rivaroxaban and Atherosclerosis

The persistence of elevated rates of ischemic recurrences despite the use of antiplatelet therapy among patients with atherosclerotic disease together with the understanding of the pivotal role of coagulation in the thrombo-inflammatory processes involved in the pathogenesis of atherosclerosis and its complications has fostered the development of treatments targeting both platelets and coagulation, a strategy known as dual-pathway inhibition (DPI).. In this review we discuss the recent advancements in the understanding of the interplay between coagulation, platelets and inflammation involved in the pathophysiology of atherosclerosis and atherothrombosis, as the rationale for the implementation of a DPI strategy. We also discuss the available pharmacodynamic (PD) evidence and clinical implications with the use of DPI in patients with atherosclerotic disease.. The implementation of a DPI by adding the so-called 'vascular dose of rivaroxaban' (i.e. 2.5 mg bis in die), on top of antiplatelet therapy has consistently been associated with reduced levels of thrombin generation in PD studies and with reduced ischemic event rates at the cost of increased bleeding compared to antiplatelet therapy alone. Further research is warranted to best define patients in whom a DPI regimen has the best safety and efficacy profile.

Topics: Aspirin; Atherosclerosis; Drug Therapy, Combination; Hemorrhage; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

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

This review aims to evaluate the major cardiovascular adverse events (MACE) and antithrombotic approaches in concomitant atrial fibrillation (AF) and atherosclerosis.. MACE in concomitant AF and atherosclerosis has been evaluated in recent studies. A recent retrospective study of 2670 patients with AF revealed that atherosclerosis burden with AF can be a marker of adverse vascular outcomes with extracranial atherosclerosis as a potent predictor of MACE. Trials to evaluate the antithrombotic approaches in concomitant atherosclerotic disease and AF has been mainly in patients with coronary artery disease (CAD). AFIRE trial demonstrated that in patients with AF and stable CAD rivaroxaban alone is not inferior to rivaroxaban plus aspirin with better safety profile. Atherosclerosis is common in AF and poses additional risk to patients. Antithrombotic management of atherosclerosis in AF is not well investigated and needs further trial to identify the subgroups that benefit from more intensive antithrombotic measures.

Topics: Anticoagulants; Atherosclerosis; Atrial Fibrillation; Coronary Artery Disease; Fibrinolytic Agents; Humans; Platelet Aggregation Inhibitors; Rivaroxaban; Treatment Outcome

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

Until recently, attempts to improve the benefit of aspirin by adding another antithrombotic agent have not resulted in a mortality reduction in patients with chronic symptomatic atherosclerosis. In this population, COMPASS is the only one among six trials to show a significant mortality reduction, thereby providing evidence of a clear net clinical benefit with the combination of low-dose rivaroxaban plus aspirin. In this systematic review, we sought to determine whether the mortality benefit of the combination arm in COMPASS is best explained by greater statistical power or by a more favorable efficacy-safety profile than the other regimens evaluated in patients with chronic symptomatic atherosclerosis.

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

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

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

Subdural hematomas (SDHs) are an uncommon, but important, complication of anticoagulation therapy. We hypothesized that the risks of SDH would be similar during treatment with oral factor Xa inhibitors compared with aspirin.. We assessed the frequency and the effects of antithrombotic treatments on SDHs in the recent international Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) randomized trial comparing aspirin 100 mg daily, rivaroxaban 5 mg twice daily, and rivaroxaban 2.5 mg twice daily plus aspirin. A systematic review/meta-analysis of randomized trials comparing oral factor Xa inhibitors vs aspirin on SDH risk was undertaken.. Among 27,395 COMPASS participants, 28 patients with SDHs were identified (mean age 72 years). SDH-associated mortality was 7%. Incidence was 0.06 per 100 patient-years (11 SDH/17,492 years observation) during the mean 23-month follow-up among aspirin-assigned patients and did not differ significantly between treatments. Three additional randomized controlled trials including 16,177 participants reported a total of 14 SDHs with an incidence ranging from 0.06 to 0.1 per 100 patient-years. Factor Xa inhibitor use was not associated with an increased risk of SDH compared to aspirin (odds ratio, 0.97; 95% confidence interval, 0.52-1.81; I. The frequency of SDH was similar in all 3 treatment arms of the COMPASS trial. The COMPASS trial results markedly increase the available evidence from randomized comparisons of oral factor Xa inhibitors with aspirin regarding SDH. From available, albeit limited, evidence from 4 randomized trials, therapeutic dosages of factor Xa inhibitors do not appear to increase the risk of SDH compared with aspirin.. NCT01776424.

Topics: Aged; Aspirin; Atherosclerosis; Factor Xa Inhibitors; Female; Hematoma, Subdural, Intracranial; Humans; Incidence; Male; Middle Aged; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Rivaroxaban

Cardiovascular disease is the leading cause of morbidity and mortality in adults in western nations. In the last decades, tremendous research has been conducted in the field of secondary prevention in order to reduce recurrent cardiovascular events. This review summarizes the novel dual pathway concept of aspirin and very low-dose rivaroxaban, from mechanisms to clinical practice.. The COMPASS trial demonstrated that in patients with stable atherosclerotic disease, very low-dose rivaroxaban, a direct factor Xa inhibitor, when combined with aspirin, reduced the rate of recurrent ischemic events, at the cost of increased bleeding. This effect was present in patients with ischemic heart disease, as well as in patients with atherosclerosis in other beds, such as in peripheral arterial disease. Sub-studies from the COMPASS trial examined other high-risk populations who might benefit the most from this regimen.. There are currently multiple antiplatelet and anticoagulation treatment regimens for patients with stable atherosclerotic disease. The dual pathway concept is a novel approach that combines both mechanisms. Identifying patients who might benefit the most in terms of ischemic events at the least bleeding events still remains a challenge, yet prescribing this combination to high-risk patients might be the most effective.

