rivaroxaban and Acute-Coronary-Syndrome

A systematic review and network meta-analysis (NMA) were conducted to explore the efficacy and safety of different antiplatelet or anticoagulation drugs in chronic coronary syndromes patients.. Electronic databases (Pubmed, Embase and Cochrane databases) were systematically searched to identify randomized controlled trials evaluating different antiplatelet or anticoagulation drugs (aspirin, aspirin + clopidogrel, aspirin + clopidogrel + cilostazol, clopidogrel/prasugrel + aspirin, aspirin + rivaoxaban 2.5 mg, aspirin + ticagrelor 60 mg, aspirin + ticagrelor 90 mg, clopidogrel or rivroxaban 5 mg) versus placebo for treatment chronic coronary syndromes patients. Outcomes included major adverse cardiovascular events, all cause death, major bleeding and myocardial infarction. A random-effect Bayesian NMA was conducted for outcomes of interest, and results were presented as odds ratios (ORs) and 95% credible intervals. The NMA was performed using R Software with a GeMTC package. A Bayesian NMA was performed and relative ranking of agents was assessed using surface under the cumulative ranking probabilities.. Ten randomized controlled trials met criteria for inclusion and finally included in this NMA. In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to primary endpoint of major adverse cardiovascular events. In head-to-head comparison, no significant difference was observed between all antithrombotic treatment strategies with respect to all cause death. Clopidogrel/prasugrel + aspirin (OR = 3.8, 95% credible intervals [CrI]: 1.3-12.0, P < .05) and aspirin + rivaroxaban 2.5 mg (OR = 3.1, 95%CrI: 1.1-9.5, P < .05) was associated with an increase of the major bleeding. Compared with aspirin alone, aspirin + clopidogrel (OR = 0.42, 95%CrI: 0.22-0.76, P < .05) and aspirin + ticagrelor 90 mg (OR = 0.42, 95%CrI: 0.17-0.95, P < .05) was associated with a decrease of the myocardial infarction.. Myocardial infarction was significantly lower when adding clopidogrel or ticagrelor 90 mg to aspirin than those in the aspirin alone group. However, clopidogrel/prasugrel and rivaroxaban 2.5 mg was associated with an increase of the major bleeding than aspirin alone.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Bayes Theorem; Clopidogrel; Fibrinolytic Agents; Hemorrhage; Humans; Myocardial Infarction; Network Meta-Analysis; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Rivaroxaban; Ticagrelor; Treatment Outcome

The optimal antithrombotic strategy for patients with a long-term indication for anticoagulation and acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) remains controversial. This meta-analysis aims to compare randomised trials' outcomes of these patients, focussing on dual versus triple antithrombotic and non vitamin K oral anticoagulants (NOACs) versus vitamin K oral anticoagulants regimens.. Medline, Embase and Cochrane databases were searched from January 1980 to March 2019 yielding 309 articles, and after careful screening, five randomized trials totalling 10 643 patients were included for analysis.. Dual antithrombotic regimens were associated with significantly less thrombolysis in myocardial infarction (TIMI) major and minor bleeding [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.40-0.71], with no significant difference in major adverse cardiovascular events (OR 0.93, 95% CI 0.72-1.22) or all-cause mortality (OR 0.89, 95% CI 0.61-1.19). NOAC regimens had significantly lower TIMI major and minor bleeding (OR 0.58, 95% CI 0.43-0.78) and intracranial bleeding (OR 0.33, 95% CI 0.16-0.66), with similar rates of major adverse cardiovascular events (OR 1.00, 95% CI 0.86-1.16) and all-cause mortality (OR 1.01, 95% CI 0.81-1.26).. Dual antithrombotic and NOAC regimens have reduced bleeding without compromising the risk of cardiovascular events or mortality, and should be preferred for patients with ACS or PCI also needing long-term anticoagulation.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Dabigatran; Drug Therapy, Combination; Dual Anti-Platelet Therapy; Factor Xa Inhibitors; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Ticagrelor; Warfarin

Although having different rationales and purposes, the PEGASUS-TIMI 54 and COMPASS trials present various points of contact and, especially after the first recommended year of dual antiplatelet therapy (DAPT) from an acute coronary syndrome, pose the clinical question of whether DAPT should be prolonged (PEGASUS strategy) or aspirin should be maintained by combining rivaroxaban 2.5 mg bid (COMPASS strategy). In this review, we try to trace the PEGASUS and COMPASS patient's profile by analyzing the design of each study with their inclusion/exclusion criteria, the main subanalyses and the real-world studies recently published in this setting.

Topics: Acute Coronary Syndrome; Aspirin; Dual Anti-Platelet Therapy; Humans; Patient Selection; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Research Design; Rivaroxaban; Time Factors

Despite advances in secondary prevention strategies in patients with cardiovascular disease, the residual risk of recurrent atherothrombotic events remains high. Dual-antiplatelet therapy is the standard of care for secondary prevention in patients with acute coronary syndrome (ACS), whereas single antiplatelet therapy, generally with aspirin, is the standard of care for secondary prevention in stable patients with coronary artery disease (CAD), peripheral artery disease (PAD), or cerebrovascular disease. However, atherosclerotic plaque disruption not only triggers platelet activation but also results in thrombin generation because of tissue factor exposure. Therefore, blocking both pathways by combining antiplatelet therapy with an anticoagulant, or dual pathway inhibition (DPI), has the potential to be more effective than inhibiting either pathway alone. The benefit of DPI has been demonstrated in the ATLAS ACS 2-TIMI 51, COMPASS, and VOYAGER PAD trials, where the combination of rivaroxaban vascular dose (2.5 mg twice daily) plus aspirin significantly reduced the risk of atherothrombotic events compared with aspirin across a broad range of patients, including those with recent ACS, those with chronic CAD and/or PAD, and patients with PAD who have undergone peripheral revascularization. This article provides the rationale for this regimen in more detail, including why the DPI regimen with the rivaroxaban vascular dose was developed for vascular protection in a broad spectrum of patients with atherosclerotic disease.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Atherosclerosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Forecasting; Hemorrhage; Humans; Peripheral Arterial Disease; Platelet Activation; Platelet Aggregation Inhibitors; Recurrence; Rivaroxaban; Secondary Prevention; Thrombin

As the management of acute coronary syndrome (ACS) continues to evolve, many old practices proved to be of a little benefit and other approaches established the new pillars of modern medicine. Treating ACS patients with dual antiplatelet therapy (DAPT) for a year by combining aspirin and a P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) has resulted in better outcomes and is currently the standard of therapy. However, owing to the persistent activation of the coagulation cascade, patients may continue to experience recurrent ischemia and high mortality rates despite compliance with the dual antiplatelet therapy. Research is underway to establish new treatment modalities for secondary prevention post-ACS, including the use of the novel direct oral anticoagulants (DOACs).. Multiple trials have been conducted to evaluate the use of DOACs for the secondary prevention after ACS. Recent emerging data showed that the addition of rivaroxaban in a very low dose of 2.5 mg twice daily to the regular DAPT regimen after ACS is beneficial in the reduction of major cardiovascular events, including recurrent myocardial infarction (MI) and strokes. On the other hand, other DOACs, including apixaban, did not show similar efficacy and did not improve the cardiovascular outcomes. Patients who experience an ACS continue to suffer long-term consequences and thromboembolic complications. Many studies have shown that after the initial ACS event, patients remain in a hypercoagulable state and are more prone to recurrent ischemic attacks including stroke, recurrent MI, or unstable angina (UA). With the objective of seeking better outcomes, it is imperative to explore more aggressive anticoagulation strategies in ACS patients. In this article, we discuss the progress that was made and the limitations we face regarding the role of different anticoagulants in this setting.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Stroke

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.

Topics: Acute Coronary Syndrome; Aged; Algorithms; Aspirin; Cardiovascular Diseases; Coronary Artery Disease; Decision Making; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Risk; Rivaroxaban; Secondary Prevention; Stroke; Ticagrelor

Patients with acute coronary syndrome (ACS) require long-term antithrombotic intervention to reduce the risk of further ischemic events; dual antiplatelet therapy with a P2Y

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Aspirin; Atrial Fibrillation; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

The significance of adding new oral anticoagulants (NOACs) to antiplatelet therapy in patients with acute coronary syndrome (ACS) is unclear. We conducted a meta-analysis to assess the safety and efficacy of adding NOACs (apixaban, rivaroxaban, and dabigatran) to single antiplatelet agent (SAP) or dual antiplatelet therapy (DAPT) in patients with ACS. Seven randomized controlled trials were selected using PubMed or MEDLINE, Scopus, and Cochrane library (inception to August 2017). The summary measure was random effects hazard ratio (HR) with 95% confidence interval (CI). The primary safety outcome was clinically significant bleeding. The secondary efficacy outcome was major adverse cardiovascular events (MACE; composite of myocardial infarction, stroke, and all-cause mortality). In 31,574 patients, addition of NOAC to SAP did not increase the risk of clinically significant bleeding (HR 0.82, 95% CI 0.56 to 1.20, p = 0.31); however, the risk of clinically significant bleeding was significantly increased with NOAC plus DAPT (HR 2.24, 95% CI 1.75 to 2.87, p < 0.001). NOACs had no statistically beneficial effect on MACE when used with SAP (HR 0.82, 95% CI 0.66 to 1.04, p = 0.10); however, a modest reduction in MACE was observed when NOACs were combined with DAPT (HR 0.86, 95% CI 0.78 to 0.93, p < 0.001). In conclusion, in patients with ACS, the addition of NOAC to DAPT resulted in increased risk of clinically significant bleeding, whereas only a modest reduction in MACE was achieved. The addition of NOACs to SAP did not result in significant reduction of MACE or increase in clinically significant bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Pyrazoles; Pyridones; Rivaroxaban

Vitamin K antagonists were the only choice for chronic oral anticoagulation for more than half a century. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). In randomised controlled trials comparing direct oral anticoagulants with traditional vitamin K antagonists, the direct oral anticoagulants all showed a favourable benefit-risk balance in their safety and efficacy profile, in prevention of thromboembolic events in patients with atrial fibrillation and in the prevention and treatment of venous thromboembolism and acute coronary syndrome. In 2008, dabigatran was the first direct oral anticoagulant approved by the European Medicine Agency. Subsequently, rivaroxaban, apixaban and edoxaban were also authorised. This article reviews the evidence related to the use of these drugs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Secondary Prevention; Stroke; Thiazoles; Venous Thromboembolism; Withholding Treatment

The optimal anti-thrombotic therapy for secondary prevention after an acute coronary syndrome is still a matter of debate. While current guidelines recommend dual anti-platelet therapy with aspirin and a P2Y12 inhibitor over 12 months especially in patients with stent implantation, the value of prolonged anticoagulation is still controversial. In the ATLAS-TIMI 52 trial, a low-dose direct factor Xa inhibition with rivaroxaban compared with placebo reduced the combined primary endpoint of cardiovascular mortality, myocardial infraction and stroke with an increase in major bleeding complications. This article discusses the value and problems of adding low-dose rivaroxaban to anti-platelet therapy as secondary prevention measure after an acute myocardial infarction. It will describe the pros and cons of intensified anti-platelet therapy versus dual pathway inhibition and give recommendations for different patient groups in clinical practice.

Topics: Acute Coronary Syndrome; Acute Disease; Anticoagulants; Aspirin; Clinical Trials as Topic; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Myocardial Infarction; Practice Guidelines as Topic; Purinergic P2Y Receptor Antagonists; Rivaroxaban

This review examines the reasons for long-term use of anticoagulants after an acute coronary syndrome, the study analysis the results of ATLAS ACS 2-TIMI 51 and with the main features of the use of rivaroxaban for the prevention of adverse outcomes in patients of this category that are important from a practical point of view.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Humans; Morpholines; Rivaroxaban; Thiophenes

The decision to prescribe anticoagulant therapy must consider the balance between reducing the risk of thromboembolic events and increasing the risk of bleeding. Although assessments of net clinical outcomes with oral anticoagulants are not new, this article presents an evaluation of benefit-risk by considering only events of substantial and comparable clinical relevance (i.e., events with serious long-term sequelae likely to have irreversible consequences, including death). This is based on the concept of the number of patients who need to be treated to elicit one beneficial [number needed to treat (NNT)] or harmful [number needed to harm (NNH)] event. The approach is illustrated using data from phase III trials of rivaroxaban, selected because it has the broadest range of approved indications of the novel oral anticoagulants. For example, in the ATLAS ACS 2 TIMI 51 trial of rivaroxaban plus standard antiplatelet therapy following an acute coronary syndrome event, the current analysis demonstrates that 63 patients need to be treated (over 24 months) to prevent one all-cause mortality event compared with placebo (NNT = 63). Conversely, 500 patients need to be treated to cause one additional intracranial hemorrhage (NNH = 500). The most relevant and clinically meaningful assessment of benefit-risk may therefore be achieved by focusing only on events of greatest concern to patients and physicians, namely those with (potentially) long-lasting, severe consequences. Although there are clear limitations to this type of analysis, rivaroxaban appears to demonstrate a broadly favorable benefit-risk profile across multiple clinical indications.

Topics: Acute Coronary Syndrome; Factor Xa Inhibitors; Humans; Numbers Needed To Treat; Risk Assessment; Rivaroxaban; Stroke; Treatment Outcome; Venous Thromboembolism; Venous Thrombosis

Topics: Acute Coronary Syndrome; Anticoagulants; Factor Xa Inhibitors; Humans; Rivaroxaban

Altering doses and regimens of a drug has consequences for the drug's pharmacokinetic and pharmacodynamic profile. Based on a half-life of 5-13 h, it is expected that the Factor Xa inhibitor rivaroxaban would be best suited to a twice-daily rather than a once-daily dose regimen. However, although rivaroxaban is used as a twice-daily regimen for the initial treatment of venous thromboembolism (VTE) and secondary prevention after acute coronary syndromes, the approved dosing is once-daily for prevention of VTE after orthopaedic surgery, long-term secondary prevention of VTE and stroke prevention in patients with non-valvular atrial fibrillation. Rivaroxaban dosing was based on the evaluation of the efficacy and safety of several rivaroxaban doses and regimens in phase II trials. A clear overall advantage of twice-daily dosing compared with once-daily dosing was not documented for indications for which once-daily dosing was subsequently selected. Once-daily dosing was therefore selected for these indications because it is expected to be associated with better compliance than twice-daily dosing, and potentially, with improved outcomes. These studies and data obtained with another Factor Xa inhibitor, edoxaban, in addition to previous experience with low molecular weight heparins, indicate that the clinical impact of once-daily versus twice-daily doses on outcome in terms of efficacy and safety cannot be reliably predicted from pharmacology data, e.g. elimination half-life, obtained during pre-clinical and early phase I clinical studies but rather should be ascertained empirically in phase II and III clinical trials.

