgroup analysis of the licensed patients who had ACS with elevated cardiac biomarkers (that is, patients with STEMI and NSTEMI) without prior stroke or transient ischaemic stroke showed that compared with standard care, the addition of rivaroxaban (2.5 mg twice daily) to existing antiplatelet therapy reduced the composite endpoint of cardiovascular mortality, myocardial infarction or stroke, but increased the risk of major bleeding and intracranial haemorrhage. However, there were a number of limitations in the evidence base that warrant caution in its interpretation. In particular, the evidence may be confounded because of the post hoc subgroup analysis, modified intention-to-treat analyses, high dropout rates and missing vital status data. Results from the company's economic evaluation showed that the deterministic incremental cost-effectiveness ratio (ICER) for rivaroxaban in combination with aspirin plus clopidogrel or with aspirin alone compared with aspirin plus clopidogrel or aspirin alone was £6203 per quality-adjusted life-year (QALY) gained. In contrast, the ERG's preferred base case estimate was £5622 per QALY gained. The ICER did no

Topics: Acute Coronary Syndrome; Coronary Thrombosis; Cost-Benefit Analysis; Double-Blind Method; Electrocardiography; Factor Xa Inhibitors; Humans; Models, Economic; Practice Guidelines as Topic; Rivaroxaban

The authors assessed the use of dual antiplatelet therapy (DAPT) and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).. The frequency, patterns, and outcomes when adding DAPT to non-vitamin K antagonist oral anticoagulants in the setting of PCI in patients with AF are largely unknown.. The study population included all patients in the treatment group of the ROCKET AF trial divided by the receipt of PCI during follow-up. Clinical characteristics, PCI frequency, and rates of DAPT were reported. Clinical outcomes were adjudicated independently as part of the trial.. Among 14,171 patients, 153 (1.1%) underwent PCI during a median 806 days of follow-up. Patients treated with rivaroxaban were significantly less likely to undergo PCI compared with warfarin-treated patients (61 vs. 92; p = 0.01). Study drug was continued during PCI in 81% of patients. Long-term DAPT (≥30 days) was used in 37% and single antiplatelet therapy in 34%. A small number switched from DAPT to monotherapy within 30 days of PCI (n = 19 [12.3%]) and 15% of patients received no antiplatelet therapy after PCI. Rates of stroke/systemic embolism and major bleeding events were high in post-PCI patients (4.5/100 patient-years and 10.2/100 patient-years) in both treatment groups.. In patients with AF at moderate to high risk for stroke, PCI occurred in <1% per year. DAPT was used in a variable manner, with the majority of patients remaining on study drug after PCI. Rates of both thrombotic and bleeding events were high after PCI, highlighting the need for studies to determine the optimal antithrombotic therapy.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Coronary Disease; Coronary Thrombosis; Double-Blind Method; Drug Substitution; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Intracranial Embolism; Male; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Risk Factors; Rivaroxaban; Stroke; Time Factors; Treatment Outcome; Vitamin K

Rivaroxaban is a factor Xa inhibitor that was recently reviewed by the Food and Drug Administration as a potential therapy to reduce the risk of recurrent atherothrombotic events in patients with acute coronary syndromes. Approval of this drug would represent a paradigm shift away from dual antiplatelet therapy toward long-term triple antithrombotic therapy. However, to date, no other experimental anticoagulant agent has demonstrated a favorable risk-benefit profile in this population, in part because of the expected increased risk in major bleeding by combining aspirin, a P2Y12 receptor inhibitor, and an anticoagulant. Approvability of rivaroxaban was considered largely on the basis of the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51) trial, which demonstrated a significant reduction in a composite of cardiovascular death, myocardial infarction, and stroke. Although the primary efficacy endpoint was met, a substantial amount of missing data was observed. We discuss the impact of missing data in this trial, its implications for informative censoring of safety events (major bleeding), and implications for future cardiovascular outcomes trials.

Topics: Acute Coronary Syndrome; Anticoagulants; Coronary Thrombosis; Double-Blind Method; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Myocardial Infarction; Randomized Controlled Trials as Topic; Reproducibility of Results; Rivaroxaban; Thiophenes; Treatment Outcome; United States; United States Food and Drug Administration

