rivaroxaban and Cardiovascular-Diseases

The aim of this study was to evaluate the efficacy and safety of antithrombotic regimens and their combinations in preventing thrombotic incidents in patients with stable atherosclerotic cardiovascular disease (S-ASCVD).. A systematic literature search was conducted in the PubMed, Embase, Cochrane Library, Scopus, and Google Scholar databases. The primary comprehensive endpoint was a major adverse cardiovascular event (MACE) composite of cardiovascular death, stroke, or myocardial infarction, while the secondary endpoints were cardiovascular death, all-cause stroke, ischemic stroke, myocardial infarction, and all-cause death. The safety endpoint was major bleeding. Bayesian network meta-regression analysis in R software was used to calculate the final effect size and to correct for the effect of follow-up time on the outcome effect size.. Twelve studies reporting 122,190 patients with eight antithrombotic regimens were included in this systematic review. For the primary composite endpoint, low-dose aspirin plus clopidogrel 75 mg (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.33-0.87) and low-dose aspirin plus rivaroxaban 2.5 mg twice daily (HR 0.53, 95% CI 0.34-0.82) showed significantly better efficacy than clopidogrel monotherapy, and the efficacy was comparable among the first two regimens. Unfortunately, none of the active regimens significantly decreased all-cause death, cardiovascular death branch, and all-cause stroke as part of the secondary endpoints. Low-dose aspirin plus ticagrelor 90 mg twice daily (HR 0.81, 95% CI 0.69-0.94) and low-dose aspirin plus ticagrelor 60 mg twice daily (HR 0.84, 95% CI 0.74-0.95) had a significant advantage in myocardial infarction compared with low-dose aspirin monotherapy, while low-dose aspirin plus 2.5 mg rivaroxaban twice daily (HR 0.62, 95% CI 0.41-0.94) was better than low-dose aspirin in the treatment of ischemic stroke. In the major bleeding branch, low-dose aspirin plus ticagrelor 90 mg twice daily (HR 2.2, 95% CI 1.70-2.90), low-dose aspirin plus ticagrelor 60 mg twice daily (HR 2.1, 95% CI 1.70-2.60), low-dose aspirin plus rivaroxaban 2.5 mg twice daily (HR 1.7, 95% CI 1.30-2.00), and rivaroxaban 5 mg twice daily (HR 1.5, 95% CI 1.20-1.90) showed higher major bleeding risk compared with low-dose aspirin.. Considering MACEs, myocardial infarction, all kinds of stroke, ischemic stroke, and major bleeding, low-dose aspirin plus rivaroxaban 2.5 mg twice daily should be considered the preferred regimen for S-ASCVD patients with low bleeding risk.

Topics: Aspirin; Atherosclerosis; Bayes Theorem; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Ischemic Stroke; Myocardial Infarction; Network Meta-Analysis; Platelet Aggregation Inhibitors; Regression Analysis; Rivaroxaban; Stroke; Ticagrelor

Atherosclerotic cardiovascular disease is characterized by some risk of major adverse events despite the availability of effective medical therapies for secondary prevention. There is emerging evidence suggesting that thrombin partly contributes to this residual risk. In fact, thrombin (i.e., activated coagulation factor II) triggers not only the conversion of fibrinogen to fibrin but also platelet activation and various pathways responsible for pro-atherogenic and/or pro-inflammatory effects through interaction with protease activated receptors. To reduce the risk associated with thrombin activation, oral anticoagulants antagonists of vitamin K showed promise, but were associated with unacceptable bleeding rates. Direct oral anticoagulants targeting the activated factors X and II carry a lower risk of bleeding than vitamin K antagonists. Rivaroxaban, a direct inhibitor of activated factor X approved at the dose of 20 mg once daily for the prevention of thromboembolic events, has been also investigated at a reduced dose of 2.5 mg twice daily in several alternative scenarios of atherosclerotic cardiovascular disease, in combination with standard of care. Current guidelines recommend that low-dose rivaroxaban is given in an adjunct to standard therapy to patients with stable atherosclerosis and acute coronary syndromes at low bleeding risk. Several studies are underway to evaluate its putative benefits in other clinical settings.

Topics: Anticoagulants; Atherosclerosis; Cardiovascular Diseases; Factor Xa Inhibitors; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombin; Vitamin K

Despite availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events. Therefore, novel therapeutic strategies are required to further reduce the residual risk present in these patients. Platelet aggregation and fibrin organization are involved in arterial thrombosis. Rivaroxaban is capable of targeting both processes and has a synergistic effect when used in combination with acetylsalicylic acid (ASA), providing the so‑called dual pathway inhibition (DPI). The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the DPI (a combination of rivaroxaban at 2.5 mg twice daily [vascular dose] and ASA at 100 mg once daily) reduced cardiovascular death, stroke, or myocardial infarction by 24% in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD). Subsequently, the VOYAGER PAD (Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) trial confirmed the effectiveness of the vascular dose of rivaroxaban in patients with PAD after lower‑extremity revascularization, as compared with ASA alone. Therefore, DPI is recommended in the patients with CAD (+/- PAD) or symptomatic PAD at a high risk of ischemia. The purpose of this review is to examine the clinical benefits and practical implications of DPI in the CAD and PAD patients.

Topics: Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Ischemia; Outpatients; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban

Low-dose (LD) direct oral anticoagulants (DOACs) in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), have been tested to prevent ischaemic events in patients with cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to determine the overall safety and efficacy of LD DOACs vs placebo on a background of antiplatelet therapy.. All randomized controlled trials (RCTs) comparing LD DOAC (defined as a dosage below the lowest approved for stroke prevention) vs placebo among patients with CVD receiving single or dual antiplatelet therapy (DAPT) in at least 50% of the population and followed for at least 6 months, were included. Incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were used to overcome different follow-up durations across trials. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint major bleeding. A pre-specified subgroup analysis was performed for different DOAC-dose regimens. A total of 49 802 patients from 7 RCTs were included. Low-dose DOACs vs placebo were associated with significant reductions in MACE (IRR 0.85, 95% CI 0.78-0.91, number needed to treat, NNT, 86) and myocardial infarction (IRR 0.86, 95% CI 0.78-0.95, NNT 355) and significant increases of major (IRR 2.05, 95% CI 1.50-2.80, number needed to harm, NNH, 89) or all bleeding (IRR 1.82, 95% CI 1.49-2.22, NNH 23). Cardiovascular death (IRR 0.90, 95% CI 0.79-1.03, NNT 784), intracranial (IRR 1.18, 95% CI 0.71-1.96, NNH 1810), and fatal bleeding (IRR 1.13, 95% CI 0.76-1.69, NNH 3170) did not differ significantly between strategies. Non-significant reductions of all-cause death (IRR 0.90, 95% CI 0.80-1.01, NNT 821) and stroke (IRR 0.73, 95% CI 0.53-1.01, NNT 315) favoured LD DOACs. Meta-regression analyses showed a significant interaction between percentage of DAPT use and increased risk of major bleeding (P = 0.04), intracranial haemorrhage (P = 0.035), and stroke (P = 0.0003). Subgroup analysis of very LD DOAC, defined as ≤1/3 of the lowest approved dose for stroke prevention (i.e. rivaroxaban 2.5 mg twice daily) seemed to mitigate the risk of bleeding without any trade-off in efficacy compared to other LD DOAC regimens.. In patients with CVD, LD DOAC vs placebo on a background of antiplatelet therapy, reduced ischaemic events at the expense of increased major and all bleeding, but without significantly increasing intracranial or fatal bleeds, while the reduction of cardiovascular or total mortality and stroke was not statistically significant. A DPI with very LD DOAC (i.e. rivaroxaban 2.5 mg twice daily) appeared particularly advantageous, especially when combined with a single antiplatelet agent and used among patients at high ischaemic and low bleeding risk.. This study is registered in PROSPERO (CRD42021232744).

Topics: Anticoagulants; Cardiovascular Diseases; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke

Patients with sleep-disordered breathing exhibit intermittent hypoxia that causes increased oxidative stress, accelerates atherosclerosis, and pulmonary hypertension, resulting in life-threatening arrhythmias and congestive heart failure. Hypoxic stress caused by intermittent hypoxia might be involved in the pathophysiology of many cardiovascular diseases, especially those involving atrial fibrillation, for which anti-coagulant therapy may be recommended. In this study, the inhibition of proteinase-activated receptor (PAR) 1/2 significantly reduced oxidative stress and fibrosis while suppressing the activation of MAPK or Smad pathways and the gene expression of molecules responsible for the pathways in the myocardium, consequently attenuating hypoxia-mediated cardiomyocyte hypertrophy. These findings suggest that the inhibition of PAR 1/2 could be a novel potential treatment option to prevent cardiac remodeling in patients with sleep apnea syndrome and atrial fibrillation or chronic thromboembolic pulmonary hypertension.

Topics: Animals; Atherosclerosis; Atrial Fibrillation; Cardiovascular Diseases; Disease Models, Animal; Humans; Hypertension, Pulmonary; Hypoxia; Mice, Inbred C57BL; Molecular Targeted Therapy; Oxidative Stress; Rats; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; Sleep Apnea Syndromes; Ventricular Remodeling

Cardiovascular disease (CVD) remains the leading cause of death in the USA. Several risk factors have been identified, and obesity has become one of prominent concern. Excessive weight is considered a risk factor for CVD based on evidence linking it to a hypercoagulable state. Considering the prevalence of CVD and obesity in the USA, along with the increased risk for thrombus-related events, anticoagulation plays a significant role in prevention and treatment. Direct oral anticoagulants have taken the place of many traditional anticoagulants. Considering the recently approved indications and continued postmarketing studies conducted with rivaroxaban, this updated review provides data on the overall impact of obesity on this compound. This includes data obtained from both healthy obese volunteers and obese patients with various CVD conditions enrolled in rivaroxaban clinical trials, along with data obtained from postmarketing real-world evidence studies. Assessment of the clinical pharmacology and population pharmacokinetics in obese individuals revealed no clinically relevant effects of increased weight. Additionally, subgroup analyses from each of the pivotal phase III trials supporting the current approved labeling also demonstrated consistent efficacy and safety results in obese patients. Lastly, these findings are further supported by several recent real-world evidence studies assessing the continued effectiveness and safety of rivaroxaban. In conclusion, rivaroxaban's overall pharmacological and clinical profile remained consistent in obese adults when assessed in both drug development and postmarketing studies, supporting the premise that higher weight does not necessitate adjustment in either dose strength or regimen.

Topics: Anticoagulants; Area Under Curve; Body Weight; Cardiovascular Diseases; Humans; Metabolic Clearance Rate; Obesity; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Venous Thrombosis

Direct oral anticoagulants (DOACs) are widely used for the prevention of stroke in nonvalvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism, and as prophylaxis after hip and knee surgery after approval by the Food and Drug Administration. In the last decade, DOACs were studied for various indications; this review is focused on rivaroxaban, a factor Xa inhibitor, which is used in an expanded evidence-based fashion for coronary artery disease, peripheral artery disease, heart failure, malignancy, and prophylaxis of deep venous thrombosis in acute medical illnesses.

Topics: Cardiovascular Diseases; Clinical Decision-Making; Factor Xa Inhibitors; Hemorrhage; Humans; Patient Selection; Risk Factors; Rivaroxaban; Treatment Outcome

Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Pearson is employed by ICER; Synnott was employed by ICER at the time of this report. Ollendorf, Campbell, and McQueen received grants from ICER for work on this review. Ollendorf also reports advisory board, consulting, and other fees from Sarepta Therapeutics, DBV Technologies, EMD Serono, Gerson Lehman Group, The CEA Registry Sponsors, Autolus, Analysis Group, Amgen, AbbVie, Cytokinetics, Aspen Institute/University of Southern California, and University of Colorado, unrelated to this review.