Topics: Aspirin; Atherosclerosis; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention

In the review article are provided the approaches to the therapy for improvement of prognosis in patients with peripheral and multifocal atherosclerosis which are available now; some limitations and a real situation are designated for the antithrombotic therapy in this category of patients. According to the clinical trial COMPASS the prospects of wide use of a combination of acetylsalicylic acid and a rivaroxsaban of 2.5 mg 2 times a day in the patients with chronic coronary heart disease and/or symptom peripheral atherosclerosis are designated.. Нуждаются ли пациенты с атеросклерозом периферических артерий в медикаментозной терапии до проведения реваскуляризации? В обзорной статье представлены имеющиеся в настоящее время подходы к назначению терапии, улучшающей прогноз у пациентов с периферическим и мультифокальным атеросклерозом, обозначены ограничения и реальная ситуация с назначением антитромботической терапии у этой категории пациентов. На основании данных исследования COMPASS обозначены перспективы широкого использования комбинации ацетилсалициловой кислоты и ривароксабана 2,5 мг 2 раза в день у пациентов с хронической ишемической болезнью сердца и/или симптомным периферическим атеросклерозом.

Topics: Aspirin; Atherosclerosis; Drug Therapy, Combination; Humans; Peripheral Arterial Disease; 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

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

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

The prevention of atherothrombotic events is an essential therapeutic goal in the treatment of patients with arteriosclerotic diseases. After plaque rupture, a rapidly growing thrombus can lead to acute vascular occlusion and thus heart attack, stroke or limb ischaemia. The acute therapy combines anticoagulation and platelet inhibition. However, the only available therapy so far in the primary and secondary prevention of stable patients is the platelet inhibitors aspirin and clopidogrel. Despite the use of antiplatelet therapies, including aspirin and P2Y. Die Verhinderung atherothrombotischer Ereignisse ist ein wesentliches therapeutisches Ziel bei der Behandlung von Patienten mit arteriosklerotischen Erkrankungen. Ein schnell wachsender Thrombus kann nach Plaqueruptur zu akutem Gefäßverschluss und damit zu Herzinfarkt, Schlaganfall oder Ischämie der Extremitäten führen. Die Akuttherapie kombiniert Antikoagulation und Thrombozytenhemmung. Die bislang einzige verfügbare Therapie in der Primär- und Sekundärprävention stabiler Patienten sind jedoch die Thrombozytenaggregationshemmer Aspirin und Clopidogrel. Trotz der Verwendung von Thrombozytenaggregationshemmern, einschließlich Aspirin und P2Y12-Rezeptorantagonisten, leiden einige Patienten mit Arterienerkrankungen weiterhin unter kardiovaskulären ischämischen Ereignissen, die auf eine übermäßige Thrombinbildung nach der akuten Phase zurückzuführen sind. Als ein Ergebnis haben Studien Nicht-Vitamin-K-Antagonist-orale Antikoagulantien (NOAKs) getestet, insbesondere die Faktor-Xa-Inhibitoren, entweder allein oder in Kombination mit einer Antiplättchen-Therapie bei der Behandlung von arteriellen Erkrankungen. Die COMPASS-Studie untersuchte erstmals die niedrig dosierte Antikoagulation bei stabiler koronarer Herzkrankheit oder peripherer arterieller Verschlusskrankheit. Die Zugabe von 2 × 2,5 mg Rivaroxaban zur Langzeit-Aspirintherapie verhinderte nicht nur kardiovaskulären Tod, Myokardinfarkt und Schlaganfall, sondern reduzierte sogar die Gesamtmortalität um 18% nach einer mittleren Nachbeobachtungszeit von 23 Monaten. Dieser Vorteil ging auf Kosten von mehr gastrointestinalen Blutungen, die durch die Zugabe eines Protonenpumpenhemmers reduziert werden könnten (Untersuchungen laufen noch). Interessanterweise gab es jedoch keine Zunahme von tödlichen oder intrakraniellen Blutungen. Daher könnte in naher Zukunft eine neue Standardtherapie für Hochrisikopatienten mit atherosklerotischer Erkrankung verfügbar werden.

Topics: Animals; Anticoagulants; Atherosclerosis; Coronary Disease; Heart Failure; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Thrombosis