Topics: Acute Coronary Syndrome; Atrial Fibrillation; Factor Xa Inhibitors; Female; Humans; Male; Morpholines; Rivaroxaban; Thiophenes; Venous Thromboembolism

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

Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents.

Topics: Acute Coronary Syndrome; Adenosine; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Enoxaparin; Fondaparinux; Heparin; Hirudins; Humans; Morpholines; Peptide Fragments; Piperazines; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Polysaccharides; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes; Ticagrelor; Ticlopidine; Warfarin

The best regimen for the long-term management of patients with atrial fibrillation who present with an acute coronary syndrome or require placement of a coronary stent remains unclear. Clinicians need to understand the risk of stroke, stent thrombosis, and major bleeding associated with treating these patients. Numerous studies and risk assessment schemes provide clinicians with an estimation of the risk of stroke, stent thrombosis, and major bleeding that may be associated with the use or avoidance of dual antiplatelet therapy with concurrent anticoagulation therapy (triple therapy). This review discusses the special antithrombotic needs in patients who have atrial fibrillation and either acute coronary syndrome or a requirement for percutaneous coronary intervention, including the published evidence for non-vitamin K oral anticoagulants, and the unanswered questions in this patient population. In conclusion, until the results of additional ongoing or planned randomized trials are known, clinicians must continue to rely on expert opinion and their own clinical judgment when treating these patients.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Atrial Fibrillation; Clopidogrel; Comorbidity; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Morpholines; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Pyrazoles; Pyridones; Risk Assessment; Rivaroxaban; Stroke; Thiophenes; Thrombosis; Ticlopidine

Rivaroxaban (Xarelto(®)) is an orally administered highly selective direct inhibitor of factor Xa that has been approved in many countries to reduce the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism. More recently, rivaroxaban at a low dosage of 2.5 mg twice daily, co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine, was approved for use in the EU for patients with a recent acute coronary syndrome (ACS). The approval of rivaroxaban in ACS was primarily based on findings of the phase III ATLAS ACS 2-TIMI 51 trial, which showed that after a median of 13.1 months of treatment with rivaroxaban 2.5 mg twice daily (combined with aspirin or aspirin plus either clopidogrel or ticlopidine) there was a statistically significant reduction in the rate of the primary composite endpoint, which was death from cardiovascular causes, myocardial infarction or stroke, compared with placebo. Rivaroxaban 2.5 mg twice daily was also associated with a reduction in all-cause and cardiovascular mortality. There was an increase in the risk of major bleeding and intracranial haemorrhage with rivaroxaban 2.5 mg twice daily compared with placebo; however, there was no increase in the risk of fatal bleeding. Aspirin plus either ticagrelor or prasugrel was not evaluated as background dual antiplatelet therapy in ATLAS ACS 2-TIMI 51 and the safety implications of rivaroxaban used in combination with such therapy are unknown. In conclusion, results of the ATLAS ACS 2-TIMI 51 trial suggest a potentially important role for rivaroxaban 2.5 mg twice daily co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine in patients with a recent ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Clinical Trials, Phase III as Topic; Drug Administration Schedule; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome

Topics: Acute Coronary Syndrome; Adenosine; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Percutaneous Coronary Intervention; Piperazines; Platelet Aggregation Inhibitors; Postoperative Complications; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombosis; Ticagrelor

There are concerns regarding increased risk of acute coronary syndrome with dabigatran. We aimed to assess whether alternative treatment options such as rivaroxaban or apixaban carry a similar risk as compared with dabigatran.. We searched MEDLINE and EMBASE for randomized controlled trials of apixaban, dabigatran or rivaroxaban against control (placebo, heparin or vitamin K antagonist). We pooled odds ratios (OR) for adverse coronary events (acute coronary syndrome or myocardial infarction) using fixed effect meta-analysis and assessed heterogeneity with I(2) . We conducted adjusted indirect comparisons to compare risk of adverse coronary events with apixaban or rivaroxaban vs. dabigatran.. Twenty-seven randomized controlled trials met the inclusion criteria. Dabigatran was associated with a significantly increased risk of adverse coronary events in pooled analysis of nine trials (OR 1.45, 95% CI 1.14, 1.86). There was no signal for coronary risk with apixaban from nine trials (pooled OR 0.89, 95% CI 0.78, 1.03) or rivaroxaban from nine trials (pooled OR 0.81, 95% CI 0.72, 0.93). Overall, adjusted indirect comparison suggested that both apixaban (OR 0.61, 95% CI 0.44, 0.85) and rivaroxaban (OR 0.54; 95% CI 0.39, 0.76) were associated with lower coronary risk than dabigatran. Restricting the indirect comparison to a vitamin K antagonist as a common control, yielded similar findings, OR 0.57 (95% CI 0.39, 0.85) for apixaban vs. dabigatran and 0.53 (95% CI 0.37, 0.77) for rivaroxaban vs. dabigatran.. There are significant differences in the comparative safety of apixaban, rivaroxaban and dabigatran with regards to acute coronary adverse events.

Topics: Acute Coronary Syndrome; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzamides; Blood Coagulation; Embolism; Factor Xa Inhibitors; Hemorrhage; Hemostatics; Humans; Morpholines; Postoperative Complications; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombophilia; Thrombosis

Despite widespread adoption of acetylsalicylic acid and P2Y12 receptor inhibitor therapy as the standard of care for secondary event prevention in patients with acute coronary syndrome (ACS), the rate of cardiovascular death or myocardial infarction following discharge is approximately 24-31% over five years, indicating an important unmet need to reduce further the risk of recurrent ACS events. Because thrombin has a role in arterial thrombus generation, a mechanistic rationale exists for adding an anticoagulant to dual antiplatelet therapy to reduce cardiovascular event rates and mortality. The direct thrombin inhibitor dabigatran and the direct Factor Xa inhibitors rivaroxaban and apixaban have been investigated for this application, with only rivaroxaban successfully completing a phase III trial. These results suggest that dose selection is of paramount importance in this indication, with lower anticoagulant doses (relative to those used in other indications, such as stroke prevention in atrial fibrillation) plus low-dose acetylsalicylic acid potentially improving cardiovascular outcomes. This article reviews clinical trial data of anticoagulants for secondary event prevention in patients with ACS; it also discusses the mechanistic reasons that may underlie these observations and looks towards the potential impact of findings from the ATLAS ACS 2 TIMI 51 trial on clinical practice.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Vitamin K

Rivaroxaban, a direct factor Xa inhibitor, is a novel oral anticoagulant approved for stroke prevention in patients with nonvalvular atrial fibrillation and also approved in Europe (but not in the United States) to prevent recurrent ischemic events in patients with recent acute coronary syndromes. Advantages of rivaroxaban over oral anticoagulants such as warfarin are the lack of need for ongoing monitoring, a fixed-dose regimen, and fewer drug and food interactions. Drawbacks include a lack of an antidote and the absence of a widely available method to reliably monitor the anticoagulant effect. In patients at risk of stroke due to atrial fibrillation, rivaroxaban was noninferior compared to warfarin in preventing stroke/systemic embolism in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial and was associated with a similar risk of major bleeding; the incidence of intracranial hemorrhage was 33% lower with rivaroxaban. Concerns raised about the trial were the adequacy of warfarin management and the increase in event rate at the end of the trial. The drug acquisition cost of rivaroxaban is higher than that of warfarin although decision-analytic models suggest that it is cost effective in atrial fibrillation. In patients with recent acute coronary syndrome, low-dose rivaroxaban reduced mortality and the composite end point of death from cardiovascular causes, myocardial infarction and stroke, but this was accompanied by an increased risk of intracranial hemorrhage and major bleeding in the Rivaroxaban in Combination With Aspirin Alone or With Aspirin and a Thienopyridine in Patients With Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction (ATLAS ACS 2-TIMI) 51 trial. Thus, rivaroxaban appears to be a valuable addition to the therapeutic armamentarium in atrial fibrillation although caution should be exercised, given the limited experience in combination with novel oral antiplatelet agents. The role of rivaroxaban as part of a modern regimen in acute coronary syndrome continues to be evaluated.

Topics: Acute Coronary Syndrome; Administration, Oral; Atrial Fibrillation; Blood Coagulation; Cost-Benefit Analysis; Drug Costs; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Practice Guidelines as Topic; Risk Factors; Rivaroxaban; Stroke; Thiophenes; Treatment Outcome

Anticoagulation therapy is one of the most important advances in modern medicine, saving thousands of lives from the complications of atrial fibrillation and mechanical heart valves and preventing recurrent venous thromboembolism. Warfarin and heparins have been the predominant anticoagulants used until the past decade. However, the arrival of newer target-specific anticoagulants has brought us easier and equally effective agents, although no specific antidotes are yet available. Being relatively newer drugs, physicians need to be familiar with the various practical issues that may be encountered with the prescription of these drugs, which are summarised in this review.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Warfarin

Arterial thrombosis in acute coronary syndrome (ACS) is associated with activation of platelets and the coagulation cascade. Persistent thrombin levels have been reported after ACS in such patients. Novel oral anticoagulants without a need of close monitoring and frequent blood tests such as warfarin can provide a chronic beneficial effect on recurrent ischaemic events in such a population. Rivaroxaban, a new oral factor Xa inhibitor, has been tried for this indication in the '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' (ATLAS ACS 2-TIMI 51) trial using a low dose regimen in an attempt to balance the adverse effects of bleeding related to chronic anticoagulation on background of dual antiplatelet therapy for ACS, and the beneficial effects on recurrent coronary ischemia. The role of rivaroxaban in this context has been discussed in detail in this review.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Rivaroxaban; Thiophenes

Despite significant advances in the management of acute coronary syndrome (ACS) and long-term antiplatelet therapy after an ACS event, patients continue to be at risk of further cardiovascular events. There is evidence that recurrent events are at least partly attributed to the persistent activation of the coagulation system after ACS. Various anticoagulants, including vitamin K antagonists (VKAs) and non-VKA oral anticoagulants, have been evaluated in patients post-ACS, in combination with antiplatelet therapy. The desired outcome would be a further reduction of recurrent cardiovascular events with low or acceptable levels of bleeding complications. Here, we provide an overview of the current clinical trial data of non-VKA oral anticoagulants, focusing on rivaroxaban in particular, for secondary prevention in patients with a recent ACS event.

Topics: Acute Coronary Syndrome; Clinical Trials as Topic; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Thiophenes; Treatment Outcome

Acute coronary syndrome (ACS) is a medical emergency often associated with an occlusive coronary event with consequent myocardial underperfusion. Patients require immediate antiplatelet therapy and long-term antithrombotic prophylaxis to reduce the risk of recurrence. Acetylsalicylic acid (ASA) alone or in combination with a platelet P2Y12 inhibitor (dual antiplatelet therapy [DAPT]) has become the clinically accepted antithrombotic prophylaxis for patients post-ACS. Historically, studies assessing the utility of adding oral anticoagulants (OACs) have not demonstrated a clinical benefit with regard to acceptable bleeding risk. Studies with vitamin K antagonists (VKAs) such as warfarin demonstrated a potential to reduce the risk of subsequent death by reinfarction but this benefit was offset by increases in bleeding. Results from studies of two targeted non-VKA OACs also proved disappointing, with little or no apparent reduction in the rate of ischemic events seen. However, the recent ATLAS studies assessing rivaroxaban (an oral factor Xa inhibitor) in patients with ACS demonstrated a reduction in the composite endpoint of deaths from cardiovascular causes, myocardial infarction (MI), or stroke, and a reduction in the rate of stent thrombosis. This review provides an overview of the pivotal studies in which the addition of OACs to antiplatelet therapy (the so-called "dual-pathway" approach) has been investigated for the management of patients post-ACS and considers the results of the ATLAS studies and their potential impact on the management of patients after an acute event.

Topics: Acute Coronary Syndrome; Anticoagulants; Clinical Trials as Topic; Factor Xa Inhibitors; Humans; Morpholines; Platelet Aggregation Inhibitors; Rivaroxaban; Thiophenes

To systematically examine discontinuation rates with new US Food and Drug Administration-approved oral anticoagulants (NOACs) in patients with various indications for long-term anticoagulation.. Poor adherence to medications is considered a potential and frequent cause of treatment failure. We searched the PubMed, Cochrane Central Register of Controlled Trials, EMBASE, EBSCO, Web of Science, and CINAHL databases for articles published from January 1, 2001, through September 15, 2013. The following Medical Subject Heading terms and/or keywords were used for our database searches: rivaroxaban, dabigatran, apixaban, new oral anticoagulants, oral thrombin inhibitors, and oral factor Xa inhibitors. Articles in English that focused on randomized controlled trials (RCTs) comparing NOACs (apixaban, dabigatran, and rivaroxaban) with conventional therapy or placebo were abstracted. Independent extraction of relevant data was performed by 2 authors. The primary end point of interest was discontinuation due to all causes. Other end points of interest were discontinuation due to adverse events, consent withdrawal, and nonadherence.. Eighteen RCTs including a total of 101,801 patients were included for analysis. Total study drug discontinuation rates were not statistically different with NOACs in comparison to pharmacologically active comparators for treatment of venous thromboembolism/pulmonary embolism (risk ratio [RR], 0.91; 95% CI, 0.74-1.13; P=.40) and for NOACs in comparison to warfarin and aspirin for prevention of stroke in patients with atrial fibrillation (RR, 1.01; 95% CI, 0.87-1.17; P=.92). In contrast, in acute coronary syndromes, total study drug discontinuation with NOACs was significantly higher than with placebo (RR, 1.40; 95% CI, 1.07-1.83; P=.01). Overall discontinuations were comparable to those with active comparators.. Study drug discontinuations with NOACs were not significantly different from those with conventional drugs in treatment of venous thromboembolism/pulmonary embolism and prevention of stroke in patients with atrial fibrillation but were worse in acute coronary syndromes as noted in evidence from contemporary RCTs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Medication Adherence; Morpholines; Pulmonary Embolism; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

Patients with acute coronary syndrome (ACS) are typically managed with long-term dual antiplatelet therapy of acetylsalicylic acid plus a P2Y12 platelet receptor antagonist; however, although effective, the risk of another vascular event within 12 months remains at approximately 10%. Considerable efforts have been made to find improved therapeutic approaches to secondary prevention in ACS. The ATLAS ACS 2-TIMI 51 trial demonstrated that rivaroxaban (2.5 mg twice daily) significantly reduced recurrent vascular events, increased the risk of major bleeding but not the risk of fatal bleeding, and resulted in reduced rates of death from cardiovascular causes. These results formed the basis for approval in Europe of rivaroxaban (2.5 mg twice daily) in conjunction with standard antiplatelet therapy for the secondary prevention of ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Drug Approval; Drug Therapy, Combination; Hemorrhage; Humans; Morpholines; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Thiophenes

Abstract The use of dual antiplatelet therapy has led to a substantial reduction in ischemic events post-acute coronary syndrome (ACS). Despite this, recurrent event rates remain high. Recent research has combined antiplatelet with anticoagulant therapy to reduce recurrent event rates further. Compared with standard medical therapy, rivaroxaban demonstrated improved efficacy outcomes and significantly reduced mortality after an ACS. Although clear benefits of novel oral anticoagulants post-ACS have been proven, concerns regarding bleeding are still a barrier to widespread use. This review explores key trials of dual antiplatelet therapy and examines the latest research in anticoagulation aiming to optimize clinical outcomes post-ACS.