Topics: Aspirin; Cardiovascular Diseases; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Costs; Drug Therapy, Combination; Eicosapentaenoic Acid; Hemorrhage; Humans; Models, Economic; Randomized Controlled Trials as Topic; Rivaroxaban; Time Factors; Treatment Outcome

Topics: Administration, Oral; Anticoagulants; Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Rivaroxaban; Secondary Prevention

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Topics: Anticoagulants; Cardiology; Cardiovascular Diseases; COVID-19; COVID-19 Drug Treatment; Europe; Heparin, Low-Molecular-Weight; Humans; Inflammation; Practice Guidelines as Topic; Risk Factors; Rivaroxaban; SARS-CoV-2; Societies, Medical; Thrombophilia; Thrombosis

Peripheral artery disease (PAD) affects an estimated 200 million people worldwide and is associated with significant cardiovascular morbidity and mortality. Cardiovascular risk is further increased among individuals with polyvascular disease, where either cerebrovascular or coronary artery disease is present in addition to PAD. In this review, we present common clinical scenarios encountered when managing patients with PAD and provide an evidence-based approach to prescribing optimal antithrombotics in this population.. The COMPASS trial recently demonstrated that rivaroxaban 2.5 mg BID + ASA daily significantly reduces major adverse cardiac and limb events in patients with PAD. Despite these advances, morbidity following MALE events remains high. With widespread approval by federal health regulators, the COMPASS regimen should be strongly considered in PAD patients who do not have a high bleeding risk. Implementing the COMPASS regimen in patients with PAD, along with other vascular risk reduction strategies, will have a substantial impact on reducing atherothromboembolic risk in patients with established vascular disease.

Topics: Anticoagulants; Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombolytic Therapy

This review provides the rationale for dual pathway inhibition with the combination of low-dose rivaroxaban (2.5 mg twice daily) to attenuate thrombin generation and aspirin (100 mg once daily) to reduce platelet activation. Such therapy has been licensed for secondary prevention in patients with coronary or peripheral artery disease.

Topics: Aspirin; Cardiovascular Diseases; Factor Xa Inhibitors; Female; Humans; Male; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Rivaroxaban

The COMPASS trial compared the impact of the selective direct factor Xa inhibitor, rivaroxaban, as monotherapy or in combination with aspirin on major adverse cardiovascular events (MACE) in patients with stable atherosclerotic disease. Patients treated with rivaroxaban 2.5 mg twice daily in combination with aspirin experienced fewer cardiovascular events but more bleeding complications than those who received aspirin monotherapy. In contrast, a higher dose of rivaroxaban (5 mg twice daily) and aspirin produced no clinical benefit and continued to be associated with greater bleeding rates than aspirin. Examining this study in the context of other trials of anticoagulant therapy in atherosclerotic vascular disease, this review attempts to place the role of very low-dose rivaroxaban in clinical context and highlights areas for future research.

Topics: Anticoagulants; Aspirin; Atherosclerosis; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD ≥60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD ≥50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce long-term ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.

Topics: Aged; Anticoagulants; Aspirin; Atherosclerosis; Cardiology; Cardiovascular Diseases; Carotid Arteries; Carotid Artery Diseases; Clopidogrel; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Revascularization; Platelet Aggregation Inhibitors; Risk; Rivaroxaban

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

Stable and unstable ischemic heart disease are a growing component in all facets of healthcare, including ER visits, hospitalizations, and financial costs. With the changing emphasis of healthcare shifting towards the outpatient setting, the onus is on clinicians to appropriately manage such patients to avoid adverse effects and complications. Antithrombotic medications, including aspirin, P2Y. Aspirin has a well-established history of safety and efficacy in management of secondary cardiovascular protection in ischemic heart disease patients. A dual-antiplatelet regimen, most commonly including aspirin plus clopidogrel, has been documented to be effective as well in achieving the same goals. Newer agents, such as rivaroxaban, are being analyzed to see if there is scope to include these agents for secondary prevention. One recent study, the COMPASS trial, revealed the major concern of these newer medications: while better cardiovascular outcomes were achieved in subjects on aspirin plus rivaroxaban, this was accomplished in the setting of a higher rate of major bleeding events. In conclusion, the evidence thus far has not been significant enough for the American College of Cardiology to recommend the incorporation of oral anticoagulants in the management of stable ischemic heart disease patients, in contrast to aspirin and clopidogrel. As the antithrombotic and antiischemic properties of these newer agents seem evident, so does their potential for increase in risk of bleeding events. Doctors have to individually tailor antithrombotic medication decisions based on the patient's risk-benefit profile.

Topics: Aspirin; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

Topics: Animals; Aspirin; Atherosclerosis; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Rivaroxaban; Secondary Prevention

The pathophysiology of atherosclerosis involves a diseased endothelium, lipid accumulation and low-grade inflammation. In later stages of coronary artery disease (CAD) and peripheral arterial disease (PAD), plaque rupture may induce atherothrombosis caused by fibrin formation and platelet activation, leading to vessel occlusion with subsequent organ damage such as myocardial infarction, stroke or limb ischaemia. Because of the high disease burden associated with CAD and PAD, there is a need for continuous vascular protection beyond currently available treatments including antiplatelet agents. Due to its central role in the coagulation cascade, inhibition of factor Xa, with the subsequent reduced thrombin formation that impacts not only fibrin but also platelets, may provide additional benefit over using antiplatelets alone. Evidence from 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) supports the use of the direct, oral, factor Xa inhibitor rivaroxaban (2.5 mg twice-daily [bid] and 5 mg bid) in reducing mortality and morbidity in patients with acute coronary syndrome, when combined with antiplatelets. Here, we review the role of rivaroxaban in three clinical trials of CAD and/or PAD: Cardiovascular OutcoMes for People using Anticoagulation StrategieS (COMPASS), Vascular Outcomes studY of ASA alonG with rivaroxaban in Endovascular or surgical limb Revascularization for PAD (VOYAGER PAD) and Cardiovascular Outcome Modification, Measurement AND Evaluation of Rivaroxaban in patients with Heart Failure (COMMANDER HF).

Topics: Blood Coagulation; Cardiovascular Diseases; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Rivaroxaban; Treatment Outcome

Four non-vitamin-K-antagonist oral anticoagulants (NOACs) have been approved for use in various cardiovascular indications. The direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors apixaban, edoxaban and rivaroxaban are now increasingly used in clinical practice. For some of these agents, available data from real-world studies support the efficacy and safety data in phase III clinical trials.. This review aims to summarize the current status of trials and observational studies of oral anticoagulant use over the spectrum of cardiovascular disorders (excluding venous thrombosis), provide a reference source beyond stroke prevention for atrial fibrillation (AF) and examine the potential for novel applications in the cardiovascular field.. We searched the recent literature for data on completed and upcoming trials of oral anticoagulants with a particular focus on rivaroxaban.. Recent data in specific patient subgroups, such as patients with AF undergoing catheter ablation or cardioversion, have led to an extended approval for rivaroxaban, whereas the other NOACs have ongoing or recently completed trials in this setting. However, there are unmet medical needs for several arterial thromboembolic-related conditions, including patients with: AF and acute coronary syndrome, AF and coronary artery disease undergoing elective percutaneous coronary intervention, coronary artery disease and peripheral artery disease, implanted cardiac devices, and embolic stroke of unknown source.. NOACs may provide alternative treatment options in areas of unmet need, and numerous studies are underway to assess their benefit-risk profiles in these settings.

Topics: Atrial Fibrillation; Cardiovascular Diseases; Drug Repositioning; Factor Xa Inhibitors; Humans; Rivaroxaban; Stroke

Residual cardiovascular risk remains high in patients with atherosclerotic cardiovascular disease despite current antithrombotic therapy. On the other hand, patients with atrial fibrillation have an increased risk of myocardial infarction and cardiovascular death. As a result, a new antithrombotic approach appears necessary to reduce this risk. Areas covered: In this article, the role of rivaroxaban on vascular protection in patients with cardiovascular disease and/or atrial fibrillation was reviewed, with a particular focus, but not limited, on clinical trials. Expert commentary: Previous data have shown that factor Xa plays a key role in the etiopathogenesis of atherothrombosis. Experimental data suggest that rivaroxaban exhibits antiinflammatory and antioxidative stress properties, and may improve endothelial dysfunction. The COMPASS trial showed that among patients with stable atherosclerotic vascular disease, the addition of rivaroxaban 2.5 mg twice daily (vascular dose) to aspirin provided a higher cardiovascular protection than aspirin alone. In ROCKET-AF trial, compared with warfarin, rivaroxaban 20 mg once daily (15 mg if moderate renal dysfunction) (anticoagulant dose) was, at least, as effective as warfarin for the prevention of stroke or systemic embolism among patients with nonvalvular atrial fibrillation, with a trend toward a reduction in the risk of cardiovascular outcomes. All these data suggest that rivaroxaban might have a vascular protective effect beyond its stroke/systemic embolism preventive activity.

Topics: Atherosclerosis; Atrial Fibrillation; Cardiovascular Diseases; Embolism; Factor Xa Inhibitors; Humans; Rivaroxaban; Stroke

Peripheral artery disease (PAD) is the third most common manifestation of atherosclerosis after coronary artery (CAD) and cerebrovascular disease (CVD). People with PAD have plaque findings in other vascular territories as well and, thus, are at increased risk of major adverse cardiovascular or cerebrovascular events (MACCE), including myocardial infarction, and stroke. In that context, the COMPASS multicenter, randomized controlled trial showed that the risk of MACCE was significantly reduced by 24% in the rivaroxaban plus aspirin arm compared with aspirin alone (4.1% vs 5.4% respectively; HR: 0.76, 95% CI: 0.66 to 0.86). Interestingly, the rivaroxaban/aspirin arm also showed a reduction in cardiovascular death (HR: 0.78; 95% CI: 0.64-0.96]) and allcause mortality (HR: 0.82; 95% CI: 0.71-0.96) by 22% and 18%, respectively. Recently, the FDA approved the use of the dual pathway approach, rivaroxaban 2.5 mg twice daily plus aspirin 75-100mg once daily, to reduce the risk of major cardiovascular (CV) events, such as CV death, myocardial infarction and stroke, in people with CAD as well as PAD. In comparing rivaroxaban plus aspirin versus aspirin alone, a preliminary economic analysis showed that saving per patient was USD 462 for events and USD 220 for procedures with a total reduction of USD 682 per participant in the US with the combination group (rivaroxaban plus aspirin). The data from COMPASS trial suggest that low dose rivaroxaban plus aspirin may be a preferred treatment strategy in PAD patients in whom the bleeding risk is deemed to be favourable.

Topics: Anticoagulants; Aspirin; Cardiovascular Diseases; Clopidogrel; Cost-Benefit Analysis; Drug Therapy, Combination; Humans; Peripheral Arterial Disease; Randomized Controlled Trials as Topic; Rivaroxaban; Treatment Outcome

The non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin for stroke prevention in many patients with nonvalvular atrial fibrillation. Edoxaban, an oral factor Xa inhibitor, is the newest entrant in this class. Results of the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation (ENGAGE AF) study demonstrate that edoxaban is noninferior to warfarin for prevention of stroke and systemic embolic events, and is associated with significantly less major bleeding, including intracranial bleeding, and reduced cardiovascular mortality. With a net clinical benefit over warfarin, edoxaban is well positioned as a choice among the NOACs, which include dabigatran, rivaroxaban, and apixaban. But how will clinicians choose amongst them? The purpose of this paper is to (a) place the ENGAGE AF trial results into context with results of the studies with the other NOACs, and (b) aid clinicians in selection of the right anticoagulant for the right atrial fibrillation patient.

Topics: Administration, Oral; Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Dabigatran; Embolism; Factor Xa Inhibitors; Female; Humans; Intracranial Hemorrhages; Male; Pyrazoles; Pyridines; Pyridones; Research Design; Rivaroxaban; Stroke; Thiazoles; Warfarin

Rivaroxaban, a direct factor Xa inhibitor, has been developed to meet clinical needs in a broad range of indications in adults: prevention of venous thromboembolism after elective hip or knee replacement surgery, treatment and secondary prevention of venous thromboembolism, prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation having one or more risk factors, and in Europe, prevention of atherothrombotic events after an acute coronary syndrome in patients with elevated cardiac biomarkers. However, the precise dose and regimen vary with the indication, leading to this effort to provide clarity concerning the appropriate use of rivaroxaban. This article reviews the clinical development program for rivaroxaban and summarizes the evidence for each approved, indication-specific dose regimen.. Although initially investigated for twice-daily dosing, early observations, including the finding that the pharmacodynamic effects of rivaroxaban last longer than the elimination half-life, suggested that once-daily dosing might be attainable and effective. These observations were evaluated within the extensive phase II program, which, together with pharmacology studies, provides the evidence underpinning the selection of once-daily regimens for most, but not all, of the approved clinical indications for rivaroxaban.. The evidence for each dosing regimen demonstrates that although pharmacology studies are of paramount importance, dose regimens must be subjected to careful empirical validation. Once-daily dosing was shown to be clinically appropriate for most rivaroxaban indications. Furthermore, a "one size fits all" approach to dosing frequency is unlikely to result in a regimen that yields optimal patient outcomes across different indications.