Direct acting oral anticoagulants (DOACs) are increasingly used for thromboembolic prophylaxis in patients with atrial fibrillation (AF). However, there is limited data to evaluate the use of DOACs for the treatment of pre-existing left atrial appendage thrombus. We aimed to determine the efficacy of DOACs in treatment of left atrial appendage (LAA) thrombus utilizing transesophageal echocardiographic (TEE) and clinical outcomes. In this single-center study, we identified 33 patients that were treated for LAA thrombus with DOAC. Eighteen were treated with apixaban, 10 with dabigatran, and 5 with rivaroxaban. The primary endpoint was defined as resolution of LAA thrombus (in patients undergoing TEE), or death, major bleeding requiring transfusion, intracranial hemorrhage, ischemic stroke, or peripheral embolization. In this study, 15 of the 16 patients treated with DOACs who underwent follow-up TEE had resolution of LAA thrombus, with a mean duration of 112 days. Of the 15 patients who achieved resolution of the LAA thrombus, 14 had resolution by their first follow-up TEE. In the 17 patients without a follow-up TEE, 1 died of a retroperitoneal bleed (28 days after DOAC initiation), and 1 suffered an ischemic stroke (484 days after DOAC initiation). In general, patients without a follow-up TEE were older and had more co-morbidities. Although these results are descriptive and limited in number of patients, we believe this is ample evidence that DOACs are relatively safe and efficacious in treatment of patients with AF and concomitant LAA thrombus.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Coronary Thrombosis; Dabigatran; Echocardiography, Transesophageal; Female; Humans; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Treatment Outcome

Topics: Aspirin; Clinical Trials as Topic; Coronary Artery Bypass; Coronary Thrombosis; Factor Xa Inhibitors; Humans; Platelet Aggregation Inhibitors; Risk Factors; Rivaroxaban; Treatment Outcome

Topics: Atrial Appendage; Atrial Fibrillation; Coronary Thrombosis; Echocardiography, Transesophageal; Factor Xa Inhibitors; Humans; Hypertension; Male; Middle Aged; Obesity; Rivaroxaban

Left ventricular (LV) thrombus is usually seen in situations with reduced LV function, and is mostly seen in patients with large anterior ST-elevation myocardial infarction (MI). Most embolic events, in patients with LV thrombus formation, occur within the first 3-4 months, thus the recommendations regarding the duration of anticoagulant therapy. According to guidelines, an oral vitamin K antagonist, warfarin, is being used as an anticoagulant for this period. Novel oral anticoagulants were found to be either non-inferior or superior compared with warfarin in prevention of thromboembolism in patients with non-valvular atrial fibrillation. However, the data about their role in the management of LV thrombus are limited to case reports. Here, we report on the dissolution of LV apical thrombus in 3 patients with anterior ST-elevation MI receiving dual antiplatelet therapy and rivaroxaban on a reduced dose for 3 months.

Topics: Aged; Combined Modality Therapy; Coronary Angiography; Coronary Thrombosis; Diagnosis, Differential; Echocardiography; Factor Xa Inhibitors; Humans; Male; Middle Aged; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Rivaroxaban; Stents; Ventricular Dysfunction, Left

Rivaroxaban, a selective inhibitor of active factor X belongs to the group of direct-acting oral anticoagulants (DOAC), more and more often replacing vitamin K antagonists (VKA) in venous thromboembolic disease and nonvalvular atrial fibrillation. Attempts are also being made to use DOAC to treat locally formed intracardiac thrombi, mainly in the left atrium and its appendage, in atrial fibrillation and in heart failure. Rarely diagnosed local right ventricular thrombus (RVT) may be a complication of dilated cardiomyopathy (DCM).. The authors present a case of a 40-year-old male with DCM and RVT located in the apex, which was imaged in echocardiography, magnetic resonance and multislice computed tomography. During treatment with rivaroksaban (2x15 mg: 4 weeks; 1x20 mg: 4 months) diminishing of RVT was not observed. After 2 months of VKA use complete resolution of RVT was noted. The case presented is probably the first described RVT treated with rivaroxaban. The authors conclude that in some cases, anticoagulation with VKA may be more effective than DOAC in intracardiac thrombi therapy, especially when it is meticulously monitored. Overlapping effect on RVT due to anticoagulants use with a different mechanism of action cannot be excluded.

Topics: Adult; Anticoagulants; Cardiomyopathy, Dilated; Coronary Thrombosis; Heart Ventricles; Humans; Male; Poland; Rivaroxaban; Treatment Outcome; Vitamin K

A 72-year-old man with non-valvular atrial fibrillation and metastatic liver and lung cancer after surgery for colon cancer developed thrombosis in the right atrium one month after decreasing the dose of warfarin due to the introduction of double anti-platelet therapy for coronary stent implantation. Restoring the warfarin dose with ordinary control for two months did not result in any changes in the size of the thrombus; however, the subsequent substitution of rivaroxaban (oral treatment with a direct Factor Xa inhibitor) for warfarin ultimately resolved the thrombosis.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Coronary Thrombosis; Factor Xa Inhibitors; Heart Atria; Humans; Male; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome; Vitamin K; Warfarin