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, there was a significant reduction in the adjudicated primary outcome among patients with stable atherosclerotic vascular disease randomized to dual pathway inhibition (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) vs aspirin monotherapy, but not with rivaroxaban 5 mg twice daily vs aspirin monotherapy. Whether the results are similar without adjudication is unknown.. To examine the impact of dual pathway inhibition (with rivaroxaban plus aspirin) or rivaroxaban monotherapy compared with aspirin monotherapy on investigator-reported CV events and to understand the extent of concordance between investigator-reported and centrally adjudicated clinical events.. This is a secondary analysis of the COMPASS trial, an international, double-blind, double-dummy, randomized clinical trial with a 3-by-2 partial factorial design that evaluated participants with stable atherosclerotic vascular disease receiving rivaroxaban plus aspirin, rivaroxaban monotherapy, or aspirin monotherapy. End points were collected by blinded site investigators and adjudicated by a blinded clinical end point committee. Data were analyzed from March 2013 through February 2017.. Participants received dual inhibition pathway (2.5 mg rivaroxaban twice daily plus 100 mg aspirin once daily), rivaroxaban monotherapy (5 mg twice daily), or aspirin monotherapy (100 mg once daily).. The primary efficacy outcome was a composite of cardiovascular (CV) death, stroke, or myocardial infarction (MI). Adjudicated and investigator-reported end points were compared.. A total of 27 395 patients (mean [SD] age, 68.2 [7.9] years; 78.0% men) were assessed, including 9152 patients randomized to dual pathway inhibition, 9117 patients randomized to rivaroxaban monotherapy, and 9126 patients randomized to aspirin monotherapy. Adjudication reduced the number of events by 10% to 15% for most end points. Among investigator-reported end points, dual pathway inhibition significantly reduced the rate of the primary efficacy outcome compared with aspirin alone (411 patients [4.5%] vs 542 patients [5.9%]; hazard ratio [HR], 0.75 [95% CI, 0.66-0.85]; P < .001), with similar reduction in adjudicated end points, (379 patients [4.1%] vs 496 patients [5.4%]; HR, 0.76 [95% CI, 0.66-0.86]; P < .001). Likewise, effects on ischemic end points were highly concordant (κ statistic = 0.94 [95% CI, 0.93-0.95] for the primary composite end point). Unlike with adjudicated outcomes, there was a significant reduction in the primary end point with rivaroxaban monotherapy vs aspirin monotherapy using investigator-reported events (477 patients [5.2%] vs 542 patients [5.9%]; HR, 0.88 [95% CI, 0.78-0.99]; P = .04) compared with adjudicated events (448 patients [4.9%] vs 496 patients [5.4%]; HR, 0.90 [95% CI, 0.79-1.03]; P = .12).. This secondary analysis of the COMPASS trial found that whether assessed by blinded site investigators or adjudicators, dual pathway inhibition significantly reduced CV events among patients with stable atherosclerotic disease compared with aspirin plus placebo. These findings suggest that using investigator-reported events in blinded clinical trials may be a more efficient alternative to adjudication.. ClinicalTrials.gov Identifier: NCT01776424.

Topics: Aged; Aspirin; Atherosclerosis; Drug Therapy, Combination; Female; Humans; Male; Myocardial Infarction; Rivaroxaban; Stroke

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

The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes.. To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes.. This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27 395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017.. Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day).. Risk of ischemic stroke subtypes during follow-up.. A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes.. For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice.. ClinicalTrials.gov identifier: NCT01776424.

Topics: Aspirin; Atherosclerosis; Atrial Fibrillation; Carotid Stenosis; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Heart Diseases; Humans; Intracranial Embolism; Rivaroxaban; Stroke

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

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

Patients treated with antithrombotic drugs are at risk of bleeding. Bleeding may be the first manifestation of underlying cancer.. We examined new cancers diagnosed in relation to gastrointestinal or genitourinary bleeding among patients enrolled in the COMPASS trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies) and determined the hazard of new cancer diagnosis after bleeding at these sites.. Of 27 395 patients enrolled (mean age, 68 years; women, 21%), 2678 (9.8%) experienced any (major or minor) bleeding, 713 (2.6%) experienced major bleeding, and 1084 (4.0%) were diagnosed with cancer during a mean follow-up of 23 months. Among 2678 who experienced bleeding, 257 (9.9%) were subsequently diagnosed with cancer. Gastrointestinal bleeding was associated with a 20-fold higher hazard of new gastrointestinal cancer diagnosis (7.4% versus 0.5%; hazard ratio [HR], 20.6 [95% CI, 15.2-27.8]) and 1.7-fold higher hazard of new nongastrointestinal cancer diagnosis (3.8% versus 3.1%; HR, 1.70 [95% CI, 1.20-2.40]). Genitourinary bleeding was associated with a 32-fold higher hazard of new genitourinary cancer diagnosis (15.8% versus 0.8%; HR, 32.5 [95% CI, 24.7-42.9]), and urinary bleeding was associated with a 98-fold higher hazard of new urinary cancer diagnosis (14.2% versus 0.2%; HR, 98.5; 95% CI, 68.0-142.7). Nongastrointestinal, nongenitourinary bleeding was associated with a 3-fold higher hazard of nongastrointestinal, nongenitourinary cancers (4.4% versus 1.9%; HR, 3.02 [95% CI, 2.32-3.91]).. In patients with atherosclerosis treated with antithrombotic drugs, any gastrointestinal or genitourinary bleeding was associated with higher rates of new cancer diagnosis. Any gastrointestinal or genitourinary bleeding should prompt investigation for cancers at these sites.. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.