Topics: Adult; Cardiovascular Diseases; Clinical Trials as Topic; Dose-Response Relationship, Drug; Evidence-Based Medicine; Factor Xa Inhibitors; Humans; Rivaroxaban; Treatment Outcome

This study investigated the efficacy and safety of novel oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) and heart failure (HF) by a meta-analysis.. AF is quite prevalent in patients with HF.. Four phase III clinical trials comparing NOACs to warfarin in patients with AF were included. Each patient was defined as affected by HF according to the criteria of the trial in which the patient was enrolled. Pre-specified outcomes were the composite of stroke/systemic embolism (SSE); major, intracranial, and any bleeding; and cardiovascular (CV) and all-cause death.. A total of 55,011 patients were enrolled, 26,384 (48%) with HF, and 28,627 (52%) without HF; 27,518 receiving NOACs and 27,493 receiving warfarin (median, 70 years of age; 36% females; follow-up: 1.5 to 2.8 years). Rates of SSE (relative risk [RR]: 0.98; 95% confidence interval [CI]: 0.90 to 1.07]; p = 0.68) and major bleeding (RR: 0.95; 95% CI: 0.88 to 1.03; p = 0.21) were comparable in patients with and without HF. HF patients had reduced rates of any (RR: 0.86; 95% CI: 0.81 to 0.91; p < 0.01) and intracranial (RR: 0.74 95% CI: 0.63 to 0.88; p < 0.01) bleeding but increased rates of all-cause (RR: 1.70 95% CI: 1.31 to 2.19; p < 0.01) and CV death (RR: 2.05 95% CI: 1.66 to 2.55; p < 0.01). NOACs, compared with warfarin significantly reduced SSE and major, intracranial, and any bleeding, regardless of the presence or absence of HF (p. Patients with AF and HF had increased mortality but reduced rates of intracranial and any bleeding compared with the no-HF patients, with no differences in rates of SSE and major bleeding. NOACs significantly reduced SSE, major bleeding, and intracranial hemorrhage in HF patients. No interactions in efficacy and safety of NOACs were observed between AF patients with and without HF.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Atrial Fibrillation; Cardiovascular Diseases; Cause of Death; Dabigatran; Embolism; Factor Xa Inhibitors; Heart Failure; Hemorrhage; Humans; Intracranial Hemorrhages; Mortality; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Treatment Outcome; Warfarin

Anticoagulation is important in the management of cardiovascular disorders; however, traditional anticoagulants such as heparins and vitamin K antagonists (VKAs) have limitations, including parenteral administration with the former and the need for coagulation monitoring and dose adjustments with the latter. Three non-VKA oral anticoagulants (OACs), dabigatran, rivaroxaban and apixaban, are available for the prevention of stroke in patients with atrial fibrillation (AF) and may change clinical practice. This article reviews current knowledge and important unanswered questions on the use of these agents in patients with cardiovascular disease.. A literature search was performed using PubMed and the search terms dabigatran, rivaroxaban, apixaban, AF and acute coronary syndrome (ACS). Peer-reviewed, published clinical trials, review articles, relevant treatment guidelines and prescribing information documents were identified and reviewed for relevance.. Dabigatran is an oral direct thrombin inhibitor; rivaroxaban and apixaban are oral direct Factor Xa inhibitors. These agents have a quicker onset and offset of action, more predictable pharmacokinetic and pharmacodynamic profiles, and fewer drug-drug interactions than VKAs, allowing use of fixed doses. For the prevention of stroke in patients with AF, the non-VKA OACs were either non-inferior or superior to warfarin with similar or improved bleeding profiles, particularly with respect to reductions in intracranial haemorrhage. In patients with ACS receiving dual antiplatelet therapy, the addition of rivaroxaban significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke without increasing fatal bleeding, but led to higher rates of major bleeding. Dose reductions with non-VKA OACs are mandated in certain circumstances in patients with AF, such as moderate renal impairment. Contraindications include creatinine clearance <15 mL/min (<30 mL/min for dabigatran in Europe and Canada) and moderate or severe hepatic impairment, but patients can be transitioned to other anticoagulants if appropriate. It is unknown which non-VKA OAC is optimal for stroke prevention in patients with AF, although factors such as co-medications (e.g. dabigatran may be preferred if a patient is taking a co-medication that is a strong cytochrome P450 3A4 inhibitor) and renal function (rivaroxaban and apixaban depend less on renal clearance than dabigatran) will be important for individual patients. Addition of rivaroxaban to antiplatelet therapy for prevention of recurrent events in patients with recent ACS is approved in Europe for patients at the highest risk (with elevated cardiac biomarkers) and must take into account the increased risk of major bleeding. Although routine coagulation monitoring is not required, an understanding of which assays are appropriate for each non-VKA OAC and how they are affected is important. In a bleeding emergency, non-specific prohaemostatic agents are suggested to reverse the action of the non-VKA OACs, but more clinical data are needed.. Non-VKA OACs provide similar or improved efficacy and, on current evidence, improved safety. They provide greater convenience, compared with traditional anticoagulants for the prevention of stroke in patients with AF. Rivaroxaban may be of benefit to selected high-risk patients with ACS. Selection of the most appropriate non-VKA OAC will depend on individual patient factors.

Topics: Administration, Oral; Animals; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Stroke; Thiophenes

The use of oral anticoagulants is increasing because of the rising prevalence of atrial fibrillation and other cardiovascular diseases that occur in an aging population. In the last decade, several new oral anticoagulants have emerged, comprising the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban. Although these new anticoagulants may not affect clear corneal cataract surgery, their use will impact the management of patients having eyelid, orbital, and nasolacrimal procedures. The objective of this review is to provide a concise and practical approach to the perioperative management of patients who require an oculoplastic procedure and are receiving these new anticoagulants.

Topics: Administration, Oral; Anticoagulants; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Cataract Extraction; Dabigatran; Humans; Morpholines; Pyrazoles; Pyridones; Rivaroxaban; Surgery, Plastic; Thiophenes

The primary objective was to assess the cost-effectiveness of new oral anticoagulants compared with warfarin in patients with nonvalvular atrial fibrillation. Secondary objectives related to assessing the cost-effectiveness of new oral anticoagulants stratified by center-specific time in therapeutic range, age, and CHADS2 score.. Cost-effectiveness was assessed by the incremental cost per quality-adjusted life-year (QALY) gained. Analysis used a Markov cohort model that followed patients from initiation of pharmacotherapy to death. Transition probabilities were obtained from a concurrent network meta-analysis. Utility values and costs were obtained from published data. Numerous deterministic sensitivity analyses and probabilistic analysis were conducted.. The incremental cost per QALY gained for dabigatran 150 mg versus warfarin was $20,797. Apixaban produced equal QALYs at a higher cost. Dabigatran 110 mg and rivaroxaban were dominated by dabigatran 150 mg and apixaban. Results were sensitive to the drug costs of apixaban, the time horizon adopted, and the consequences from major and minor bleeds with dabigatran. Results varied by a center's average time in therapeutic range, a patient's CHADS2 score, and patient age, with either dabigatran 150 mg or apixaban being optimal.. Results were highly sensitive to patient characteristics. Rivaroxaban and dabigatran 110 mg were unlikely to be cost-effective. For different characteristics, apixaban or dabigatran 150 mg were optimal. Thus, the choice between these two options may come down to the price of apixaban and further evidence on the impact of major and minor bleeds with dabigatran.

Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Cost-Benefit Analysis; Dabigatran; Drug Costs; Hemorrhage; Humans; Markov Chains; Middle Aged; Morpholines; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Rivaroxaban; Stroke; Thiophenes; Time Factors; Warfarin

Oral anticoagulation has been limited to vitamin K antagonists (VKAs) for over 60 years. VKAs are effective and recommended for the prevention of venous and arterial thromboembolism in cardiovascular disease, but their pharmacodynamics are difficult to predict and the highly variable interindividual and intraindividual response to treatment accounts for the need of continuous monitoring. This prompted the intensive exploration of numerous substances within the last decade in an attempt to meet the shortcomings of current oral anticoagulation with VKAs. The development and clinical investigation of two novel groups of oral anticoagulants targeting central factors of the coagulation system either factor Xa or thrombin (factor IIa) has now reached the daily clinical practice with the approval of the oral direct thrombin inhibitor dabigatran etexilate and the oral direct factor Xa inhibitor rivaroxaban. Ongoing clinical trials are investigating these substances and other novel oral anticoagulants with similar mechanisms of action in patients with atrial fibrillation and acute coronary syndromes. This review article discusses the clinical evaluation and pharmacological properties of novel oral anticoagulants in late and earlier stages of clinical development, thereby providing a critical analysis and an outlook on the future of oral anticoagulation in cardiovascular disease.

Topics: Administration, Oral; Animals; Anticoagulants; Benzimidazoles; Cardiovascular Diseases; Dabigatran; Factor Xa Inhibitors; Humans; Morpholines; Prothrombin; Pyridines; Rivaroxaban; Thiophenes; Vitamin K

For more than 50 years, warfarin has single-handedly ruled the world of anti-coagulation without any competition, whatsoever! The anticoagulant was made available in 1940 and since then no other anti-coagulant has ever been able to match it in the clinical arena. But it looks like that the advances in the field of anti-coagulation, for the first time, have seriously started to erode its base. This review takes a look at rivaroxaban, a direct factor Xa inhibitor and one of the most foremost competitors of warfarin.

Topics: Anticoagulants; Biological Availability; Blood Coagulation; Cardiovascular Diseases; Drug Monitoring; Factor Xa Inhibitors; Humans; Morpholines; Outcome Assessment, Health Care; Pharmacovigilance; Rivaroxaban; Thiophenes

Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation.. We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2-20 years), subclinical inflammation (high-sensitivity C-reactive protein 2-10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro.. Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl. Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding.. ClinicalTrials.gov NCT02164578.. The study was supported by a research grant from Bayer Vital AG, Germany.

Topics: Aspirin; Biomarkers; Cardiovascular Diseases; Cell-Derived Microparticles; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Prospective Studies; Pulse Wave Analysis; Risk Factors; Rivaroxaban

Topics: Aged; Aspirin; Cardiovascular Diseases; China; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Prospective Studies; Rivaroxaban; Secondary Prevention

Low-dose rivaroxaban reduced major adverse cardiac and limb events among patients with stable atherosclerotic vascular disease (ASCVD) in the COMPASS trial. The objective of our study was to evaluate the eligibility and budgetary impact of the COMPASS trial in a real-world population.. The VA administrative and clinical databases were utilized to conduct a cross-sectional study to identify patients eligible for low-dose rivaroxaban receiving care at all 141 facilities between October 1, 2014 and September 30, 2015. Proportion of patients with stable ASCVD eligible for low-dose rivaroxaban and prevalence of multiple risk enrichment criteria among eligible patients. Pharmaceutical budgetary impact using VA pharmacy pricing. Chi-squared and Student's t tests were used to compare patients eligible versus ineligible patients.. From an initial cohort of 1,248,214 patients with ASCVD, 488,495 patients (39.1%) met trial eligibility criteria. Eligible patients were older (74.2 vs 64.5 years) with higher proportion of hypertension (84.1% vs 82.1%) and diabetes (46.2% vs 32.9) compared with ineligible patients (p < 0.001 for all comparisons). A median of 38.7% (IQR 4.6%) of total ASCVD patients per facility were rivaroxaban eligible. Estimated annual VA pharmacy budgetary impact would range from $0.47 billion to $1.88 billion for 25% to 100% treatment penetration. Annual facility level pharmaceutical budgetary impact would be a median of $12.3 million (IQR $8.0-$16.3 million) for treatment of all eligible patients. Among eligible patients, age greater than 65 years was the most common risk enrichment factor (86.9%). Prevalence of eligible patients with multiple enrichment factors varied from 34.2% (one factor) to 6.2% (four or more).. Over one third of patients with stable ASCVD may qualify for low-dose rivaroxaban within the VA. Additional studies are needed to understand eligibility in other populations and a formal cost-effectiveness analysis is warranted.

Topics: Age Factors; Aged; Aged, 80 and over; Aspirin; Atherosclerosis; Budgets; Cardiovascular Diseases; Cigarette Smoking; Cross-Sectional Studies; Diabetes Mellitus; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Health Expenditures; Hemorrhage; Humans; Male; Middle Aged; Peripheral Arterial Disease; Renal Insufficiency, Chronic; Rivaroxaban; United States; United States Department of Veterans Affairs

Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin.. To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities.. This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020.. A combination of low-dose rivaroxaban and aspirin compared with aspirin alone.. Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding.. The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%).. Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk.