Topics: Acute Coronary Syndrome; Anticoagulants; Drug Therapy, Combination; Hemorrhage; Humans; Morpholines; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Thiophenes

Despite an early invasive strategy and the use of dual antiplatelet therapy, patients with acute coronary syndrome (ACS) continue to be at substantial risk for recurrent ischemic events. It is believed that this risk is, at least in part, due to an intrinsic coagulation pathway that remains activated for a prolonged period after ACS. Earlier studies using warfarin showed a reduction in ischemic events, but the overall benefits were offset by increased bleeding complications. Recently, there has been increased interest in the potential role of new oral anticoagulants, some of which target factor Xa, after ACS. Factor Xa is important for the coagulation pathway and also plays a role in cellular proliferation and inflammation. It may thus be an attractive target for therapeutic intervention in ACS. Recently, various oral factor Xa inhibitors have been studied as potential treatment options for ACS. This review will focus on currently available data to evaluate the possible role of factor Xa inhibitors in the management of patients with ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Azepines; Benzamides; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome

Secondary prevention of atherothrombotic events is the domain of antiplatelet therapy and according to present risk is used one drug strategy or combination of acetylsalicylic acid with ADP receptor blockers. The importance of the combination of dual antiplatelet therapy together with xabans or dabigatran was investigated in 6 clinical trials. Only one of them (ATLAS ACS 2-TIMI 51) indicated that treatment with small dose of rivaroxaban (2 × 2.5 mg) may be added to dual strategy of acetylsalicylic acid and clopidogrel. The risk of major bleeding event is increased and net clinical benefit is only about 0.5 % per year. Dual therapy with aspirin and prasugrel or tikagrelor is beneficial. In the second part of the review is discussed higher incidence of myocardial infarction in controlled group in the trial comparing treatment of dabigatran with warfarin. This relationship has not been resolved, however, in patients with higher risk of coronary events and indication of anticoagulant treatment with direct oral anticoagulants it is recommended to choose from xabans (apixaban and rivaroxaban).

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Aspirin; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Clopidogrel; Dabigatran; Hemorrhage; Humans; Morpholines; Myocardial Infarction; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Secondary Prevention; Thiophenes; Ticlopidine; Warfarin

Recurrent ischemic events after an acute coronary syndrome (ACS) are frequent, despite current antiplatelet therapies and revascularization. Warfarin reduces recurrent ischemia but increases bleeding. Warfarin is difficult to administer with the proportion of time achieving therapeutic international normalized ratios varying within and among individuals. The newer oral anticoagulants have predictable dose-effect relationships and no monitoring is required.. The pharmacology of rivaroxaban , evidence for the use of rivaroxaban in ACS, and the management of bleeding complications are covered in this article.. Arterial thrombosis is traditionally thought to be more platelet mediated than clotting factor mediated. Nonetheless, in the acute therapy for ACS, anticoagulation is a cornerstone treatment and there is persistent thrombin generation. Research has focused on finding a "sweet spot" of anticoagulation with high anti-ischemic and low bleeding effects. It follows that with chronic therapy post-ACS, there could also be a "sweet-spot" of anticoagulation. This may depend on the intrinsic vascular disease burden, the intervention delivered (stenting or bypass surgery), and background antiplatelet therapy. Rivaroxaban, a new oral factor Xa inhibitor, in a low-dose regimen-reduced ischemic events including mortality across a broad ACS population in the ATLAS-ACS trial with increased bleeding but without increasing fatal bleeding. Rivaroxaban is an attractive new treatment option for ACS.

Topics: Acute Coronary Syndrome; Anticoagulants; Drug Approval; Drug Interactions; Europe; Humans; Morpholines; Platelet Membrane Glycoproteins; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; United States; United States Food and Drug Administration

Acute coronary syndrome (ACS) encompasses acute myocardial infarction (MI) and unstable angina. Activation of platelets and coagulation cascade plays a central role in the development of ACS. Over the past decade, there have been substantial improvements in the strategies for secondary prevention of ACS, including the development of more potent oral antiplatelet agents such as prasugrel and ticagrelor. However, therapies with even better efficacy and safety profiles and more rapid onset and offset of action would be desirable.. This review discusses the advantages and disadvantages of the currently available antithrombotic agents and describes the findings from recent clinical trials of three novel agents; cangrelor (an intravenous P2Y12 receptor antagonist), vorapaxar (protease-activated receptor-1 inhibitor) and rivaroxaban (an oral factor Xa inhibitor).. Cangrelor appears more promising than clopidogrel when a very rapid onset and reversal of antiplatelet effect is needed. Vorapaxar in addition to standard oral antiplatelet therapy was effective in patients with prior MI, but was not safe in patients with a prior stroke. Low dose rivaroxaban decreased cardiovascular events and mortality in patients post-ACS compared to placebo, although bleeding was increased.

Topics: Acute Coronary Syndrome; Adenosine Monophosphate; Fibrinolytic Agents; Humans; Lactones; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Thiophenes

New oral anticoagulants (NOACs) have been developed that may further decrease the mortality and morbidity of ACS by complementing antiplatelet therapy. Optimal use of these agents can be achieved by maximum reduction in thrombotic events at the minimum bleeding risk when combining a long-term oral anticoagulant with anti-platelet therapy in patients with coronary heart disease. Although, based on the pharmacokinetics and -dynamics of NOACs, these agents could improve the current management of ACS patients, multiple trials consistently demonstrate a trend toward increased major and clinically relevant non major bleeding almost diminishing the benefits in reduction of ischemic events. Therefore, some critical issues need to be further evaluated in future trials.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Intracranial Hemorrhages; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thromboembolism

The novel oral anticoagulant drugs, comprising dabigatran, rivaroxaban, and apixaban, have emerged as compelling alternatives to vitamin K antagonists for stroke prevention in atrial fibrillation, and low‑molecular‑weight heparin for thromboprophylaxis following hip and knee arthroplasty. Rivaroxaban has also been approved for treatment of venous thromboembolism. However, the role of these drugs for the management of patients with an acute coronary syndrome (ACS) is less certain. The purpose of this review was to summarize the randomized trials evaluating novel oral anticoagulants in patients with an ACS and consider the reasons why these drugs have not been incorporated into routine clinical practice. In addition, the situation involving rivaroxaban, which has been approved for use in patients with an acute coronary syndrome in Europe but not in North America, is discussed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

As acute coronary syndrome (ACS) becomes more common nationwide and current anticoagulation regimens used in patients with ACS continue to possess their shortcomings, the need for new anticoagulants is on the rise. Although heparin and warfarin are used effectively in patients with ACS, they both have significant side effects and delivery issues. New factor Xa inhibitors offer an oral alternative that functions early in the coagulation cascade. The role of these new drugs in ACS is explored here. Electronic search strategies were used to collect reviews, randomized controlled trials, and other studies. Databases used included Medline and Cochrane Library and hand selection. Sources selected were limited to those that discussed factor Xa inhibitors in the context of ACS. Selected studies were then assessed for quality and relevance and those deemed relevant included for analysis. Some of the factor Xa inhibitors such as rivaroxaban offer anticoagulation as effective as, if not more effective, heparin and warfarin with lower risks of bleeding and other adverse effects such as heparin-induced thrombocytopenia. Many of these new agents also come in oral form, making them easy for patients to manage and use daily.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Cyclic N-Oxides; Factor Xa Inhibitors; Fondaparinux; Heparin; Humans; Morpholines; Naphthalenes; Polysaccharides; Propionates; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; Warfarin

Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide with a prevalence that has now reached pandemic levels as a consequence of the rapid modernization of the developing world. Its presentation as an acute coronary syndrome (ACS) is a frequent reason for hospital admission and of profound implications for personal, societal and global health. Despite improvements in the management of ACS with anti-platelet and anticoagulant therapy and revascularization techniques, many patients continue to suffer recurrent ischemic events. The need to reduce future cardiovascular events has led to the development of novel therapies to prevent coronary thrombosis, targeting thrombin-mediated pathways. These include direct Xa inhibitors (apixaban, rivaroxaban and darexaban), direct thrombin inhibitors (dabigatran) and PAR 1 antagonists (vorapaxar and atopaxar). This article critically reviews the comparative mechanisms of action, the risks and benefits, together with the clinical evidence base for the use of these novel oral agents in the management of ACS patients.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Benzimidazoles; beta-Alanine; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes

Effective prophylaxis and treatment of thromboembolic disorders remain suboptimal in many healthcare systems, partly owing to limitations of traditional anticoagulants. New oral anticoagulants have been developed and among these, rivaroxaban, apixaban and dabigatran etexilate are in the most advanced stage of clinical development.. A literature search using the PubMed and ClinicalTrials.gov databases was performed to identify English-language publications. The search was performed up to 31 December 2011 with the terms rivaroxaban OR Xarelto, apixaban OR Eliquis and dabigatran OR Pradaxa. Ongoing, completed and published phase III randomised controlled trials were selected as the primary source of information for the clinical development programme of each drug.. The new oral agents demonstrate several advantages over traditional anticoagulants, including administration at fixed doses and no requirement for routine coagulation monitoring On the basis of phase III clinical trials, rivaroxaban, apixaban and dabigatran etexilate have been approved in many countries for the prevention of venous thromboembolism after hip and knee replacement surgery. Dabigatran etexilate and rivaroxaban have also been approved for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Europe and the US. In addition, rivaroxaban has been approved in Europe for the treatment of acute deep vein thrombosis and prevention of recurrent venous thromboembolism. Approval of these agents and postapproval monitoring of their safety and efficacy will have implications for primary care.. Rivaroxaban, apixaban and dabigatran etexilate offer the possibility of simplified prevention and treatment strategies for thromboembolic disorders in the outpatient setting.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Hip; Arthroplasty, Replacement, Knee; Benzimidazoles; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

Acute coronary syndrome (ACS) occurs as a result of atherosclerotic plaque rupture and subsequent platelet activation and coagulation leading to thrombus formation and coronary occlusion. Thrombin and activated factor X (FXa) are key elements in the coagulation cascade. The use of anticoagulants in ACS, both in the acute phase and in the long term, has improved prognosis by reducing thrombotic events, but is associated with an increased risk of bleeding. In recent years, new oral anticoagulants have been developed that do not require monitoring and produce a lower risk of bleeding. Rivaroxaban is the only drug with a favorable risk-benefit profile in patients with ACS. The ATLAS ACS TIMI 2-51 is the first phase III trial demonstrating that the addition of low-dose rivaroxaban to optimal antiplatelet therapy reduces mortality, cardiovascular mortality, infarct or stroke without significantly increasing fatal bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Azepines; Azetidines; Benzamides; Benzimidazoles; Benzylamines; beta-Alanine; Clinical Trials, Phase III as Topic; Dabigatran; Drug Administration Schedule; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes

After more than 50 years of thrombosis treatment and prophylaxis being based on heparin and vitamin K antagonists, a new generation of oral, direct anticoagulants is now available. The past 5 years have brought a strikingly large number of trials that evaluated these new oral anticoagulants in a range of clinical trials, particularly nonvalvular atrial fibrillation, thrombosis prophylaxis after major joint replacement surgery, treatment of venous thromboembolic events, and, most recently, acute coronary syndrome. These studies have been notably similar in design between the drugs for specific indication. This review focuses on the 3 drugs that either have recently been approved by the US Food and Drug Administration (dabigatran and rivaroxaban) or have the most mature phase III clinical data (apixaban).

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Hemorrhage; Humans; Morpholines; Orthopedic Procedures; Pyrazoles; Pyridones; Risk Assessment; Risk Factors; Rivaroxaban; Thiophenes; Thrombosis; Treatment Outcome

Venous thromboembolism (VTE) is a major public health concern since the incidence of VTE rises substantially with age. Furthermore, the diagnosis can be elusive since patients can present differently, causing delay in diagnosis and initiation of treatment and resulting in major morbidity and mortality. In addition to accuracy and precision in diagnosis, antithrombotic therapies are the cornerstones of VTE management. In traditional paradigm, vitamin K antagonists (warfarin), indirect factor Xa inhibitors, and heparin are the foundation in management of VTE. Warfarin has been the only available oral anticoagulant therapy for several decades. Although warfarin is effective in both treatment and prophylaxis against VTE, there are several limitations. Therefore, the novel anticoagulation therapies, including rivaroxaban, apixaban, and dabigatran etexilate, have apparent advantages over warfarin in terms of clinical efficacy and adverse effects. The objective of this review is to describe the background and clinical implications of these novel anticoagulants.

Topics: Acute Coronary Syndrome; Administration, Oral; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism; Vitamin K; Warfarin

Thrombosis plays a key role in the pathophysiology of acute coronary syndromes (ACS). The management of patients with ACS includes interventional procedures and use of antithrombotic agents acutely, and dual antiplatelet therapy (aspirin and a P2Y12 receptor antagonist) for secondary prevention. However, patients with recent ACS remain at a substantial residual risk for recurrent ischemic events or death. The idea of follow-up treatment with an oral anticoagulant on top of standard therapy seems promising. Warfarin was the first oral anticoagulant thoroughly investigated in this direction, but the widespread long-term use of warfarin in ACS has been limited by challenges associated with pharmacodynamic/pharmacokinetic deficiencies of the drug and the risk of bleeding. Novel oral anticoagulants, such as direct thrombin inhibitors (DTIs) and FXa inhibitors overcome the downsides of VKAs. Ximelagatran was the first DTI, investigated and proven to be effective in prevention of recurrent ischemic events in ACS patients, but the drug association with hepatotoxicity prompted its withdrawal. Dabigatran etexilate, apixaban, darexaban (YM150) and TAK-442 were studied in phase II dose-escalation trials in order to determine the balance between clinical effectiveness and bleeding risk in daily use with dual antiplatelet therapy, with both positive and negative results. Rivaroxaban is the only agent that completed a phase III trial, showing reduction in recurrent ischemic events rate and death from cardiovascular causes as well as all-cause death. This review summarizes the data from completed and ongoing clinical trials of the new oral anticoagulants in patients with ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Clinical Trials as Topic; Drug Discovery; Factor Xa; Factor Xa Inhibitors; Humans; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome

Arterial and venous thrombotic states, including myocardial infarction (MI), stroke and deep vein thrombosis with subsequent pulmonary embolism, are a significant cause of cardiovascular mortality and morbidity. Factor Xa (FXa) plays a pivotal role in thrombus formation. Its inhibition following acute coronary syndromes (ACS) blocks amplification of thrombin generation and subsequent clot formation, resulting in a risk reduction in recurrent MI, stroke and death. For this reason, a predictable form of oral anticoagulation continues to be an ongoing need. Rivaroxaban , the first oral FXa inhibitor, acts by direct inhibition of FXa and does not require an antithrombin cofactor for its activity.. This paper describes the pharmacokinetics (PK) of low-dose rivaroxaban tested in patients with ACS. Age, gender, renal function and body weight have no clinically significant effects on the PK of the drug in treatment of ACS. Caution should be maintained during co-administration of strong CYP3A4 inducers and inhibitors. Among patients with moderate and severe hepatic impairment and in those with associated coagulopathies, rivaroxaban however is contraindicated.. The mortality benefit with low-dose rivaroxaban in ACS patients was first demonstrated in ATLAS ACS2 TIMI-51 trial. With its rapid oral bioavailability, predictable PK, low drug-drug interaction and no need for monitoring, the use of low-dose rivaroxaban in addition to dual antiplatelet therapy offers an appealing new option in improving outcomes following ACS in the modern era of novel oral FXa inhibitors.