Topics: Aged; Aspirin; Atherosclerosis; Coronary Artery Disease; Drug Therapy, Combination; Female; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Myocardial Infarction; Neoplasms; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Stroke

Topics: Aged; Aorta, Thoracic; Aspirin; Atherosclerosis; Double-Blind Method; Echocardiography, Transesophageal; Female; Humans; Intracranial Embolism; Male; Middle Aged; Prevalence; Risk Factors; Rivaroxaban; Stroke

Topics: Aspirin; Atherosclerosis; Double-Blind Method; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Follow-Up Studies; Humans; Rivaroxaban; Treatment Outcome; Vascular Diseases

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

Dual pathway inhibition (DPI) with low-dose rivaroxaban and aspirin in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) reduces the occurrence of cardiovascular (CV) events; however, the underlying mechanisms explaining these latter CV benefits are not clearly understood. Our explorative observational study aimed to evaluate the effect of dual pathway inhibition on plasma inflammation and coagulation markers among real-world patients with CAD and/or PAD. We prospectively included all consecutive patients with an established diagnosis of CAD and/or PAD treated with aspirin 100 mg once daily (OD) and rivaroxaban 2.5 mg twice daily (TD). Clinical evaluation and laboratory analyses, including hemoglobin, renal function (creatinine, urea, and cystatin-C), coagulation markers (INR and aPTT), inflammation markers (IL-6, CRP, lipoprotein-associated phospholipase A2, and copeptin), and growth differentiation factor-15 (GDF-15), were conducted at baseline, before starting treatment, and at 4 and 24 weeks after study drug administration. Fifty-four consecutive patients (mean age 66 ± 7 years; male 83%) who completed the 6-month follow-up were included. At 24-week follow-up, a statistically significant reduction in IL-6 serum levels [4.6 (3.5-6.5) vs. 3.4 (2.4-4.3) pg/mL ; P = 0.0001] and fibrinogen [336 (290-390) vs. 310 (275-364) mg/dL; P = 0.04] was shown; moreover, a significant increase in GDF-15 serum level [1309 (974-1961) vs. 1538 (1286-2913) pg/mL; P = 0.002] was observed. Hemoglobin, renal function, and cardiovascular homeostasis biomarkers remain stable over the time. The anti-Xa activity at both [0.005 (0-0.02) vs. 0.2 (0.1-0.34); P < 0.0001) significantly increased. The dual pathway inhibitions with low-dose rivaroxaban and aspirin in patients with CAD and/or PAD were associated with the reduction of inflammation biomarkers.

Topics: Aged; Aspirin; Atherosclerosis; Biomarkers; Coronary Artery Disease; Drug Therapy, Combination; Factor Xa Inhibitors; Female; Growth Differentiation Factor 15; Humans; Inflammation; Interleukin-6; Male; Middle Aged; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Anticoagulants; Atherosclerosis; Blood Coagulation; Factor Xa Inhibitors; Humans; Inflammation; Rivaroxaban

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

The platelet inhibitor aspirin reduces inflammation and atherosclerosis in both apolipoprotein E deficient (apoE. Contrary to our expectation, the combination of aspirin and rivaroxaban did not further reduce atherosclerosis in Ldlr

Topics: Animals; Aorta; Apolipoproteins E; Aspirin; Atherosclerosis; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, LDL; Rivaroxaban

Atherosclerosis is associated with a haemostatic imbalance characterized by excessive activation of pro-inflammatory and pro-coagulant pathways. Non-vitamin K antagonists oral anticoagulant (NOACs) may reduce the incidence of cardiovascular events, cerebral ischemia, thromboembolic events and atherosclerosis. Chronic inflammation, vascular proliferation and the development of atherosclerosis is also influenced by 25-hydroxycholesterol (25-OHC). The aim of the study was to assess the effect of rivaroxaban and dabigatran on the messenger RNA (mRNA) expression of anti-inflammatory cytokines transforming growth factor β (TGF-β), interleukin (IL)-37, IL-35 as well as of pro-inflammatory cytokines IL-18 and IL-23, in endothelial cells damaged by 25-OHC. Human umbilical vascular endothelial cells (HUVECs) were treated with 25-OHC (10 μg/mL), rivaroxaban (100, 500 ng/mL), dabigatran (100, 500 ng/mL), 25-OHC + rivaroxaban, and 25-OHC + dabigatran. The mRNA expression of TGF-β, IL-37, IL-35 subunits EBI3 and p35, IL-18, and IL-23 was analysed using real-time polymerase chain reaction (PCR). The results showed that 25-OHC decreased TGF-β and IL-37 mRNA expression and increased EBI3, p35, IL-18, IL-23 mRNA expression in endothelial cell as compared to an untreated control (P < .05). Messenger RNA expression of TGF-β and IL-37 significantly increased following stimulation with rivaroxaban and dabigatran as compared to an untreated control (P < .01). In HUVECs pre-treated with oxysterol, rivaroxaban and dabigatran increased mRNA expression of TGF-β, IL-37 and decreased mRNA expression of EBI3, p35, IL-23 and IL-18 as compared to 25-OHC (P < .01). Our finding suggests that both rivaroxaban and dabigatran inhibit the inflammatory activation caused by oxysterol in vitro.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Cytokines; Dabigatran; Endothelial Cells; Human Umbilical Vein Endothelial Cells; Humans; Hydroxycholesterols; Interleukin-18; Interleukin-23; Oxysterols; Rivaroxaban; RNA, Messenger; Transforming Growth Factor beta

Topics: Aspirin; Atherosclerosis; Drug Therapy, Combination; Factor Xa Inhibitors; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban; Venous Thromboembolism

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

Topics: Aspirin; Atherosclerosis; Coronary Artery Disease; Factor Xa Inhibitors; Humans; Rivaroxaban; Treatment Outcome