Topics: Aged; Amputation, Surgical; Aspirin; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Double-Blind Method; Factor Xa Inhibitors; Female; Heart Failure; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prognosis; Renal Insufficiency; Rivaroxaban; Severity of Illness Index; Stroke

In patients with normal renal function or early stage CKD, the risk-benefit profile of direct oral anticoagulants (DOACs) is superior to that of vitamin K antagonists (VKAs). In patients on hemodialysis, the comparative efficacy and safety of DOACs versus VKAs are unknown.. In the Valkyrie study, 132 patients on hemodialysis with atrial fibrillation were randomized to a VKA with a target INR of 2-3, 10 mg rivaroxaban daily, or rivaroxaban and vitamin K2 for 18 months. Patients continued the originally assigned treatment and follow-up was extended for at least an additional 18 months. The primary efficacy end point was a composite of fatal and nonfatal cardiovascular events. Secondary efficacy end points were individual components of the composite outcome and all-cause death. Safety end points were life-threatening, major, and minor bleeding.. Median (IQR) follow-up was 1.88 (1.01-3.38) years. Premature, permanent discontinuation of anticoagulation occurred in 25% of patients. The primary end point occurred at a rate of 63.8 per 100 person-years in the VKA group, 26.2 per 100 person-years in the rivaroxaban group, and 21.4 per 100 person-years in the rivaroxaban and vitamin K2 group. The estimated competing risk-adjusted hazard ratio for the primary end point was 0.41 (95% CI, 0.25 to 0.68;. In patients on hemodialysis with atrial fibrillation, a reduced dose of rivaroxaban significantly decreased the composite outcome of fatal and nonfatal cardiovascular events and major bleeding complications compared with VKA.. Oral Anticoagulation in Hemodialysis, NCT03799822.

Topics: Aged; Aged, 80 and over; Antifibrinolytic Agents; Atrial Fibrillation; Cardiovascular Diseases; Factor Xa Inhibitors; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Mortality; Renal Dialysis; Renal Insufficiency, Chronic; Rivaroxaban; Vitamin K; Vitamin K 2

Subclinical leaflet thickening and reduced leaflet motion of bioprosthetic aortic valves have been documented by four-dimensional computed tomography (CT). Whether anticoagulation can reduce these phenomena after transcatheter aortic-valve replacement (TAVR) is not known.. In a substudy of a large randomized trial, we randomly assigned patients who had undergone successful TAVR and who did not have an indication for long-term anticoagulation to a rivaroxaban-based antithrombotic strategy (rivaroxaban [10 mg] plus aspirin [75 to 100 mg] once daily) or an antiplatelet-based strategy (clopidogrel [75 mg] plus aspirin [75 to 100 mg] once daily). Patients underwent evaluation by four-dimensional CT at a mean (±SD) of 90±15 days after randomization. The primary end point was the percentage of patients with at least one prosthetic valve leaflet with grade 3 or higher motion reduction (i.e., involving >50% of the leaflet). Leaflet thickening was also assessed.. A total of 231 patients were enrolled. At least one prosthetic valve leaflet with grade 3 or higher motion reduction was found in 2 of 97 patients (2.1%) who had scans that could be evaluated in the rivaroxaban group, as compared with 11 of 101 (10.9%) in the antiplatelet group (difference, -8.8 percentage points; 95% confidence interval [CI], -16.5 to -1.9; P = 0.01). Thickening of at least one leaflet was observed in 12 of 97 patients (12.4%) in the rivaroxaban group and in 33 of 102 (32.4%) in the antiplatelet group (difference, -20.0 percentage points; 95% CI, -30.9 to -8.5). In the main trial, the risk of death or thromboembolic events and the risk of life-threatening, disabling, or major bleeding were higher with rivaroxaban (hazard ratios of 1.35 and 1.50, respectively).. In a substudy of a trial involving patients without an indication for long-term anticoagulation who had undergone successful TAVR, a rivaroxaban-based antithrombotic strategy was more effective than an antiplatelet-based strategy in preventing subclinical leaflet-motion abnormalities. However, in the main trial, the rivaroxaban-based strategy was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than the antiplatelet-based strategy. (Funded by Bayer; GALILEO-4D ClinicalTrials.gov number, NCT02833948.).

Topics: Aged; Aged, 80 and over; Aortic Valve; Aspirin; Atrial Fibrillation; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Four-Dimensional Computed Tomography; Heart Valve Prosthesis; Hemorrhage; Humans; Intention to Treat Analysis; Male; Platelet Aggregation Inhibitors; Rivaroxaban; Thromboembolism; Transcatheter Aortic Valve Replacement

Whether the direct factor Xa inhibitor rivaroxaban can prevent thromboembolic events after transcatheter aortic-valve replacement (TAVR) is unclear.. We randomly assigned 1644 patients without an established indication for oral anticoagulation after successful TAVR to receive rivaroxaban at a dose of 10 mg daily (with aspirin at a dose of 75 to 100 mg daily for the first 3 months) (rivaroxaban group) or aspirin at a dose of 75 to 100 mg daily (with clopidogrel at a dose of 75 mg daily for the first 3 months) (antiplatelet group). The primary efficacy outcome was the composite of death or thromboembolic events. The primary safety outcome was major, disabling, or life-threatening bleeding. The trial was terminated prematurely by the data and safety monitoring board because of safety concerns.. After a median of 17 months, death or a first thromboembolic event (intention-to-treat analysis) had occurred in 105 patients in the rivaroxaban group and in 78 patients in the antiplatelet group (incidence rates, 9.8 and 7.2 per 100 person-years, respectively; hazard ratio with rivaroxaban, 1.35; 95% confidence interval [CI], 1.01 to 1.81; P = 0.04). Major, disabling, or life-threatening bleeding (intention-to-treat analysis) had occurred in 46 and 31 patients, respectively (4.3 and 2.8 per 100 person-years; hazard ratio, 1.50; 95% CI, 0.95 to 2.37; P = 0.08). A total of 64 deaths occurred in the rivaroxaban group and 38 in the antiplatelet group (5.8 and 3.4 per 100 person-years, respectively; hazard ratio, 1.69; 95% CI, 1.13 to 2.53).. In patients without an established indication for oral anticoagulation after successful TAVR, a treatment strategy including rivaroxaban at a dose of 10 mg daily was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding than an antiplatelet-based strategy. (Funded by Bayer and Janssen Pharmaceuticals; GALILEO ClinicalTrials.gov number, NCT02556203.).

Topics: Aged; Aged, 80 and over; Aspirin; Atrial Fibrillation; Cardiovascular Diseases; Clopidogrel; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Heart Valve Prosthesis; Hemorrhage; Humans; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Platelet Aggregation Inhibitors; Rivaroxaban; Thromboembolism; Transcatheter Aortic Valve Replacement

Patients with peripheral artery disease who have undergone lower-extremity revascularization are at high risk for major adverse limb and cardiovascular events. The efficacy and safety of rivaroxaban in this context are uncertain.. In a double-blind trial, patients with peripheral artery disease who had undergone revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) plus aspirin or placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. The principal safety outcome was major bleeding, defined according to the Thrombolysis in Myocardial Infarction (TIMI) classification; major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) was a secondary safety outcome.. A total of 6564 patients underwent randomization; 3286 were assigned to the rivaroxaban group, and 3278 were assigned to the placebo group. The primary efficacy outcome occurred in 508 patients in the rivaroxaban group and in 584 in the placebo group; the Kaplan-Meier estimates of the incidence at 3 years were 17.3% and 19.9%, respectively (hazard ratio, 0.85, 95% confidence interval [CI], 0.76 to 0.96; P = 0.009). TIMI major bleeding occurred in 62 patients in the rivaroxaban group and in 44 patients in the placebo group (2.65% and 1.87%; hazard ratio, 1.43; 95% CI, 0.97 to 2.10; P = 0.07). ISTH major bleeding occurred in 140 patients in the rivaroxaban group, as compared with 100 patients in the placebo group (5.94% and 4.06%; hazard ratio, 1.42; 95% CI, 1.10 to 1.84; P = 0.007).. In patients with peripheral artery disease who had undergone lower-extremity revascularization, rivaroxaban at a dose of 2.5 mg twice daily plus aspirin was associated with a significantly lower incidence of the composite outcome of acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes than aspirin alone. The incidence of TIMI major bleeding did not differ significantly between the groups. The incidence of ISTH major bleeding was significantly higher with rivaroxaban and aspirin than with aspirin alone. (Funded by Bayer and Janssen Pharmaceuticals; VOYAGER PAD ClinicalTrials.gov number, NCT02504216.).

Topics: Aged; Aspirin; Cardiovascular Diseases; Combined Modality Therapy; Double-Blind Method; Drug Therapy, Combination; Endovascular Procedures; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban

Patients with established coronary artery disease or peripheral artery disease often have diabetes mellitus. These patients are at high risk of future vascular events.. In a prespecified analysis of the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies), we compared the effects of rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg daily) versus placebo plus aspirin in patients with diabetes mellitus versus without diabetes mellitus in preventing major vascular events. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included all-cause mortality and all major vascular events (cardiovascular death, myocardial infarction, stroke, or major adverse limb events, including amputation). The primary safety end point was a modification of the International Society on Thrombosis and Haemostasis criteria for major bleeding.. In stable atherosclerosis, the combination of aspirin plus rivaroxaban 2.5 mg twice daily provided a similar relative degree of benefit on coronary, cerebrovascular, and peripheral end points in patients with and without diabetes mellitus. Given their higher baseline risk, the absolute benefits appeared larger in those with diabetes mellitus, including a 3-fold greater reduction in all-cause mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01776424.

Topics: Aged; Anticoagulants; Aspirin; Cardiovascular Diseases; Diabetes Mellitus; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Rivaroxaban

The effects of rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve remain uncertain.. In this randomized trial, we compared rivaroxaban (20 mg once daily) with dose-adjusted warfarin (target international normalized ratio, 2.0 to 3.0) in patients with atrial fibrillation and a bioprosthetic mitral valve. The primary outcome was a composite of death, major cardiovascular events (stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding at 12 months.. A total of 1005 patients were enrolled at 49 sites in Brazil. A primary-outcome event occurred at a mean of 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group (difference calculated as restricted mean survival time, 7.4 days; 95% confidence interval [CI], -1.4 to 16.3; P<0.001 for noninferiority). Death from cardiovascular causes or thromboembolic events occurred in 17 patients (3.4%) in the rivaroxaban group and in 26 (5.1%) in the warfarin group (hazard ratio, 0.65; 95% CI, 0.35 to 1.20). The incidence of stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (hazard ratio, 0.25; 95% CI, 0.07 to 0.88). Major bleeding occurred in 7 patients (1.4%) in the rivaroxaban group and in 13 (2.6%) in the warfarin group (hazard ratio, 0.54; 95% CI, 0.21 to 1.35). The frequency of other serious adverse events was similar in the two groups.. In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months. (Funded by PROADI-SUS and Bayer; RIVER ClinicalTrials.gov number, NCT02303795.).

Topics: Aged; Anticoagulants; Atrial Fibrillation; Bioprosthesis; Cardiovascular Diseases; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Mitral Valve; Rivaroxaban; Single-Blind Method; Stroke; Warfarin

Adding rivaroxaban to aspirin in patients with stable atherosclerotic disease reduces the recurrence of cardiovascular disease (CVD) but increases the risk of major bleeding. The aim of this study was to estimate the individual lifetime treatment benefit and harm of adding low-dose rivaroxaban to aspirin in patients with stable cardiovascular disease.. Patients with established CVD from the COMPASS trial (n = 27 390) and SMART prospective cohort study (n = 8139) were used. Using the pre-existing lifetime SMART-REACH model for recurrent CVD, and a newly developed Fine and Gray competing risk-adjusted lifetime model for major bleeding, individual treatment effects from adding low-dose rivaroxaban to aspirin in patients with stable CVD were estimated, expressed in terms of (i) life-years free of stroke or myocardial infarction (MI) gained; and (ii) life-years free from major bleeding lost. Calibration of the SMART-REACH model for prediction of recurrent CVD events in the COMPASS study was good. The major bleeding risk model as derived in the COMPASS trial showed good external calibration in the SMART cohort. Predicted individual gain in life expectancy free of stroke or MI from added low-dose rivaroxaban had a median of 16 months (range 1-48 months), while predicted individualized lifetime lost in terms of major bleeding had a median of 2 months (range 0-20 months).. There is a wide distribution in lifetime gain and harm from adding low-dose rivaroxaban to aspirin in individual patients with stable CVD. Using these lifetime models, benefits and bleeding risk can be weighed for each individual patient, which could facilitate treatment decisions in clinical practice.