Topics: Acute Coronary Syndrome; Administration, Oral; Blood Coagulation Tests; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Evaluation, Preclinical; Drug Interactions; Factor Xa; Factor Xa Inhibitors; Half-Life; Humans; Morpholines; Myocardial Infarction; Pulmonary Embolism; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Thrombin; Thrombosis

The oral direct factor Xa inhibitors include rivaroxaban and apixaban that recently have been evaluated comprehensively in multiple randomized clinical trials. Based on the efficacy and safety data from these trials, these novel anticoagulants are disseminating throughout clinical practice for thromboprophylaxis in major lower-extremity joint replacement, acute medical illness, atrial fibrillation, and acute coronary syndromes. The advantages of the xabans over vitamin K antagonists include no requirement for routine anticoagulation monitoring as well as a fast and reliable onset of action. The first perioperative limitation of the xabans is the lack of a routine coagulation test for monitoring their anticoagulant effect in scenarios, such as the timing of surgical procedures, the reversal of xaban-related bleeding, and the conduct of regional anesthesia. A second perioperative limitation is the lack of fully validated clinical reversal agents although prothrombin complex concentrate, recombinant factor VIIa, and factor X concentrate are options for xaban reversal in life-threatening bleeding scenarios. Given their clinical efficacy and advantages, further xabans are in clinical development, with edoxaban already in phase III clinical trials. Although the xabans have ushered in a new paradigm for clinical anticoagulation, further clinical trials are indicated to refine their clinical indications even further, such as anticoagulation for patients with mechanical heart valves.

Topics: Acute Coronary Syndrome; Anesthesia, Conduction; Animals; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Humans; Morpholines; Perioperative Care; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Acute coronary syndromes (ACS) cause cessation of myocardial blood flow leading to coronary ischemia. The standard medical treatment includes heparin or low molecular weight heparin in the hospital, antiplatelet agents in the hospital and long term, and occasionally warfarin long term. All of these therapies are associated with bleeding complications. Furthermore, warfarin, with its narrow therapeutic window and need for frequent laboratory monitoring, poses several disadvantages. The development of novel oral factor Xa inhibitors and oral direct thrombin inhibitors may provide an alternative to warfarin. In this review, we discuss the new agents, rivaroxaban, apixaban, and dabigatran, for the potential treatment of ACS. We also review the relevant clinical trials evaluating their effects in ACS. These novel anticoagulants allow convenience of use with no requirement for laboratory monitoring and limited drug interactions, which may provide multifaceted treatment options for ACS and anticoagulation in the future.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Antithrombins; Aspirin; Benzimidazoles; beta-Alanine; Clopidogrel; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Heparin; Humans; Morpholines; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Ticlopidine; Warfarin

Emergency department (ED) clinicians are not typically involved in the long-term management of patients' anticoagulation therapy, but they are responsible for decision making for emergency conditions requiring anticoagulation, such as acute venous thromboembolism (VTE). In addition, emergency physicians are often faced with patients who present first to the ED with conditions that may prompt long-term anticoagulation upon hospital discharge, such as atrial fibrillation (AF), or who have acute or potential bleeding complications from anticoagulation.. In this review, clinical trials of new oral anticoagulants evaluated for treatment of VTE and stroke prophylaxis in AF, as well as practical management aspects, will be discussed. In addition, clinical trials evaluating the adjunctive use of the new oral anticoagulants with antiplatelet therapy in patients who have experienced acute coronary syndrome will be explored.. Both dabigatran etexilate and rivaroxaban have successfully completed phase III trials for acute VTE treatment and are currently approved for the reduction of risk of stroke and systemic embolism in patients with nonvalvular AF. In a recently completed phase III trial, apixaban also demonstrated promising efficacy and safety in that indication. Rivaroxaban represents the only new anticoagulant to date to have shown promising phase III results as an adjunct to antiplatelet therapy after acute coronary syndrome.. Knowledge of the appropriate clinical use and safety concerns of the new anticoagulants is imperative as they become more frequently prescribed, and their potential uses in the ED setting represent an important aspect of continuing education for emergency physicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Dabigatran; Emergency Service, Hospital; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

The occurrence of disabling stroke, the major fatal consequence of atrial fibrillation, can be reduced by almost two-thirds with warfarin oral anticoagulation. Recent estimates on the prevalence of atrial fibrillation in the USA suggest that approximately 3 million people suffer from this common cardiac arrhythmia, therefore, the socioeconomic impact of adequate oral anticoagulation is enormous. Rivaroxaban, a direct orally available factor Xa inhibitor, is the first of a new class of drugs that target a central factor of the coagulation cascade upstream of thrombin. In the ROCKET AF clinical trial, rivaroxaban demonstrated noninferiority compared with warfarin for stroke prevention in patients with atrial fibrillation, while intracranial and fatal bleeding occurred less frequently with rivaroxaban treatment. Rivaroxban has recently been approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation by the US FDA and EMA. Very recently, rivaroxaban in addition to dual antiplatelet therapy, was shown to reduce mortality in patients with a recent acute coronary syndrome in the ATLAS ACS 2-TIMI 51 clinical trial. The clinical evaluation of rivaroxaban in cardiovascular disease and the results of the ROCKET AF study, the landmark clinical trial of rivaroxaban for stroke prevention, are discussed along with the unique pharmacological profile of rivaroxaban.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Drug Approval; Factor Xa Inhibitors; Humans; Morpholines; Rivaroxaban; Secondary Prevention; Stroke; Thiophenes; Warfarin

Orally active direct inhibitors of thrombin and factor Xa have now been approved for treatment or prevention of deep vein thrombosis,and stroke associated with atrial fibrillation. The factor Xa inhibitor, rivaroxaban, has shown promising results in the treatment of acute coronary syndrome but is not yet approved for that indication. These agents share a rapid onset and are cleared with half lives of approximately 10 hours. At present there is no approved antidote for either class of anticoagulant, making the treatment of life-threatening bleeding episodes problematic. These agents have fewer drug interactions than warfarin, have a predictable clearance, and hence do not require monitoring. Patients with renal insufficiency have delayed clearance and hence may have elevated levels of the drug leading to increased risk of bleeding.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Blood Coagulation; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Half-Life; Hemorrhage; Humans; Metabolic Clearance Rate; Morpholines; Rivaroxaban; Stroke; Thiophenes; Venous Thrombosis

New oral anticoagulants used as single target inhibitors of coagulation enzymes have been developed and tested in extensive trial programmes. Results of most of these trials showed non-inferior and/or superior efficacy and safety compared to standard treatment with LMWH or VKA. These results led to registration of these agents for the prophylaxis or treatment of thrombosis, as well as stroke prophylaxis in atrial fibrillation. In addition to good efficacy and safety these agents are more convenient in their use and promise advantages in quality of life. Caution is needed, though, since drug-interactions, interferences with coagulation tests and risk of accumulation in case of renal failure should always be taken into consideration when planning a treatment. In the present current-opinion review these advantages and disadvantages are discussed and expressed options are analysed.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Benzimidazoles; beta-Alanine; Dabigatran; Drug Interactions; Factor Xa Inhibitors; Humans; Morpholines; Prothrombin; Rivaroxaban; Stroke; Thiophenes; Thromboembolism

Patients with acute coronary syndrome (ACS) continue to be at risk for recurrent ischemic events, despite an early invasive strategy and the use of dual antiplatelet therapy. The anticoagulant pathway remains activated for a prolonged period after ACS and, consequently, has been a target for treatment. Early studies with warfarin indicated its benefit, but the risk of bleeding and the complexities of warfarin anticoagulation resulted in little use of this strategy. Rivaroxaban, apixaban, and dabigatran are new specific inhibitors of anticoagulant factors (Xa or IIa) currently available for the prevention of thrombosis and/or thromboembolism. Thus far, studies with dabigatran and apixaban in ACS have shown no clinical benefit and bleeding has been increased. The ATLAS ACS 2-TIMI 51 trial observed the impact of rivaroxaban 2.5 mg and 5 mg twice daily in patients with recent ACS receiving current management (both early invasive strategy and dual antiplatelet therapy with aspirin and clopidogrel) over a follow-up period of over 1 year. Rivaroxaban 2.5 mg twice daily reduced cardiovascular death, myocardial infarction, or stroke by 16%, and both cardiovascular and all-cause mortality by approximately 20%. Although major bleeding increased from 0.6% to 2.1% and intracranial hemorrhage from 0.2% to 0.6%, there was no increase in fatal bleeding. The role of rivaroxaban in the management of ACS is discussed in this review. The reduction in mortality is the main finding that could lead to the use of rivaroxaban in the management of ACS in high-risk individuals with a low bleeding risk.

Topics: Acute Coronary Syndrome; Anticoagulants; Dose-Response Relationship, Drug; Hemorrhage; Humans; Intracranial Hemorrhages; Morpholines; Risk; Rivaroxaban; Thiophenes; Thromboembolism; Thrombosis; Warfarin

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cyclic N-Oxides; Fondaparinux; Hirudins; Humans; Morpholines; Peptide Fragments; Polysaccharides; Pyrazoles; Pyridines; Pyridones; Recombinant Proteins; Rivaroxaban; Thiophenes

The last decade has seen the evaluation of several new oral anticoagulants that directly target thrombin or activated factor X (FXa). All demonstrate a rapid onset of action, a low potential for food and drug interactions, and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. Those agents at the most advanced stages of clinical development are a direct thrombin inhibitor, dabigatran, and direct FXa inhibitors, rivaroxaban and apixaban. Dabigatran and rivaroxaban are approved in more than 70 countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and apixaban is being considered for approval by regulatory agencies for this indication. Dabigatran was shown in a large phase III trial to be more effective and safer than warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and has recently been approved for this indication. Edoxaban, an oral FXa inhibitor, is also being evaluated in phase III clinical trials. This review summarizes the pharmacology, clinical trial results, and future role of the new oral anticoagulants in clinical practice.

Topics: Acute Coronary Syndrome; Amidines; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Thromboembolism; Treatment Outcome; Vitamin K

A number of new oral anticoagulant drugs that selectively and directly inhibit factor Xa (FXa) appear as promising alternatives to the existing anticoagulant agents. These compounds present a convenient route of administration with predictable pharmacokinetics and pharmacodynamics that allow fixed dosing regimens without requiring coagulation monitoring. Rivaroxaban is the first of this new class of drugs that was approved for the prevention of venous thromboembolism (VTE) after elective total hip replacement or total knee replacement surgery in the EU, Canada and several other countries. Clinical trials with rivaroxaban in patients with acute VTE and in patients with atrial fibrillation have been recently completed. Numerous other compounds are under different developing stages (apixaban, edoxaban, otamixaban, LY517717, PRT-054021, YM150).. This review provides an overview of the two oral anti-FXa drugs at the most advanced stage of development (rivaroxaban and apixaban) and briefly describes and comments on the results of the most important studies.. Undoubtedly, these new drugs will offer several advantages over the previous compounds, but a number of issues still require some attention during the phase of translation from clinical trials into daily clinical practice.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Clinical Trials, Phase III as Topic; Drugs, Investigational; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes; Thrombosis; Venous Thromboembolism

Anticoagulation for the long-term treatment and prevention of thrombo-embolic diseases as well as for stroke prevention in atrial fibrillation (AF) has been accomplished by vitamin K antagonists for the last half century. Although effective under optimal conditions, the imminent risk of a recurrent event vs. the risk of bleeding due to the narrow therapeutic window, numerous food- and drug interactions, and the need for regular monitoring complicate the long-term use of these drugs and render treatment with these agents complicated. As a result, novel anticoagulants which selectively block key factors in the coagulation cascade are being developed. The efficacy and safety of the direct thrombin inhibitor dabigatran etexilate, as well as of the selective factor Xa inhibitors rivaroxaban and apixaban, have been demonstrated in Phase III trials for stroke prevention in AF and the treatment and secondary prophylaxis of venous thrombo-embolism. This review summarizes the results from recently published pivotal clinical trials and discusses the opportunities as well as uncertainties in the clinical applications of these novel agents.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Cost-Benefit Analysis; Dabigatran; Drug Approval; Factor X; Humans; Morpholines; Off-Label Use; Pyrazoles; Pyridines; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism

Rivaroxaban is the first orally bioavailable direct factor Xa inhibitor and its role in acute coronary syndrome is not fully understood. A significant residual risk of recurrent ischemia remains in patients with acute coronary syndrome despite optimal medical therapy. Warfarin has demonstrated modest benefit that is offset by the risk of bleeding and complexity in its management. Rivaroxaban may be an attractive agent for the treatment of acute coronary syndromes given its predictable pharmacodynamics and favorable safety profile.. The current guideline-based antithrombotic and adjunctive medical therapies in acute coronary syndrome are summarized in this review. Rivaroxaban's drug profile, its current applications, ongoing trials and experience in patients with acute coronary syndrome are also described.. Current experience of rivaroxaban in acute coronary syndrome demonstrates its safety and a trend towards benefit when added to current optimal medical therapy. The benefits were observed primarily in patients receiving aspirin monotherapy and increased bleeding among those receiving dual anti-platelet therapy. This suggests that there may be a narrow window between the optimal clinically achievable antithrombotic effect and the point where bleeding risk outweighs the benefits. Though promising, it remains to be seen if this drug will achieve the right balance between efficacy and bleeding risk.