To evaluate the current interpretation of the lower doses of direct oral anticoagulants (DOAC) dabigatran, apixaban, edoxaban and rivaroxaban in nonvalvular atrial fibrillation.. A questionnaire of 14 statements to which the possible answers were fully agree/partially agree/partially disagree/fully disagree or yes/no was prepared within the board of the Italian Atherosclerosis, Thrombosis and Vascular Biology Study Group and forwarded to individual Italian physicians.. A total of 620 complete questionnaires were received from nearly all the Italian regions and physicians of various medical specialists, either enabled or not for the prescription of DOAC. A wide agreement was found as regards the pharmacological, as well as clinical consequences of the administration of the lower dose of factor-Xa inhibitors both in patients with and without clinical and/or laboratory criteria requiring dose reduction. Wide agreement was also found as regards the presence of moderate kidney insufficiency in selecting the dose of DOAC. Instead, more debated were issues regarding the proportionality between dabigatran dose and plasma concentration and selection of dabigatran dose, as well as the role of measuring drug plasma concentration and/or determine the anticoagulant activity of factor-Xa inhibitors when used at the lower dose.. The interpretation of the lower doses of DOAC in current Italian clinical practice appears largely correct and shared. Because of the persistence of some residual uncertainties, essentially regarding dabigatran, however, continuous educational effort still appears warranted.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Atrial Fibrillation; Dabigatran; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Humans; Italy; Pyrazoles; Pyridines; Pyridones; Renal Insufficiency; Rivaroxaban; Surveys and Questionnaires; Thiazoles; Thrombosis; Treatment Outcome

Topics: Aspirin; Atherosclerosis; Fibrinolytic Agents; Goals; Humans; Rivaroxaban

Following the publication of the COMPASS trial, the European Medicines Agency has approved a regimen of combination of rivaroxaban 2.5mg twice daily and a daily dose of 75-100mg acetylsalicylic acid (ASA) for patients with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk of ischemic events. However, the applicability of such a therapeutic strategy in France is currently unknown.. To describe the proportion of patients eligible to COMPASS in France, their baseline clinical characteristics and the rate of major adverse cardiovascular events, using the REACH registry.. From the the REduction of Atherothrombosis for Continued Health (REACH) registry database, a large international registry of patients with, or at risk, of atherothrombosis, we analyzed patients included in France with either established CAD and/or PAD and fulfilling the inclusion and exclusion criteria of the COMPASS trial. The ischemic outcome was a composite of cardiovascular (CV) death, myocardial infarction (MI), or stroke, and serious bleeding were defined as haemorrhagic stroke or bleeding leading to hospitalization or transfusion.. Among more than 65000 patients enrolled in REACH, 2.012 patients were evaluable and enrolled in France. Among them, 1194 patients (59.3%) were eligible to COMPASS. The main reasons for exclusion of the COMPASS trial, were high bleeding risk (59.1%), anticoagulant use (43.4%), requirement for dual antiplatelet therapy within 1 year of an ACS or PCI (24.7%). In the "COMPASS eligible population", the rate of MACE (CV, MI and stroke) at 4 years follow-up was 13.4% [11.3-15.8], and serious bleeding was 2.5% at 4 years [1.6-3.4]. Patients with polyvascular disease (n=219) had the highest rate of MACE, compared with patients with CAD only and PAD only (19.1% [13.9-26.1] vs. 11.6% [9.1-14.8] vs 13.2% [9.2-18.8], P<0.0001, respectively).. The COMPASS therapeutic strategy in France appears to be applicable to more than half of CAD or PAD patients. This population appears at high residual risk of atherothrombotic events, and patients with polyvascular disease experienced the highest rate of events.

Topics: Aged; Analysis of Variance; Anticoagulants; Aspirin; Atherosclerosis; Coronary Artery Disease; Drug Administration Schedule; Female; Follow-Up Studies; France; Hemorrhage; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Myocardial Infarction; Patient Selection; Percutaneous Coronary Intervention; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Prospective Studies; Registries; Risk Factors; Rivaroxaban; Stroke; Thrombosis; Time Factors; Treatment Outcome

Low-dose rivaroxaban was effective in secondary prevention of atherosclerotic cardiovascular disease (ASCVD) in the COMPASS trial. There is no established role, however, for oral anticoagulants in primary prevention. We evaluated whether coronary artery calcium (CAC) scoring identifies a high-risk primary prevention adult population who may benefit from low-dose rivaroxaban to prevent ASCVD events. We modeled expected outcomes of low-dose rivaroxaban in 5,196 Multiethnic Study of Atherosclerosis (MESA) cohort participants not already on antiplatelet or anticoagulant therapy. We applied relative risk ratios from COMPASS to absolute MESA event rates in order to estimate number needed to treat (NNT) to avoid a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, as well as number needed to harm (NNH) to cause 1 hospitalized bleed; with both NNT and NNH stratified by calculated ASCVD risk and by baseline CAC. MESA participants with CAC ≥300 had crude ASCVD event rate of 20 per 1000 patient-years, which is comparable to that observed in the COMPASS control-arm. CAC was independently associated with the composite ASCVD outcome (p <0.001 for trend). However, CAC was not independently associated with adjusted hazard ratio for hospitalized major bleeding. Predicted 5-year NNT (modeled from COMPASS) was 75 in persons with CAC 100-299 and 45 with CAC ≥300 despite NNH values of 252 and 98, respectively. In conclusion, CAC helps to distinguish estimated ASCVD benefit from estimated bleeding harm, thereby identifying very high-risk primary prevention adults without established cardiovascular disease who may derive net-benefit from low-dose rivaroxaban.