Topics: Aged; Aspirin; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Prospective Studies; Risk Assessment; Rivaroxaban; Stroke

Although acetylsalicylic acid is of proven benefit for secondary prevention in patients with cardiovascular disease, the risk of recurrent ischemic events remains high. Intensification of antithrombotic therapy with more potent antiplatelet drugs, dual antiplatelet therapy, or vitamin K antagonists further reduces the risk of major adverse cardiovascular events compared with acetylsalicylic acid alone but increases the risk of bleeding without reducing mortality. In patients with prior coronary artery disease or peripheral arterial disease the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial revealed that compared with acetylsalicylic acid alone, dual pathway inhibition with low-dose rivaroxaban (2.5 mg twice-daily), an oral factor Xa inhibitor, plus acetylsalicylic acid reduced major adverse cardiovascular event by 24%, major adverse limb events by 47%, and mortality by 18%. Major bleeding was increased by 70%, but there was no increase in fatal or intracranial bleeding. This article (1) reviews the results of the COMPASS trial, (2) explains why dual pathway inhibition is superior to antiplatelet or anticoagulant therapy alone, (3) compares the results with rivaroxaban plus aspirin with those with other antithrombotic regimens, and (4) provides insight into how best to apply the COMPASS results into practice.

Topics: Aged; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Diseases; Chronic Disease; Coronary Artery Disease; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Recurrence; Research Design; Rivaroxaban; Secondary Prevention; Stroke

Antiplatelets and anticoagulants are associated with increased upper gastrointestinal bleeding. We evaluated whether proton pump inhibitor therapy could reduce this risk.. We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease. Participants were randomly assigned to groups given pantoprazole 40 mg daily or placebo, as well as rivaroxaban 2.5 mg twice daily with aspirin 100 mg once daily, rivaroxaban 5 mg twice daily, or aspirin 100 mg alone. The primary outcome was time to first upper gastrointestinal event, defined as a composite of overt bleeding, upper gastrointestinal bleeding from a gastroduodenal lesion or of unknown origin, occult bleeding, symptomatic gastroduodenal ulcer or ≥5 erosions, upper gastrointestinal obstruction, or perforation.. There was no significant difference in upper gastrointestinal events between the pantoprazole group (102 of 8791 events) and the placebo group (116 of 8807 events) (hazard ratio, 0.88; 95% confidence interval [CI], 0.67-1.15). Pantoprazole significantly reduced bleeding of gastroduodenal lesions (hazard ratio, 0.52; 95% confidence interval, 0.28-0.94; P = .03); this reduction was greater when we used a post-hoc definition of bleeding gastroduodenal lesion (hazard ratio, 0.45; 95% confidence interval, 0.27-0.74), although the number needed to treat still was high (n = 982; 95% confidence interval, 609-2528).. In a randomized placebo-controlled trial, we found that routine use of proton pump inhibitors in patients receiving low-dose anticoagulation and/or aspirin for stable cardiovascular disease does not reduce upper gastrointestinal events, but may reduce bleeding from gastroduodenal lesions. ClinicalTrials.gov ID: NCT01776424.

Topics: Administration, Oral; Aged; Anticoagulants; Aspirin; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Pantoprazole; Peptic Ulcer; Proton Pump Inhibitors; Rivaroxaban; Treatment Outcome

Topics: Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Fibrinolytic Agents; Hemorrhage; Humans; Rivaroxaban

Proton pump inhibitors (PPIs) are effective at treating acid-related disorders. These drugs are well tolerated in the short term, but long-term treatment was associated with adverse events in observational studies. We aimed to confirm these findings in an adequately powered randomized trial.. We performed a 3 × 2 partial factorial double-blind trial of 17,598 participants with stable cardiovascular disease and peripheral artery disease randomly assigned to groups given pantoprazole (40 mg daily, n = 8791) or placebo (n = 8807). Participants were also randomly assigned to groups that received rivaroxaban (2.5 mg twice daily) with aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg) alone. We collected data on development of pneumonia, Clostridium difficile infection, other enteric infections, fractures, gastric atrophy, chronic kidney disease, diabetes, chronic obstructive lung disease, dementia, cardiovascular disease, cancer, hospitalizations, and all-cause mortality every 6 months. Patients were followed up for a median of 3.01 years, with 53,152 patient-years of follow-up.. There was no statistically significant difference between the pantoprazole and placebo groups in safety events except for enteric infections (1.4% vs 1.0% in the placebo group; odds ratio, 1.33; 95% confidence interval, 1.01-1.75). For all other safety outcomes, proportions were similar between groups except for C difficile infection, which was approximately twice as common in the pantoprazole vs the placebo group, although there were only 13 events, so this difference was not statistically significant.. In a large placebo-controlled randomized trial, we found that pantoprazole is not associated with any adverse event when used for 3 years, with the possible exception of an increased risk of enteric infections. ClinicalTrials.gov Number: NCT01776424.

Topics: Aged; Aspirin; Cardiovascular Diseases; Double-Blind Method; Drug Administration Schedule; Enterocolitis, Pseudomembranous; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Pantoprazole; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Proton Pump Inhibitors; Risk Assessment; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the combination of low-dose rivaroxaban and aspirin reduced major vascular events in patients with stable vascular disease.. The purpose of this study was to identify subsets of patients at higher risk of recurrent vascular events, which may help focus the use of rivaroxaban and aspirin therapy.. COMPASS patients with vascular disease were risk stratified using 2 methods: the REACH (REduction of Atherothrombosis for Continued Health) atherothrombosis risk score and CART (Classification and Regression Tree) analysis. The absolute risk differences for rivaroxaban with aspirin were compared to aspirin alone over 30 months for the composite of cardiovascular death, myocardial infarction, stroke, acute limb ischemia, or vascular amputation; for severe bleeding; and for the net clinical benefit.. High-risk patients using the REACH score were those with 2 or more vascular beds affected, history of heart failure (HF), or renal insufficiency, and by CART analysis were those with ≥2 vascular beds affected, history of HF, or diabetes. Rivaroxaban and aspirin combination reduced the serious vascular event incidence by 25% (4.48% vs. 5.95%, hazard ratio: 0.75; 95% confidence interval: 0.66 to 0.85), equivalent to 23 events prevented per 1,000 patients treated for 30 months, at the cost of a nonsignificant 34% increase in severe bleeding (1.34; 95% confidence interval: 0.95 to 1.88), or 2 events caused per 1,000 patients treated. Among patients with ≥1 high-risk feature identified from the CART analysis, rivaroxaban and aspirin prevented 33 serious vascular events, whereas in lower-risk patients, rivaroxaban and aspirin treatment led to the avoidance of 10 events per 1,000 patients treated for 30 months.. In patients with vascular disease, further risk stratification can identify higher-risk patients (≥2 vascular beds affected, HF, renal insufficiency, or diabetes). The net clinical benefit remains favorable for most patients treated with rivaroxaban and aspirin compared with aspirin.

Topics: Aged; Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Fibrinolytic Agents; Humans; Male; Middle Aged; Risk Assessment; Rivaroxaban

Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.. In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.. Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65-0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78-1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37-2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23-1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65-0·90, p=0·0012).. In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.. Bayer AG.

Topics: Aged; Aspirin; Cardiovascular Diseases; Coronary Artery Disease; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Morbidity; Myocardial Infarction; Platelet Aggregation Inhibitors; Rivaroxaban; Stroke

Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.. This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.. Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).. Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.. Bayer AG.

Topics: Aged; Amputation, Surgical; Aspirin; Cardiovascular Diseases; Carotid Artery Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Incidence; Lower Extremity; Male; Middle Aged; Morbidity; Myocardial Infarction; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Stroke

In light of the Cardiovascular Outcomes for People using Anticoagulation Strategies (COMPASS) trial, our objective was to assess the cost-effectiveness, from the Australian healthcare perspective, of rivaroxaban in combination with aspirin versus aspirin alone for the prevention of recurrent cardiovascular disease among patients with stable atherosclerotic vascular disease.. A Markov model was developed using input data from the COMPASS trial to predict the clinical course and costs of patients over a 20-year time-horizon. The model comprised of three health states: 'Alive without recurrent CVD', 'Alive after recurrent CVD' and 'Dead'. Costs were from the Australian public healthcare system perspective, and estimated from published sources, as were utility data. The costs of rivaroxaban were based on current acquisition prices on the Australian Pharmaceutical Benefits Schedule (PBS) and assumed as AUD$3.09/day. The main outcome of interest was the incremental cost-effectiveness ratio (ICER) in terms of cost per quality adjusted life year (QALY) gained, and cost per year of life saved (YoLS). Costs and benefits were discounted by 5.0% per year.. Compared to aspirin alone, rivaroxaban plus aspirin was estimated to cost an additional AUD$12,156 (discounted) per person, but lead to 0.516 YoLS (discounted) and 0.386 QALYs gained (discounted), over 20 years. These equated to ICERs of AUD$23,560/YoLS and AUD$31,436/QALY gained. We have assumed a threshold of AUD$50,000/QALY gained to signify cost-effectiveness.. Compared to aspirin, rivaroxaban in combination with aspirin is likely to be cost-effective in preventing recurrent cardiovascular events in patients with stable atherosclerotic vascular disease.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Australia; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Humans; Male; Markov Chains; Middle Aged; Rivaroxaban

Topics: Adult; Aged; Cardiovascular Diseases; Double-Blind Method; Female; Humans; Internal Medicine; Male; Middle Aged; Patient Discharge; Pulmonary Disease, Chronic Obstructive; Respiratory Insufficiency; Risk Factors; Rivaroxaban; Stroke; Thromboembolism

We evaluated whether rivaroxaban alone or in combination with aspirin would be more effective than aspirin alone for secondary cardiovascular prevention.. In this double-blind trial, we randomly assigned 27,395 participants with stable atherosclerotic vascular disease to receive rivaroxaban (2.5 mg twice daily) plus aspirin (100 mg once daily), rivaroxaban (5 mg twice daily), or aspirin (100 mg once daily). The primary outcome was a composite of cardiovascular death, stroke, or myocardial infarction. The study was stopped for superiority of the rivaroxaban-plus-aspirin group after a mean follow-up of 23 months.. The primary outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; hazard ratio, 0.76; 95% confidence interval [CI], 0.66 to 0.86; P<0.001; z=-4.126), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; hazard ratio, 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P=0.01; threshold P value for significance, 0.0025). The primary outcome did not occur in significantly fewer patients in the rivaroxaban-alone group than in the aspirin-alone group, but major bleeding events occurred in more patients in the rivaroxaban-alone group.. Among patients with stable atherosclerotic vascular disease, those assigned to rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes and more major bleeding events than those assigned to aspirin alone. Rivaroxaban (5 mg twice daily) alone did not result in better cardiovascular outcomes than aspirin alone and resulted in more major bleeding events. (Funded by Bayer; COMPASS ClinicalTrials.gov number, NCT01776424 .).

Topics: Aged; Aspirin; Atherosclerosis; Cardiovascular Diseases; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

Optimal antithrombotic treatment after transcatheter aortic valve replacement (TAVR) is unknown and determined empirically. The direct factor Xa inhibitor rivaroxaban may potentially reduce TAVR-related thrombotic complications and premature valve failure.. GALILEO is an international, randomized, open-label, event-driven, phase III trial in more than 1,520 patients without an indication for oral anticoagulation who underwent a successful TAVR (ClinicalTrials.govNCT02556203). Patients are randomized (1:1 ratio), 1 to 7days after a successful TAVR, to either a rivaroxaban-based strategy or an antiplatelet-based strategy. In the experimental arm, subjects receive rivaroxaban (10mg once daily [OD]) plus acetylsalicylic acid (ASA, 75-100mg OD) for 90days followed by rivaroxaban alone. In the control arm, subjects receive clopidogrel (75mg OD) plus ASA (as above) for 90days followed by ASA alone. In case new-onset atrial fibrillation occurs after randomization, full oral anticoagulation will be implemented with maintenance of the original treatment assignment. The primary efficacy end point is the composite of all-cause death, stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep venous thrombosis, and systemic embolism. The primary safety end point is the composite of life-threatening, disabling, and major bleeding, according to the Valve Academic Research Consortium definitions.. GALILEO will test the hypothesis that a rivaroxaban-based antithrombotic strategy reduces the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with the currently recommended antiplatelet therapy-based strategy in subjects without need of chronic oral anticoagulation.