Topics: Acute Coronary Syndrome; Administration, Oral; Animals; Anticoagulants; Biological Availability; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Practice Guidelines as Topic; Rivaroxaban; Thiophenes

The prevalence of obesity has increased substantially over recent years. Clinicians are increasingly being challenged with making uncertain anticoagulant dosing decisions, as the optimal dosing strategy for most anticoagulants in the obese patient population remains unknown. Research published to date suggests that the clearance of anticoagulants increases with weight. As obesity is associated with an increased risk of venous thromboembolism and arterial disease, there is an urgent need to establish appropriate anticoagulation regimens for this patient group. Research studies applying the method of pharmacokinetic-pharmacodynamic modelling and simulation could establish an appropriate evidence base and provide direction and reassurance to prescribing clinicians.

Topics: Acute Coronary Syndrome; Anticoagulants; Benzimidazoles; beta-Alanine; Clinical Trials as Topic; Dabigatran; Double-Blind Method; Factor Xa Inhibitors; Fondaparinux; Hemorrhage; Heparin; Humans; Morpholines; Multicenter Studies as Topic; Obesity; Polysaccharides; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Thrombin; Thrombophilia; Venous Thrombosis; Warfarin

As an alternative to the inconvenient and labor intensive traditional anticoagulants, Factor Xa inhibitors may offer new options for the prevention and treatment of acute coronary syndromes (ACS) and venous thromboembolism (VTE). Fondaparinux, an indirect FXa inhibitor, has equivalent efficacy but decreased bleeding risk. It has been recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) as the preferred anticoagulant in ACS patients with higher bleeding risk managed with a noninvasive strategy. Based on the composite results of several clinical trials, fondaparinux is also recommended for VTE prevention in the setting of major orthopedic surgery. Rivaroxaban, a direct FXa inhibitor, appears to have at least equal efficacy and safety to established anticoagulants in the prevention of VTE. With advantages such as oral administration and a wide therapeutic window, it may provide a useful alternative to current anticoagulants. Ongoing studies are exploring its use in treatment of VTE and ACS, as well as prevention of stroke among patients with atrial fibrillation. In this review, we examine the key recent studies on efficacy and safety of FXa inhibitors in ACS and VTE management.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Factor Xa Inhibitors; Fondaparinux; Humans; Morpholines; Polysaccharides; Rivaroxaban; Thiophenes; Venous Thromboembolism

Important clinical data with a significant impact on the clinical management of venous thromboembolism (VTE) were presented at The International Society of Thrombosis and Haemostasis (ISTH) meeting, held in Geneva, Switzerland in July of 2007. In addition, 2 new guidelines for the management of patients with acute coronary syndromes (ACS) were published in 2007, and will have a significant impact on daily practice. Finally, the approval of new practice-changing, paradigm-shifting oral anticoagulants is on the horizon. This article will review the top 4 advances in antithrombotic care and discuss their impact on the clinical management of VTE.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Humans; Morpholines; Practice Guidelines as Topic; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Venous Thromboembolism

Indirect systemic and direct oral factor Xa and direct oral factor IIa inhibitors with improved pharmacologic profiles compared with heparins and vitamin K antagonists are currently in clinical development. This overview focuses on the indirect antithrombin dependent pentasaccharide derivatives of idraparinux and on the most advanced oral direct inhibitors to factor Xa (rivaroxaban and apixaban) and IIa (dabigatran). Specifically, the results of dose-finding studies for the prevention of venous thromboembolism after elective orthopedic surgery, the results of dose-finding studies for treatment of acute venous thromboembolism including prolonged prophylaxis of recurrent events, and the designs of ongoing clinical trials are reviewed.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Azetidines; Benzimidazoles; Benzylamines; Clinical Trials as Topic; Dabigatran; Factor Xa Inhibitors; Glycine; Humans; Infusions, Parenteral; Morpholines; Oligosaccharides; Piperazines; Prothrombin; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Thrombin; Thrombosis; Venous Thromboembolism

Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. A broad search of Medline, clinicaltrials.gov and the annual proceedings of the American Society of Hematology and the International Society on Thrombosis and Hemostasis was conducted. This review addresses the findings of this systematic search, including the need for new oral anticoagulants, the development and pharmacology of rivaroxaban, and the results of completed as well as ongoing trials with rivaroxaban. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The drug may have its greatest impact in providing a much-needed and attractive alternative to warfarin. Further data (especially large Phase III trials) are required.

Topics: Acute Coronary Syndrome; Administration, Oral; Aged; Aged, 80 and over; Animals; Anticoagulants; Atrial Fibrillation; Binding Sites; Clinical Trials as Topic; Comorbidity; Drug Evaluation, Preclinical; Factor Xa; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Morpholines; Postoperative Complications; Rats; Rivaroxaban; Stroke; Thiophenes; Thrombosis; Warfarin

Parenteral enoxaparin is a preferred anticoagulant used in the acute phase for patients with acute coronary syndrome (ACS). The safety and efficacy of short-term low-dose rivaroxaban in this clinical setting remain unknown.. To compare the safety and efficacy of rivaroxaban vs enoxaparin in the acute phase of ACS.. This multicenter, prospective, open-label, active-controlled, equivalence and noninferiority trial was conducted from January 2017 through May 2021 with a 6-month follow-up at 21 hospitals in China. Participants included patients with ACS missing the primary reperfusion window or before selective revascularization. Data were analyzed from November 2021 to November 2022.. Participants were randomized 1:1:1 to oral rivaroxaban 2.5 mg or 5 mg or 1 mg/kg subcutaneous enoxaparin twice daily in addition to dual antiplatelet therapy (DAPT; aspirin 100 mg and clopidogrel 75 mg once daily) for a mean of 3.7 days.. The primary safety end point was bleeding events, as defined by the International Society on Thrombosis and Haemostasis, and the primary efficacy end point was major adverse cardiovascular events (MACEs), including cardiac death, myocardial infarction, rerevascularization, or stroke during the 6-month follow-up.. Of 2055 enrolled patients, 2046 (99.6%) completed the trial (mean [SD] age 65.8 [8.2] years, 1443 [70.5%] male) and were randomized to enoxaparin (680 patients), rivaroxaban 2.5 mg (683 patients), or rivaroxaban 5 mg (683 patients). Bleeding rates were 46 patients (6.8%) in the enoxaparin group, 32 patients (4.7%) in the rivaroxaban 2.5 mg group, and 36 patients (5.3%)in the rivaroxaban 5 mg group (rivaroxaban 2.5 mg vs enoxaparin: noninferiority hazard ratio [HR], 0.68; 95% CI, 0.43 to 1.07; P = .005; rivaroxaban 5 mg vs enoxaparin: noninferiority HR, 0.88; 95% CI, 0.70 to 1.09; P = .001). The incidence of MACEs was similar among groups, and noninferiority was reached in the rivaroxaban 5 mg group (HR, 0.60; 95% CI, 0.31 to 1.16, P = .02) but not in the rivaroxaban 2.5 mg group (HR, 0.68; 95% CI, 0.36 to 1.30; P = .05) compared with the enoxaparin group.. In this equivalence and noninferiority trial, oral rivaroxaban 5 mg showed noninferiority to subcutaneous enoxaparin (1 mg/kg) for patients with ACS treated with DAPT during the acute phase. Results of this feasibility study provide useful information for designing future randomized clinical trials with sufficient sample sizes.. ClinicalTrials.gov Identifier: NCT03363035.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Enoxaparin; Female; Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Prospective Studies; Rivaroxaban

The optimal anti-thrombotic therapy to prevent recurrent ischemic events in patients with acute coronary syndrome and coronary artery ectasia (CAE) remains unclear.. To assess the efficacy and safety of antiplatelet plus anticoagulant therapy versus dual antiplatelet therapy in patients with acute coronary syndromes and coronary artery ectasia.. OVER-TIME is an investigator initiated, exploratory, open label, single center, randomized clinical trial comparing dual antiplatelet therapy (acetyl-salicylic acid plus a P2Y12 inhibitor) with the combination of an antiplatelet monotherapy (a P2Y12 inhibitor) plus a low dose anticoagulant (rivaroxaban, 15mg oral dose) for the prevention of recurrent ischemic events among patients with CAE. We aim to enroll approximately 60 patients with CAE and acute coronary syndromes. After recruitment, patients are randomized to (a) standard of care (dual antiplatelet regimen) or (b) the combination of antiplatelet monotherapy and low dose anticoagulant. Patients will be followed for at least 12 months. The OVER-TIME study aims to assess the efficacy of the regimen in prevention of major cardiovascular events and its security in bleeding events in acute coronary syndromes among patients with CAE. Expected results and conclusions: OVER-TIME is the first randomized controlled trial to assess different antithrombotic strategies in patients with CAE and acute coronary syndrome, and its results will offer preliminary data for the prevention of major cardiovascular events and bleeding events in this group of patients.. NCT05233124 (ClinicalTrials.gov), date of registration: February 10, 2022.

Topics: Acute Coronary Syndrome; Anticoagulants; Coronary Vessels; Dilatation, Pathologic; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Rivaroxaban; Salicylic Acid; Treatment Outcome

Acute coronary syndrome (ACS) is a serious and life-threatening condition. Anticoagulation during the acute phase of ACS is effective in reducing ischemic events. The most widely used parenteral anticoagulation agent in ACS patients is enoxaparin. Rivaroxaban is a novel oral anticoagulant with potent anti-Xa activity, which might be an attractive alternative drug to enoxaparin. In fact, rivaroxaban was consistently shown to be non-inferior to enoxaparin therapy in terms of reduction of recurrent venous thromboembolism events.. This prospective, randomized, open-label, active-controlled, multicenter study is designed to compare the safety and efficacy of rivaroxaban versus enoxaparin in patients with ACS, who missed the primary reperfusion therapy window and before selective revascularization.. Up to 2055 participants receiving background treatment of aspirin plus clopidogrel or ticagrelor will be randomly assigned to either oral rivaroxaban 2.5 mg twice daily or rivaroxaban 5 mg twice daily or subcutaneous enoxaparin 1 mg/kg twice daily until hospital discharge for a maximum of 8 days or 12 h before revascularization therapy. The primary safety endpoint is the International Society on Thrombosis and Hemostasis definition of bleeding events [minor, clinically relevant non-major and major bleeding]. The primary efficacy endpoint is a composite of major adverse cardiac events (MACE), including cardiac death, myocardial infarction, re-revascularization or stroke, and major bleeding events. Secondary endpoints include cardiac-related rehospitalization and all-cause death. Patients will be followed for 12 months after randomization.. The H-REPLACE trial offers an opportunity to assess clinical outcomes of rivaroxaban versus enoxaparin during the acute phase of ACS and may provide an alternative anticoagulation strategy for ACS patients, who missed the primary reperfusion therapy window and before selective revascularization.. ClinicalTrials.gov; NCT03363035.

Topics: Acute Coronary Syndrome; Anticoagulants; Asian People; Dose-Response Relationship, Drug; Enoxaparin; Hemorrhage; Hospitalization; Humans; Platelet Aggregation Inhibitors; Prospective Studies; Rivaroxaban

Impaired endogenous fibrinolysis is novel biomarker that can identify patients with ACS at increased cardiovascular risk. The addition of Very Low Dose Rivaroxaban (VLDR) to dual antiplatelet therapy has been shown to reduce cardiovascular events but at a cost of increased bleeding and is therefore not suitable for all-comers. Targeted additional pharmacotherapy with VLDR to improve endogenous fibrinolysis may improve outcomes in high-risk patients, whilst avoiding unnecessary bleeding in low-risk individuals. The VaLiDate-R study (ClinicalTrials.gov Identifier: NCT03775746, EudraCT: 2018-003299-11) is an investigator-initiated, randomised, open-label, single centre trial comparing the effect of 3 antithrombotic regimens on endogenous fibrinolysis in 150 patients with ACS. Subjects whose screening blood test shows impaired fibrinolytic status (lysis time > 2000s), will be randomised to one of 3 treatment arms in a 1:1:1 ratio: clopidogrel 75 mg daily (Group 1); clopidogrel 75 mg daily plus rivaroxaban 2.5 mg twice daily (Group 2); ticagrelor 90 mg twice daily (Group 3), in addition to aspirin 75 mg daily. Rivaroxaban will be given for 30 days. Fibrinolytic status will be assessed during admission and at 2, 4 and 8 weeks. The primary outcome measure is the change in fibrinolysis time from admission to 4 weeks follow-up, using the Global Thrombosis Test. If VLDR can improve endogenous fibrinolysis in ACS, future large-scale studies would be required to assess whether targeted use of VLDR in patients with ACS and impaired fibrinolysis can translate into improved clinical outcomes, with reduction in major adverse cardiovascular events in this high-risk cohort.

Topics: Acute Coronary Syndrome; Clopidogrel; Dose-Response Relationship, Drug; Dual Anti-Platelet Therapy; Factor Xa Inhibitors; Female; Fibrinolysis; Humans; Male; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombelastography; Thrombosis; Ticagrelor

Despite dual antiplatelet therapy, persistent thrombin generation and thrombin-mediated platelet activation account in part for the residual risk of atherothrombotic disease among patients with prior acute coronary syndrome (ACS). Inhibition of thrombin generation among high-risk ACS patients (biomarker-positive ACS) with the factor Xa inhibitor rivaroxaban may limit ongoing thrombus formation and myocardial necrosis and thereby improve clinical outcomes.. ATLAS ACS 2-TIMI 51 was a double-blind, placebo-controlled clinical trial that randomized ACS patients to either rivaroxaban 2.5 mg b.i.d., rivaroxaban 5 mg b.i.d., or placebo plus standard-of-care antiplatelet therapy for a mean of 13.1 months and up to 31 months ( N=15,526). This post-hoc analysis evaluates the safety and efficacy of rivaroxaban among biomarker-positive ACS patients with and without a history of prior stroke of transient ischemic attack in the ATLAS ACS 2-TIMI 51 trial.. A total of 12,626 biomarker-positive ACS patients were included in this analysis. Among biomarker-positive patients without a prior history of stroke or transient ischemic attack, rivaroxaban 2.5 b.i.d. was associated with a reduction in the primary efficacy endpoint (composite of cardiovascular death, myocardial infarction, or stroke) as compared with placebo (hazard ratio=0.80, 95% confidence interval (0.68-0.94), p=0.007) at the expense of an increase in non-coronary-artery-bypass-graft-related Thrombolysis in Myocardial Infarction major bleeding (1.9% vs. 0.7%, p<0.0001), but not a significant increase in either intracranial hemorrhage (0.4% vs. 0.2%, p=0.11) or fatal bleeding (0.1% vs. 0.3%, p=0.16).. Rivaroxaban 2.5 mg b.i.d. was associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, or stroke with no increase in fatal bleeding. Biomarker-positive patients with no prior history of stroke or transient ischemic attack may be a optimal target population to receive "dual pathway" therapy with rivaroxaban plus dual antiplatelet therapy for secondary prevention following ACS.