Topics: Aged; Aged, 80 and over; Atherosclerosis; Calcium; Coronary Vessels; Dose-Response Relationship, Drug; Ethnicity; Factor Xa Inhibitors; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Primary Prevention; Prognosis; Prospective Studies; Risk Assessment; Risk Factors; Rivaroxaban; Survival Rate; Thrombosis; Tomography, X-Ray Computed; United States

In the conclusion of the council of experts (list of participants see text) the following issues are discussed: regional specifics of diagnostics and therapy of patients with ischemic heart disease (IHD) and / or peripheral arterial disease (PAD), methods of risk assessment in patients with stable course of atherosclerotic disease, pathogenetic validity of simultaneous inhibition of coagulation and platelet thrombus formation, as well as clinical significance of a novel therapeutic approach - combined use of rivaroxaban and acetylsalicylic acid (ASA). Possible problems and ways to their solution at implementation in clinical practice of the novel scheme of antithrombotic therapy are presented. Importance of multidisciplinary approach to management of patients with IHD and concomitant diseases is stressed. Experts have noted that after registration of the corresponding indication therapy with rivaroxaban 2.5 mg twice daily and ASA 75-100 mg once daily might be recommended to majority of patients with atherosclerotic involvement of blood vessels. In real clinical practice prescription of this therapy is appropriate first of all in patients with IHD and high risk of complications - with multifocal atherosclerosis, with history of myocardial infarction after stoppage of dual antiplatelet therapy, - patients with concomitant diabetes, heart failure, and other prognosis worsening comorbid diseases. Experts express hope that in the nearest time combined antithrombotic therapy will be included into corresponding national clinical recommendations.

Topics: Aspirin; Atherosclerosis; Blood Coagulation; Humans; Platelet Aggregation Inhibitors; Rivaroxaban

Dual antithrombotic therapy (DAT) with low-dose rivaroxaban in combination with acetylsalicylic acid (ASA) is available to patients with stable atherosclerotic disease as a new therapeutic option.The results of the COMPASS trial demonstrate a significant relative risk reduction of cardiovascular outcomes by 24 % with low-dose DAT in patients with stable peripheral arterial disease or coronary heart disease.Despite a guideline adherent secondary prevention therapy, the cardiovascular event rate with ASA alone during the mean study period of almost two years was 5.4 %. The absolute reduction of the event rate by the low-dose DAT is low at 1.3 %. Consequently, it is important to identify groups of patients at high risk for cardiovascular events. These patients are particularly qualified to receive a DAT regimen and can be characterized using high-risk features.The individual ischemic risk profile may be further defined by the presence of polyvascular atherosclerosis, concomitant diseases, and ischemic events in the past. The quo ad vitam reduced prognosis of patients with polyvascular atherosclerosis advocates a polyvascular screening, even in supposedly stable patients with coronary heart disease and peripheral arterial disease.An intensification of antithrombotic therapy is naturally associated with an increased risk of bleeding. Therefore, the risk-reduction of ischemic events should be weighed individually against the risk of bleeding.A low-dose DAT is particularly suitable for patients with a high ischemic risk and a low risk of bleeding.. Die duale antithrombotische Therapie (DAT) mit Rivaroxaban in niedriger Dosis in Kombination mit Acetylsalicylsäure (ASS) steht für Patienten mit STABILER: Atherosklerose als neue therapeutische Option zur Verfügung 1.Die Ergebnisse der COMPASS-Studie zeigen unter der niedrig dosierten DAT eine deutliche relative Risikoreduktion der kardiovaskulären Endpunkte um 24 % bei Patienten mit stabiler peripherer arterieller Verschlusskrankheit (PAVK) oder koronarer Herzerkrankung (KHK) 2.Trotz einer leitliniengerechten medikamentösen Sekundärprophylaxe liegt die kardiovaskuläre Ereignisrate unter ASS während der mittleren Studiendauer von fast 2 Jahren bei 5,4 %. Die absolute Reduktion der Ereignisrate durch die niedrig dosierte DAT ist mit 1,3 % gering. Umso wichtiger ist es, anhand von HOCHRISIKOMERKMALEN: Patientengruppen mit einer schlechteren kardiovaskulären Prognose und höherer Ereignisrate zu identifizieren, die sich für diesen Therapieansatz besonders qualifizieren 3. POLYVASKULäRE ATHEROSKLEROSE:  Die quo ad vitam reduzierte Prognose der Patienten mit einer polyvaskulären Atherosklerose spricht für ein polyvaskuläres Screening, auch bei vermeintlich stabilen KHK- und PAVK-Patienten. Das individuelle ischämische Risikoprofil kann durch das Vorhandensein einer polyvaskulären Atherosklerose, von Begleiterkrankungen und bereits stattgehabten ischämischen Ereignissen näher bestimmt werden. EINSCHRäNKUNGEN DER ANWENDUNG:  Die niedrig dosierte Gabe von Rivaroxaban zusätzlich zur ASS-Therapie ersetzt keine therapeutische Antikoagulation. Ebenfalls liegen für die stabile Atherosklerose bisher keine Daten zu einer niedrig dosierten Rivaroxaban-Therapie und einer begleitenden dualen Thrombozytenaggregationshemmung (DAPT) vor. Aus diesem Grund kann eine Therapie nach dem „COMPASS-Schema“ nach einer endovaskulären Therapie in der klinischen Praxis frühestens nach dem Ende der DAPT begonnen werden.. Eine Intensivierung der antithrombotischen Therapie ist naturgemäß mit einer Erhöhung des Blutungsrisikos verknüpft. Daher ist die Reduktion des ischämischen Risikos individuell gegenüber dem Risiko einer Blutung abzuwägen. Eine niedrig dosierte DAT kommt besonders für Patienten mit hohem Ischämie-Risiko und niedrigem Blutungsrisiko infrage.