Topics: Aortic Valve Stenosis; Aspirin; Cardiovascular Diseases; Cause of Death; Clopidogrel; Drug Therapy, Combination; Embolism; Factor Xa Inhibitors; Heart Valve Diseases; Humans; Mortality; Myocardial Infarction; Platelet Aggregation Inhibitors; Postoperative Care; Pulmonary Embolism; Rivaroxaban; Stroke; Thrombosis; Ticlopidine; Transcatheter Aortic Valve Replacement; Venous Thrombosis

Andexanet alfa (andexanet) is a recombinant modified human factor Xa decoy protein that has been shown to reverse the inhibition of factor Xa in healthy volunteers.. In this multicenter, prospective, open-label, single-group study, we evaluated 67 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor. The patients all received a bolus of andexanet followed by a 2-hour infusion of the drug. Patients were evaluated for changes in measures of anti-factor Xa activity and were assessed for clinical hemostatic efficacy during a 12-hour period. All the patients were subsequently followed for 30 days. The efficacy population of 47 patients had a baseline value for anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.5 IU per milliliter for those receiving enoxaparin) and had confirmed bleeding severity at adjudication.. The mean age of the patients was 77 years; most of the patients had substantial cardiovascular disease. Bleeding was predominantly gastrointestinal or intracranial. The mean (±SD) time from emergency department presentation to the administration of the andexanet bolus was 4.8±1.8 hours. After the bolus administration, the median anti-factor Xa activity decreased by 89% (95% confidence interval [CI], 58 to 94) from baseline among patients receiving rivaroxaban and by 93% (95% CI, 87 to 94) among patients receiving apixaban. These levels remained similar during the 2-hour infusion. Four hours after the end of the infusion, there was a relative decrease from baseline of 39% in the measure of anti-factor Xa activity among patients receiving rivaroxaban and of 30% among those receiving apixaban. Twelve hours after the andexanet infusion, clinical hemostasis was adjudicated as excellent or good in 37 of 47 patients in the efficacy analysis (79%; 95% CI, 64 to 89). Thrombotic events occurred in 12 of 67 patients (18%) during the 30-day follow-up.. On the basis of a descriptive preliminary analysis, an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-factor Xa activity in patients with acute major bleeding associated with factor Xa inhibitors, with effective hemostasis occurring in 79%. (Funded by Portola Pharmaceuticals; ANNEXA-4 ClinicalTrials.gov number, NCT02329327 .).

Topics: Acute Disease; Aged; Aged, 80 and over; Cardiovascular Diseases; Enoxaparin; Factor Xa; Factor Xa Inhibitors; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Infusions, Intravenous; Intracranial Hemorrhages; Male; Prospective Studies; Pyrazoles; Pyridones; Recombinant Proteins; Rivaroxaban; Thrombosis

In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) with placement of stents, standard anticoagulation with a vitamin K antagonist plus dual antiplatelet therapy (DAPT) with a P2Y. We randomly assigned 2124 participants with nonvalvular atrial fibrillation who had undergone PCI with stenting to receive, in a 1:1:1 ratio, low-dose rivaroxaban (15 mg once daily) plus a P2Y. The rates of clinically significant bleeding were lower in the two groups receiving rivaroxaban than in the group receiving standard therapy (16.8% in group 1, 18.0% in group 2, and 26.7% in group 3; hazard ratio for group 1 vs. group 3, 0.59; 95% confidence interval [CI], 0.47 to 0.76; P<0.001; hazard ratio for group 2 vs. group 3, 0.63; 95% CI, 0.50 to 0.80; P<0.001). The rates of death from cardiovascular causes, myocardial infarction, or stroke were similar in the three groups (Kaplan-Meier estimates, 6.5% in group 1, 5.6% in group 2, and 6.0% in group 3; P values for all comparisons were nonsignificant).. In participants with atrial fibrillation undergoing PCI with placement of stents, the administration of either low-dose rivaroxaban plus a P2Y

Topics: Aged; Atrial Fibrillation; Cardiovascular Diseases; Confidence Intervals; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Rivaroxaban; Stents; Vitamin K

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

Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users.. In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers.. In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1 years, Netherlands -2.4 years; P < .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P < .001) than nonusers.. There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice.

Topics: Atherosclerosis; Cardiovascular Diseases; Cross-Sectional Studies; Female; Humans; Male; Netherlands; Rivaroxaban; United Kingdom

Cardiovascular disease (CVD) is the leading cause of death in various complications of type 2 diabetes mellitus (T2DM). Rivaroxaban (Xarelto; Bayer), an oral direct factor Xa (FXa) inhibitor, prevents the activation of the coagulation cascade in CVD. Considering its anticoagulant and anti-inflammatory effects, we assessed the hypothesis that rivaroxaban treatment may attenuate the vascular lesion and dysfunction in T2DM mice. C57BL/6, BKS-db/db, BKS-db/+, wild-type (WT), and NLRP3

Topics: Animals; Cardiovascular Diseases; Carotid Intima-Media Thickness; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelial Cells; Inflammasomes; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Rivaroxaban

The population of elderly with cardiovascular diseases and multimorbidity is rapidly growing. For decades, different antithrombotic therapies have been studied to find the most effective therapy in reducing the risk of cardiovascular events. Recently, large trials have investigated a new antithrombotic therapy consisting of a platelet aggregation inhibitor and a low-dose anticoagulant (aspirin plus rivaroxaban). This combination inhibits both primary and secondary haemostasis, and is therefore called 'dual pathway inhibition' (DPI). DPI leads to a further reduction of the risk of ischemic cardiovascular events as compared to aspirin monotherapy, but increases the risk of bleeding. The population at high risk of ischemic events, but without an increased bleeding risk, is expected to experience the highest risk reduction and therefore the highest net clinical benefit of DPI. This population consists of patients with polyvascular disease, heart failure, renal insufficiency, diabetes mellitus and other uncontrolled risk factors.

Topics: Aged; Anticoagulants; Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

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

This study aimed to investigate the cost-effectiveness of low-dose rivaroxaban plus aspirin versus aspirin alone for patients with stable cardiovascular diseases in the Taiwan setting.. We constructed a Markov model to project the lifetime direct medical costs and quality-adjusted life-years of both therapies. Transitional probabilities were derived from the COMPASS trial, and the costs and utilities were obtained from the Taiwan National Health Insurance Database and published studies. One-way, scenario, subgroup, and probabilistic sensitivity analyses were performed to assess the uncertainty. Incremental cost-effectiveness ratio was presented as the outcome. The threshold of willingness-to-pay was set at US$76,368 (3 times the gross domestic product per capita of Taiwan). All analyses were operated by TreeAge 2019 and Microsoft Excel.. The incremental cost-effectiveness ratios of rivaroxaban plus aspirin versus aspirin alone in the patients with stable cardiovascular diseases, coronary artery diseases, and peripheral artery diseases were US$83,459, US$69,852 and -US$13,823 per quality-adjusted life-year gained, respectively. The probabilistic sensitivity analyses showed that the probabilities of cost-effectiveness for the regimen with rivaroxaban among those with cardiovascular diseases and coronary artery diseases were 44.1% and 65.3% at US$76,368.. Low-dose rivaroxaban plus aspirin is less likely to be a cost-effective alternative to aspirin in secondary prevention for the patients with stable cardiovascular diseases; however, among these patients, the regimen may have pharmacoeconomic incentives for the group merely having chronic coronary artery diseases from the Taiwan national payer's perspective. The pharmacoeconomic incentives are influenced by the drug price, event treatment fees, and willingness-to-pay threshold.

Topics: Anticoagulants; Aspirin; Cardiovascular Diseases; Coronary Artery Disease; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Factor Xa Inhibitors; Health Expenditures; Humans; Markov Chains; Peripheral Arterial Disease; Quality-Adjusted Life Years; Rivaroxaban; Secondary Prevention; Taiwan

Crossover between direct oral anticoagulants (DOACs) has been underinvestigated, but happens frequently in clinical practice. The purpose of this study was to evaluate causes, rates and outcomes of a DOAC-to-DOAC switch.. Patients receiving their first DOAC prescription at the Anticoagulation Center, Cardiology Dept, Bologna-Bellaria Hospital in 2017-2018 were consecutively included and prospectively followed up. DOAC-to-DOAC switch was the main outcome; causes of switch (cardiovascular events and noncardiovascular drug-related adverse events) had direct biannual assessment before and after the switch.. Among 300 patients enrolled (mean age = 79.3 years, mean follow-up = 1.5 years), with no difference in cardiovascular risk factors depending on index DOAC, 13% underwent DOAC-to-DOAC switch, minor bleeding and noncardiovascular adverse events being the most frequent causes. Dabigatran carried a three-fold increase in risk of switch compared with other DOACs, but the mean age of patients who switched was 83. Factors leading to switch resolved in 87% of cases afterwards. Annual rates of cardiovascular/noncardiovascular V events did not differ before and after the switch.. DOAC-to-DOAC switch happens in 9% of patients using DOAC each year, and seems not to impact rates of cardiovascular events after switch. Dabigatran, in the elderly, might be associated with a higher risk of DOAC-to-DOAC switch. Further studies are needed to confirm the long-term safety and effectiveness of switching paradigm.

Topics: Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Dabigatran; Drug Monitoring; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Factor Xa Inhibitors; Female; Heart Disease Risk Factors; Humans; Italy; Long Term Adverse Effects; Male; Medication Therapy Management; Risk Adjustment; Rivaroxaban

Rivaroxaban reduces the risk of thromboembolism in atrial fibrillation (AF) patients, who often also receive antiarrhythmic drugs (AADs) to maintain sinus rhythm. Current guidelines contraindicate concomitant use of rivaroxaban with the popular AAD dronedarone, despite little data demonstrating interactions with AADs. This study investigates the outcomes of concomitant rivaroxaban and AAD drug use in a real-world cohort.. This retrospective study included 1777 non-permanent AF patients taking rivaroxaban for ≥ 1 month between 2011 and 2016 from a multicenter cohort in Taiwan, and compared concomitant AAD use against clinical outcome endpoints for safety, effectiveness, and major adverse cardiac events (MACE). Multivariate Cox proportional hazard analyses were used to evaluate the association between concomitant AAD use and outcomes.. Patients were divided into rivaroxaban alone (n = 1205) and with concomitant amiodarone (n = 177), dronedarone (n = 231), or propafenone (n = 164) groups. The proportion of patients using rivaroxaban 10 mg was highest in the concomitant dronedarone group: rivaroxaban alone, 53.6%; with amiodarone, 57.6%; with dronedarone, 77.1%; and with propafenone, 46.3% (p < 0.001). The cumulative incidences of safety (p = 0.892), effectiveness (p = 0.336), and MACE (p = 0.674) were similar between the four groups; however, there were significantly fewer new systemic thromboembolisms in the dronedarone group: rivaroxaban alone, 2.5%; with amiodarone, 0.6%; with dronedarone, 0%; and with propafenone, 1.2% (p = 0.029). The all-cause death rate was also lowest in the dronedarone group: rivaroxaban alone, 9.0%; with amiodarone, 9.6%; with dronedarone, 3.0%; and with propafenone: 6.1% (p = 0.013). After covariate adjustment, there were no differences in the safety, effectiveness, and MACE endpoints between patients receiving or not receiving AADs.. Concomitant use of rivaroxaban with AADs appears to be well tolerated, warranting further investigation into the apparent benefits of a reduced dose of rivaroxaban combined with dronedarone.