Topics: Acute Coronary Syndrome; Administration, Oral; Biomarkers; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Follow-Up Studies; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Thrombolytic Therapy; Thrombosis; Time Factors; Treatment Outcome; Troponin

Physician behavior in response to knowledge of a patient's CYP2C19 clopidogrel metabolizer status is unknown.. To investigate the association of mandatory reporting of CYP2C19 pharmacogenomic testing, provided to investigators with no direct recommendations on how to use these results, with changes in P2Y12 inhibitor use, particularly clopidogrel, in the Randomized Trial to Compare the Safety of Rivaroxaban vs Aspirin in Addition to Either Clopidogrel or Ticagrelor in Acute Coronary Syndrome (GEMINI-ACS-1) clinical trial.. The GEMINI-ACS-1 trial compared rivaroxaban, 2.5 mg twice daily, with aspirin, 100 mg daily, plus open-label clopidogrel or ticagrelor (provided), in patients with recent acute coronary syndromes (ACS). The trial included 371 clinical centers in 21 countries and 3037 patients with ACS. Data were analyzed between May 2017 and February 2019.. Investigators were required to prestipulate their planned response to CYP2C19 metabolizer status. In response to a regulatory mandate, results for all patients were reported to investigators approximately 1 week after randomization.. Reasons for switching P2Y12 inhibitors and occurrence of bleeding and ischemic events were collected.. Of 3037 patients enrolled (mean [SD] age, 62.8 [9.0] years; 2275 men [74.9%], and 2824 white race/ethnicity [93.0%]), investigators initially treated 1704 (56.1%) with ticagrelor and 1333 (43.9%) with clopidogrel. Investigators prestipulated that they would use CYP2C19 metabolizer status to change P2Y12 inhibitor in 48.5% of genotyped clopidogrel-treated patients (n = 642 of 1324) and 5.5% of genotyped ticagrelor-treated patients (n = 93 of 1692). P2Y12 inhibitor switching for any reason occurred in 197 patients and was more common in patients treated with ticagrelor (146 of 1704 [8.6%]) compared with clopidogrel (51 of 1333 [3.8%]). Of patients initially treated with ticagrelor, only 1 (0.1% overall; 0.7% of all who switched) was switched based on CYP2C19 status. Of patients initially treated with clopidogrel, 23 (1.7% overall,;45.1% of all who switched) were switched owing to metabolizer status. Of 48 patients (3.6%) with reduced metabolizer status treated initially with clopidogrel, 15 (31.3%) were switched based on metabolizer status, including 48.1% (13 of 27) in which switching was prestipulated.. Physicians were evenly split on how to respond to knowledge of CYP2C19 metabolizer status in clopidogrel-treated patients. Mandatory provision of this information rarely prompted P2Y12 inhibitor switching overall, including a minority of patients with reduced metabolizer status. These findings highlight the clinical equipoise among physicians regarding use of this information and the reluctance to use information from routine genotyping in the absence of definitive clinical trial data demonstrating the efficacy of this approach.. ClinicalTrials.gov identifier: NCT02293395.

Topics: Acute Coronary Syndrome; Aspirin; Clopidogrel; Cytochrome P-450 CYP2C19; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Hemorrhage; Humans; Ischemia; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Rivaroxaban; Ticagrelor

Topics: Acute Coronary Syndrome; Factor Xa Inhibitors; Humans; Rivaroxaban; Stroke; Treatment Outcome

Net clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact.. A comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact.. In the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding.. Rivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: -11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking 2.5 mg orally twice per day.. Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965).

Topics: Acute Coronary Syndrome; Factor Xa Inhibitors; Hemorrhage; Humans; Risk Assessment; Rivaroxaban; Secondary Prevention

D-dimer has been used as both a diagnostic and prognostic biomarker in the assessment of patients with venous thromboembolism, but its prognostic value in the setting of arterial acute coronary syndromes (ACS) and the ability of pharmacotherapy to reduce D-dimer in ACS is less well characterized. It was hypothesized that elevated baseline D-dimer would be associated with poor clinical outcomes in ACS, and that Factor Xa inhibition with Rivaroxaban would reduce D-dimer acutely and chronically. The ATLAS ACS TIMI-46 trial assessed the safety and efficacy of rivaroxaban compared with placebo in ACS patients. A subset of subjects had a D-dimer measured at baseline (n = 1,834, 52.5%). A univariate and multivariable logistic regression assessed the relation between baseline D-dimer and a composite end point of cardiovascular death, myocardial infarction, or stroke through 6 months. The Wilcoxon rank sum test was used to compare change in D-dimer level between the treatment groups from baseline. Baseline D-dimer was associated with the composite efficacy outcome in a univariate logistic regression (odds ratio 1.15, 95% confidence interval 1.03 to 1.29, p = 0.015) and a multivariable logistic regression (odds ratio 1.13, 95% confidence interval 1.00 to 1.28, p = 0.048). Rivaroxaban administration lowered D-dimer levels compared wth placebo after administration of the first dose of study drug (p = 0.026), at day 30 (p < 0.001) and day 180 (p < 0.001). In conclusion, elevated baseline D-dimer was associated with an increased risk of the composite outcome within 6 months of the ACS event and administration of the Factor Xa inhibitor rivaroxaban was associated with lower D-dimer levels compared with placebo after the first dose, at day 30 and day 180.

Topics: Acute Coronary Syndrome; Biomarkers; Factor Xa Inhibitors; Female; Fibrin Fibrinogen Degradation Products; Humans; Male; Middle Aged; Myocardial Infarction; Risk; Rivaroxaban; Stroke

Patients with both acute coronary syndromes (ACS) and congestive heart failure are at an increased risk of recurrent cardiovascular (CV) events attributed in part to both excess thrombin generation and impaired fibrinolysis. We hypothesized that patients with the overlap of ACS and CHF would thus derive particular benefit from antithrombotic therapy with rivaroxaban. ATLAS-ACS-2 Thrombolysis in Myocardial Infarction-51 was a double-blind, multicenter, phase 3 clinical trial that randomized patients within 7 days of an ACS event to standard of care plus either rivaroxaban 2.5 mg BID, 5 mg BID, or placebo (n = 15,526). In this post hoc subgroup analysis, subjects with a history of CHF at randomization (n = 1,694) were evaluated. Among subjects with a history of CHF, both rivaroxaban doses reduced the primary composite end point of CV death, myocardial infarction, or stroke (2.5 mg BID vs placebo: hazard ratio [HR] 0.59, 95% confidence interval [CI] (0.42, 0.81), p = 0.001; 5 mg BID vs placebo: HR 0.61, 95% CI (0.44, 0.84), p = 0.002; p interaction = 0.006). Both doses of rivaroxaban reduced CV mortality (rivaroxaban 2.5 mg BID vs placebo: 4.1% vs 9.0%, HR 0.45, 95% CI [0.27, 0.74], p = 0.002; rivaroxaban 5 mg BID vs placebo: 5.8% vs 9.0%, HR 0.62, 95% CI [0.40, 0.96], p = 0.031) as well as all-cause mortality. There was no significant increase in noncoronary artery bypass graft-related Thrombolysis in Myocardial Infarction major bleeding with either dose of rivaroxaban as compared with placebo (rivaroxaban 2.5 mg BID = 0.4% vs rivaroxaban 5 mg BID = 1.1% vs placebo = 0.5%). Rivaroxaban also did not increase either intracranial hemorrhage or fatal bleeding. In conclusion, in ACS subjects with a history of CHF, secondary prevention with rivaroxaban reduced the composite of CV death, myocardial infarction, or stroke without an increase in noncoronary artery bypass graft-related major bleeding. These findings require further prospective evaluation in an adequately powered phase 3 study.

Topics: Acute Coronary Syndrome; Cause of Death; Dose-Response Relationship, Drug; Double-Blind Method; Factor Xa Inhibitors; Female; Follow-Up Studies; Heart Failure; Humans; Incidence; Male; Middle Aged; Prospective Studies; Rivaroxaban; Secondary Prevention; Thrombolytic Therapy; Treatment Outcome; United States

Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months.. In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395.. Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840).. A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach.. Janssen Research & Development and Bayer AG.

Topics: Acute Coronary Syndrome; Adenosine; Aged; Aspirin; Clopidogrel; Coronary Angiography; Double-Blind Method; Drug Therapy, Combination; Electrocardiography; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Rivaroxaban; Thrombolytic Therapy; Ticagrelor; Ticlopidine; Treatment Outcome

The GEMINI-ACS-1 trial has recently been published. It was designed to test whether low dose rivaroxaban as an antithrombotic agent is as safe as aspirin in patients with acute coronary syndromes (ACS). The trial is important to set light to future of ACS management.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Humans; Rivaroxaban; Thrombosis

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

Dual antiplatelet therapy (DAPT), the combination of aspirin and a P2Y12 inhibitor, given for 12 months remains the standard of care after presentation with acute coronary syndrome (ACS) because it has been shown to be associated with a significant reduction in ischemic events compared with aspirin monotherapy. The factor Xa inhibitor rivaroxaban was shown to be associated with a significant reduction in the composite of cardiovascular death, myocardial infarction, and stroke, and resulted in a nominal reduction in cardiovascular death, when added to background DAPT in the ATLAS ACS 2-TIMI 51 trial; however, there was excessive bleeding with this "triple-therapy" approach. The combination of rivaroxaban with P2Y12 inhibition in a "dual-pathway" approach may be an effective therapeutic regimen for the treatment of ACS, given the known importance of P2Y12 inhibition after stenting and intriguing data that the combination of an anticoagulant with clopidogrel after stenting in patients with atrial fibrillation appears an attractive option to this patient population. GEMINI-ACS-1 is a prospective, randomized, double-dummy, double-blind, active-controlled trial that will assess the safety of dual antithrombotic therapy (rivaroxaban [2.5 mg twice daily] + P2Y12 inhibitor) as compared with DAPT (aspirin [100 mg] + P2Y12 inhibitor) within 10 days of an ACS event in 3,000 patients. Patients will be randomized in a 1:1 ratio stratified by intended P2Y12 inhibitor use (clopidogrel 75 mg daily or ticagrelor 90 mg twice daily), with 1500 patients expected in each P2Y12 inhibitor strata. The primary end point is Thrombolysis in Myocardial Infarction clinically significant bleeding (major, minor, or requiring medical attention). The exploratory efficacy determination will be a composite of cardiovascular death, myocardial infarction, ischemic stroke, and stent thrombosis. GEMINI-ACS-1 will assess the safety and feasibility of dual antithrombotic therapy with rivaroxaban and a P2Y12 inhibitor compared with conventional DAPT for the treatment for patients with recent ACS.

Topics: Acute Coronary Syndrome; Adenosine; Adolescent; Adult; Aspirin; Clopidogrel; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Rivaroxaban; Ticagrelor; Ticlopidine; Treatment Outcome; Young Adult

Rivaroxaban reduces cardiovascular death, myocardial infarction (MI), or stroke in patients following acute coronary syndrome (ACS). We aimed to characterize the specific effects of rivaroxaban on the size and type of MI.. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) study randomized 15,526 patients with a recent ACS to rivaroxaban 2.5 mg BID, rivaroxaban 5 mg BID, or placebo. An independent clinical events committee adjudicated each MI that occurred during the study and further classified them based on type. Data are presented as two-year Kaplan-Meier event rates and hazard ratios (HRs) and 95% confidence intervals (CI).. In total, 665 patients experienced a post-randomization MI. The majority (n=535, 80.5%) were spontaneous (Type 1) events. Rivaroxaban reduced spontaneous MI when compared with placebo (4.4% vs 5.7%, HR 0.80, 95% 0.67-0.95, p=0.01), and there were directionally consistent reductions with both the 2.5 mg BID (4.7% vs 5.7%, HR 0.84, 95% 0.68-1.02, p=0.08) and 5 mg BID doses (4.1% vs 5.7%, HR 0.77, 95% 0.62-0.94, p=0.01) as compared with placebo. Rivaroxaban reduced MI with large elevations in troponin or creatine kinase-MB (CK-MB) fraction (1.8% vs 2.4%, HR 0.73, 95% CI 0.56-0.96, p=0.03) and STEMI events (1.7% vs 2.5%, HR 0.74, 95% CI 0.56-0.99, p=0.04).. In patients stabilized and followed after ACS, the majority of MIs that occur are spontaneous and rivaroxaban significantly reduced the incidence of these events. Notably, rivaroxaban reduced MIs with extensive biomarker release and ST-segment elevation.

Topics: Acute Coronary Syndrome; Biomarkers; Creatine Kinase, MB Form; Drug Administration Schedule; Factor Xa Inhibitors; Humans; Middle Aged; Myocardial Infarction; Rivaroxaban; Secondary Prevention; Thrombolytic Therapy; Treatment Outcome; Troponin

Atherogenesis is a complex inflammatory process stemming from the accumulation and oxidation of low density lipoproteins (LDL). IgM autoantibodies against phosphorylcholine (anti-PC) bind to the PC epitope on oxidized LDL (OxLDL), inhibiting the uptake of oxLDL by macrophages in atherosclerotic lesions. Anti-PC autoantibodies have been reported to be protective against atherothrombosis. We investigated the relationship of anti-PC concentrations with cardiovascular outcomes in patients with acute coronary syndromes (ACS). We measured anti-PC levels within 7 days of an ACS in 3,356 patients enrolled in the ATLAS ACS-TIMI 46 trial, a randomized dose ranging study of rivaroxaban versus placebo. The primary endpoint was death, myocardial infarction (MI), stroke, or severe recurrent ischemia (SRI) requiring revascularization during 6 months. The median baseline anti-PC concentration was 40.9 U/mL (25th, 75th percentiles: 25.4, 67.4). There was no significant association between anti-PC levels and the primary endpoint (Q1: 6.8 %, Q2: 4.2 %, Q3: 7.8 %, Q4: 5.4 %, p-trend = 0.87), all-cause mortality (Q1: 1.4 %, Q2: 0.7 %, Q3: 2.4 %, Q4: 0.9 %, p-trend = 0. 96), or any of the other individual endpoint components (MI: p-trend = 0.87, Stroke: p-trend = 0.43, SRI: p-trend = 0.66). Using the previously reported anti-PC cutpoint of 17 U/mL did not reveal a significant relationship between anti-PC concentrations and cardiovascular outcomes (<17 U/mL: 8.1 % vs. ≥17 U/mL: 5.8 %; p = 0.11). Similarly, evaluation of anti-PC as a continuous variable did not reveal a significant association (p = 0.30). In this study of patients early after ACS undergoing intensive secondary preventive therapy, IgM anti-PC titers did not exhibit a significant relationship with cardiovascular outcomes.