Topics: Aspirin; Atherosclerosis; Factor Xa Inhibitors; Heart Diseases; Hemorrhage; Humans; Peripheral Arterial Disease; Platelet Aggregation Inhibitors; Rivaroxaban

Topics: Aspirin; Atherosclerosis; Chronic Disease; Clinical Trials as Topic; Death; Drug Therapy, Combination; Factor Xa Inhibitors; Fibrinolytic Agents; Hemorrhage; Humans; Myocardial Infarction; Platelet Aggregation Inhibitors; Rivaroxaban; Secondary Prevention; Stroke; Thrombosis; Vascular Diseases

Oral anticoagulants (OACs) are widely used for prevention of systemic thromboembolism, including the reduction of the risk of stroke in patients with atrial fibrillation (AF) and prosthetic heart valves. There is also an increasing population of patients who require not only OACs, but also double antiplatelet therapy (DAPT). A typical example is a patient with AF and stable coronary artery disease or acute coronary syndrome (ACS), treated by percutaneous coronary intervention. In recent years, with the introduction of NOACs, triple or dual therapy has become safer. Regardless of these indications for the use of NOACs, rivaroxaban at a reduced dose has proved to efficiently reduce the risk of further thrombotic events when added to DAPT in patients who have suffered an ACS. However, such therapy increases the incidence of bleeding complications. Interesting was also the potential impact of the pleiotropic mechanism of action of non-vitamin K antagonist oral anticoagulants (NOACs) through protease‑activated receptors 1 and 2, present on the platelets and many other cells, and changing the course of arterial atherosclerosis. The COMPASS trial has shown that in the group treated with rivaroxaban combined with aspirin, the primary outcome (cardiovascular death, stroke, and myocardial infarction) occurred significantly less frequently than in the group treated only with aspirin. However, a significantly higher number of bleedings was observed. In the subgroup of patients with peripheral artery disease, a significant reduction of the incidence of amputations was shown. The outcomes of the COMPASS trial might be a breakthrough in the treatment of coronary and peripheral atherosclerosis.

Topics: Administration, Oral; Anticoagulants; Aspirin; Atherosclerosis; Cardiology; Coronary Artery Disease; Drug Therapy, Combination; Female; Humans; Male; Poland; Rivaroxaban; Societies, Medical; Thromboembolism

Topics: Animals; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Blood Coagulation; Disease Models, Animal; Factor Xa Inhibitors; Mice; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Plaque, Atherosclerotic; Rivaroxaban; Signal Transduction

Coagulant factor Xa inhibitors (XaIs) are prescribed for patients with atrial fibrillation for years.. Human umbilical venous endothelial cells (HUVECs) were cultured with or without (w/wo) a XaI (rivaroxaban) under high glucose (HG: 22 mM). Endothelial senescence was investigated by assessing senescence-associated-β-galactosidase (SA-β-gal), p53, and telomere length. Endothelial function and atherosclerosis were examined by nitric oxide-related-products (NOx: NO2- and NO3-), O2-, endothelial NO synthase (eNOS), NADPH oxidase (p22phox), and ICAM1. PAR1 (protease-activated receptor 1) and PAR2, which were reported to regulate eNOS phosphorylation, were inhibited by small interfering RNAs (siRNAs). Thirty-two male dyslipidemic type 2 diabetic rats (ZFDM LepRfa/fa) were fed a high-cholesterol diet w/wo XaI (50 µg/day/kg) for 1-4 weeks.. SA-β-gal, p53, p21, and p16INK4a were increased by HG and restored by XaI (50 nM) in HUVECs. XaI restored telomerase activity and preserved telomere length. XaI suppressed O2-, p22phox, and ICAM1 and restored NOx and eNOS. XaI decreased PAR1 following elevation by HG, which was confirmed by PAR1 siRNA and PAR2 siRNA. In in vivo experiments, plasma glucose, total cholesterol, and triglycerides were increased for 4 weeks but were not changed by XaI. XaI decreased SA-β-gal and telomerase and preserved telomere length in the aortic endothelium. XaI activated eNOS, inhibited p22phox, increased plasma NOx, and decreased O2-.. Rivaroxaban prevents replicative senescence in HUVECs and aortic endothelial cells in dyslipidemic diabetic mice. It restores endothelial function and prevents the progression of atherosclerosis.

Topics: Animals; Aortic Diseases; Atherosclerosis; Blood Glucose; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Cellular Senescence; Diabetes Mellitus, Type 2; Diet, High-Fat; Disease Models, Animal; Dyslipidemias; Factor Xa Inhibitors; Female; Human Umbilical Vein Endothelial Cells; Humans; Lipids; Nitric Oxide; Rats, Zucker; Reactive Oxygen Species; Receptors, Proteinase-Activated; Rivaroxaban; Signal Transduction; Telomerase

Vitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma-carboxylation of Matrix-Gla-Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification.. To compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice.. 42 ApoE-/- mice fed with Western-type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over-expression of COX-2 induced by inflammatory mediators.. We showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression.