Topics: Aged; Aged, 80 and over; Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Cardiovascular Diseases; Dronedarone; Drug Therapy, Combination; Female; Hemorrhage; Humans; Male; Middle Aged; Propafenone; Retrospective Studies; Rivaroxaban; Taiwan

Topics: Body Mass Index; Cardiovascular Diseases; Fibrinolytic Agents; Humans; Rivaroxaban; Warfarin

Dual pathway inhibition with 2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily may be a promising alternative to 100 mg aspirin antiplatelet therapy for the prevention of cardiovascular events in patients with coronary artery disease and/or peripheral arterial disease. However, treatment costs and bleeding risks are higher, and there is another treatment option for peripheral arterial disease, 75 mg clopidogrel. A comprehensive assessment of benefits, risks and costs of dual pathway inhibition versus standard of care is needed.. We used a state transition model including cardiovascular, ischaemic limb and bleeding events to compare dual pathway inhibition to aspirin antiplatelet therapy in coronary artery disease, and additionally to clopidogrel antiplatelet therapy in peripheral arterial disease patients. We calculated the incremental cost-effectiveness ratio from costs and quality-adjusted life-years of lifelong treatment, and the cost-effectiveness probability at a €50,000/quality-adjusted life-year threshold.. Quality-adjusted life-years and costs of dual pathway inhibition were highest, the incremental cost-effectiveness ratios versus aspirin were €32,109 in coronary artery disease and €26,381 in peripheral arterial disease patients, with 92% and 56% cost-effectiveness probability, respectively (clopidogrel was extendedly dominated). Incremental cost-effectiveness ratios were below €20,000 in comorbid peripheral arterial disease patients and coronary artery disease patients younger than 65 years, incremental cost-effectiveness ratios were above €50,000 in carotid artery disease patients and coronary artery disease patients older than 75 years.. Lifelong preventive treatment of coronary artery disease and peripheral arterial disease patients at risk of cardiovascular events with dual pathway inhibition improves health outcomes and seems overall cost-effective relative to aspirin antiplatelet therapy and also to clopidogrel antiplatelet therapy for peripheral arterial disease, particularly in comorbid patients, but not in older patients and in carotid artery disease patients. These findings may warrant a targeted approach.

Topics: Aspirin; Cardiovascular Diseases; Cost-Benefit Analysis; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Models, Economic; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Quality-Adjusted Life Years; Rivaroxaban

In patients with stable ischemic heart disease (IHD) and/or peripheral artery disease (PAD), current secondary prevention, including the antiplatelet monotherapy, is associated with a significant residual risk of recurrent cardiovascular complications (CVC). Practical application of results from many modern studies evaluating the effect of secondary prevention of atherothrombosis is complicated. An additional influence on coagulation may play a key role in prevention of atherothrombosis. In the COMPASS study, adding rivaroxaban 2.5 mg, b.i.d., to the acetylsalicylic acid (ASA) monotherapy significantly reduced the risk of death from cardiovascular complications, myocardial infarction or stroke, or all-cause death compared to the ASA monotherapy, in patients with IHD or PAD. The combination antithrombotic therapy was associated with an increased risk of major, but not fatal, or intracranial bleeding. In addition, PAD patients had a reduced risk of severe ischemic lower limb complications, including amputations. According to the subgroup analysis in the COMPASS study, supplementing ASA with rivaroxaban 2.5 mg, b.i.d., may appear most beneficial for patients with stable atherosclerotic disease and with a high risk of severe CVC without causing an increased risk of bleeding.

Topics: Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

No outside funding supported this commentary. The authors have nothing to disclose.

Topics: Age Factors; Aspirin; Cardiovascular Diseases; Cost-Benefit Analysis; Dose-Response Relationship, Drug; Drug Costs; Drug Therapy, Combination; Drug Utilization Review; Early Termination of Clinical Trials; Eicosapentaenoic Acid; Hemorrhage; Humans; Medicare; Models, Economic; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Rivaroxaban; Time Factors; Treatment Outcome; United States

Up to 10% of the >3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.

Topics: Aged; Anticoagulants; Aspirin; Cardiovascular Diseases; Gastrointestinal Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Rivaroxaban

Topics: Aspirin; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cardiovascular Diseases; Factor Xa Inhibitors; Health Knowledge, Attitudes, Practice; Humans; Middle Aged; Patient Education as Topic; Rivaroxaban; Surveys and Questionnaires; Video Recording; Young Adult

Atrial fibrillation (AF) prevalence increases with age; > 80% of US adults with AF are aged ≥ 65 years. Compare the risk of stroke/systemic embolism (SE), major bleeding (MB), net clinical outcome (NCO), and major adverse cardiac events (MACE) among elderly non-valvular AF (NVAF) Medicare patients prescribed direct oral anticoagulants (DOACs) VS warfarin. NVAF patients aged ≥ 65 years who initiated DOACs (apixaban, dabigatran, and rivaroxaban) or warfarin were selected from 01JAN2013-31DEC2015 in CMS Medicare data. Propensity score matching was used to balance DOAC and warfarin cohorts. Cox proportional hazards models estimated the risk of stroke/SE, MB, NCO, and MACE. 37,525 apixaban-warfarin, 18,131 dabigatran-warfarin, and 55,359 rivaroxaban-warfarin pairs were included. Compared to warfarin, apixaban (HR: 0.69; 95% CI 0.59-0.81) and rivaroxaban (HR: 0.82; 95% CI 0.73-0.91) had lower risk of stroke/SE, and dabigatran (HR: 0.88; 95% CI 0.72-1.07) had similar risk of stroke/SE. Apixaban (MB: HR: 0.61; 95% CI 0.57-0.67; NCO: HR: 0.64; 95% CI 0.60-0.69) and dabigatran (MB: HR: 0.79; 95% CI 0.71-0.89; NCO: HR: 0.84; 95% CI 0.76-0.93) had lower risk of MB and NCO, and rivaroxaban had higher risk of MB (HR: 1.08; 95% CI 1.02-1.14) and similar risk of NCO (HR: 1.04; 95% CI 0.99-1.09). Compared to warfarin, apixaban had a lower risk for stroke/SE, MB, and NCO; dabigatran had a lower risk of MB and NCO; and rivaroxaban had a lower risk of stroke/SE but higher risk of MB. All DOACs had lower risk of MACE compared to warfarin.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antithrombins; Atrial Fibrillation; Cardiovascular Diseases; Dabigatran; Factor Xa Inhibitors; Hemorrhage; Humans; Medicare; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; United States; Warfarin

To assess the effectiveness and safety of rivaroxaban versus warfarin for the prevention of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with type 2 diabetes (T2D) and non-valvular atrial fibrillation (NVAF).. Using MarketScan data from January 2012 to December 2017, we identified oral anticoagulant-naïve patients with NVAF and comorbid T2D and ≥12 months of insurance coverage prior to rivaroxaban or warfarin initiation. Differences in baseline covariates between cohorts were adjusted for using inverse probability of treatment weights based on propensity scores (absolute standardized differences <0.1 achieved for all covariates after adjustment). Patients were followed until a MACE, MALE or major bleeding event, oral anticoagulant discontinuation/switch, insurance disenrolment or end of data availability. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing the cohorts were calculated using Cox regression.. We identified 10 700 rivaroxaban users (24.1% received a reduced dose) and 13 946 warfarin users. The median (25%, 75% range) age was 70 (62, 79) years, CHA2DS2-VASc score was 4 (3, 5) and duration of available follow-up was 1.4 (0.6, 2.7) years. Eleven percent of patients had peripheral artery disease, 5.1% had coronary artery disease, and 5.1% had a prior MALE, at baseline. Rivaroxaban was associated with a 25% (95% CI 4-41) reduced risk of MACE and a 63% (95% CI 35-79) reduced risk of MALE compared to warfarin. Major bleeding risk did not significantly differ between cohorts (HR 0.95).. Among patients with NVAF and T2D treated in routine practice, rivaroxaban was associated with lower risks of both MACE and MALE versus warfarin, with no significant difference in major bleeding.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Peripheral Arterial Disease; Propensity Score; Retrospective Studies; Rivaroxaban; Treatment Outcome; Warfarin; Young Adult

The development of non-vitamin K-dependent oral anticoagulants (NOACs) is a new alternative to treatment with warfarin. The purpose of this study was to explore drug prescription decisions of NOACs or warfarin from hospital physicians in cardiovascular departments.. A qualitative study with focus group interviews was conducted in three different hospitals. The interview guide explored the background of prescribing anticoagulants (warfarin, dabigatran, rivaroxaban, and apixaban) and experiences with effect and side-effects they had observed in patients.. The systematic text condensation eluded four main themes: when to prescribe NOACs, concern about side-effects, pharmaceutical properties and patient adherence, and prescribing policy and intra-professional communication. All available anticoagulants were prescribed. However, no specific NOAC was preferred. Factors perceived as contraindications for NOACs varied among the doctors. Most had observed side-effects of NOACs; however, these rarely influenced prescribing decisions due to small differences in safety profiles. Few drug-drug interactions and fixed daily doses made NOACs easy to prescribe; but some doctors had experienced lack of drug effect for some patients. Non-adherence with NOACs was harder to spot. Some different prescribing cultures had evolved between the different hospitals and between general practitioners.. The hospital physicians chose anticoagulants based on patient conditions as renal function, bleeding risks, and drug interactions being the most common taken into account. They could not say which NOAC was best, and wish that future studies could compare the different NOACs, and not just compare with warfarin.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Cardiovascular Diseases; Clinical Decision-Making; Dabigatran; Drug Monitoring; Drug Resistance; Factor Xa Inhibitors; Focus Groups; General Practitioners; Hemorrhage; Humans; Medical Staff, Hospital; Medication Adherence; Norway; Practice Patterns, Physicians'; Pyrazoles; Pyridones; Qualitative Research; Risk; Rivaroxaban; Warfarin

Topics: Aspirin; Blood Coagulation; Cardiovascular Diseases; Clinical Decision-Making; Evidence-Based Medicine; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Platelet Activation; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; Rivaroxaban; Thrombosis; Treatment Outcome

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Topics: Anticoagulants; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

Clinical variables including hypertension could be linked with major bleeding events and death beyond vitamin K antagonist (warfarin) or direct oral anti-coagulants (DOACs) treatment strategy.. Subgroup analysis of major bleeding (primary endpoint) associated with clinical variables, site of bleeding, ongoing antithrombotics, reversal treatment or blood transfusion, outcomes (secondary endpoints) was performed in patients with bleeding events submitted to hard 5:1 propensity-score matching for hypertension.. Enrolled patients were 2,792 (mean age, 65.6 ± 19.9 years) during 2-year survey including 166,000 visits, of 200,000 inhabitants catchment area; 8,239 patients received warfarin and 3,797 DOACs. Hypertension account for 1,077 (39%) patients; major bleeding for 474 (17%); death for 29 (1%), and 72 (3%) on 1-month and 1-year, respectively. Hypertension, age, glucose, cancer, ischemic vascular disease, and CHA2D2VASc score were more likely to link with major bleeding. On multivariate analysis, only age (odds ratio [OR], 1.02; P < 0.001), CHA2DS2VASc score ≥ 2 (OR, 2.14; P = 0.001), and glucose (OR, 1.01; P = 0.005) were predictors of major bleeding. Kaplan-Meier analysis demonstrated patients with hypertension as compared with patients without showed 60% versus 20% death on 1-month (P < 0.001). Warfarin compared with DOACs was more likely to present with major bleeding (0.7% versus 0.2%; OR, 2.8; P = 0.005). Receiver operator characteristics analysis showed high value (0.61) of age and glucose over creatinine and systolic arterial pressure (P = NS).. Four in 10 patients with major bleeding showed hypertension; of these 8 in 10 will die within 1 month. Warfarin compared with DOACs was more likely to present with major bleeding.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Blood Glucose; Blood Transfusion; Cardiovascular Diseases; Creatinine; Dabigatran; Emergency Service, Hospital; Epistaxis; Female; Gastrointestinal Hemorrhage; Hematuria; Hemoptysis; Hemorrhage; Humans; Hypertension; Intracranial Hemorrhages; Kaplan-Meier Estimate; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Prognosis; Propensity Score; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Severity of Illness Index; Sex Factors; Thiazoles; Warfarin

Topics: Aspirin; Cardiovascular Diseases; Humans; Orientation; Rivaroxaban

Topics: Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Hemorrhage; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Adjustment; Rivaroxaban; Secondary Prevention

The cardiovascular outcomes for people using anticoagulation strategies (NCT01776424) trial randomized 27,395 patients with stable coronary artery disease or peripheral artery disease (PAD) to receive rivaroxaban 5 mg twice-daily alone, the combination of rivaroxaban 2.5 mg twice-daily and aspirin 100 mg daily, or aspirin 100 mg daily alone. The combination arm resulted in a 24% reduction in the primary end point of cardiovascular death, stroke or myocardial infarction, and an 18% reduction in mortality. Rivaroxaban alone did not produce any additional benefit compared with aspirin. The combination therapy also reduced major adverse limb events, including amputation, in patients with PAD. Based on these results, the addition of rivaroxaban to aspirin is expected to substantially reduce morbidity and mortality in patients with stable coronary or PAD.

