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In a randomized trial involving patients who had a first stroke from an embolus of unknown source, rivaroxaban at a daily dose of 15 mg did not result in a lower incidence of recurrent stroke than aspirin at a dose of 100 mg. Bleeding rates were higher with rivaroxaban.

In a trial, patients who had undergone successful TAVR were assigned to rivaroxaban or antiplatelet therapy. In this substudy in patients who underwent CT, leaflet thickening and reduced leaflet motion at 90 days were less common with rivaroxaban. However, in the main trial, rivaroxaban was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding.

Patients discharged from the hospital carry an increased risk of venous thromboembolism after discharge. A randomized trial of rivaroxaban for 6 weeks after hospital discharge had no significant effect on the risk of venous thromboembolism as compared with placebo.

In patients with venous thromboembolism at high risk of recurrence for whom extended treatment with direct oral anticoagulants has been indicated, the optimal dose is unknown. We aimed to assess efficacy and safety of reduced-dose versus full-dose direct oral anticoagulants in patients in whom extended anticoagulation has been indicated. RENOVE was a non-inferiority, investigator-initiated, multicentre, randomised, open-label, blinded endpoint trial done in 47 hospitals in France. Ambulatory patients aged 18 years or older with acute symptomatic venous thromboembolism (pulmonary embolism or proximal deep vein thrombosis) who had received 6–24 uninterrupted months of full-dose anticoagulation and for whom extended anticoagulation has been indicated were eligible. Eligible participants were categorised as having either a first unprovoked venous thromboembolism, recurrent venous thromboembolism, presence of persistent risk factors, or other clinical situations considered to be a high risk of recurrence. Participants were randomly assigned (1:1) to receive oral treatment with either a reduced dose of apixaban (2·5 mg twice daily) or rivaroxaban (10 mg once daily) or a full dose of apixaban (5 mg twice daily) or rivaroxaban (20 mg once daily) using a centralised randomisation procedure with an interactive web response system. The sequence generation method was a computerised random number generator and was balanced by blocks of different sizes. Randomisation was stratified by centre, type of direct oral anticoagulant, and antiplatelet drug. Physicians and participants were unmasked to treatment allocation; recurrent venous thromboembolism, clinically relevant bleeding, and all-cause death were adjudicated by an independent committee blinded to treatment allocation. The primary outcome was symptomatic recurrent venous thromboembolism, including recurrent fatal or non-fatal pulmonary embolism or isolated proximal deep vein thrombosis (non-inferiority hypothesis 90% power to exclude a hazard ratio [HR] of 1·7). The primary outcome and first two secondary outcomes were included in a hierarchical testing procedure. This trial is registered with ClinicalTrials.gov, NCT03285438. From Nov 2, 2017, to July 6, 2022, 2768 patients were enrolled and randomly assigned to the reduced-dose group (n=1383) or the full-dose group (n=1385). 970 (35·0%) participants were female, 1797 (65·0%) were male, and one (<0·1%) had sex not reported. Median follow-up was 37·1 months (IQR 24·0–48·3). Recurrent venous thromboembolism occurred in 19 of 1383 patients in the reduced-dose group (5-year cumulative incidence 2·2% [95% CI 1·1–3·3]) versus 15 of 1385 patients in the full-dose group (5-year cumulative incidence 1·8% [0·8–2·7]; adjusted HR 1·32 [95% CI 0·67–2·60]; absolute difference 0·40% [95% CI –1·05 to 1·85]; p=0·23 for non-inferiority). Major or clinically relevant bleeding occurred in 96 patients in the reduced-dose group (5-year cumulative incidence 9·9% [95% CI 7·7–12·1]) and 154 patients in the full-dose group (5-year cumulative incidence 15·2% [12·8–17·6]; adjusted HR 0·61 [95% CI 0·48–0·79]). 1136 (82·1%) of 1383 patients in the reduced-dose group and 1150 (83·0%) of 1385 in the full-dose group had an adverse event; 374 (27·0%) patients in the reduced-dose group and 420 (30·3%) in the full-dose group has a serious adverse event. 35 (5-year cumulative incidence 4·3% [95% CI 2·6–6·0]) patients in the reduced-dose group and 54 (5-year cumulative incidence 6·1% [4·3–8·0]) patients in the full-dose group died during the study period. In patients with venous thromboembolism requiring extended anticoagulation, reduction of the direct oral anticoagulant dose did not meet the non-inferiority criteria. However, the low recurrence rates in both groups and substantial reduction of clinically relevant bleeding with the reduced dose could support this regimen as an option. Further research will be needed to identify subgroups for whom the anticoagulation dose should not be reduced. French Ministry of Health.

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.

Patients who had undergone successful TAVR were randomly assigned to receive either a rivaroxaban-based antithrombotic regimen or an antiplatelet-based antithrombotic regimen. At 17 months, the primary outcome of death or thromboembolic complications occurred more frequently with rivaroxaban.

COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population. We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed. From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61–8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group. In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation. Coalition COVID-19 Brazil, Bayer SA.

Patients with peripheral artery disease who underwent revascularization were randomly assigned to receive rivaroxaban (2.5 mg twice daily) or placebo. All patients received aspirin. The primary outcome of acute limb ischemia, major amputation for vascular causes, MI, ischemic stroke, or cardiovascular death occurred less frequently with rivaroxaban.

A placebo-controlled trial assessed the efficacy of rivaroxaban to prevent venous thrombosis in patients with cancer at high risk for thrombosis. The thrombosis rate was lower with rivaroxaban, but for the 180-day assessment period, the difference was not significant. Bleeding was approximately twice as common in the rivaroxaban group.