Activation of coagulation and platelets is closely linked, and arterial thrombosis involves coagulation activation as well as platelet activation and aggregation. In these studies, we investigated the possible synergistic effects of rivaroxaban in combination with antiplatelet agents on thrombin generation and platelet aggregation in vitro and on arterial thrombosis and hemostasis in rat models.. Thrombin generation was measured by the Calibrated Automated Thrombogram method (0.5 pmol/L tissue factor) using human platelet-rich plasma (PRP) spiked with rivaroxaban (15, 30, or 60 ng/mL), ticagrelor (1.0 µg/mL), and acetylsalicylic acid (ASA; 100 µg/mL). Tissue factor-induced platelet aggregation was measured in PRP spiked with rivaroxaban (15 or 30 ng/mL), ticagrelor (1 or 3 µg/mL), or a combination of these. An arteriovenous (AV) shunt model in rats was used to determine the effects of rivaroxaban (0.01, 0.03, or 0.1 mg/kg), clopidogrel (1 mg/kg), ASA (3 mg/kg), and combinations on arterial thrombosis.. Rivaroxaban inhibited thrombin generation in a concentration-dependent manner and the effect was enhanced with ticagrelor and ticagrelor plus ASA. Rivaroxaban and ticagrelor also concentration-dependently inhibited tissue factor-induced platelet aggregation, and their combination increased the inhibition synergistically. In the AV shunt model, rivaroxaban dose-dependently reduced thrombus formation. Combining subefficacious or weakly efficacious doses of rivaroxaban with ASA or ASA plus clopidogrel increased the antithrombotic effect.. These data indicate that the combination of rivaroxaban with single or dual antiplatelet agents works synergistically to reduce platelet activation, which may in turn lead to the delayed/reduced formation of coagulation complexes and vice versa, thereby enhancing antithrombotic potency.

Topics: Adenosine; Adult; Animals; Arteriovenous Shunt, Surgical; Aspirin; Blood Coagulation; Clopidogrel; Coronary Thrombosis; Dose-Response Relationship, Drug; Female; Humans; Male; Platelet Activation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Rivaroxaban; Thrombin; Ticagrelor; Ticlopidine

Topics: Adult; Coronary Angiography; Coronary Thrombosis; Coronary Vessels; Electrocardiography; Factor Xa Inhibitors; Humans; Male; Rivaroxaban; Treatment Outcome

Rivaroxaban, an oral, direct factor Xa inhibitor, has been approved in several countries for thromboprophylaxis after elective hip or knee arthroplasty based on favorable benefit-risk profile and improved efficacy compared to enoxaparin in reducing the composite of symptomatic and asymptomatic deep vein thrombosis, nonfatal pulmonary embolism, and all-cause mortality. Given the potential therapeutic utility of factor Xa inhibition in arterial thrombosis, we evaluated the antithrombotic activity of rivaroxaban in a model of arterial thrombosis in anesthetized rats in which thrombotic occlusion was induced by electrolytic injury of the carotid artery. Rivaroxaban, 0.3, 1 or 3 mg/kg, enoxaparin, 10 mg/kg, or vehicle were infused intravenously to anesthetized rats and time to occlusion as well as coagulation parameters monitored following carotid electrolytic injury. Although the lowest dose of rivaroxaban (0.3 mg/kg) did not prolong occlusion time compared to vehicle, rivaroxaban at 1 or 3 mg/kg prevented occlusion in all vessels during the 30-min observation period (median occlusion time >30 min), which was greater than that following a single dose of enoxaparin infused at a dose of 10 mg/kg (median time to occlusion = 21.6 min). Rivaroxaban was also effective following oral dosing at 3 mg/kg. Rivaroxaban's antithrombotic activity was paralleled by dose-dependent increases in prothrombin time (PT) and activated clotting time (ACT) without significant changes in activated partial thromboplastin time. Rivaroxaban also markedly increased Russell's viper venom time (RVVT) and decreased thrombin-antithrombin complex concentrations at all doses. These findings support the potential utility of rivaroxaban in arterial thrombotic disorders such as acute coronary syndrome, stroke and peripheral arterial disease.

Topics: Administration, Oral; Animals; Anticoagulants; Blood Coagulation; Carotid Artery Injuries; Coronary Occlusion; Coronary Thrombosis; Disease Models, Animal; Electrolytes; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Injections, Intravenous; Male; Morpholines; Partial Thromboplastin Time; Prothrombin Time; Rats; Rats, Sprague-Dawley; Rivaroxaban; Thiophenes

Topics: Anticoagulants; Controlled Clinical Trials as Topic; Coronary Thrombosis; Dose-Response Relationship, Drug; Humans; Morpholines; Myocardial Infarction; Risk Assessment; Rivaroxaban; Secondary Prevention; Survival Rate; Thiophenes