Topics: Aspirin; Cardiovascular Diseases; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Rivaroxaban; Treatment Outcome

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: Aspirin; Blood Coagulation; Cardiovascular Diseases; Drug Interactions; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Recurrence; Rivaroxaban; Secondary Prevention; Treatment Outcome

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Cardiology; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban; Transcatheter Aortic Valve Replacement

Topics: Aspirin; Cardiovascular Diseases; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

Topics: Aspirin; Cardiovascular Diseases; Factor Xa Inhibitors; Humans; Rivaroxaban

To examine the long-term persistence and safety of the non-vitamin-K-antagonist oral anticoagulants (NOACs) dabigatran (D), rivaroxaban (R) and apixaban (A) in patients with non-valvular atrial fibrillation (AF) treated in the framework of a well structured, nurse-based AF unit for initiation and follow-up of NOAC.. Retrospective clinical data were collected for 766 consequent patients from a single cardiology outpatient clinic incorporating the AF unit.. The follow-up time, median (q1-q3), was 367 days (183-493) for D patients (n = 233), 432 days (255-546) for R patients (n = 282) and 348 days (267-419) for A patients (n = 251). No significant differences were found between the three groups with regard to age, sex, renal function, or CHA2DS2-VASc score. For all bleeding events the incidence rates per 100 patient-years of follow-up (95% confidence interval [CI], p-value) were reported more often for treatment with R (17.2, 12.7-22.8) than for D (7.0, 4.0-11.3, p = 0.001) and A (8.7, 5.2-13.6, p = 0.013). The differences remained significant after adjustment for clinically relevant variables. Discontinuation rates (n = 167) were lower for A (11.5, 7.5-16.8) than for D (30, 23.4-37.9, p < 0.001) and R (23.9, 18.6-30.1, p = 0.001), and were mainly attributed to drug-specific side effects and bleedings. The majority of discontinued patients (n = 142, 85%) proceeded with other types of oral anticoagulants.. The main limitation of the study is the small patient population with a short follow-up time.. In a retrospective study at a single AF clinic, NOACs showed significantly different bleeding rates and varied discontinuation rates when compared to each other, related mainly to agent-specific side effects and bleedings. The majority of patients that discontinued proceeded with other types of oral anticoagulant.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Dabigatran; Female; Gastrointestinal Hemorrhage; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Patient Safety; Pyrazoles; Pyridones; Retrospective Studies; Rivaroxaban; Stroke; Treatment Outcome; Vitamin K

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

Atrial fibrillation (AF) affects an estimated 1.5 million individuals in Japan, increasing their stroke risk and imposing considerable costs on the Japanese healthcare system. To reduce stroke incidence, guidelines recommend using anticoagulants in moderate-to-high risk non-valvular AF (NVAF) patients; however, many patients receive no treatment, aspirin only, or remain poorly-controlled on vitamin K antagonists (VKAs) due to high VKA discontinuation rates and non-adherence to guidelines. A prevalence-based Markov model was developed to estimate the clinical and budgetary impact of treating these patients with Xarelto(TM) (rivaroxaban, Bayer AG) in Japan.. Population, baseline risk of events, and associated management costs were estimated using data from Japanese publications where available. Treatment efficacy and safety were derived from published data and the J-ROCKET AF trial. Drug and physician visit costs were based on data from the Ministry of Health, Labor, and Welfare, the J-ROCKET AF trial, and Japanese clinical guidelines.. This model demonstrates that increased use of rivaroxaban in inadequately-managed NVAF patients could avoid 456 081 non-fatal ischemic strokes (IS) and 76 975 cardiovascular deaths over 10 years in Japan. This clinical benefit offsets the increased incidence of myocardial infarctions and anticoagulant-related bleeding. Decreased event costs could lead to a ¥188.4 billion decrease in net spending over the analysis time horizon.. Introducing rivaroxaban may decrease the burden of NVAF in Japanese society. From a clinical perspective, the reduction in IS and embolic events outweighs the increased risk of anticoagulant-related bleeding; from an economic perspective, reduced event costs offset drug and physician visit costs, resulting in cost savings.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anticoagulants; Aspirin; Atrial Fibrillation; Cardiovascular Diseases; Female; Humans; Japan; Male; Markov Chains; Middle Aged; Models, Econometric; Practice Guidelines as Topic; Rivaroxaban; Stroke; Warfarin

Rivaroxaban has been shown to reduce overall death from cardiovascular causes in patients with recent acute coronary syndrome. Therefore, we evaluated the secondary prevention of cardiovascular events after myocardial ischemia reperfusion injury and its mechanisms in mice.. After myocardial reperfusion injury, C57BL/6J mice were randomized to receive either no treatment or treatment for 14days with low and high doses of rivaroxaban. After 7days, mice were administered tissue factor as a secondary event.. Based on a Kaplan-Meier curve analysis, the high-dose rivaroxaban group showed a significantly higher % survival than the no-treatment group from day 7 (after the administration of tissue factor) to day 14 (at the end of the experimental period). Left ventricular (LV) ejection fraction in both the low- and high-dose rivaroxaban groups improved compared to that in the no-treatment group. Moreover, mRNA levels of interleukin-6 and collagens 1α2 and 3α1 in the LV in the high-dose group were significantly suppressed compared to those in the no-treatment group.. Rivaroxaban improved the survival rate, probably by improving cardiac function through the reduction of inflammatory and fibrotic factors in the LV. This effect may be due to the pleiotropic effects of rivaroxaban beyond its main effect as an anti-coagulant.

Topics: Animals; Cardiovascular Diseases; Factor Xa Inhibitors; Male; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Random Allocation; Rivaroxaban; Secondary Prevention

The new direct oral anticoagulants (DOA) such as dabigatran, rivaroxaban or apixaban are an evolution in the management of patients requiring curative anticoagulation. However, behind the simplicity of prescribing and monitoring, several questions remain about their daily use. The aim of this prospective study was to measure the feelings of general practitioners (GP), angiologists (AP) and cardiologists (CP), potential prescribers of this new anticoagulant family.. Between December 2012 and May 2013, a questionnaire including five open questions and 11 questions using a positioning on an analogic visual scale (AVS 0 to 10) was subjected to GP, AP and CP in Alsace.. Responses from 224 physicians (150 GP, 35 AP and 39 CP) were collected. Thus, 83% of GP, 83% of AP and 100% of CP were prescribers of DOA. However, among these prescribing doctors, the feeling was not the same and the trend of prescription was lower in GP (2.0 [1.1-3.2] AVS units) than in AP (3.1 [2.0-5.6]) and in CP (5.0 [1.2-8.7]) (P<0.0001 in multivariate analysis). The female doctors tended to prescribe DOA in younger patients than male doctors (respectively 66.1 [52.5-76.7] vs. 75.0 [65.7-81.0] years; P=0.004). The DOA were more considered as progress by AP and CP (respectively 7.8 [5.3-9.0] and 7.9 [7.0-8.7] AVSu) than by GP (6.1 [4.8-8.2] AVSu; P=0.02 in multivariate analysis). The answer about the eventual replacement of vitamin K antagonists by the DOA was very mixed whatever the practitioner group (5.1 [3.0-7.8] AVSu; P=0.139). The ease to use and the lack of biological monitoring were the main arguments leading to the prescription but the attitude of practitioners was very balanced by the lack of experience on the bleeding risk and the lack of available antidote.. If the DOA are considered as an improvement for the physicians, the enthusiasm remains cautious whatever the type of practiced medicine. The results of clinical trials and the clinical experience should better appreciate the ongoing change in the field of anticoagulation.

Topics: Administration, Oral; Anticoagulants; Antithrombins; Cardiology; Cardiovascular Diseases; Dabigatran; Factor Xa Inhibitors; Female; France; General Practice; Humans; Male; Middle Aged; Practice Patterns, Physicians'; Prospective Studies; Pyrazoles; Pyridones; Rivaroxaban; Surveys and Questionnaires; Thromboembolism; Treatment Outcome

Non-vitamin K antagonist oral anticoagulants (NOACs) are broadly preferable to vitamin K antagonists (VKAs) for stroke prevention in non-valvular atrial fibrillation (AF) given their overall net clinical benefit. We report an audit of the profile of OAC usage and adverse events in patients attending a specialist AF clinic.. Patients attending our specialist AF clinic who were commenced on NOACs for SPAF between January 2013 and August 2014 were included and electronic medical records were retrospectively reviewed between August 2014 and November 2014, to collect demographic, clinical and outcome data. Outcomes included cerebrovascular and bleeding events, death, switching between NOACs or to VKA, dose changes, cessation of NOACs and the reasons for these. To provide perspective, descriptive comparisons were made with a historical cohort of warfarin users attending the specialist AF clinic prior to the introduction of NOACs.. We report data on 813 patients as follows: (i) 233 consecutive patients (mean (standard deviation) age 74 (10) years, 45.1% female) initiated on NOACs, with median (interquartile range) CHA2 DS2 -VASc score 3 (2-5) and HAS-BLED score 1 (1-2); and (ii) a historical cohort of 580 patients on warfarin (mean (SD) age 75 (10) years, 42.1% female) with broadly similar demographics. Overall, 54.5% (127/233) were started on rivaroxaban, 22.7% (53/233) on dabigatran and 22.7% on apixaban. Two patients experienced a transient ischaemic attack; 31 patients (13%) contributed to 37 documented bleeding events of which five bleeds (in four patients, 1.7%) were classified as major. There were seven deaths; cause of death was not available for three and the others were not related to NOACs. Eighteen (7.7%) patients switched NOACs, 2 (0.9%) patients switched to warfarin and 8 (3.4%) had their NOACs stopped. There were no ischaemic strokes in the NOAC cohort, compared with nine in the warfarin cohort, with a similar rate of major bleeding (1.7% for NOACs and 1.6% for warfarin). There were more gastrointestinal haemorrhages in the NOAC cohort (3.4% vs. 0.7% with warfarin).. In this specialist AF clinic, patients prescribed NOACs had a favourable adverse event profile with good efficacy for stroke prevention, with a low rate of cessation or switch to warfarin.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cardiovascular Diseases; Clinical Audit; Dabigatran; Drug Substitution; Female; Fibrinolytic Agents; Hemorrhage; Humans; Ischemic Attack, Transient; Male; Middle Aged; Pyrazoles; Pyridones; Retrospective Studies; Risk Factors; Rivaroxaban; Stroke; Warfarin

Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate , is among these novel agents that have been developed to overcome limitations with warfarin.. In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe.. Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient-specific characteristics.

Topics: Antithrombins; Arthroplasty, Replacement, Knee; Atrial Fibrillation; Cardiovascular Diseases; Clinical Trials as Topic; Dabigatran; Enoxaparin; Humans; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Stroke; Thiazoles; Venous Thromboembolism

Topics: Adenosine; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Clopidogrel; Dabigatran; Fibrinolytic Agents; Guideline Adherence; Humans; Morpholines; Piperazines; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Pyrazoles; Pyridones; Rivaroxaban; Thiophenes; Thromboembolism; Ticagrelor; Ticlopidine; Treatment Outcome

Alternative anticoagulants to warfarin (dabigatran, rivaroxaban, and apixaban) are becoming available for the prevention of thromboembolic stroke in atrial fibrillation (AF), but there is a lack of information on their comparative effectiveness. Using a discrete event simulation method adopting a lifetime horizon of analysis, we made an indirect comparison of the RE-LY, ROCKET-AF, and ARISTOTLE trial results for AF patients in the US population. Over a lifetime, apixaban, dabigatran, and rivaroxaban accrued 0.130 (95% central range (CR) -0.030 to 0.264), 0.106 (95% CR -0.048 to 0.248), and 0.095 (95% CR -0.052 to 0.242) more quality-adjusted life-years (QALYs), respectively, than warfarin, with apixaban having a 55% probability of accruing the highest total QALYs. In the absence of a definitive trial, and acknowledging the limitations of an indirect comparison, the available evidence suggests apixaban to be the most effective anticoagulant.

Topics: Age Factors; Aged; Antithrombins; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Cardiovascular Diseases; Comorbidity; Computer Simulation; Dabigatran; Female; Hemorrhage; Humans; Male; Morpholines; Pyrazoles; Pyridones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Rivaroxaban; Thiophenes; Time Factors; Warfarin

Topics: Anticoagulants; Benzimidazoles; Cardiovascular Diseases; Dabigatran; Drug Approval; Drug Interactions; Food-Drug Interactions; Hemorrhage; Humans; Morpholines; Pyrazoles; Pyridines; Pyridones; Rivaroxaban; Thiophenes; Warfarin

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

Topics: Anticoagulants; Benzimidazoles; Carboxypeptidase B2; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Dabigatran; Fibrinolytic Agents; Humans; Morpholines; Pyridines; Receptor, PAR-1; Rivaroxaban; Thiophenes; Thrombin; Thrombomodulin; Thrombosis; Treatment Outcome; Warfarin