Topics: Acute Coronary Syndrome; Aged; Antibodies, Antiphospholipid; Factor Xa Inhibitors; Female; Humans; Immunoglobulin M; Male; Middle Aged; Morpholines; Myocardial Infarction; Phosphorylcholine; Rivaroxaban; Stroke; Thiophenes

The present analysis reports on the pre-specified subgroup of ST-elevation myocardial infarction (STEMI) patients, in whom anticoagulant therapy has been of particular interest.. In ATLAS ACS-2-TIMI-51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51), rivaroxaban reduced cardiovascular events across the spectrum of acute coronary syndrome (ACS).. Seven thousand eight hundred seventeen patients in ATLAS ACS-2-TIMI 51 presented with a STEMI. After being stabilized (1 to 7 days), they underwent randomization to twice daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Data are presented as 2-year Kaplan-Meier rates, and for intention-to-treat (ITT) and modified ITT (mITT) analyses.. Among STEMI patients, rivaroxaban reduced the primary efficacy endpoint of cardiovascular death, myocardial infarction, or stroke, compared with placebo (ITT: 8.4% vs. 10.6%, hazards ratio [HR]: 0.81, 95% confidence interval [CI]: 0.67 to 0.97, p = 0.019; mITT: 8.3% vs. 9.7%, HR: 0.85, 95% CI: 0.70 to 1.03, p = 0.09). This reduction emerged by 30 days (ITT and mITT: 1.7% vs. 2.3%, p = 0.042) and was evident in analyses that included events while patients received background dual antiplatelet therapies (ITT: 7.9% vs. 11.9%, p = 0.010; mITT: 7.7% vs. 10.1%, p = 0.061). In terms of the individual doses, rivaroxaban 2.5 mg reduced cardiovascular death (ITT: 2.5% vs. 4.2%, p = 0.006; mITT: 2.2% vs. 3.9%, p = 0.006), which was not seen with 5 mg of rivaroxaban. Rivaroxaban versus placebo increased non-coronary artery bypass grafting Thrombolysis In Myocardial Infarction major bleeding (2.2% vs. 0.6%, p < 0.001) and intracranial hemorrhage (0.6% vs. 0.1%, p = 0.015) without a significant increase in fatal bleeding (0.2% vs. 0.1%, p = 0.51).. In patients with a recent STEMI, rivaroxaban reduced cardiovascular events. This benefit emerged early and persisted during continued treatment with background antiplatelet therapies. Rivaroxaban compared with placebo increased the rate of major bleeding, but there was no significant increase in fatal bleeding. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Morpholines; Myocardial Infarction; Prospective Studies; Rivaroxaban; Thiophenes; Thrombolytic Therapy; Treatment Outcome

The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial.. Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis.. The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months.. Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014).. Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Topics: Acute Coronary Syndrome; Aged; Aspirin; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Morpholines; Platelet Aggregation Inhibitors; Pyridines; Rivaroxaban; Stents; Thiophenes; Thrombosis; Treatment Outcome

The dosing of anticoagulants is critical when balancing efficacy and safety. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Aspirin With/Without Thienopyridine Therapy in Subjects With Acute Coronary Syndrome 2-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2-TIMI 51) trial was designed to evaluate 2 low doses of rivaroxaban compared with placebo in patients with recent acute coronary syndromes being treated with antiplatelet therapies. Because the 2 doses significantly reduced the primary efficacy end point, a further comparison of the 2 treatment strategies was deemed important. In total, 15,526 patients were randomized to twice-daily rivaroxaban 2.5 mg, rivaroxaban 5 mg, or placebo. Comparing the 2 active doses, there were no significant differences between 2.5 and 5 mg for the primary efficacy end point of cardiovascular death, myocardial infarction, or stroke (9.1% vs 8.8%, p = 0.89), myocardial infarction (6.1% vs 4.9%, p = 0.23), or stent thrombosis (2.2% vs 2.3%, p = 0.59). However, there was a divergence in cardiovascular death, which included ischemic and hemorrhagic events, with the 2.5-mg dose resulting in lower rates than the 5-mg dose (2.7% vs 4.0%, p = 0.009). Notably, with 2.5 versus 5 mg, there were fewer study drug discontinuations (p = 0.004) and fewer non-coronary artery bypass grafting TIMI major or minor bleeds (p = 0.021) and fatal bleeds (p = 0.044). Of the patients who died, 8 in the 2.5-mg group and 20 in the 5-mg group experienced non-coronary artery bypass grafting TIMI major or minor bleeding events before death. In conclusion, the 2 doses of rivaroxaban reduced cardiovascular events in patients with recent acute coronary syndromes treated with antiplatelet therapies; however, the 2.5-mg dose was associated with lower mortality and fewer bleeding complications than the 5-mg dose. Thus, the addition of rivaroxaban 2.5 mg twice daily offers a more favorable balance of efficacy and safety in patients with recent acute coronary syndromes.

Topics: Acute Coronary Syndrome; Adult; Aged; Anticoagulants; Dose-Response Relationship, Drug; Endpoint Determination; Female; Humans; Male; Middle Aged; Morpholines; Rivaroxaban; Thiophenes; Treatment Outcome

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

Acute coronary syndromes arise from coronary atherosclerosis with superimposed thrombosis. Since factor Xa plays a central role in thrombosis, the inhibition of factor Xa with low-dose rivaroxaban might improve cardiovascular outcomes in patients with a recent acute coronary syndrome.. In this double-blind, placebo-controlled trial, we randomly assigned 15,526 patients with a recent acute coronary syndrome to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. The primary efficacy end point was a composite of death from cardiovascular causes, myocardial infarction, or stroke.. Rivaroxaban significantly reduced the primary efficacy end point, as compared with placebo, with respective rates of 8.9% and 10.7% (hazard ratio in the rivaroxaban group, 0.84; 95% confidence interval [CI], 0.74 to 0.96; P=0.008), with significant improvement for both the twice-daily 2.5-mg dose (9.1% vs. 10.7%, P=0.02) and the twice-daily 5-mg dose (8.8% vs. 10.7%, P=0.03). The twice-daily 2.5-mg dose of rivaroxaban reduced the rates of death from cardiovascular causes (2.7% vs. 4.1%, P=0.002) and from any cause (2.9% vs. 4.5%, P=0.002), a survival benefit that was not seen with the twice-daily 5-mg dose. As compared with placebo, rivaroxaban increased the rates of major bleeding not related to coronary-artery bypass grafting (2.1% vs. 0.6%, P<0.001) and intracranial hemorrhage (0.6% vs. 0.2%, P=0.009), without a significant increase in fatal bleeding (0.3% vs. 0.2%, P=0.66) or other adverse events. The twice-daily 2.5-mg dose resulted in fewer fatal bleeding events than the twice-daily 5-mg dose (0.1% vs. 0.4%, P=0.04).. In patients with a recent acute coronary syndrome, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction, or stroke. Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage but not the risk of fatal bleeding. (Funded by Johnson & Johnson and Bayer Healthcare; ATLAS ACS 2-TIMI 51 ClinicalTrials.gov number, NCT00809965.).

Topics: Acute Coronary Syndrome; Aged; Anticoagulants; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Rivaroxaban; Secondary Prevention; Thiophenes

• Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation.. • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally.. The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated.. The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients.. The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

Topics: Acute Coronary Syndrome; Adult; Aged; Aged, 80 and over; Anticoagulants; Clinical Trials, Phase I as Topic; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Models, Biological; Morpholines; Prothrombin; Rivaroxaban; Thiophenes; Young Adult

Topics: Acute Coronary Syndrome; Anticoagulants; Double-Blind Method; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Rivaroxaban; Thiophenes

Although therapy with aspirin or aspirin plus a thienopyridine reduces the incidence of long-term adverse cardiovascular events among patients with acute coronary syndrome (ACS), there remains a significant residual risk of cardiovascular death, recurrent myocardial infarction (MI), and stroke. In a phase 2 trial (ClinicalTrials.gov NCT00402597) in which the addition of the factor Xa inhibitor rivaroxaban was compared with placebo, among ACS patients receiving either aspirin alone or dual-antiplatelet therapy with aspirin and a thienopyridine, the end point of death, MI, or stroke compared with placebo was reduced (87/2331 [3.9%] vs 62/1160 [5.5%]; hazard ratio 0.69, [95% CI 0.50-0.96], P = .027). Two candidate doses of rivaroxaban were selected for further evaluation in a pivotal phase 3.. The second ATLAS-ACS 2 TIMI 51 Trial is an international, randomized, double-blind, event-driven (n = 983) phase 3 trial involving more than 15,570 patients hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with a background of standard therapy including low-dose aspirin, and patients are stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients are randomly assigned in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is thrombolysis in MI major bleeding not associated with coronary artery bypass graft surgery.. The ATLAS-ACS 2 TIMI 51 is testing the hypothesis that anticoagulation with the oral factor Xa inhibitor rivaroxaban reduces cardiovascular death, MI, and stroke among patients with ACS treated with guideline-based therapies for ACS.

Topics: Acute Coronary Syndrome; Adolescent; Adult; Anticoagulants; Coronary Angiography; Double-Blind Method; Electrocardiography; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Male; Middle Aged; Morpholines; Myocardial Infarction; Prospective Studies; Rivaroxaban; Thiophenes; Thrombolytic Therapy; Treatment Outcome; Young Adult

Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen.. In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597.. Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]).. The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway.. Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Topics: Acute Coronary Syndrome; Administration, Oral; Aspirin; Chest Pain; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Morpholines; Myocardial Infarction; Proportional Hazards Models; Pyridines; Recurrence; Risk Reduction Behavior; Rivaroxaban; Safety; Statistics, Nonparametric; Stroke; Thiophenes; Treatment Outcome

Topics: Acute Coronary Syndrome; Anticoagulants; Humans; Morpholines; Rivaroxaban

Atherosclerotic cardiovascular disease (ASCVD), which includes coronary artery disease (CAD), cerebrovascular disease, and peripheral arterial disease (PAD) is associated with significant morbidity, mortality, and healthcare costs. Antiplatelet therapy has long been the mainstay of antithrombotic therapy for the prevention of first-ever and recurrent ASCVD events. More recently, however, randomized trials have demonstrated the benefits and cost-effectiveness of a dual pathway inhibition (DPI) strategy in acute and chronic ASCVD. When used in combination, aspirin and low-dose rivaroxaban work synergistically to inhibit platelet activation and thrombin generation, thereby preventing thrombus formation. Among patients with recent acute coronary syndrome (ACS), those with positive cardiac biomarkers or ST-segment elevation myocardial infarction, or a history of heart failure derive the greatest absolute benefits. Among patients with chronic ASCVD, those with involvement of two or more vascular beds, heart failure, chronic kidney disease, or diabetes derive the greatest absolute benefits. Additional trials are underway to assess the impact of DPI therapy in other populations of interest, including patients with ACS at high risk of left ventricular thrombus formation, intracranial atherosclerotic disease with recent transient ischemic attack or stroke, peripheral arterial disease with limiting claudication or post lower extremity revascularization, and advanced chronic kidney disease with ASCVD or risk factors for ASCVD. Further work is required to assess the possible added benefit of combining rivaroxaban with clopidogrel or ticagrelor instead of aspirin.

Topics: Acute Coronary Syndrome; Aspirin; Atherosclerosis; Cardiovascular Diseases; Drug Therapy, Combination; Heart Failure; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Renal Insufficiency, Chronic; Rivaroxaban; Thrombosis

Aim      To evaluate outcomes in patients with acute coronary syndrome and atrial fibrillation who receive rivaroxaban and the patients' compliance with the antithrombotic therapy.Material and methods  The study was performed from October 2017 through December 2019 and included 129 patients. Events between the discharge from the hospital and 12 months of follow-up were recorded. The primary endpoint was development of major, minor or requiring medical attention bleeding according to the TIMI scale. The secondary endpoint was a combination of recurrent myocardial infarction, nonfatal acute ischemic cerebrovascular disease, nonfatal systemic embolism, stent thrombosis, and cardiovascular mortality.Results 32 (24.8%) patients early terminated the antiplatelet treatment and 22 (17.1%) patients terminated the rivaroxaban treatment. 26 (20.2 %) patients had hemorrhagic complications. The highest incidence of hemorrhage was observed within the first 2 months after the discharge. None of the bleedings was fatal. Composite endpoint events were observed in 24 (18.6 %) patients, including 14 (10.9 %) who died from cardiovascular causes.Conclusion      The compliance with the antiplatelet therapy was insufficient. The incidence of hemorrhagic complications was relatively high; minor and requiring medical attention hemorrhages mostly contributed to the structure of these complications. The observed incidence of recurrent ischemic events associated with a high mortality presents a more serious problem compared to hemorrhagic complications of the combination antiplatelet therapy and warrants a more aggressive tactics of the antiplatelet treatment in high-risk patients.

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Acute Coronary Syndrome; Acute Disease; Aspirin; Atrial Fibrillation; Clopidogrel; Combined Modality Therapy; Cyclophosphamide; Dabigatran; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Stents; Stroke; Vitamin K

See Article by Gibson et al.

Topics: Acute Coronary Syndrome; Humans; Rivaroxaban; Treatment Outcome

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Humans; Platelet Aggregation Inhibitors; Pyrazoles; Pyridones; Recurrence; Risk Factors; Rivaroxaban; Secondary Prevention; Time Factors; Treatment Outcome

Topics: Acute Coronary Syndrome; Factor Xa Inhibitors; Hemorrhage; Humans; Rivaroxaban

Topics: Acute Coronary Syndrome; Aspirin; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Rivaroxaban; Thrombosis; Treatment Outcome

Topics: Acute Coronary Syndrome; Factor Xa Inhibitors; Hemorrhage; Humans; Rivaroxaban

New oral anticoagulants (NOAC) have been introduced in Swedish health care as first line treatment of atrial fibrillation and venous thromboembolism. NOAC have also been studied in combination with platelet antiaggregation in both patients with coronary and peripheral arterial disease, and reduced doses will presumably emerge as routine treatment also in these conditions.

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Cardiovascular Diseases; Coronary Artery Disease; Dabigatran; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Myocardial Infarction; Myocardial Ischemia; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Sweden; Thiazoles

Topics: Acute Coronary Syndrome; Aspirin; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

To analyze prioritized outcomes, Buyse (2010) and Pocock et al. (2012) proposed the win loss approach. In this paper, we first study the relationship between the win loss approach and the traditional survival analysis on the time to the first event. We then propose the weighted win loss statistics to improve the efficiency of the unweighted methods. A closed-form variance estimator of the weighted win loss statistics is derived to facilitate hypothesis testing and study design. We also calculated the contribution index to better interpret the results of the weighted win loss approach. Simulation studies and real data analysis demonstrated the characteristics of the proposed statistics. Copyright © 2017 John Wiley & Sons, Ltd.