Topics: Animals; Anticoagulants; Aortic Valve; Aortic Valve Stenosis; Atherosclerosis; Calcinosis; Cattle; Cells, Cultured; Cyclooxygenase 2; Disease Models, Animal; Disease Progression; Factor Xa Inhibitors; Female; Male; Mice, Knockout, ApoE; Risk Assessment; Rivaroxaban; Time Factors; Vascular Calcification; Warfarin

Topics: Aspirin; Atherosclerosis; Atrial Fibrillation; Humans; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Postoperative Complications; Receptors, Purinergic P2Y12; Rivaroxaban; Thrombosis

Warfarin, a vitamin K antagonist, is associated with systemic vascular calcification. We evaluated whether rivaroxaban (a direct oral factor Xa inhibitor with no interaction with vitamin K) will slow the progression in coronary plaque volumes compared with warfarin in patients with nonvalvular atrial fibrillation using coronary computed tomography angiography.

Topics: Administration, Oral; Anticoagulants; Atherosclerosis; Coronary Angiography; Coronary Artery Disease; Dose-Response Relationship, Drug; Factor Xa Inhibitors; Female; Humans; Male; Middle Aged; Randomized Controlled Trials as Topic; Rivaroxaban; Warfarin

Topics: Aspirin; Atherosclerosis; Biomedical Research; Blood Platelets; Cardiology; Drug Therapy, Combination; Factor Xa Inhibitors; Hemorrhage; History, 20th Century; History, 21st Century; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Risk Factors; Rivaroxaban; Treatment Outcome

Activated factor X (FXa) plays a key role in the coagulation cascade, whereas accumulating evidence suggests that it also contributes to the pathophysiology of chronic inflammation on the vasculature. In this study, we assessed the hypothesis that rivaroxaban (Riv), a direct FXa inhibitor, inhibits atherogenesis by reducing macrophage activation.. Expression levels of PAR-1 and PAR-2, receptors for FXa, increased in the aorta of apolipoprotein E-deficient (ApoE(-/-)) mice compared with wild-type mice (P < 0.01, P < 0.05, respectively). Administration of Riv (5 mg/kg/day) for 20 weeks to 8-week-old ApoE(-/-) mice reduced atherosclerotic lesion progression in the aortic arch as determined by en-face Sudan IV staining compared with the non-treated group (P < 0.05) without alteration of plasma lipid levels and blood pressure. Histological analyses demonstrated that Riv significantly decreased lipid deposition, collagen loss, macrophage accumulation and matrix metallopeptidase-9 (MMP-9) expression in atherosclerotic plaques in the aortic root. Quantitative RT-PCR analyses using abdominal aorta revealed that Riv significantly reduced mRNA expression of inflammatory molecules, such as MMP-9, tumor necrosis factor-α (TNF-α). In vitro experiments using mouse peritoneal macrophages or murine macrophage cell line RAW264.7 demonstrated that FXa increased mRNA expression of inflammatory molecules (e.g., interleukin (IL)-1β and TNF-α), which was blocked in the presence of Riv.. Riv attenuates atherosclerotic plaque progression and destabilization in ApoE(-/-) mice, at least in part by inhibiting pro-inflammatory activation of macrophages. These results indicate that Riv may be particularly beneficial for the management of atherosclerotic diseases, in addition to its antithrombotic activity.

Topics: Animals; Anticoagulants; Aorta; Aorta, Thoracic; Apolipoproteins E; Atherosclerosis; Blood Pressure; Cell Line; Disease Progression; Factor Xa Inhibitors; Human Umbilical Vein Endothelial Cells; Humans; Immunohistochemistry; Inflammation; Macrophages; Male; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Platelet Membrane Glycoproteins; Receptor, PAR-1; Receptor, PAR-2; Rivaroxaban; RNA, Messenger

Thrombin not only plays a central role in thrombus formation and platelet activation, but also in induction of inflammatory processes. Activated factor X (FXa) is traditionally known as an important player in the coagulation cascade responsible for thrombin generation. We assessed the hypothesis that rivaroxaban, a direct FXa inhibitor, attenuates plaque progression and promotes stability of advanced atherosclerotic lesions in an in vivo model.. Rivaroxaban (1 or 5 mg/kg body weight/day) or standard chow diet was administered for 26 weeks to apolipoprotein E-deficient mice (n = 20 per group) with already established atherosclerotic lesions. There was a nonsignificant reduction of lesion progression in the high-concentration group, compared to control mice. FXa inhibition with 5 mg Rivaroxaban/kg/day resulted in increased thickness of the protective fibrous caps (12.3 ± 3.8 μm versus 10.1 ± 2.7 μm; P < .05), as well as in fewer medial erosions and fewer lateral xanthomas, indicating plaque stabilizing properties. Real time-PCR from thoracic aortas revealed that rivaroxaban (5 mg/kg/day) treatment reduced mRNA expression of inflammatory mediators, such of IL-6, TNF-α, MCP-1, and Egr-1 (P < .05).. Chronic administration of rivaroxaban does not affect lesion progression but downregulates expression of inflammatory mediators and promotes lesion stability in apolipoprotein E-deficient mice.

Topics: Animals; Anticoagulants; Apolipoproteins E; Atherosclerosis; Factor Xa Inhibitors; Female; Humans; Lipids; Mice; Mice, Knockout; Morpholines; Plaque, Atherosclerotic; Random Allocation; Rivaroxaban; Thiophenes