Topics: Acute Coronary Syndrome; Angiotensin-Converting Enzyme Inhibitors; Biostatistics; Clinical Trials as Topic; Computer Simulation; Coronary Artery Disease; Data Interpretation, Statistical; Endpoint Determination; Factor Xa Inhibitors; Humans; Models, Statistical; Proportional Hazards Models; Randomized Controlled Trials as Topic; Rivaroxaban; Survival Analysis; Treatment Outcome

Topics: Acute Coronary Syndrome; Aspirin; Double-Blind Method; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Acute Coronary Syndrome; Anticoagulants; Factor Xa Inhibitors; Humans; Rivaroxaban; Secondary Prevention

The potential impact of missing data on the results of clinical trials has received heightened attention recently. A National Research Council study provides recommendations for limiting missing data in clinical trial design and conduct, and principles for analysis, including the need for sensitivity analyses to assess robustness of findings to alternative assumptions about the missing data. A Food and Drug Administration advisory committee raised missing data as a serious concern in their review of results from the ATLAS ACS 2 TIMI 51 study, a large clinical trial that assessed rivaroxaban for its ability to reduce the risk of cardiovascular death, myocardial infarction or stroke in patients with acute coronary syndrome. This case study describes a variety of measures that were taken to address concerns about the missing data.. A range of analyses are described to assess the potential impact of missing data on conclusions. In particular, measures of the amount of missing data are discussed, and the fraction of missing information from multiple imputation is proposed as an alternative measure. The sensitivity analysis in the National Research Council study is modified in the context of survival analysis where some individuals are lost to follow-up. The impact of deviations from ignorable censoring is assessed by differentially increasing the hazard of the primary outcome in the treatment groups and multiply imputing events between dropout and the end of the study. Tipping-point analyses are described, where the deviation from ignorable censoring that results in a reversal of significance of the treatment effect is determined. A study to determine the vital status of participants lost to follow-up was also conducted, and the results of including this additional information are assessed.. Sensitivity analyses suggest that findings of the ATLAS ACS 2 TIMI 51 study are robust to missing data; this robustness is reinforced by the follow-up study, since inclusion of data from this study had little impact on the study conclusions.. Missing data are a serious problem in clinical trials. The methods presented here, namely, the sensitivity analyses, the follow-up study to determine survival of missing cases, and the proposed measurement of missing data via the fraction of missing information, have potential application in other studies involving survival analysis where missing data are a concern.

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Double-Blind Method; Factor Xa Inhibitors; Humans; Lost to Follow-Up; Multicenter Studies as Topic; Myocardial Infarction; Patient Dropouts; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Survival Analysis

Venous thromboembolism and atrial fibrillation are two important indications of direct oral anticoagulants. Acute coronary syndrome is another potential indication of prolonged antithrombotic therapy in addition to antiplatelet therapy. Phase 2 and 3 studies were conducted with different molecules at different doses in acute coronary syndrome in addition to dual antiplatelet therapy. Studies have not shown a reduction of ischemic events for dabigatran and apixaban, but an excess of bleeding complications was observed. A reduction of ischemic events and stent thrombosis was observed with low dose of rivaroxaban taken twice a day but with an increased risk of major bleeding complications. This data was used to obtain a European marketing authorization but the positioning of the molecule remains difficult. A new study is currently being conducted to test rivaroxaban in association with a P2Y12 inhibitor without aspirin. Direct oral anticoagulants can also be used after percutaneous coronary intervention in patients requiring long-term oral anticoagulants. Dedicated studies are currently being conducted to confirm the optimal doses and the ideal association of antithrombotic drugs.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Clinical Trials as Topic; Humans; Rivaroxaban

Patients with acute coronary syndromes (ACS) require a specific antithrombotic therapy in the immediate and the post ACS phase. The current antithrombotic therapy in the acute phase of an ACS combines antiplatelet and anticoagulant drugs in order to reduce ischemic cardiovascular events. In the post ACS phase, dual antiplatelet therapy (DAPT; aspirin and a P2Y12 receptor antagonist) is the current mainstay of antithrombotic treatment and is recommended in the guidelines of the major North American and European clinical cardiology associations (AHA, ACC, and ESC). Recently, the addition of rivaroxaban, a low dose oral direct factor Xa inhibitor (2.5 mg twice daily), to DAPT (aspirin plus second-generation P2Y12 inhibitor) showed a significant reduction of cardiovascular and overall mortality in the major phase III clinical trial ATLAS ACS 2 TIMI 51. This led to the approval of low-dose rivaroxaban in addition to aspirin and clopidogrel by the European Medicines Agency (EMA) in 2013. Other direct oral anticoagulants (apixaban, dabigatran etexilate) have also been assessed in phase II (dabigatran etexilate) and phase III (apixaban) post ACS clinical trials. In the studied dosing regimens, these drugs failed to show a net clinical benefit in addition to dual antiplatelet therapy. The major clinical phase II and III post ACS studies of direct oral anticoagulants are summarized and discussed in this article along with the concept of long-term anticoagulation for the secondary prevention of ischemic events after ACS and implications for the future of antithrombotic therapy in the current era of third-generation P2Y12 receptor inhibitors (Prasugrel and Ticagrelor).

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Factor Xa; Factor Xa Inhibitors; Humans; Ischemia; Morpholines; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes

Topics: Acute Coronary Syndrome; Adult; Humans; Male; Pacemaker, Artificial; Rivaroxaban; Thrombosis; Treatment Outcome

Aspirin is the antithrombotic drug of choice for preventing recurrences after a first acute coronary syndrome. The addition of clopidogrel, another antiplatelet agent, is helpful in case of angioplasty with stenting. Following the acute phase, warfarin, an anticoagulant, alone or in combination with aspirin, may be used only in specific situations, particularly for patients with a high thrombotic risk (due to atrial fibrillation for example). Rivaroxaban, an oral factor Xa inhibitor anticoagulant, has been authorised for use following an acute coronary syndrome, but at a new dose strength of 2.5 mg, in combination with aspirin alone or aspirin plus clopidogrel. Rivaroxaban has not been compared with warfarin in patients with a high thrombotic risk following an acute coronary syndrome. In a double-blind, randomised, placebo-controlled trial in 15 526 patients, who were not at particularly high risk of thrombosis, the addition of the rivaroxaban to aspirin or to aspirin plus clopidogrel appeared to reduce mortality during the first year of treatment (2.6% versus 3.8% with placebo). However, there is a large amount of missing data, exceeding the inter-group difference in the number of deaths, seriously undermining the results. In the subgroup of about 1000 patients in whom antiplatelet therapy consisted of aspirin alone, addition of rivaroxaban did not lead to a statistically significant decrease in the incidence of cardiovascular events or death. The addition of rivaroxaban increased the incidence of "clinically relevant" bleeding episodes, as defined in the study protocol (11.2% of patients per year in the rivaroxaban group versus 6.4% in the placebo group), as well as the incidence of major bleeding events (respectively 1.2% and 0.3% of patients per year) and intracranial haemorrhage (14 versus 5 cases). The patients selected for this trial were considered to have a low risk of bleeding, so the risk is likely to be higher in many patients who have had an acute coronary syndrome. In practice, it has not yet been demonstrated that adding rivaroxaban to aspirin or to aspirin plus clopidogrel is beneficial following an acute coronary syndrome. In addition, the bleeding risk is likely to be higher in routine practice than in the conditions under which the comparative trial was conducted. It is therefore best not to use rivaroxaban in this setting but to stick with best-known antithrombotic drugs.

Topics: Acute Coronary Syndrome; Administration, Oral; Drug Dosage Calculations; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Morpholines; Patient Selection; Platelet Aggregation Inhibitors; Recurrence; Risk Assessment; Risk Factors; Rivaroxaban; Secondary Prevention; Thiophenes; Treatment Outcome

Topics: Acute Coronary Syndrome; Anticoagulants; Factor Xa Inhibitors; Female; Humans; Male; Morpholines; Rivaroxaban; Thiophenes

Several key reports from the American Heart Association meeting, held in Orlando (FL, USA) in November 2011, are presented related to anti-thrombotic therapy in acute coronary syndrome and the use of dronedarone in permanent atrial fibrillation is discussed in this brief (and selective) overview of this meeting. A summary of the ATLAS-TIMI-51, TRACER and PALLAS trials is provided.

Topics: Acute Coronary Syndrome; American Heart Association; Amiodarone; Anti-Arrhythmia Agents; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Dronedarone; Fibrinolytic Agents; Humans; Lactones; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome; United States; Venous Thromboembolism

Topics: Acute Coronary Syndrome; Altitude; Blood Coagulation Disorders; Coffee; Factor Xa Inhibitors; Heparin; Humans; Lipoproteins; Lymphatic Diseases; Morpholines; Myocardial Infarction; Platelet Aggregation Inhibitors; Rivaroxaban; Thiophenes; Thrombocytopenia; Thrombosis; Troponin; Venous Thrombosis; von Willebrand Diseases

The combination of antiplatelet and anticoagulant drugs, a common practice in the setting of acute coronary syndromes, constitutes an important practical problem involving difficult decisions, that lack support both in terms of clinical evidence (adequate clinical studies are not available) and strong guidelines. The problem was particularly aggravated from the moment when practically all the patients with acute coronary syndromes started to be submitted to double antiplatelet therapy, especially those treated with drug eluting stents. Simply reminding that 10% of these patients have or will have atrial fibrillation gives us the dimension of the problem. In this paper we discuss the benefits and risks of an eventual triple therapy and present the data obtained from the scarce evidence at our disposal, both from clinical studies and registries. The evidence about the combination of the double antiplatelet therapy with the new anticoagulants is derived from the phase II and phase III studies, conducted with dabigatran, apixaban, darexaban and rivaroxaban. The results from the only phase III study concluded with good results, the ATLAS-ACS 2 TIMI 51 study, conducted with rivaroxaban, are presented. The author also presents some of the recommendations extracted from the consensus document published on this matter by the Working Group on Thrombosis of the European Society of Cardiology.

Topics: Acute Coronary Syndrome; Anticoagulants; Drug Therapy, Combination; Humans; Morpholines; Platelet Aggregation Inhibitors; Practice Guidelines as Topic; Rivaroxaban; Thiophenes

Topics: Acute Coronary Syndrome; Cardiovascular Diseases; Double-Blind Method; Factor Xa Inhibitors; Humans; Morpholines; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes

New oral anticoagulants constitute an important breakthrough for cardiologists and their patients. After reviewing their mechanism of action, their role in the context of interventional cardiology, particularly for patients with acute coronary syndromes, is discussed.

Topics: Acute Coronary Syndrome; Administration, Oral; Angioplasty, Balloon, Coronary; Anticoagulants; Benzimidazoles; beta-Alanine; Blood Coagulation Factors; Cardiac Surgical Procedures; Cardiology; Dabigatran; Humans; Morpholines; Percutaneous Coronary Intervention; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Treatment Outcome

Topics: Acute Coronary Syndrome; Anticoagulants; Atrial Fibrillation; Clinical Trials as Topic; Electrocardiography; Expert Testimony; Humans; Morpholines; Myocardial Infarction; Practice Guidelines as Topic; Rivaroxaban; Stroke; Survival Analysis; Thiophenes; Treatment Outcome

Although currently available anticoagulants are effective for the prevention and treatment of thromboembolic disorders, they have several drawbacks. Low molecular weight heparin and fondaparinux produce a predictable level of anticoagulation that obviates the need for coagulation monitoring, but they must be given parenterally, which renders them inconvenient for long-term use. Vitamin K antagonists, such as warfarin, are administered orally, but produce a variable anticoagulant response because genetic polymorphisms, dietary vitamin K intake and multiple drug-drug interactions affect their metabolism. Consequently, coagulation monitoring and frequent dose adjustments are needed to ensure that a therapeutic level of anticoagulation is achieved. This is burdensome for patients and physicians, and costly for the healthcare system. These limitations have prompted the development of new oral anticoagulants that target thrombin or factor Xa. The new agents produce such a predictable anticoagulant response that they can be given in fixed doses without monitoring. This paper focuses on the new oral anticoagulants in the most advanced stages of development.

Topics: Acute Coronary Syndrome; Administration, Oral; Anticoagulants; Atrial Fibrillation; Benzimidazoles; Clinical Trials as Topic; Dabigatran; Drug Discovery; Factor Xa Inhibitors; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Thiophenes; Thrombin; Venous Thromboembolism; Vitamin K

Vitamin K antagonists (VKA) are the only registered oral anticoagulants for the treatment of venous thromboembolism (VTE). VKA have an unpredictable and highly variable effect on coagulation, with a high risk of under- and over-treatment. Novel anticoagulants, such as dabigatran and rivaroxaban, could be a very welcome replacement for VKA, as they show a predictable anticoagulant effect. Results of several phase II and III studies have shown the efficacy and safety of dabigatran and rivaroxaban in the prophylaxis and treatment of VTE, and for the prevention of stroke in atrial fibrillation. It remains to be shown whether these new anticoagulants have the same safety profile in daily clinical practice, where more vulnerable patients will be treated. Lack of information on the proper monitoring method or antidote in case of bleeding may also hinder the translation from science to clinical practice.

Topics: Acute Coronary Syndrome; Anticoagulants; Arthroplasty, Replacement, Hip; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Dabigatran; Diet; Drug Interactions; Factor VIIa; Factor Xa Inhibitors; Humans; Kidney; Life Style; Monitoring, Physiologic; Morpholines; Recombinant Proteins; Rivaroxaban; Stroke; Thiophenes; Venous Thromboembolism; Vitamin K

The standard antithrombotic therapy for treatment of patients with acute coronary syndrome (ACS) is dual antiplatelet therapy with aspirin and clopidogrel (Plavix) or another thienopyridine, plus a parenteral anticoagulant while the patient is hospitalized, followed by antiplatelet therapy alone after discharge. The addition of the oral anticoagulant warfarin (Coumadin, and others) to dual antiplatelet therapy is generally not recommended for this indication because of fluctuations in its anticoagulant effect and the risk of bleeding. A recently published trial found that addition of a low dose of the oral anticoagulant rivaroxaban (Xarelto) to antiplatelet therapy after discharge reduced the risk of major cardiovascular events without increasing the incidence of fatal bleeding.

Topics: Acute Coronary Syndrome; Anticoagulants; Aspirin; Dose-Response Relationship, Drug; Drug Approval; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Morpholines; Pyridines; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; United States; United States Food and Drug Administration

Topics: Acute Coronary Syndrome; Anticoagulants; Antithrombins; Benzimidazoles; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Pyridines; Rivaroxaban; Thiophenes; Thromboembolism; Thrombosis

Topics: Acute Coronary Syndrome; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Humans; Morpholines; Randomized Controlled Trials as Topic; Rivaroxaban; Secondary Prevention; Thiophenes; Treatment Outcome

Topics: Acute Coronary Syndrome; Clinical Trials, Phase II as Topic; Data Interpretation, Statistical; Hemorrhage; Humans; Morpholines; Research Design; Rivaroxaban; Thiophenes; Treatment Outcome; Young Adult